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Synthesis 2013; 45(4): 459-462
DOI: 10.1055/s-0032-1317983
paper
© Georg Thieme Verlag Stuttgart · New York

One-Pot Two-Step Synthesis of Quinoxalinones and Diazepinones via a Tandem Oxidative Amidation–Deprotection–Cyclization Sequence

Arthur Y. Shaw
a   Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA   Fax: +1(520)6260794   Email: hulme@pharmacy.arizona.edu
,
Christine R. Denning
a   Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA   Fax: +1(520)6260794   Email: hulme@pharmacy.arizona.edu
,
Christopher Hulme*
a   Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA   Fax: +1(520)6260794   Email: hulme@pharmacy.arizona.edu
b   Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
› Author Affiliations
Further Information

Publication History

Received: 25 October 2012

Accepted after revision: 12 December 2012

Publication Date:
10 January 2013 (online)

 
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Abstract

This report discloses novel concise syntheses of quinoxalinones and diazepinones via a tandem oxidative amidation–deprotection–cyclization sequence. A selenium dioxide mediated oxidative amidation of arylglyoxals with secondary amines was carried out under microwave irradiation to give the corresponding α-keto amides, followed by an acid-promoted deprotection and cyclization to afford the desired products in moderate to good yields.


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Key words

multicomponent reaction - selenium - oxidation - cyclization - tandem reaction

Quinoxalinones are a class of nitrogen-containing fused heterocyclic compounds, which have attracted a great deal of attention due to their preponderance as scaffolds in bioactive small molecules.[ 1 ] These molecules exhibit a broad spectrum of biological properties such as antimicrobial,[ 2 ] antifungal,[ 3 ] antidiabetic,[ 4 ] antiviral,[ 5 ] and anticancer[ 6 ] activities. In addition, quinoxalinone derivatives have shown to be inhibitors of aldose reductase,[ 7 ] partial agonists for complex receptors γ-aminobutyric acid (GABA)/ benzodiazepine[ 8 ] as well as antagonists of multidrug-resistance-related proteins (MRPs).[ 9 ] In light of their biological relevance, a variety of methodologies for the synthesis of quinoxalinones have been developed. Indeed, for more than a century the Hinsberg reaction has been a practical method to obtain 3-substituted quinoxalinones from o-phenylenediamines and α-keto acids along with a number of modifications.[ 10 ]

Recently, we have developed a novel method to synthesize α-keto amides 3 from arylglyoxals 1 and secondary amines 2 via a selenium dioxide mediated oxidative amidation (Scheme [1]).[ 11 ]

To continue a research theme of developing robust, concise, and attractive methodology for the pharmaceutical sector, we herein reveal new synthetic routes to quinoxalinones 7 and diazepinones 8 via a tandem oxidative amidation–deprotection–cyclization sequence in a one-pot two-step manner (Scheme [2]).

As indicated in Scheme [3], phenylglyoxal (1a) and secondary amine 2a were dissolved in dichloromethane in the presence of selenium dioxide and heated at 100 °C for 20 minutes under microwave irradiation.[ 11 ] Reaction progression was monitored by TLC evaluating the disappearance of the starting material phenylglyoxal (1a). Without purification, the crude α-keto amide 3a was dissolved in a solution of 10% TFA (trifluoroacetic acid) in dichloromethane and stirred at room temperature for one hour. Boc group removal from 3a afforded the intermediate 9a, which subsequently underwent cyclodehydration through 10a to give the desired quinoxalinone 7a in 65% isolated yield (two steps).

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Scheme 1 Proposed mechanism of oxidative amidation

Encouraged by the robustness of this protocol, a series of arylglyoxals 1a–g bearing electron-donating and -withdrawing groups and N-Boc phenylenediamines 2a–c were thus subjected to the oxidative amidation/deprotection/ cyclization sequence to furnish quinoxazolinones 7a–i in moderate to good yields (Table [1]). Interestingly, upon treatment of 4-methylphenylglyoxal (1d) and amine 2b with selenium dioxide and heating at 100 °C for 30 minutes under microwave irradiation (Table [1], entry 5), the desired quinoxazolinone 7e was obtained in 55% isolated yield without the need for acid treatment, equivalent to a one-step, one-pot conversion.

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Scheme 2 Synthesis of quinoxalinones 7 and diazepinones 8
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Scheme 3 Synthesis of quinoxazolinone 7a
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Scheme 4 Synthesis of quinoxalinone 7j

In attempts to prepare quinoxazolinones 7 (R2 = H, Table [1]), the acid labile 2,4-dimethoxybenzyl group in the secondary amine 2d was evaluated for compatibility with our established procedure (Scheme [4]). Thus, the SeO2 driven oxidative amidation was carried out with arylglyoxal 1h and secondary amine 2d to afford the intermediate α-keto amide 3b. Without further purification, the α-keto amide 3b was treated with 10% TFA–dichloromethane to promote sequential deprotection/cyclization reactions to afford quinoxalinone 7j in 46% isolated yield.

Table 1 Synthesis of Quinoxazolinones 7a–i

Entry

R1

R2

Product, yield (%)a

1

H (1a)

isobutyl (2a)

7a, 65

2

4-CF3 (1b)

isobutyl (2a)

7b, 42

3

H (1a)

cyclopropylmethyl (2b)

7c, 75

4

3-CF3 (1c)

cyclopropylmethyl (2b)

7d, 66

5

4-Me (1d)

cyclopropylmethyl (2b)

7e, 55b

6

4-F (1e)

cyclopropylmethyl (2b)

7f, 71

7

H (1a)

benzyl (2c)

7g, 46

8

3-OMe (1f)

benzyl (2c)

7h, 54

9

4-Cl (1g)

benzyl (2c)

7i, 67

a Isolated yield.

b The product was obtained without TFA treatment.

Ring expansion to seven-membered-ring diazepinone 8a proved feasible via the use of N-Boc benzylamine 2e in 47% isolated yield (Scheme [5]).

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Scheme 5 Synthesis of N-substituted diazepinone 8a

Taken together, we have articulated a sequential one-pot two-step synthesis of functionalized quinoxalinones and diazepinones via an oxidative amidation–deprotection–cyclization sequence mediated by selenium dioxide and concomitant acid treatment.

NMR spectra were recorded on a Varian Mercury 400 instrument (1H, 400 MHz;13C, 100 MHz). Chemical shifts were calculated from the residual solvent signals of δH7.24 and δC77.0 in CDCl3.Column chromatography was performed using ISCO chromatographic systems. Melting points were determined in an open glass capillary and are uncorrected. Low-resolution mass spectra were obtained using ESI methods.


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Quinoxalinones 7; 1-Isobutyl-3-phenylquinoxalin-2(1H)-one (7a); Typical Procedure

To a mixture of phenylglyoxal monohydrate (1a; 152 mg, 1.0 mmol) and tert-butyl [2-(isobutylamino)phenyl]carbamate (2a; 397 mg, 1.5 mmol) in CH2Cl2 (1.8 mL) was added SeO2 (111 mg, 1.0 mmol). The resulting mixture was heated at 100 °C for 20 min under microwave irradiation. The reaction mixture was further treated with TFA (0.2 mL) and stirred at r.t. for 1 h. The solution was neutralized with sat. aq NaHCO3 (15 mL), washed with brine (5 mL), dried (MgSO4), and evaporated in vacuo to give the crude product. The crude product was further purified by silica gel chromatography (eluent: EtOAc–hexanes, 0 to 20%) to afford 7a as a yellowish oil; yield: 181.4 mg (65%).

1H NMR (400 MHz, CDCl3): δ = 8.29 (dt, J = 8.5, 1.6 Hz, 2 H), 7.96–7.89 (m, 1 H), 7.67–7.59 (m, 1 H), 7.57–7.47 (m, 3 H), 7.43 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.36 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 4.47 (d, J = 7.5 Hz, 2 H), 2.41–2.14 (m, 1 H), 0.93 (d, J = 6.7 Hz, 7 H).

13C NMR (100 MHz, CDCl3): δ = 186.8, 146.6, 141.8, 137.1, 136.3, 133.4, 131.1, 128.3, 125.5, 123.4, 122.0, 111.2, 52.2, 29.8, 20.2.

ESI-MS: m/z (%) = 279 ([M + H]+, 100).


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1-Isobutyl-3-[4-(trifluoromethyl)phenyl]quinoxalin-2(1H)-one (7b)

Yield: 146 mg (42%); yellowish oil.

1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 8.0 Hz, 2 H), 7.98–7.87 (m, 1 H), 7.80 (t, J = 8.7 Hz, 2 H), 7.49 (dt, J = 14.1, 8.2 Hz, 2 H), 7.39 (dd, J = 10.9, 4.1 Hz, 1 H), 4.51 (dd, J = 7.4, 0.8 Hz, 2 H), 0.97 (ddd, J = 6.7, 5.4, 2.6 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 185.79, 145.94, 141.85, 140.20, 136.77, 131.38, 126.09, 125.29, 125.25, 123.84, 122.25, 111.32, 55.96, 52.39, 29.88, 20.18.

ESI-MS: m/z = 347 ([M + H]+, 100).


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1-(Cyclopropylmethyl)-3-phenylquinoxalin-2(1H)-one (7c)

Yield: 208 mg (75%); brown oil.

1H NMR (400 MHz, CDCl3): δ = 8.31 (ddd, J = 7.3, 2.9, 1.6 Hz, 2 H), 8.00–7.91 (m, 1 H), 7.68–7.61 (m, 1 H), 7.58–7.49 (m, 3 H), 7.49–7.42 (m, 1 H), 7.37 (ddd, J = 10.7, 5.9, 2.4 Hz, 1 H), 4.53 (d, J = 7.0 Hz, 2 H), 2.94 (d, J = 6.9 Hz, 1 H), 0.65–0.39 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 183.38, 142.64, 138.84, 133.68, 132.67, 130.03, 127.94, 124.97, 122.43, 120.26, 118.56, 107.50, 46.10, 24.75, 8.34.

ESI-LRMS: m/z (%) = 277 ([M + H]+, 100), 223 (10).


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1-(Cyclopropylmethyl)-3-[3-(trifluoromethyl)phenyl]quinoxalin-2(1H)-one (7d)

Yield: 228 mg (66%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.71–8.49 (m, 2 H), 7.91 (dd, J = 23.9, 7.9 Hz, 2 H), 7.68 (t, J = 7.8 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.48 (dd, J = 8.3, 7.0 Hz, 1 H), 7.44–7.36 (m, 1 H), 4.66–4.50 (m, 2 H), 1.50–1.31 (m, 1 H), 0.71–0.38 (m, 4 H).

13C NMR (101 MHz, CDCl3): δ = 185.41, 145.71, 142.13, 137.66, 134.54, 129.63, 128.88, 127.92, 126.13, 123.84, 122.32, 111.03, 49.63, 11.97, 4.10.

ESI-MS: m/z (%) = 345 ([M + H]+, 100).


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1-(Cyclopropylmethyl)-3-(p-tolyl)quinoxalin-2(1H)-one (7e)

Yield: 160 mg (55%); yellow solid; mp 83–85 °C.

1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.1 Hz, 2 H), 7.92 (t, J = 10.6 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.49–7.41 (m, 1 H), 7.41–7.29 (m, 3 H), 4.51 (d, J = 6.9 Hz, 2 H), 2.43 (d, J = 15.1 Hz, 3 H), 1.46–1.33 (m, 1 H), 0.67–0.37 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 186.65, 146.80, 144.65, 141.88, 135.91, 134.42, 131.21, 129.28, 125.47, 123.53, 122.03, 110.99, 49.59, 28.03, 21.85, 11.85, 4.15.

ESI-MS: m/z (%) = 291 ([M + H]+, 100).


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1-(Cyclopropylmethyl)-3-(4-fluorophenyl)quinoxalin-2(1H)-one (7f)

Yield: 212.4 mg (72%); yellow solid; mp 75–77 °C.

1H NMR (400 MHz, CDCl3): δ = 8.46–8.36 (m, 2 H), 7.97–7.90 (m, 1 H), 7.57–7.34 (m, 3 H), 7.25–7.16 (m, 2 H), 4.53 (d, J = 7.0 Hz, 2 H), 1.50–1.32 (m, 1 H), 0.65–0.37 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 184.97, 141.87, 136.04, 134.06, 133.97, 133.38, 125.73, 123.66, 122.03, 115.66, 115.44, 110.97, 49.50, 11.97, 4.11.

ESI-MS: m/z (%) = 295 ([M + H]+, 100).


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1-Benzyl-3-phenylquinoxalin-2(1H)-one (7g)

Yield: 144 mg (46%); yellow solid; mp 57–59 °C.

1H NMR (400 MHz, CDCl3): δ = 8.33–8.28 (m, 1 H), 8.23–8.11 (m, 2 H), 7.98–7.93 (m, 1 H), 7.84–7.72 (m, 1 H), 7.67–7.35 (m, 4 H), 7.34–7.22 (m, 3 H), 7.19 (dd, J = 5.2, 3.0 Hz, 2 H), 5.86 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 186.66, 151.88, 146.15, 143.62, 141.90, 136.98, 133.40, 129.17, 128.76, 128.35, 127.76, 127.53, 126.83, 125.88, 123.68, 122.28, 111.14.

ESI-MS: m/z (%) = 313 ([M + H]+, 100).


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1-Benzyl-3-(3-methoxyphenyl)quinoxalin-2(1H)-one (7h)

Yield: 185.2 mg (54%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.05–7.69 (m, 3 H), 7.62–6.95 (m, 11 H), 5.84 (s, 2 H), 3.99–3.78 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 186.16, 159.49, 146.48, 141.97, 138.03, 136.57, 136.12, 129.35, 128.79, 127.75, 126.75, 125.93, 124.30, 123.77, 122.17, 120.32, 114.97, 111.09, 55.46, 48.71.

ESI-MS: m/z (%) = 343 ([M + H]+, 100).


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1-Benzyl-3-(4-chlorophenyl)quinoxalin-2(1H)-one (7i)

Yield: 232.5 mg (67%); brown solid; mp 78–80 °C.

1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 6.8, 1.8 Hz, 2 H), 7.97–7.91 (m, 1 H), 7.52–7.35 (m, 5 H), 7.32–7.21 (m, 3 H), 7.18 (d, J = 8.0 Hz, 2 H), 5.86 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 185.17, 140.12, 136.53, 135.17, 132.63, 128.82, 128.65, 127.81, 126.85, 126.20, 123.98, 122.26, 111.14, 76.83, 48.94.

ESI-MS: m/z (%) = 347 ([M + H]+, 100).


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3-(Benzo[d][1,3]dioxol-5-yl)quinoxalin-2(1H)-one (7j)

Yield: 122.8 mg (46%); yellow solid; mp 216–218 °C.

1H NMR (400 MHz, CDCl3): δ = 8.41–8.24 (m, 2 H), 7.93 (d, J = 1.2 Hz, 1 H), 7.67–7.60 (m, 1 H), 7.39–7.26 (m, 2 H), 6.98–6.83 (m, 2 H), 6.09–5.97 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 189.63, 152.77, 148.29, 130.39, 128.90, 110.55, 108.37, 102.04, 97.94, 60.49, 50.41.

ESI-MS: m/z (%) = 267 ([M + H]+, 100).


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4-Isobutyl-2-phenyl-4,5-dihydro-3H-benzo[e][1,4]diazepin-3-one (8a)

Yield: 137.7 mg (47%); yellow solid; mp 78–80 °C.

1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 7.6 Hz, 1 H), 7.73–7.62 (m, 1 H), 7.56–7.39 (m, 3 H), 7.36 (dd, J = 10.9, 4.2 Hz, 1 H), 7.29–7.23 (m, 2 H), 7.20 (dd, J = 10.4, 4.2 Hz, 1 H), 4.37 (d, J = 14.9 Hz, 1 H), 3.88 (d, J = 14.9 Hz, 1 H), 3.68 (dd, J = 13.4, 8.0 Hz, 1 H), 3.05 (dd, J = 13.5, 7.1 Hz, 1 H), 2.20–1.87 (m, 1 H), 0.94 (dd, J = 53.2, 6.6 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 194.96, 162.25, 146.96, 136.15, 134.51, 131.29, 129.39, 128.58, 126.59, 124.23, 120.16, 53.38, 49.59, 27.44, 20.10, 19.98.

ESI-MS: m/z (%) = 293 ([M + H]+, 100).


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Acknowledgment

We would like to thank the Office of the Director, NIH, and the National Institute of Mental Health for funding (1RC2MH090878-01).

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


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Zoom Image
Scheme 1 Proposed mechanism of oxidative amidation
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Scheme 2 Synthesis of quinoxalinones 7 and diazepinones 8
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Scheme 3 Synthesis of quinoxazolinone 7a
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Scheme 4 Synthesis of quinoxalinone 7j
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Scheme 5 Synthesis of N-substituted diazepinone 8a