Synlett 2018; 29(01): 85-88
DOI: 10.1055/s-0036-1589099
letter
© Georg Thieme Verlag Stuttgart · New York

Symmetrical Trichlorotriazine Derivatives as Efficient Reagents for One-Pot Synthesis of 3-Acetyl-2-chloroquinolines from Acetanilides under Vilsmeier–Haack Conditions

Bhooshan Muddam
Department of Chemistry, Osmania University, Hyderabad-500 007, T. S., India   Email: [email protected]
,
P. Venkanna
Department of Chemistry, Osmania University, Hyderabad-500 007, T. S., India   Email: [email protected]
,
M. Venkateswarlu
Department of Chemistry, Osmania University, Hyderabad-500 007, T. S., India   Email: [email protected]
,
M. Satish Kumar
Department of Chemistry, Osmania University, Hyderabad-500 007, T. S., India   Email: [email protected]
,
K. C. Rajanna*
Department of Chemistry, Osmania University, Hyderabad-500 007, T. S., India   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 11 June 2017

Accepted after revision: 28 August 2017

Publication Date:
28 August 2017 (online)

 


Abstract

Symmetrical trichlorotriazine derivatives such as 2,4,6-trichloro-1,3,5-triazine and trichloroisocyanuric acid were explored as Vilsmeier–Haack type reagents in the presence of N,N-dimethylacetamide for the effective synthesis of 3-acetyl-2-chloroquinolines from acetanilides. Ultrasonication led to shorter reaction times than conventional heating and gave yields comparable to those obtained under reflux conditions.


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Quinolines form an important group of heterocyclic compounds that have been found to exhibit bactericidal, antitumor, antimalarial, antiinflammatory, and antiviral activities.[1] [2] [3] [4] [5] [6] [7] [8] More specifically, 3-acetyl-2-chloroquinolines occupy a prominent position among the family of quinolines, as they are key intermediates for the synthesis of thieno[2,3-b]quinolines. In an earlier publication, Bhat and Bhaduri reported a synthesis of quinolines involving two or three steps.[8] In our earlier papers, we have reported a one-pot synthesis of formyl- and acetylquinolines from acetanilides under Vilsmeier–Haack conditions[9] [10] [11] by using N,N-dimethylacetamide (DMA)/POCl3. N,N-Dialkyl amides (DMF or DMA) and oxychlorides such as phosphoryl chloride, thionyl chloride, or phosgene form chloromethyleniminium salts in situ.[11] [12] [13] [14] [15] [16] However, oxychlorides are moisture sensitive and toxic.

Efforts have been made to avoid the use of oxychlorides by replacing them with 2,4,6-trichlorotriazine (cyanuric chloride, TCTA)[17] [18] to give the corresponding DMF adducts as alternative Vilsmeier–Haack reagents. Symmetrical 1,3,5-triazine derivatives have also been used to promote transformations such as Friedel–Crafts acylations, Beckman rearrangements, Lossen rearrangements, carboxylic-acid activations, and Swern oxidations.[19–27]

Encouraged by these results, we embarked on a comparative study using two different adducts of DMA with TCTA or trichloroisocyanuric acid (1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione, TCCA) for the synthesis of 3-acetylquinolines through simultaneous cyclization and acetylation of acetanilides under conventional and ultrasonically assisted conditions (Scheme [1]).

Zoom Image
Scheme 1 Synthesis of 3-acetyl-2-chloroquinolines from acetanilides by using TCTA/DMA or TCCA/DMA as Vilsmeier–Haack reagents

With conventional heating at the reflux in CH2Cl2, reaction times for most of the studied reactions were in the range five to nine hours, depending on the structure of the acetanilide and reagent used (Table [1]).

Table 1 Synthesis of 3-Acetyl-2-chloroquinolines from Acetanilides by Using TCTA/DMA or TCCA/DMA as a Vilsmeier–Haak Reagenta

Entry

Acetanilide

Product

TCCA

TCTA

Time (h)

Yield (%)

Time (h)

Yield (%)

1

acetanilide

3-acetyl-2-chloroquinoline

7

85

8

80

2

4-bromoacetanilide

3-acetyl-6-bromo-2-chloroquinoline

6

85

7

80

3

2-chloroacetanilide

3-acetyl-2,8-dichloroquinoline

8

85

8

85

4

4-chloroacetanilide

3-acetyl-2,6-dichloroquinoline

7

90

6

90

5

4-methoxyacetanilide

3-acetyl-2-chloro-6-methoxyquinoline

6

91

5

89

6

4-nitroacetanilide

3-acetyl-2-chloro-6-nitroquinoline

8

75

9

72

7

3-nitroacetanilide

3-acetyl-2-chloro-7-nitroquinoline

7

69

8

70

8

4-methylacetanilide

3-acetyl-2-chloro-6-methylquinoline

5

82

5

80

9

2-ethylacetanilide

3-acetyl-2-chloro-8-ethylquinoline

5

87

6

86

10

2-nitroacetanilide

3-acetyl-2-chloro-8-nitroquinoline

6

85

7

85

a Reaction conditions: acetanilide (9.8 mmol), TCCA/DMA or TCTA/DMA,[32] CH2Cl2 (50 mL), reflux.

The mechanism of the reaction can be explained through the formation of TCTA/DMA or TCCA/DMA adducts containing a chloromethyleniminum moiety. The formation of a chloromethyleniminum cation intermediate is supported by spectroscopic observations. In the IR spectrum of the TCCA/DMA adduct, absorption bands associated with the starting materials showed marked shifts, significant absorptions being observed at 3215 (broad), 1706 (broad), and 1750 (weak) cm–1. These observations are largely similar to those in our earlier reports on the formation of TCTA/DMF and TCCA/DMF adducts, respectively.[29] [30]

Zoom Image
Scheme 2 Mechanism of the formation of 3-acetyl-2-chloroquinolines from acetanilide by using the TCCA/DMA Vilsmeier–Haack adduct

The chloromethyleniminum cation thus formed reacts with the acetanilide to afford 3-acetyl-2-chloroquinolines. (Spectroscopic data for the isolated 3-acetyl-2-chloroquinolines are given in supplementary data.) The results in Table [1] show that the reactions using both TCTA/DMA and ­TCCA/DMA adducts[31] were too sluggish under conventional reflux conditions.[32] However, under sonication at r.t.,[33] the reaction times were reduced significantly from 5–9 hours to 35–90 minutes (Table [2]).

Table 2 Ultrasonically Assisted Synthesis of 3-Acetyl-2-chloroquinolines from acetanilides by Using TCTA/DMA or TCCA/DMA as a Vilsmeier–Haak ­Reagenta

Entry

Acetanilide

Product

TCCA

TCTA

time (min)

Yield (%)

Time (min)

Yield (%)

1

acetanilide

3-acetyl-2-chloroquinoline

75

85

80

80

2

4-bromoacetanilide

3-acetyl-6-bromo-2-chloroquinoline

85

85

90

85

3

2-chloroacetanilide

3-acetyl-2,8-dichloroquinoline

80

80

91

79

4

4-chloroacetanilide

3-acetyl-2,6-dichloroquinoline

75

85

85

85

5

4-methoxyacetanilide

3-acetyl-2-chloro-6-methoxyquinoline

60

89

60

90

6

4-nitroacetanilide

3-acetyl-2-chloro-6-nitroquinoline

65

85

65

85

7

3-nitroacetanilide

3-acetyl-2-chloro-7-nitroquinoline

70

81

70

79

8

4-methylacetanilide

3-acetyl-2-chloro-6-methylquinoline

60

85

60

80

9

2-ethylacetanilide

3-acetyl-2-chloro-8-ethylquinoline

55

90

55

90

10

2-nitroacetanilide

3-acetyl-2-chloro-8-nitroquinoline

70

85

75

80

a Reaction conditions: acetanilide (9.8 mmol), TCCA/DMA or TCTA/DMA,[33] CH2Cl2 (50 mL), ultrasound, r.t.

In summary, we have developed TCCA/DMA and ­TCTA/DMA adducts as efficient modified Vilsmeier-Haack reagents for the effective synthesis of 3-acetyl-2-chloroacetylquinolines from acetanilides. The reactions afforded good yields and, depending on the structure of the acetanilide, reaction times recorded were reduced from 5–9 hours under conventional conditions to 55–85 minutes under sonication. Even the most sluggish reactant (4-nitroacetanilide) underwent rate acceleration from 8–9 hours to 65 minutes. Product yields are also increased under sonication as compared with conventional heating.


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Acknowledgment

The authors thank Professor T. Navaneeth Rao [former Vice-Chancellor, Osmania University (OU)], and Professor P. K. Saiprakash (Former Dean, Faculty of Science, OU, and Head, Department of Chemistry, OU) for their constant encouragement and the use of facilities. B.M. thanks the management and authorities of M.V.S.R. Engineering College for constant encouragement.

Supporting Information

  • References and Notes

    • 2a Oehme G. Paetzold E. Selke R. J. Mol. Catal. 1992; 71: L1
    • 2b Grassert I. Paetzold E. Oehme G. Tetrahedron 1993; 49: 6605
    • 2c Kumar A. Ohem G. Roque JP. Schwarze M. Selke R. Angew. Chem. Int. Ed. Engl. 1994; 33: 2197
    • 2d Grassert I. Vill V. Oehme G. J. Mol. Catal. A: Chem. 1997; 116: 231
    • 3a Grasset I. Schinkowski K. Valhardt D. Oehme G. Chirality 1998; 10: 754
    • 3b Oehme G. Grassert I. Ziegler S. Meisel R. Fuhrmann H. Catal. Today 1998; 42: 459
    • 3c Oehme G. Grassert I. Paetzold E. Meisel R. Drexler K. Fuhrmann H. Coord. Chem. Rev. 1999; 185: 585
    • 4a In Heterocyclic Compounds . Vol. 4, Chap. 1. Elderfield R. Chapman & Hall; New York: 1952: 1
    • 4b Meth-Cohn O. Narine B. Tetrahedron Lett. 1978; 19: 2045
  • 5 Patel HV. Vyas KV. Fernandes PS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990; 29: 836
  • 6 Craig JC. Pearson PE. J. Med. Chem. 1971; 14: 1221
  • 7 Dillard RD. Pavey DE. Benslay DN. J. Med. Chem. 1973; 16: 251
  • 8 Bhat B. Bhaduri AP. Synthesis 1984; 673
  • 9 Ali MM. Tasneem, Rajanna KC. Prakash PK. S. Synlett 2001; 251
  • 10 Ali MM. Sana S. Tasneem, Rajanna KC. Saiprakash PK. Synth. Commun. 2002; 32: 1351
  • 11 Rajanna KC. Ali MM. Sana S. Tasneem, Saiprakash PK. J. Dispersion Sci. Technol. 2004; 25,17; and references cited therein
    • 12a Vilsmeier A. Haack A. Ber. Dtsch. Chem. Ges. 1927; 60: 119
    • 12b Arnold Z. Collect. Czech. Chem. Commun. 1959; 24: 4048
    • 12c Meth-Cohn O. Stanforth SP. In Comprehensive Organic Synthesis . Vol. 2. Trost BM. Fleming I. Chap. 3.5 Pergamon; Oxford: 1991: 777
    • 12d Marson CM. Tetrahedron. 1992; 48: 3659
  • 13 Ho T.-L. In Fieser and Fieser’s Reagents for Organic Synthesis. Wiley; New York: 2017
  • 14 Amaresh RR. Perumal PT. Synth. Commun. 1997; 27: 337
    • 15a Meth-Cohn O. Narine AB. Tetrahedron Lett. 1978; 19: 2045
    • 15b Khan AK. Shoeb A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1985; 24: 62
    • 15c Su W. Weng Y. Jiang L. Yang Y. Zhao L. Chena Z. Li Z. Li J. Org. Prep. Proced. Int. 2010; 42: 503
    • 16a Sreenivasulu M. Rao KG. S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1989; 28: 584
    • 16b Mahata PK. Venkatesh C. Syam Kumar UK. Ila H. Junjappa H. J. Org. Chem. 2003; 68: 3966
    • 16c Chupp JP. Metz S. J. Heterocycl. Chem. 1979; 16: 65
    • 16d Katritzky AR. Arend M. J. Org. Chem. 1998; 63: 9989
  • 17 Hou D.-R. Sun C.-S. Sie W.-S. Jian J.-Y. Hsu Y. J. Chin. Chem. Soc. (Taipei) 2004; 51: 671
  • 18 Venkanna P. Rajanna KC. Satish Kumar M. Bismillah Ansari M. Ali MM. Tetrahedron Lett. 2015; 56: 5164
  • 19 Smolin EM. Rapoport L. s-Triazines and Derivatives . Interscience; New York: 1959
  • 20 Quirke ME. In Comprehensive Heterocyclic Chemistry . Vol. 3, Chap. 2.2. Katritzky AR. Rees CW. Pergamon; Oxford: 1984: 457
  • 21 Bartholomew D. In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR. Chap. 6.12 Rees, C. W.; Scriven, E. F. V.; Pergamon; Oxford: 1996: 575
  • 22 Comins DL. O’Connor S. Adv. Heterocycl. Chem. 1988; 44: 243
  • 23 Giacomelli G. Porcheddu A. De Luca L. Curr. Org. Chem. 2004; 8: 1497
    • 24a Luo G. Xu L. Poindexter GS. Tetrahedron Lett. 2002; 43: 8909
    • 24b Venkataraman K. Wagle DR. Tetrahedron Lett. 1979; 20: 3037
    • 24c De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem. 2001; 66: 7907
  • 25 Kangani CO. Day BW. Org. Lett. 2008; 10: 2645
    • 26a De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem. 2002; 67: 6272
    • 26b Furuya Y. Ishihara K. Yamamoto H. J. Am. Chem. Soc. 2005; 127: 11240
    • 26c Betti C. Landini D. Maia A. Pasi M. Synlett 2008; 908
  • 27 Hamon F. Prié G. Lecornué F. Papot S. Tetrahedron Lett. 2009; 50: 6800
  • 28 De Luca L. Giacomelli G. Porcheddu A. Org. Lett. 2002; 4: 553
  • 29 Venkanna P. Satish Kumar M. Rajanna K. C. Ali M. M. Synth. React. Inorg. Metal-Org. Nano-Met. Chem. 2015; 45: 97
  • 30 Venkanna P. Rajanna K. C. Satish Kumar M. Ansari M. B. Ali M. M. Tetrahedron Lett. 2015; 56: 5164
  • 31 TCTA/DMA and TCCA/DMA ReagentsTCTA or TCCA (0.110 mol) and DMA (0.13 mol) were added to CH2Cl2 (50 mL) in a round-bottomed flask and the mixture was stirred for about 3 h at r.t. to give a white precipitate.
  • 32 Cyclization/Acetylation of Acetanilides by Using TCTA/DMA or TCCA/DMA; General ProcedureThe appropriate acetanilide (9.8 mmol) was added to the TCTA/DMA or TCCA/DMA reagent, prepared as above, and the mixture was stirred constantly under reflux. When the reaction was complete (TLC), H2O (50.0 mL) was added, and the mixture was stirred to extract the inorganic components into the H2O and the crude product into the organic layer. The crude product was purified by column chromatography [Merck Silica Gel 60 (230–400 mesh), EtOAc–hexane].
  • 33 Cyclization/Acetylation of Acetanilides by Using TCTA/DMA or TCCA/DMA with Sonication; General ProcedureThe method for the ultrasonically assisted reactions was similar to the classical method. The flask containing the reaction mixture, prepared as detailed above, was placed in a sonicator (KQ-250B; Kunshan Ultrasonic Instruments, Kunshan) at r.t., and the progress of the reaction was monitored by TLC. The product was separated and worked up by similar procedure to that described above.3-Acetyl-2-chloroquinoline (Tables 1 and 2, entry 1) solid; yield: (85%); mp 74–76 °C (Lit. 75–76 °C); IR (KBr): 1705 (C=O) cm–1. 1H NMR (CDCl3): δ = 2.70 (s, 3 H, COCH3), 7.0–8.25 (m, 5 H, arom). MS ESI: m/z = 205 [M+].

  • References and Notes

    • 2a Oehme G. Paetzold E. Selke R. J. Mol. Catal. 1992; 71: L1
    • 2b Grassert I. Paetzold E. Oehme G. Tetrahedron 1993; 49: 6605
    • 2c Kumar A. Ohem G. Roque JP. Schwarze M. Selke R. Angew. Chem. Int. Ed. Engl. 1994; 33: 2197
    • 2d Grassert I. Vill V. Oehme G. J. Mol. Catal. A: Chem. 1997; 116: 231
    • 3a Grasset I. Schinkowski K. Valhardt D. Oehme G. Chirality 1998; 10: 754
    • 3b Oehme G. Grassert I. Ziegler S. Meisel R. Fuhrmann H. Catal. Today 1998; 42: 459
    • 3c Oehme G. Grassert I. Paetzold E. Meisel R. Drexler K. Fuhrmann H. Coord. Chem. Rev. 1999; 185: 585
    • 4a In Heterocyclic Compounds . Vol. 4, Chap. 1. Elderfield R. Chapman & Hall; New York: 1952: 1
    • 4b Meth-Cohn O. Narine B. Tetrahedron Lett. 1978; 19: 2045
  • 5 Patel HV. Vyas KV. Fernandes PS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990; 29: 836
  • 6 Craig JC. Pearson PE. J. Med. Chem. 1971; 14: 1221
  • 7 Dillard RD. Pavey DE. Benslay DN. J. Med. Chem. 1973; 16: 251
  • 8 Bhat B. Bhaduri AP. Synthesis 1984; 673
  • 9 Ali MM. Tasneem, Rajanna KC. Prakash PK. S. Synlett 2001; 251
  • 10 Ali MM. Sana S. Tasneem, Rajanna KC. Saiprakash PK. Synth. Commun. 2002; 32: 1351
  • 11 Rajanna KC. Ali MM. Sana S. Tasneem, Saiprakash PK. J. Dispersion Sci. Technol. 2004; 25,17; and references cited therein
    • 12a Vilsmeier A. Haack A. Ber. Dtsch. Chem. Ges. 1927; 60: 119
    • 12b Arnold Z. Collect. Czech. Chem. Commun. 1959; 24: 4048
    • 12c Meth-Cohn O. Stanforth SP. In Comprehensive Organic Synthesis . Vol. 2. Trost BM. Fleming I. Chap. 3.5 Pergamon; Oxford: 1991: 777
    • 12d Marson CM. Tetrahedron. 1992; 48: 3659
  • 13 Ho T.-L. In Fieser and Fieser’s Reagents for Organic Synthesis. Wiley; New York: 2017
  • 14 Amaresh RR. Perumal PT. Synth. Commun. 1997; 27: 337
    • 15a Meth-Cohn O. Narine AB. Tetrahedron Lett. 1978; 19: 2045
    • 15b Khan AK. Shoeb A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1985; 24: 62
    • 15c Su W. Weng Y. Jiang L. Yang Y. Zhao L. Chena Z. Li Z. Li J. Org. Prep. Proced. Int. 2010; 42: 503
    • 16a Sreenivasulu M. Rao KG. S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1989; 28: 584
    • 16b Mahata PK. Venkatesh C. Syam Kumar UK. Ila H. Junjappa H. J. Org. Chem. 2003; 68: 3966
    • 16c Chupp JP. Metz S. J. Heterocycl. Chem. 1979; 16: 65
    • 16d Katritzky AR. Arend M. J. Org. Chem. 1998; 63: 9989
  • 17 Hou D.-R. Sun C.-S. Sie W.-S. Jian J.-Y. Hsu Y. J. Chin. Chem. Soc. (Taipei) 2004; 51: 671
  • 18 Venkanna P. Rajanna KC. Satish Kumar M. Bismillah Ansari M. Ali MM. Tetrahedron Lett. 2015; 56: 5164
  • 19 Smolin EM. Rapoport L. s-Triazines and Derivatives . Interscience; New York: 1959
  • 20 Quirke ME. In Comprehensive Heterocyclic Chemistry . Vol. 3, Chap. 2.2. Katritzky AR. Rees CW. Pergamon; Oxford: 1984: 457
  • 21 Bartholomew D. In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR. Chap. 6.12 Rees, C. W.; Scriven, E. F. V.; Pergamon; Oxford: 1996: 575
  • 22 Comins DL. O’Connor S. Adv. Heterocycl. Chem. 1988; 44: 243
  • 23 Giacomelli G. Porcheddu A. De Luca L. Curr. Org. Chem. 2004; 8: 1497
    • 24a Luo G. Xu L. Poindexter GS. Tetrahedron Lett. 2002; 43: 8909
    • 24b Venkataraman K. Wagle DR. Tetrahedron Lett. 1979; 20: 3037
    • 24c De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem. 2001; 66: 7907
  • 25 Kangani CO. Day BW. Org. Lett. 2008; 10: 2645
    • 26a De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem. 2002; 67: 6272
    • 26b Furuya Y. Ishihara K. Yamamoto H. J. Am. Chem. Soc. 2005; 127: 11240
    • 26c Betti C. Landini D. Maia A. Pasi M. Synlett 2008; 908
  • 27 Hamon F. Prié G. Lecornué F. Papot S. Tetrahedron Lett. 2009; 50: 6800
  • 28 De Luca L. Giacomelli G. Porcheddu A. Org. Lett. 2002; 4: 553
  • 29 Venkanna P. Satish Kumar M. Rajanna K. C. Ali M. M. Synth. React. Inorg. Metal-Org. Nano-Met. Chem. 2015; 45: 97
  • 30 Venkanna P. Rajanna K. C. Satish Kumar M. Ansari M. B. Ali M. M. Tetrahedron Lett. 2015; 56: 5164
  • 31 TCTA/DMA and TCCA/DMA ReagentsTCTA or TCCA (0.110 mol) and DMA (0.13 mol) were added to CH2Cl2 (50 mL) in a round-bottomed flask and the mixture was stirred for about 3 h at r.t. to give a white precipitate.
  • 32 Cyclization/Acetylation of Acetanilides by Using TCTA/DMA or TCCA/DMA; General ProcedureThe appropriate acetanilide (9.8 mmol) was added to the TCTA/DMA or TCCA/DMA reagent, prepared as above, and the mixture was stirred constantly under reflux. When the reaction was complete (TLC), H2O (50.0 mL) was added, and the mixture was stirred to extract the inorganic components into the H2O and the crude product into the organic layer. The crude product was purified by column chromatography [Merck Silica Gel 60 (230–400 mesh), EtOAc–hexane].
  • 33 Cyclization/Acetylation of Acetanilides by Using TCTA/DMA or TCCA/DMA with Sonication; General ProcedureThe method for the ultrasonically assisted reactions was similar to the classical method. The flask containing the reaction mixture, prepared as detailed above, was placed in a sonicator (KQ-250B; Kunshan Ultrasonic Instruments, Kunshan) at r.t., and the progress of the reaction was monitored by TLC. The product was separated and worked up by similar procedure to that described above.3-Acetyl-2-chloroquinoline (Tables 1 and 2, entry 1) solid; yield: (85%); mp 74–76 °C (Lit. 75–76 °C); IR (KBr): 1705 (C=O) cm–1. 1H NMR (CDCl3): δ = 2.70 (s, 3 H, COCH3), 7.0–8.25 (m, 5 H, arom). MS ESI: m/z = 205 [M+].

Zoom Image
Scheme 1 Synthesis of 3-acetyl-2-chloroquinolines from acetanilides by using TCTA/DMA or TCCA/DMA as Vilsmeier–Haack reagents
Zoom Image
Scheme 2 Mechanism of the formation of 3-acetyl-2-chloroquinolines from acetanilide by using the TCCA/DMA Vilsmeier–Haack adduct