Key words trichlorotriazines - Vilsmeier–Haack reaction - acetanilides - chloroacetylquinolines - sonication
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 ]).
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 CH2 Cl2 , 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 ] CH2 Cl2 (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 ]
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 ] CH2 Cl2 (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.
