[529-23-7]  · C7H7NO  · 2-Aminobenzaldehyde  · (MW 121)

(Friedländer synthon; quinoline synthesis; o-amino aldehyde)

Alternate Names: 2-formylaniline; 1-amino-2-formylbenzene.

Physical Data: mp 38-39 °C.

Solubility: sol ether, alcohol.

Preparative Methods: the reagent is best when freshly prepared. At one time it was commercially available but samples more than a few months old were found to be essentially useless due to oligomerization. The propensity of the reagent to self-react and the resulting oligomer structures have been extensively discussed.1a A useful preparative method involves Iron(II) Sulfate reduction of 2-nitrobenzaldehyde.2 The key to success is limiting the reaction time to 8-10 min and immediate, rapid steam distillation of the reaction product. The precursor is commercially available from a variety of sources and its preparation has also been reported.3 A supposedly simplified procedure has been suggested but it does not differ significantly from the earlier method.4

Purification: can be effected by steam distillation from saturated NaCl solution.

Handling, Storage, and Precautions: the reagent can be stored for periods of up to several months under an inert atmosphere at 0 °C in the dark. The mp is a good general indicator of purity and the NMR spectrum should show an aldehyde proton integrating 1:4 against the aromatic protons. Use in a fume hood.

Quinoline Synthesis.

The reagent is most useful for the preparation of quinolines via the Friedländer condensation where 2-aminobenzaldehyde (2-AB) is the prototype o-amino aldehyde reaction partner. The reaction with acetaldehyde to form quinoline was first reported in 18825 and involves two dehydration steps, the sequence of which is not well established although initial formation of an imine intermediate appears more likely (eq 1).

The reaction is normally not suitable for the formation of quinolines unsubstituted on the pyridine ring and aldehyde partners are generally unsatisfactory under base-catalyzed conditions. Ketones react more smoothly and even cyclobutanone gives an acceptable yield 2,3-cyclobutaquinoline (eq 2).6 A review on the Friedländer synthesis which appeared in 1982 gives an extensive compilation of this reaction involving 2-AB as well as other o-amino aldehydes.1b

The regiochemistry of condensations with unsymmetrical ketones is often pH dependent. In the base-catalyzed reaction of 2-AB with ethyl 3-oxopyrrolidine-1-carboxylate, two products were formed with the dominant one resulting from the more stable enolate or iminate intermediate (eq 3).7 The same reaction carried out in acetic acid containing sulfuric acid gives a nearly equal mixture of the two regiochemistries.

Activation of the carbonyl component considerably facilitates the reaction and only one regioisomer is observed when 2-AB condenses with acetylacetone (eq 4).8

Appropriate b-diketones will condense in a 2:1 fashion to create two quinolines in a single step. Thus 1,2-cyclohexanedione gives a bridged 2,2-biquinoline (eq 5).9 In a similar fashion, 1,1-diacetylferrocene provides a ferrocene substituted with quinoline on each Cp ring.10

Friedländer condensations are not limited to simple keto groups. In the reaction of 2-AB with naphthalene-1,3-diol the latter may be considered as a bis-enol (eq 6). Under basic conditions the first step involves condensation between the aldehyde group and the enolate at C-4.11

A modification developed by Borsche overcomes some of the difficulties associated with the instability of 2-AB. By employing an arylimine derivative of 2-AB in its place, smooth condensations occur in alkaline ethanolic solution or in the presence of Piperidine to provide quinolines in yields of 60-90% (eq 7).12

Related Reagents.

(Z)-b-Aminoacrolein; 2-Aminonicotinaldehyde; Cyclobutanone; 2,4-Pentanedione; Piperidine; Quinoline.

1. (a) Caluwe, P. T 1980, 36, 2359. (b) Cheng, C.-C.; Yan, S.-J. OR 1982, 28, 37. (c) Thummel, R. P. SL 1992, 1.
2. Smith, L. I.; Opie, J. W. OSC 1955, 3, 56.
3. Kalir, A. OSC 1973, 5, 825.
4. Mann, F. G.; Wilkinson, A. J. JCS 1957, 3346.
5. Friedlaender P. CB 1882, 15, 2572.
6. Markgraf, J. H.; Scott, W. L. CC 1967, 296.
7. Zalkow, L. H.; Nabors, J. B.; French, K.; Bisarya, S. C. JCS(C) 1971, 3551.
8. Stark, O. CB 1907, 40, 3425.
9. Thummel, R. P.; Lefoulon, F. JOC 1985, 40, 666.
10. Gelin, F.; Thummel, R. P. JOC 1992, 57, 3780.
11. Mock, J.; Ritchie, E.; Taylor, W. C. AJC 1973, 26, 2315.
12. Borsche, W.; Barthenheier, J. LA 1941, 548, 50.

Randolph P. Thummel

University of Houston, TX, USA

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