Allylbenzenes -> Phenylacetamides

[Rhodium]

The reaction of an Allylbenzene with CrO₃ and trimethylsilylnitrate (Me₃SiCl + AgNO₃ Me₃C-O-NO₂ + AgCl) gives rise to 1-phenyl-3-nitro-2-propanone^1,2, which can be aminated by simply stirring with an amine³. If ammonia does not work neat, then take it a step further and use benzylamine, which then easily can be removed by CTH hydrogenolysis. There are also many other methods available for preparation of the intermediate nitroketone³.




References:
[1]

https://www.thevespiary.org/rhodium/Rhodium/pdf/alkene2nitroketone-1.pdf

[2]

https://www.thevespiary.org/rhodium/Rhodium/pdf/alkene2nitroketone-2.pdf

[3]

https://www.thevespiary.org/rhodium/Rhodium/pdf/nitroketone2amide.pdf

[GC_MS]

Might look nice for anisaldehyde > p-MeO-phenol > Claisen rearrangement > DMS.
Only "concern" I have is the application of AgNO3. Could have been cheaper... Or AgCl can be recovered and electrochemically reduced to Ag in order to sell or reuse.

[Barium]

Do you have any reference for easy C-N hydrogenolysis by CTH? I have a few refs but they aren´t pretty since they all uses something like 0.5-2 mol Pd/mol substrate, 15-30 mol HCOONH4/mol substrate and 12-48 hours reflux in MeOH.

[Rhodium]

Rapid Debenzylation of N-Benzylamino Derivatives To Amino-Derivatives Using Ammonium Formate As Catalytic Hydrogen Transfer Agent [1,2]

Tetrahedron Letters, Vol. 28, No. 5, pp 515-616, (1987)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/cth.n-debenzylation.html)

Summary: Various N-benzyl derivatives of amino acids and amines were deprotected to the corresponding free amino acids and amines using ammonium formate as the hydrogen source.

Catalytic transfer hydrogenation has been successfully applied for removal of a benzyl group from protected benzyloxycarbonyl. benzylester and benzylester derivatives of peptides and amino acids using cyclohexene [3,4], 1,4-cyclohexadiene [5], hydrazine-hydrate[6] and ammonium formate[7,8] as the hydrogen donor. Deprotection of the N-benzyl group, however, is still most often carried out by traditional high pressure catalytic hydrogenation [9,10]. Recently, B. El Amin. et al.[11] reported that removal of a benzyl group from Z-amino acids using formic acid as the hydrogen donor. provides formate salts of amino acids as end products instead of free amino acids.

In our on-going program to develop rapid synthesis of radio-labeled tracer molecules for Positron Emission Tomography (PET), we are interested in the radioisotopic synthesis of ¹¹C-amino acids (¹¹C-half life=20.4 min) such as [¹¹C-carboxyl)-Y-amino butyric acid. [¹¹C-carboxyl]-p-alanine, etc. via N-benzyl derivatives of bromoalkanes. In this paper we wish to report a rapid deprotection of the N-benzyl group to the corresponding free amino derivatives using ammonium formate as shown in Scheme I (R=H/Alkyl; R₁ H/C₂H₅; n=1-3).

A typical procedure for debenzylation is as follows. To a stirred suspension of an appropriate N-benzyl compound (3 mmol) and an equal weight of 10% Pd-C in dry methanol (20 ml). anhydrous ammonium formate (15 mmol) was added in a single portion under nitrogen. The resulting reaction mixture was stirred at reflux temperature and the reaction was monitored by TLC. After completion of reaction, the catalyst was removed by filtration through a celite pad, which was then washed with 20 ml of chloroform. The combined organic filtrate, on evaporation under reduced pressure, afforded the desired amino derivative. In the case of free amino acids. the reaction mixture was filtered while hot and the celite pad was washed with boiling water (20 ml). Characterization of this new procedure is shown in Table 1.

In most cases, the reaction is over within 6-10 min: however, for N-benzyl-2-methylimidazole. the reaction requires 60 min for completion. These results demonstrate a rapid and versatile system for removal of an N-benzyl group from a wide variety of compounds including protected amino acids under moderate reaction conditions.

[Table 1]

(a) Unoptimized. isolated yields are based on a single experiment:
(b) characterized via comparison with authentic samples (IR, ¹H-NMR, TLC and mp.).
(c) relative Rf value = distance travelled by product chromatograph/distance travelled by starting material chromatograph, using E Merck silica gel plates, mobile phase: CHCl₃:MeOH:58% NH₄OH.
(d) 9:1:3 drops.
(e) CHCl₃:MeOH (96:4).
(f) BuOH:AcOH:H₂O (4:1:1).

References:

1) S. Ram and R.E. Ehrenkaufer: Tetrahedron Letters, 25, 3415 (1984).
2) S. Ram and R.E. Ehrenkaufer: Synthesis, 133 (1986).
3) S.A. Khan and K.M. Sivanandaiah: Synthesis, 750 (1978).
4) A.E. Jackson and R.A.W. Johnstone: Synthesis. 685 (1976).
5) A.M. Felix, E.P. Heimer, T.J. Lambros, C. Tzougraki and J. Meienhofer: J. Org. Chem., 43. 4194 (1978).
6) M.K. Anwer, S.A. Khan and K.M. Sivanandaiah: Synthesis, 751 (1978).
7) M.K. Anwer and A.F. Spatola: Tetrahedron Letters: 22, 4369 (1981).
M.K. Anwer and A.F. Spatola: J. Org. Chem. 48, 3503 (1983).
9) L. Velluz. G. Amiard and R. Heymes: Bull. Soc. Chim. Fr., 1012 (1954).
10) W.H. Hartung and R. Simonoff: Organic Reactions, VII. 263 (1953).
11) B. El Amin, G. Anantharamaiah. G. Royer and G. Means: J. Org. Chem., 44. 3442 (1979).

[Rhodium]

Patent US2682474

2-Hydroxy-5-methoxy-allylbenzene

A mixture of 120 grams (2.0 mols) of 85% potassium hydroxide, 248 grams (2.0 mols) of 4-methoxyphenol, 153 grams (2.0 mols) of allyl chloride, 400 ml. of water, and 400 ml. of acetone was refluxed for five hours. The resulting mixture was cooled to 30°C. and 200 ml. of hexane was added. Two layers were formed which were separated and the nonaqueous organic layer was washed twice with water and then dried over calcium chloride. This resulting residue was then mixed with 300 ml. of diethylaniline and heated at 190-210°C. for four hours, allowing the hexane to distill off. The residue was then allowed to cool and was mixed with 300 ml. of hexane and extracted twice with 400 ml. portions of a 10% sodium hydroxide solution. The extract which was obtained was acidified with hydrochloric acid resulting in the formation of an oily layer which was then separated, dried over calcium chloride, and then distilled under greatly reduced pressure. A yield of 196 grams (60%) of 2-Hydroxy-5-methoxy-allylbenzene was obtained which had a boiling point of 101-104°C/3mmHg.

2-Hydroxy-5-methoxy-propenylbenzene

A mixture of 82 grams (0.5 mol) of 2-Hydroxy-5-methoxy-allylbenzene, 164 grams (2.9 mols) of potassium hydroxide, and 82 grams of water was heated with stirring and under a nitrogen atmosphere at 170°C. for one hour. After cooling the reaction mixture, 800 mL of water was added and the resulting solution was then acidified with hydrochloric acid. The oily layer which formed upon the acidification was dried over calcium chloride and then distilled under greatly reduced pressure. A yield of 63 grams (77%) of 2-Hydroxy-5-methoxy-propenylbenzene was obtained which had a boiling point at 110-114°C/3mmHg.

[Osmium]

The first step produces the allylether of the phenol which is then rearranged (Claisen rearrangement) by refluxing in a high-boiling organic solvent.

The second step isomerizes the phenol using a procedure which was originally used for eugenol ----> isoeugenol isomerisation.

This patent is 50 years old, so the yields which can be achieved should be higher. If I wanted to produce these compounds as precursors to 2,5-DMA I'd use different reaction conditions:
1. Make the allylether with K2CO3 and acetone.
2. Rearrange it without dilution by heating it to 200°C or so. The rearrangement is exothermic and might get out of control for bigger batches, so limit the reflux temperature by applying vacuum.
3. Methylate using one of the high-yielding (95+%) methods on Rhodium's page, e.g. the solventless methylation with dimethylsulfate, or methylation with a carbonate base in acetone.
4. Isomerize if desired by using the KOH vacuum reflux or any other method which works for isosafrole.

This should give better yields, is way less toxic (diethylaniline *shudder*) and also cheaper.

[Rhodium]

Conventional and Microwave Assisted Hydrogenolysis Using Zinc and Ammonium Formate
G. R. Srinivasa, S. N. Narendra Babu, C. Lakshmi, D. Channe Gowda

Synth. Commun. 34(10), 1831-1837 (2004)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/debenzylation.zn-af.html)

Abstract
The selective deprotection of several N-Bzl amino derivatives to the corresponding amines and the removal of S-Bzl and O-Bzl groups from the protected amino acids with ammonium formate and commercial zinc dust are reported. Many other reducible or hydrogenolysable substituents such as halogens, methoxy, phenol, ester, acid, ethene, and Boc groups are unaffected.

[Rhodium]

Debenzylation of N-Benzylamino Derivatives by Catalytic Transfer Hydrogenation with Ammonium Formate
Siya Ram and Leonard D. Spicer

Synth. Commun. 17(4), 415-418 (1987)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/debenzylation.pd-af.html)

Abstract
A method for deprotection of several N-benzyl derivatives of amines to the corresponding amino derivatives with ammonium formate and 10% Pd-C is reported.

[Kinetic]

Is this the elusive paper we've all been waiting for? A systematic study of CTH N-debenzylation using less than 20% w/w of 10% Pd/C with ammonium formate, hydrazine hydrate or sodium hypophosphite as hydrogen donor:

Catalytic Transfer Hydrogenolysis of N-Benzyl Protecting Groups
B. M. Adger, C. O'Farrell, N. J. Lewis, M. B. Mitchell
Synthesis, 1987, 53-55

Abstract
The catalytic transfer hydrogenolysis of a number of N-benzyl compounds has been examined. Of the three hydrogen donors studies, ammonium formate and hydrazine hydrate were more effective than sodium hypophosphite. In general, debenzylation of secondary and tertiary benzylamines could be readily accomplished by refluxing the substrate with an excess of the hydrogen donor in alcoholic solvents for a few hours using catalytic amounts of 10% palladium on carbon. The two N-benzyl heteroaromatic amines studied were stable to the above conditions.