Synthesis of Aminobenzoic Acid Derivatives via Chemoselective

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Synthesis of Amino Benzoic Acid Derivatives via Chemoselective Carbene Insertion into the -NH Bond Catalyzed by Cu(I) Complex Kankanala Ramakrishna, and Chinnappan Sivasankar J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01249 • Publication Date (Web): 08 Jul 2016 Downloaded from http://pubs.acs.org on July 10, 2016

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The Journal of Organic Chemistry

Synthesis of Amino Benzoic Acid Derivatives via Chemoselective Carbene Insertion into the -NH Bond Catalyzed by Cu(I) Complex Kankanala Ramakrishna and Chinnappan Sivasankar*

Catalysis and Energy Laboratory, Department of Chemistry, Pondicherry University (A Central University), Puducherry, India 605014. E-mail: [email protected]. Tel.: +91 413 2654709. Fax: +91 413 2655987.

TOC Graphic

ABSTRACT: Phosphine ligand stabilized air stable Cu(I) complexes have been successfully used to functionalize the aromatic amino benzoic acids in a chemoselective manner without implementing protection and deprotection strategy under mild reaction conditions. This chemoselective carbene insertion into -NH bond over -COOH and -OH bonds leads to the wide range of carboxy and hydroxy functionalized α-amino esters (27 examples). All the isolated new products have been fully characterized using standard analytical methods.

Keywords: Carbene insertion, amino benzoic acid, copper catalyst, N-H bond insertion and chemoselective reaction. 1 ACS Paragon Plus Environment


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INTRODUCTION: Aromatic amino benzoic acid derivatives are important building blocks for many of nature as well as synthetic made molecules.1 These derivatives have been used to alter bio-chemical and structural properties of peptides.2a Derivatives of anthranilic acid are synthons for acridines synthesis, which shows potential activity against cancer and malaria.2b,2c In this regard direct synthesis of amino benzoic acid derivatives without protection and deprotection strategy is a long time challenging task for synthetic chemists. It can be noted from the literature that only few methods are known to do this chemistry effectively. Widely used methods are (i) selective nucleophilic substitution using corresponding halide derivative in the presence of base3 (Scheme 1a), (ii) imine formation using the corresponding aldehyde followed by reduction1b,4 (Scheme 1b) and (iii) Transition metal complexes promoted coupling reactions such as BuchwaldHartwig,5 Ullmann6 and Chan-Lam cross coupling7 reactions (Scheme 1c and 1d). Along with these conventional methods few more methods are appeared in the literature.8 Owing to the low solubility of amino benzoic acids in an aprotic solvent, one has to use protic or more polar solvent. Mostly, protic solvent or solvent which can act as a nucleophile produces solvent substituted side products. In case of imine formation followed by reduction method, one has to use reducing agent which is cost in-efficient. Among all the cross coupling reactions, the Ullmann coupling reaction shows wide scope compared to other methods. It can be noted from the literature that the Buchwald-Hartwig cross coupling reaction proceeds via protection and deprotection of acid functional group whenever an acid functional group is present in the substarte.5a,5c In case of the Chan-Lam coupling, best of our knowledge there is no report on amino benzoic acids, however it is an important method for making C-N bond. These Cross coupling

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reactions proceed under harsh reaction conditions, which causes unwanted side products and functional group intolerance. Mostly, the above mentioned methods work for simple aromatic amines and shows less tolerance for acid and alcohol substituted amines. Although considerable amount of progress made in the past years, still the known methods suffer owing to poor selectivity and low yield and leaves much room for further development of cheap, atom efficient and viable method to improve the product selectivity and yield.



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Scheme 1. Different Approaches to Access Aromatic Amino Acid Derivatives, Some Representative Examples

On the other hand, transition metal complexes mediated (isolated complexes or in-situ generated) carbene insertion into X-H (X=NH, O, R3Si, S, R3C or R2B) bond is also one of the fast developing synthetic strategies.9 Thus far most successfully employed transition metal catalysts for carbene insertion into X-H bonds are Rh,10 Fe11 and Cu12 etc. along with N, O, C and P based ligands. One of the promising and challenging tasks in this strategy is selectively inserting the carbene into the desired X-H bond in the presence of other functional groups (which are equally capable of undergoing insertion) without using any functional group protecting agent.13 It is also worthwhile to mention here that the phosphine based ligands are less explored for the carbene chemistry in particular with Cu(I) ion.14

Scheme 2. Proposed Chemoselective Carbene insertion into -NH Bond over –COOH Bond

In this regard, recently we reported a chemoselective carbene insertion into -NH bond over -OH bond.13a In order to gain a wider scope for our catalyst (1) and considering the importance of aromatic amino benzoic acid derivatives, in this report we have developed a strategy to derivatize the aromatic amino acids by inserting the carbene selectively into -NH bond over COOH and -OH bonds (Scheme 2).


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RESULTS AND DISCUSSION:

Scheme 3. Copper Complexes used as Catalysts in the Current Study

We have synthesized catalysts 1, 2 and 3 (Scheme 3) using the literature procedures12h and confirmed with the reported analytical data and used for carbene insertion into -NH bonds as follows. The catalysts 1-3 are stabilized by bis-phosphine ligands. Although the catalysts 1 and 2 contains pincer type ligands, these bis-phosphine ligands are known to coordinate to the Cu(I) center in a ɳ2 fashion only.

Scheme 4. Reaction of α-Phenyl Diazoacetate with 4-Amino Benzoic Acid

We started our investigation with 4-amino benzoic acid and α-phenyl diazoacetate in methanol using 2 mol % of catalyst 1 (Scheme 4). The reaction was completed in 2 h and furnished -NH 5 ACS Paragon Plus Environment


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inserted product in 81% yield. Evidences for selective carbene insertion into -NH bond was obtained from 1H-NMR and IR spectroscopy. We observed a broad singlet at 12.10 ppm and a sharp band at 3388 cm-1 respectively for the presence of free acid in the product. In order to gain more evidences, we subjected a suitable single crystal to X-Ray diffraction studies and we found that the carbene is inserted only into -NH bond and not into -COOH bond (Figure S1 in Supporting Information).

Table 1. Screening of Various Copper Sources as Catalysts for Chemoselective Carbene Insertion into the -NH Bond of 4-Amino Benzoic Acid

entrya

catalyst

1 2 3 4 5 6 7b

1 2 3 CuOTf CuCl (CH3CN)4CuClO4 (CH3CN)4CuClO4 + 1, 10Phenanthroline (CH3CN)4CuClO4 + 2PPh3 (CH3CN)4CuClO4 + dppe (CH3CN)4CuClO4 + dppm --

8 9 10 11c

time (h) 2 2 6 2 2 2 1

yield (%) (-NH/-COOH) 81/54/31/47/9 42/46/5 51/8

3

25/-

3

37/4

3

34/-

12

10/8

a

All the reactions were carried out with 0.5 mmol (with respect to 4-amino benzoic acid) in 5 mL of methanol with 2 mol % of catalyst in a 25 mL Schlenk flask under dinitrogen atmosphere. bWe observed 16% of mixture of unidentified product. cReaction carried out at 60 °C, we observed many unidentified compounds on TLC.


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Based on our previous experience with catalyst 113a and solubility issue of amino benzoic acids, we were forced to choose methanol as a solvent for further optimization of reaction conditions. We anticipated that the phosphine coordinated Cu(I) complexes (2 and 3) with similar rigid structural and electronic features of catalyst 1 will also give similar selective carbene insertion into -NH bond over -COOH bond. Therefore we have tested two more copper complexes of 1,1′bis(diphenylphosphino)ferrocene

(dppf)

and

4,5-bis(diphenylphosphino)-9,9-

dimethylxanthen(xantphos) (complexes 2 and 3) as catalysts for carbene insertion reaction. We have also screened various Cu(I) sources as catalysts for carbene insertion reaction (Table 1).

We have chosen p-amino benzoic acid and α-phenyl diazoacetate to yield carbene inserted product. For catalyst 1, we observed 81% of -NH inserted product in 2 h (Table 1, entry 1), contradictory to our anticipation, catalysts 2 and 3 offered low yields, though these catalysts compete with catalyst 1 in case of simple anilines.12h Catalyst 2 offered 54% of -NH inserted product in 2 h (Table 1, entry 2), and catalyst 3 offered only 31% -NH inserted product in 6 h (Table 1, entry 3). We have also examined readily available copper salts such as Cu(OTf) and [(CH3CN)4Cu]ClO4 for carbene insertion reaction and observed 47% and 46% yields of -NH inserted product along with

Synthesis of Aminobenzoic Acid Derivatives via Chemoselective

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