1-{(1S,2S,4R)-7,7-Dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo [2.2.1]heptan-2-yl}-1H-benzo[d]imidazole

Round 1

Reviewer 1 Report

The authors report on the preparation of a potential bifunctional chiral organocatalyst, derived from camphor, containing both a pyrrolidine and a benzoimidazole moiety. the most interesting feature is the (unanticipated) observation that after treatment of a 1,2-benzene diamine derivative 3 with 2-(ethoxymethylene)malononitrile, the camphor-derived benzimidazole 5 was obteined in good yield, instead of the deisred enamine derivative 4. 

A satisfactory mechanistic rationalization is provided, although the authors omitted the fact that a precedent for this exact transformation can be found in a a patent dating from 2003 (US2003/60624, 2003, to Pfizer Inc.)

Also,  the authors should comment on the fact that this same transformation (N-substituted benzene-1,2-diamine into benzo[d]imidazole) is commonly performed by C1 reagents (CO₂, DMF, trimethyl or triethyl ortoformate, DMSO...), and provide some selected references.

Experimental procedures and product characterization are satisfactory.

I recommend publication after minor revision.

Author Response

Response to Reviewer 1 Comments

A satisfactory mechanistic rationalization is provided, although the authors omitted the fact that a precedent for this exact transformation can be found in a patent dating from 2003 (US2003/60624, 2003, to Pfizer Inc.)

The patent literature was included with the accompanying text in the discussion.

1. Robert A. Singer, Paul H. Ginsburg, PROCESS FOR THE PREPARATION OF 1,3-SUBSTITUTED INDENES AND ARYL-FUSEDAZAPOLYCYCLIC COMPONUNDS, US 2003/0060624 A1, filed 17 April 2002, and issued 27 March 2003.

Also, the authors should comment on the fact that this same transformation (N-substituted benzene-1,2-diamine into benzo[d]imidazole) is commonly performed by C1 reagents (CO₂, DMF, trimethyl or triethyl ortoformate, DMSO...), and provide some selected references.

Selected references have been included the accompanying text in the discussion.

2. Faheem, M.; Rathaur, A.; Pandey, A.; Kumar Singh, V.; Tiwari, A.K. A Review on the Modern Synthetic Approach of Benzimidazole Candidate. ChemistrySelect 2020, 5, 3981– https://doi.org/10.1002/slct.201904832.
3. Zhu, X.; Zhang, F.; Kuang, D.; Deng, G.; Yang, Y.; Yu, J.; Liang Y. K₂S as Sulfur Source and DMSO as Carbon Source for the Synthesis of 2-Unsubstituted Benzothiazoles. Lett. 2020 22, 3789–3793. https://doi.org/10.1021/acs.orglett.0c00994.
4. Ryabukhin, S.V.; Plaskon, A.;Volochnyuk, D.M.; Tolmachev A.A.Synthesis of Fused Imidazoles and Benzothiazoles from (Hetero)Aromatic ortho-Diamines or ortho-Aminothiophenol and Aldehydes Promoted by Chlorotrimethylsilane. Synthesis 2006, 3715–3726. DOI: 10.1055/s-2006-950289.
5. Bahrami, K; Khodaei, M.M.; Naali F. Mild and Highly Efficient Method for the Synthesis of 2-Arylbenzimidazoles and 2-Arylbenzothiazoles. Org. Chem. 2008, 73, 6835–6837. https://doi.org/10.1021/jo8010232.
6. Bastug, G.; Eviolitte, C.; Markó I.E. Functionalized Orthoesters as Powerful Building Blocks for the Efficient Preparation of Heteroaromatic Bicycles. Lett. 2012, 14, 3502–3505. https://doi.org/10.1021/ol301472a.
7. Nale D.B.; Bhanage B.M. N-Substituted Formamides as C₁-Sources for the Synthesis of Benzimidazole and Benzothiazole Derivatives by Using Zinc Catalysts. Synlett 2015, 26, 2835– DOI: 10.1055/s-0035-1560319.
8. Wang, Y.; Sarris, K.; Sauer, D.R.; Djuric S.W. A simple and efficient one step synthesis of benzoxazoles and benzimidazoles from carboxylic acids.Tetrahedron Lett. 2006, 47, 4823– https://doi.org/10.1016/j.tetlet.2006.05.052.