• 10.1021/ja412578t
  • Journal of the American Chemical Society
  • Volume 136
  • February 2014
  • pp 2268-2271

Good but some limitations


Description of Study

Szostak and coworkers reported highly chemoselective reduction of amides ( primary, secondary, Tertiary) to alcohols using SmI2  /Amine /H2O under mild conditions.  They  reduced amide to alcohol by stirring amide (0.1mmol) with SmI2 ( 0.8 mmol), water (7.2 mmol) and Et3N  (7.2 mmol ) at room  temperature for 18 h.

Strong points of Study

  1. The reaction under mild conditions.

(ii)     Highly chemoselective reduction of amide in to alcohol   in    

          very high yield in most of the cases (> 90% yield) via C-N      

           cleavage e.g.; amides (1a-1n) reduced to alcohol, 2a >95%

          conversion in 18 h.  However, the amide, 1o which has bulky

          N-substituted group was converted to alcohol, 2a only <5%. 

Limitations of Study

  1.  One of the limitations is the conversion of amide, 1i to alcohol , 2a was reduced from 97% to 49% by reducing the amount of SmI2   from 0.8 mmol to 0.2 mmol, water from 7.2 mmol to 2.4 mmol and Et3N from 7.2 mmol to 2.4 mmol.  It would have been a study of greater benefit if they explored the effect of amount of reagent on the product yield.
  2.  The other limitation is that they did not report any results regarding the controlled reaction condition for amide conversion to alcohol.
  3.   It seems that they had ignored the steric effect of substituent.  Therefore, they must have not studied the  bulky N-substituted amides other than amide, 1o.
  4. They also ignored the amine formation reaction. They reported the formation of amine along with alcohol, 2a from reaction of the secondary amide like, 1c.   However, they apparently have not observed the yield of the amine formation reaction in other similar type of amides.
  5. The mechanism of the reaction is studied by methods, more complicated than necessary such as cyclopropyl clock experiments, deuterium incorporation studies, kinetic isotope effect studies, H218O incorporation experiments and Hammett and Taft studies.  The simpler methods such as controlled reaction method would have produced the same results.

Improvement of Study

  1.  At first, I would check the reproducibility of the method. I would synthesize the fresh SmI2 (0.1M) by following the existing procedure.  I will mix SmI2  (0.8 mmol) with water (3.6 mmol) and Et3N (3.6 mmol). The reaction should be stirred for 3 h and 18 h subsequently.  The effect of reaction time on the alcohol yield should be observed immediately by using 1HNMR or GC-MS.
  2. The reaction mechanism should have been studied using an    

easier method. I would changed the amount of one of the reagent (SmI2 or water, or Et3N) one at a time .  Similarly I would change the duration of the reaction from 5 min to several h.

  1. In my opinion , the method would have been more  useful if     

both amine and alcohol had been produced simutaneously. Therefore, I would have run the reaction with other longer chain N-substituted amides and checked the amine and alcohol formation reaction in the given set of the conditions.

Overall evaluation

       This paper is best characterized as “useful” and “thorough”.  It is a solid summary of a lot of laboratory work in organic synthesis, and the results include a list of amides for producing various alcohols as well as amines in some cases, e.g, amide,1c

      The authors developed a new and valuable alternative to the existing method of reduction of primary, secondary and tertiary amides to alcohols using SmI2/amine/ H2O.  This method has been shown to result in an excellent conversion of amide to corresponding alcohols with an excellent yield (up to 97%) of chemo-selectivity.

       The authors have provided a convincing explanation of the mechanism involving reversible first electron transfer and electrophilic activation of the amide bond.   They have successfully proved the high selectively for C-N bond cleavage by conducting cyclopropyl clock experiments, incorporating deuterium studies, kinetic isotope effect studies, H218O incorporation experiments and Hammett and Taft studies.

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