The Developing Green Chemistry for Multi-Step Synthesis

Chao-Jun Li

When designing strategies for multi-step chemical synthesis, some
fundamental skills include the delicate balance of protection and
deprotection, the choice of oxidation and reduction, and the change of
acidity and basicity. An alternative green chemistry approach would call
fundamental scientific breakthroughs in developing innovative chemistry
that can eliminate the use of protection-deprotection steps, the change
of oxidation state, and the variations of acidity and basicity.

One example for the use of the concept is the related to carbanion-based
chemistry. The importance of carbanions in synthesis is exemplified by
the Grignard reaction and the Wittig reaction. Although they are among
the most versatile and useful reactions in organic chemistry,
carbanion-based reactions are generally known to be incompetible with
air and water as well as various functional groups. The required
deviation from ambient conditions along with the commonly used methods
for their generation leads to several fundamental drawbacks when the
Principles of Green Chemistry \[1\] are applied (Figure 1): (1) large
volumes of anhydrous organic solvents are required which could
potentially increase volatile organic emissions; (2) anhydrous
conditions require excess drying agents which will lead to unwanted
waste; (3) anhydrous conditions also require the protection of
functional groups such as hydroxy groups and carboxylic acids; (4) the
requirement of inert gas atmosphere implies that the catalyst is prone
to deactivation, which will increase the amount of heavy metal waste;
(5) requirement of stoichiometric metals also leads to a large amount of
metal waste; and (6) the general use of organic halides as the carbanion
source will generate a stoichiometric amount of halide waste, as well as
requires multi-step synthesis of the halides. In addition, such
transformations require an unnecessary change of oxidation states.

To green these carbanion-based reactions, we developed chemistry that
can eliminate various auxiliary factors were eliminated through the
development of fundamental reactions. Ultimately, reactions with 100%
atom-efficiency \[2\] are possible. To do this, the development of
related reactions through C-H activation in air and water is possible
\[3\]. The activation of the sp3 allylic C-H bond was developed by using
ruthenium catalysts in air and water or ionic liquids \[4\]. Another
example is the addition reaction of acetylenes to aldehydes in air and
water or ionic liquids via C-H activation \[5\]. The reaction has been
extended to other electrophiles and the strategy has been extended to
other reaction types.

We are grateful to NSF and the NSF-EPA Joint Program for a Sustainable
Environment for support of our research.

References:

1.  Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice,
    Oxford University Press, Oxford 1998.

2.  Trost, B. M. Science 1991, 254, 1471; Sheldon, R. A. Chemtech 1994,
    24, 38; Wender, P. A.; Miller, B. L. in Organic Synthesis: Theory
    and Applications, Hudlicky, T. Ed. JAI Press, Vol. 2 1993.

3.  Naota, T.; Takaya, H.; Murahashi, S. I. Chem. Rev. 1998, 98, 2599;
    Dyker, G. Angew. Chem. 1999, 38, 1698.

4.  Li, C. J.; Wang, D.; Chen, D. L. J. Am. Chem. Soc. 1995, 117, 12867;
    Tetrahedron 1998, 54, 5129.

5.  Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638; Green Chem.
    2002, 4, 1; Chem. Commun. 2002, 268; Wei, C. M.; Li, Z. G.;
    Li, C. J. Org. Lett, 2003, 5, 4473-4475; Wei, C. M.; Li, C. J. J.
    Am. Chem. Soc. 2003, 125, 9584; Li, Z. G.; Wei, C. M.; Chen, L.;
    Varma, R. S.; Li, C. J., Tetrahedron Lett. 2004, 45, 2443-2446;
    Wei, C. M.; Mague, J. T.; Li, C. J. Proc. Nat. Acad. Sci.
    (Washington DC), 2004, in press.