Research Synopsis, McDonald Lab
The Development of New Ligands for Samarium (II)
Samarium (II) iodide (SmI2)
is a versatile reductant used by organic chemists. Its uses include direct reductions of alkyl
halides1, aldehydes/ketones2, and a,b- unsaturated carbonyl compounds.2 Its most important synthetic application is
in the area of carbon-carbon bond formation.
It can be used to couple a pair of aldehydes (or ketones) as well as a
carbonyl to a C-C pi bond.3
This research laboratory has previously uncovered a route to cyclize
unsaturated amides with SmI2 after electrophilic activation of the
amide by triflic anhydride.4
Several research groups have explored the use of various ligands to
‘tune” the reductive power of the SmI2.5,6 Hexamethylphosphoric triamide (HMPA, 1) is the most important ligand used to
increase the reducing power of SmI2, unfortunately this ligand has
been associated with nasopharangeal cancer.7 Much effort has gone into finding an
innocuous yet effective replacement for HMPA.
To date, no alternative ligand has proven wholly satisfactory as a
We have developed two neutral phosphoramide
alternatives to HMPA which are considerably less toxic and with similar
abilities to activate SmI2.
We first examined the dehydro dimer of HMPA (diHMPA, 2) which is less mutagenic than HMPA by
virtue of its lower volatility.8 The lower volatility is important
because HMPA is known to cause cancer by the inhalation route but not by oral
Tripyrrolidinophosphoramide (TPPA, 3) is a particularly intriguing surrogate for HMPA due to ease of synthesis (Scheme 1) and its powerful activating ability.
The complex formed between SmI2 and four equivalents of TPPA is deep purple with the same lmax as the SmI2/HMPA complex. We have several pieces of evidence which indicate that SmI2/TriPy is substantially more reactive than SmI2/HMPA from a kinetic standpoint. Alkyl chlorides are known to be reluctant substrates for reduction by SmI2/HMPA.2 Our recent reduction of 1-chlorodecane by both complexes indicates that SmI2/TPPA reduces 1-chlorodecane four times faster than SmI2/HMPA (Scheme 2).9 The ligand DMPU, the most common nonmutagenic alternative to HMPA is not effective at activating SmI2 to reduction of alkyl chlorides.
Very recently we have examined the use of anionic phosphoramides (phosphoramidates) in the hope that they will deliver even more electron density to the Sm(II) center and thus further enhance the reductive capabilities of the resultant complex. Initial efforts are illustrated in Scheme 3. This phosphoramidate was designed with a single N-methyl group, to minimize mutagenicity, and two pyrrolidino groups, because of their proven utility in the case of TPPA. Addition of four equivalents of pyrrolidine to POCl3 cleanly affords dipyrrolidinophosphoryl chloride (after removal of solid pyrrolidinium hydrochloride by filtration). Addition of CH3NH3Cl and Et3N provides crystalline dipyrrolidinomethylamino phosphoric triamide (DPMPA) in multigram quantities and 77 % yield from POCl3 after distillation. Addition of BuLi to DPMPA yields the desired anionic species, DPMPA-.
Addition of one equivalent of SmI2 in THF to four equivalents of DPMPA- yields a deep brown (not blue or purple) THF-soluble complex. Our initial efforts at characterization of SmI2 /4 DPMPA- suggest that it is a complex of extreme reactivity.
1-Chlorodecane, a reluctant substrate for reduction by most SmI2 species, was chosen for these initial tests. Complexes were formed from SmI2 and four equivalents of each ligand (either a neutral phosphoramide or DPMPA-). Ten minutes after the addition of 1-chlorodecane and tetradecane (internal standard), an aliquot was removed and quenched with I2. All complexes composed of SmI2 and neutral phosphoramides produced a 0-1% yield of decane at the 10 minute mark (Table 1). However, the SmI2/4 DPMPA- complex afforded a 91% yield of decane under these conditions! Inanaga has reported that SmI2 with 5% HMPA requires 8 h at 60 oC to reduce 1-chlorododecane (89% yield). Dahlen and coworkers have used 7 SmI2 /35 H2O/28 Et3N to reduce 1-chlorodecane (14 h, 20oC, 95%). These results indicate that this new complex is hundreds of times more reactive than any previously known non-aquo SmI2 complex.
We are now in the process of determining the synthetic scope and limitations of this new complex. We are also attempting to characterize the new complex by visible spectroscopy, cyclic voltammetry, and X-ray analysis.
Student Researchers: Laura Anderson, Robert Beamon, Julie Butler, Michael Cecchini,
Jordan Krebs, Evan Holland, James Grant, David Sampsell, Kyle Totaro
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