M. E. Lanning, S. Fletcher / Tetrahedron Letters 54 (2013) 4624–4628
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chromatography as they were readily separable from the target
compounds. Alternatively, after concentration of the THF reaction
solvent, ADDM/ADDM-H2 could be triturated with ether, or ex-
tracted into water from CH2Cl2 or EtOAc, as anticipated.
Next, we examined the scope of the ADDM-mediated Mitsun-
obu reaction with a range of pro-nucleophiles; our results are
shown in Table 3. Benzoic acid, phenol, phthalimide, and N-benzyl-
benzenesulfonamide12 all underwent condensations with benzyl
alcohol with excellent isolated yields of the expected products in
yields of >80%. Although the Mitsunobu reaction did not proceed
with diethyl malonate, employing the more acidic di(2,2,2-trifluo-
roethyl) malonate13 afforded a 60% yield of a mixture of mono- and
di-benzylated malonates.
Since ADDM-H2 has excellent solubility in water and limited
solubility in ether, we reasoned that it should be readily isolable
from the reaction mixture and subsequently recycled by oxidation
back to ADDM. To this end, we repeated the condensation of benzyl
alcohol and phenol in THF with ADDM and PBu3, and recovered
about 60% of ADDM-H2 by trituration with ether. Re-oxidation of
ADDM-H2 with silver(I) oxide (Ag2O) delivered ADDM (Scheme 2).
The regenerated ADDM was utilized in another otherwise identical
round of Mitsunobu chemistry with no detriment to the yield rel-
ative to fresh ADDM that was prepared from DEAD and
morpholine.14
Finally, we investigated whether a chromatography-free Mits-
unobu reaction with ADDM would be possible. A mixture of
1 equiv of benzoic acid, 2 equiv of each of 1-butanol and ADDM,
and 3 equiv of PPh3 on resin in CH2Cl2 was gently agitated for
16 h at room temperature (Scheme 3). TLC analysis of the reaction
mixture confirmed all of the phenol had been consumed, and only
one new UV-active species was generated. Filtration of the reaction
mixture removed the PPh3/PPh3O on resin. After the filtrate had
been concentrated, the residue was resuspended in ether, and
washed thoroughly with water to afford the product 1-butyl
benzoate in >95% purity, as judged by 1H NMR.15
In summary, we have demonstrated that commercially avail-
able ADDM is a versatile Mitsunobu reagent, facilitating the dehyd-
rative couplings of a variety of primary and secondary alcohols to
a diverse collection of pro-nucleophiles spanning a pKa range from
5 to 12. Furthermore, the greater polarities of ADDM and ADDM-
H2, relative to the more traditional Mitsunobu reagent DIAD (and
DIAD-H2), results in simpler flash chromatographic purification.
Alternatively, ADDM and ADDM-H2 may be conveniently removed
from the reaction mixture by trituration with ether, or by extrac-
tion into water. ADDM may be regenerated by brief treatment of
recovered ADDM-H2 with Ag2O. By employing PPh3 on resin, we
also showed that ADDM allows for a chromatography-free Mitsun-
obu reaction.
Acknowledgment
The authors wish to thank the University of Maryland School of
Pharmacy for financial support of this work.
References and notes
Sierra, M. L.; and Ramsden N. G. PCT Int. Appl., 2002092590, 2002.; (d) Bell, R.;
Beswick, P. J.; Gosmini, R. L. M.; Hamlett, C. C. F.; King, N. P.; Patel, V. K. PCT Int.
Appl., 2004000315, 2003.
9. Synthesis of ADDM from DEAD: To a stirred solution of diethyl azodicarboxylate
(40 wt% in toluene; 5 mL, 11.5 mmol, 1 equiv) in Et2O (25 mL) at 0 °C was
added a solution of morpholine (1.98 mL, 23 mmol, 2 equiv) in Et2O (25 mL)
over 3 h with
a dropping funnel. The reaction mixture was stirred for a
further 2 h whilst slowing warming to room temperature. The yellow-
orange precipitate was collected by vacuum filtration, washed with cold
Et2O, and dried on the filter to furnish ADDM as a yellow-orange solid (1.62 g,
55% yield): dH (CDCl3, 400 MHz) 3.61 (m, 4H, 2CH2), 3.74 (m, 8H, 4CH2), 3.83
(m, 4H, 2CH2).
11. Typical procedure: A solution of phenol (47 mg, 0.5 mmol, 1 equiv), benzyl
alcohol (108 ll, 1.0 mmol, 2 equiv) and PBu3 (250 ll, 1.0 mmol, 2 equiv) in
anhydrous THF (7 mL) was stirred at RT for 2 min. ADDM (256 mg, 1.0 mmol,
2 equiv) was added in one portion. The reaction mixture was stirred at RT for
16 h under an inert atmosphere. The solvent was concentrated under reduced
pressure, and then the residue was adsorbed onto silica gel from CH2Cl2, and
purified by flash column chromatography (eluent: Hex/EtOAc, 9:1) to give
(benzyloxy)benzene as a colourless oil (92 mg, 94%): dH (CDCl3, 400 MHz) 5.08
(s, 2H, CH2), 7.28–7.49 (m, 10H, Ar).
Scheme 2. Yields for the Mitsunobu reaction with (a) ADDM prepared from DEAD
and (b) recycled ADDM prepared by re-oxidation of ADDM-H2.
14. Regeneration of ADDM: Trituration of the crude residue from an ADDM/PBu3
Mitsunobu reaction afforded about 60% recovery of reduced ADDM, or ‘ADDM-
H2’. To a solution of ADDM-H2 (235 mg, 0.910 mmol, 1 equiv) in MeOH (9 mL)
was added silver(I) oxide (211 mg, 0.910 mmol, 1 equiv). The reaction mixture
was stirred for 15 min, by which time it had turned a dark orange colour, at
which point it was dried with anhydrous MgSO4, and then filtered. The filtrate
was concentrated, resuspended in minimal acetonitrile, filtered and
concentrated once more to deliver regenerated ADDM (133 mg, 60% yield).
15. Solid phase procedure: A solution of benzoic acid (122 mg, 1.0 mmol, 2 equiv),
1-butanol (45.7 ll, 0.5 mmol, 1 equiv) and PPh3 on resin (718 mg, 2.09 mmol/g,
1.5 mmol, 3 equiv) in anhydrous CH2Cl2 (7.5 mL) was gently stirred for 5 min.
Then, ADDM (256 mg, 1.0 mmol, 2 equiv) was added in one portion. The
Scheme 3. A chromatography-free Mitsunobu reaction.