C O M M U N I C A T I O N S
Scheme 4. Enantioselectivity in the Rearrangement
Figure 1. Transition structures for (a) 1,2-acyl transfer and (b) 1,4-aryl
transfer. Coordinated THF solvent molecules and the Me- counterion have
been omitted for clarity. Interatomic distances are given in angstroms.
showed that rearrangement proceeded with inversion at the lithium-
bearing center.
We are currently working to broaden the scope of this new
reaction to other N-aryl-substituted carbamate analogues.
To illuminate the mechanism of the rearrangement and the
selectivity with regard to the competition between 1,2-acyl shift
and 1,4-aryl transfer, the stationary structures involved in the
conversion of the organolithium intermediate 2 to both 4 and 5
with inversion at the carbanion center (Scheme 5) were determined
using density functional theory (DFT) calculations.15 A simple
carbamate 1a with R1 ) Ph, R2 ) Me, and R3 ) H was chosen as
the substrate. The anionic intermediate 2a was coordinated with
two Li+ cations [one as an alkyllithium (methyllithium, for
simplicity) to represent the excess RLi] and three THF solvent
molecules, and a continuum description of the bulk solvent was
used.
Acknowledgment. We are grateful to the Deutscher Akade-
mischer Austauschdienst (DAAD) for a postdoctoral fellowship (to
U.H.) and to the EPSRC and the Leverhulme Trust for support.
Supporting Information Available: Full experimental procedures
and characterization data for compounds reported in the paper, together
with details of computational studies. This material is available free of
References
(1) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon: Oxford,
U.K., 2002.
(2) (a) Hoppe, D.; Hanko, R.; Bro¨nneke, A. Angew. Chem., Int. Ed. Engl. 1980,
19, 625. (b) Hoppe, D.; Bro¨nneke, A. Synthesis 1982, 1045. (c) Peters,
J. G.; Seppi, M.; Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synthesis 2002,
381.
Scheme 5. Mechanism and Selectivity: 1,4-Aryl versus 1,2-Acyl
Transfer
(3) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. (b) Hoppe, D.;
Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl. 1990, 29, 1422. (c)
Hintze, F.; Hoppe, D. Synthesis 1992, 1216.
(4) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008,
456, 778.
(5) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(6) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097.
(7) (a) Zhang, P.; Gawley, R. E. J. Org. Chem. 1993, 58, 3223. (b) Superchi,
S.; Sotomayor, N.; Miao, G.; Babu, J.; Campbell, M. G.; Snieckus, V.
Tetrahedron Lett. 1996, 37, 6061. (c) Slana, G. B. C. A.; de Azevedo,
M. S.; Lopes, R. S. C.; Lopes, C. C.; Cardoso, J. N. Beilstein J. Org. Chem.
2002, 2, 1.
(8) DMPU ) N,N′-dimethyl-N,N′-propylideneurea. We routinely add DMPU
to reactions where we wish to promote organolithium nucleophilicity,
particularly toward aromatic rings. See ref 13 and: (a) Clayden, J.; Parris,
S.; Cabedo, N.; Payne, A. H. Angew. Chem., Int. Ed. 2008, 47, 5060. (b)
Clayden, J.; Knowles, F. E.; Menet, C. J. Synlett 2003, 1701.
(9) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153.
(10) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. For recent
reviews on the synthesis of tertiary alcohols, see: (b) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (c) Goldfuss, B. Synthesis
2005, 2271. (d) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem.
Soc. ReV. 2006, 35, 454. (e) Riant, O.; Hannedouche, J. Org. Biomol. Chem.
2007, 873. (f) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853.
(11) Only recently has 11 been made in enantiomerically enriched form by
methods other than resolution. See ref 4 and: (a) Hatano, M.; Miyamoto,
T.; Ishihara, K. Org. Lett. 2007, 9, 4535. (b) Chen, C.-A.; Wu, K.-H.; Gau,
H.-M. Angew. Chem., Int. Ed. 2007, 46, 5373. (c) Forrat, V. J.; Ramo´n,
D. J.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 537. (d) Forrat, V. J.;
Ramo´n, D. J.; Yus, M. Tetrahedron: Asymmetry 2006, 17, 2054. (e) Forrat,
V. J.; Prieto, O.; Ramo´n, D. J.; Yus, M. Chem.sEur. J. 2006, 12, 4431.
(12) Ebno¨ther, A.; Weber, H.-P. HelV. Chim. Acta 1976, 59, 2462.
(13) We have reported related rearrangements of lithiated ureas that proceed
with retentiVe stereospecificity via a configurationally stable nitrogen-
substituted organolithium. See: (a) Clayden, J.; Dufour, J.; Grainger, D. M.;
Helliwell, M. J. Am. Chem. Soc. 2007, 129, 7488. (b) Clayden, J.; Hennecke,
U. Org. Lett. 2008, 10, 3567.
The structures identified for the transition states from 2a en route
to 4a (1,2-acyl shift) and 5a (1,4-aryl transfer) are shown in Figure
1a,b. The calculated free energy barrier for the attack on the
aromatic ring (3.6 kJ mol-1) is considerably lower (by 14.4 kJ
mol-1) than that for attack on the carbonyl group (18.0 kJ mol-1).
For a 1,2-acyl shift in the N,N-dimethyl carbamate 1b, the
corresponding barrier (22.7 kJ mol-1) is close to the value for the
conversion of 2a, showing that the N-phenyl group favors aryl
transfer simply by opening up an alternative pathway rather than
by disfavoring the 1,2-acyl shift.
Rearrangement yields were best in the presence of DMPU and
excess alkyllithium, and the calculations illuminate the possible role
of these additives. We find that during the course of the reaction,
one Li+ ion remains close to the carbonyl oxygen atom while a
second lithium ion migrates from the carbanion center to the
adjacent oxygen atom (Figure 1), thus freeing the carbanion for
nucleophilic attack. We also find that in the absence of the THF,
(14) See the Supporting Information for evidence of the stereochemical
assignment of (+)-(S)-11 and hence the invertive nature of the rearrange-
ment. Electrophilic quenching of lithiated benzylic carbamates may proceed
with either retention or inversion; see ref 6 and: Gawley, R. E. Tetrahedron
Lett. 1999, 40, 4297.
(15) DFT calculations were carried out at the B3LYP/6-31++G** level, with
thermodynamic corrections (including zero-point effects) at the B3LYP/
6-31G level (see the Supporting Information for details.
Li+, and CH3 species, the conversion of 2a leading to 5a is
-
calculated to proceed without a barrier, showing the stabilization
of the reactant 2a and suggesting that the role of DMPU may be to
solvate the Li+ cation and generate a reactive ion pair.7
JA808959E
9
J. AM. CHEM. SOC. VOL. 131, NO. 10, 2009 3411