C O M M U N I C A T I O N S
trophile activation by H-bonding to the leaving group in either of two
limiting mechanisms: (1) general acid catalysis to induce a concerted,
SN2-like substitution or (2) formation of an ion-pair intermediate and
promotion of an SN1-like pathway (Scheme 2). In an effort to
distinguish between these possibilities, we analyzed the effects of
isotopic and electronic substitution of the electrophile on the reaction
rate. A normal secondary kinetic isotope effect (kH/kD) of 1.12 was
observed upon deuterium-substitution of the benzhydryl proton,
indicating a change in hybridization of the electrophilic carbon from
sp3 to sp2 in the transition state.15,16 A Hammett study revealed a strong
dependence on the electronic properties of the electrophile, with
benzhydryl derivatives bearing electron-donating substituents reacting
more rapidly (F ) -1.95).17,18 The results of both experiments provide
strong evidence that this transformation proceeds through a discrete,
catalyst-associated carbocation in an SN1-like substitution mechanism.
This work demonstrates that urea and thiourea derivatives effectively
induce alkylation pathways through simple carbocations via anion
abstraction and can control the reactivity of such cationic intermediates
in asymmetric bond-forming reactions. The possibility of extending
this activation mode to enantioselective additions to prochiral car-
bocations is under investigation.
Acknowledgment. This work was supported by the NIH (GM-
43214). We thank Abigail Doyle for helpful discussions and for experi-
mental contributions in the secondary kinetic isotope effect studies.
Supporting Information Available: Complete experimental procedures
and characterization data for products and all isolated intermediates. This
References
(1) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
(b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 13404. (c) Reisman, S. E.; Doyle, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2008, 130, 7198.
Scheme 2. Possible Electrophile Activation Modes
(2) For other key examples of thiourea catalysis of anion-binding pathways, see:
(a) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434. (b) Kotke, M.;
Schreiner, P. R. Synthesis 2007, 779. (c) De, C. K.; Klauber, E. G.; Seidel,
D. J. Am. Chem. Soc. 2009, 131, 17060. For a review of this emerging
topic, see: (d) Zhang, Z.; Schreiner, P. R. Chem. Soc. ReV. 2009, 38, 1187.
(3) For alternative approaches to asymmetric catalysis with carbocation
intermediates, see: (a) Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004,
43, 514. (b) Feducia, J. A.; Campbell, A. N.; Doherty, M. Q.; Gagne´, M. R.
J. Am. Chem. Soc. 2006, 128, 13290. (c) Luzung, M. R.; Mauleo´n, P.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402. (d) Cozzi, P. G.; Benfatti,
F.; Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313.
(4) (a) Deno, N. C.; Jaruzelski, J. J.; Schriesheim, A. J. Am. Chem. Soc. 1955,
77, 3044. (b) Deno, N. C.; Schriesheim, A. J. Am. Chem. Soc. 1955, 77,
3051. (c) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am.
Chem. Soc. 2001, 123, 9500.
(5) (a) Winstein, S.; Gall, J. S.; Hojo, M.; Smith, S. J. Am. Chem. Soc. 1960, 82,
1010. (b) Winstein, S.; Gall, J. S. Tetrahedron Lett. 1960, 1, 31. (c)
Winstein, S.; Ledwith, A.; Hojo, M. Tetrahedron Lett. 1961, 2, 341. (d)
Goering, H. L.; Briody, R. G.; Levy, J. F. J. Am. Chem. Soc. 1963, 85,
3059.
(6) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, pp 1-110. (b) Seebach, D.; Imwinkelried,
R.; Weber, T. In Modern Synthetic Synthesis; Scheffold, R., Ed.; Springer:
Berlin-Heidelberg, 1986; Vol. 4, pp 125-259. (c) Crosby, J. Tetrahedron
1991, 47, 4789.
(7) For alternative approaches to catalytic asymmetric aldehyde alkylation, see:
(a) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (b) Fu, A.;
List, B.; Thiel, W. J. Org. Chem. 2006, 71, 320. (c) Xie, H.; Zu, L.; Li,
H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886. (d) Rios,
R.; Sundén, H.; Vesely, J.; Zhao, G.-L.; Eriksson, L.; Córdova, A. AdV.
Synth. Catal. 2007, 349, 1028. (e) Rios, R.; Vesely, J.; Sundén, H.; Ibrahem,
I.; Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48, 5835. (f) Ibrahem,
I.; Córdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952. (g) Beeson, T. D.;
Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science
2007, 316, 582. (h) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129,
11336. (i) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(j) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47,
7539. (k) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2008, 47, 8707. For recent highlights, see: (l)
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360. (m) Alba, A.-N.;
Viciano, M.; Rios, R. ChemCatChem 2009, 1, 437.
Additional evidence for a catalyst-induced SN1 pathway was
provided through the evaluation of benzyl bromide as a potential
electrophile in the alkylation reaction. In competition experiments,
alkylation of 1-cyclohexenylpyrrolidine was found to proceed exclu-
sively with benzyl bromide in the presence of equimolar amounts of
bromodiphenylmethane, a degree of selectivity attributable to the
relative reactivity of these electrophiles in SN2 pathways. In contrast,
under the catalytic conditions using either 1 or 2, no alkylation of
2-phenylpropionaldehyde was obtained with benzyl bromide (Table
3, entries 1-2). This absence of reactivity was not ascribable to catalyst
deactivation, as experiments with mixtures of benzyl bromide and
bromodiphenylmethane (7a) demonstrated that the catalyst maintained
activity (Table 3, entries 3-4).
Table 3. Electrophile Competition Experiments
(8) Details of catalyst and reaction optimization studies are provided in the
Supporting Information. Solvent, concentration, and the presence of
additives are also important factors that influence both enantioselectivity
and reactivity. The presence of water and acetic acid accelerates the reaction,
presumably by influencing the imine and enamine formation and imine
hydrolysis steps, while NEt3 serves to trap the HBr byproduct. Water and
weak acid have been shown to be beneficial in other primary amine thiourea
catalyzed reactions (see ref 9b-c).
(9) (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (b) Huang, H.;
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (c) Lalonde, M. P.;
Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366.
(10) The fact that both urea 2 and thiourea 1 display catalytic activity and similar
enantioselectivity in this transformation (Table 1, entries 1 and 3) would appear
to rule out any direct role of the thiocarbonyl moiety in the alkylation
mechanism.
(11) (a) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan,
W.; Wang, W. Org. Lett. 2009, 11, 2864. (b) Zhang, X.-J.; Liu, S.-P.; Lao,
J.-H.; Du, G.-J.; Yan, M.; Chan, A. S. C. Tetrahedron: Asymmetry 2009,
20, 1451. (c) Uehara, H.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2009,
48, 9848.
(12) Moderate yields are a result of starting material aldehyde decomposition
via R-oxidation and incomplete conversion.
(13) Benzhydryl electrophiles bearing strongly electron-withdrawing groups were
unreactive under the catalytic conditions. In contrast, analogs bearing
electron-donating groups such as (p-MeOC6H4)2CH(Br) effected alkylation
7a
(equiv)
9
(equiv)
yield 8a
(%)
ee 8a
(%)
yield 8j
(%)
entry
catalyst
1
2
3
4
1
2
1
2
0
0
2
2
2
2
2
2
-
-
49
42
n.a.
n.a.
90
0
0
0
0
85
Alkylations using enantioenriched p-chlorobenzhydryl chloride were
found to proceed with nearly complete (95%) stereospecificity,19 which
requires that addition of the catalyst-associated enamine to the ion-
pair intermediate is rapid relative to ion-pair reorganization.20 This
observation is in line with the known reactivity of benzhydryl cations
and enamines as analyzed by Mayr,21 which would predict that these
partners should undergo intermolecular reaction at a rate near the
diffusion limit.22 This stands in sharp contrast to solvolyses of
benzhydryl electrophiles, wherein substitution has been shown to be
slow relative to racemization.5
9
J. AM. CHEM. SOC. VOL. 132, NO. 27, 2010 9287