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DOI: 10.1039/C8CC01479E
COMMUNICATION
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conversion decreases when the size of the halide becomes
larger, which could be explained due to the large
delocalization of the positive charge throughout the iminium,
leading to a greater interaction with bulkier anions. This
experimental result evidences the theoretical assumption of
an electrostatic interaction (between the cationic chiral pocket
and the anionic oxyanion of the ketimine), triggering formation
of the PAC and a kinetic control exerted by the C-N bond
formation once the complex is formed.
In conclusion, we have found that 2-hydroxybenzophenone
is a suitable candidate to form an intramolecular six-
membered ring via hydrogen bonding that can enhance the
reactivity of the corresponding ketimine while also increasing
the enantioselectivity in the addition to α,β-unsaturated
aldehydes.
Spanish Government (CTQ2015-64561-R, CTQ2016-76061-
P, MDM-2014-0377) and CCC-UAM are acknowledged. A. G.
thanks MINECO for Ph. D. fellowship (FPI), A. M. S. thanks CAM
for a postdoctoral contract (2016-T2/IND-1660).
Notes and references
Figure 2. Gibbs free energy profile for the addition of ketimine 1b to
aldehyde 2a catalysed by 3b. Three different orientations for the
attack of 1b to the iminium are considered. The TSs for the C-N bond
formation and H transfer in the lowest energy path are shown.
1
H. Hiemstra and H. Wynberg, J. Am. Chem. Soc. 1981, 103,
417.
2
For selected reviews, see: (a) Z. Zhang and P. R. Schreiner,
Chem. Soc. Rev. 2009, 38, 1187; (b) J. Alemán, A. Parra, H.
Jiang and K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890.
T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.
2006, 128, 9413.
the iminium ion and the negative charge of the deprotonated
ketimine suggest that the interaction between them to form
the PAC must be of electrostatic nature. To understand the
relative orientation of both reactants in the PAC, we computed
the electrostatic potential mapped on the surface of the
electron density (see bottom-right, Figure 2). The analysis of
the Molecular Electrostatic Potential (MEP) shows that the
attraction between the two molecules is purely electrostatic.
The negative area (red) of the ketimine, localised in the
nitrogen-oxygen region, interacts with the positive area of the
iminium ion. The bulky part of the catalyst prevents the
approach from the upper face, while in the bottom face, the
cationic pocket created around the C=N bond in the iminium
leads to the three possible orientations of the ketimine (green,
blue and black traces, Figure 2) of the PAC considered in the
computed mechanism. Only images of TSs of the kinetically
most favourable pathway (black trace) have been shown for
clarity (see ESI‡ for green and blue traces). To prove this
hypothesis, we performed the reaction between 1b and 2a in
the presence of tetrabutylammonium halide salts (TBAX, X =
Cl, Br, I). The positive iminium ion would interact with the
anionic halide. We found that the reaction
3
4
5
6
C. K. Jung and M. J. Krische, J. Am. Chem. Soc. 2006, 128
17051.
,
G. Talavera, E. Reyes, J. L. Vicario and L. Carrillo, Angew.
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7
8
S. Bertelsen, P. Dinér, R. L. Johansen, and K. A. Jørgensen, J.
Am. Chem. Soc. 2007, 129, 1536.
The 1,3-aminoalcohols can be obtained via nitrogen
surrogates via iminium ion, see e.g.: For Cbz or Boc-N
derivatives, see: a) Y. K. Chen, M. Yoshida and D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128, 9328. b) I. Ibrahem,
R. Rios, J. Vesely, G.L. Zhao and A. Córdova, Chem. Commun.
2007, 849. For succinamide derivatives, see c) H. Jiang, J. B.
Nielsen, M. Nielsen and K. A. Jørgensen, Chem. Eur. J. 2007,
13, 9068. d) I. Arenas, A. Ferrali, C. Rodríguez-Escrich,
F.Bravo and M. A. Pericàs, Adv. Synth. Catal. 2017, 359
2414.
,
9
A. J. Burke, S. G. Davies, A. C. Garner, T. D. McCarthy, P. M.
Roberts, A. D. Smith, H. Rodriguez-Solla and R. J. Vickers,
Org. Biomol. Chem. 2004, 2, 1387.
10 M. J. Frisch, et al. Gaussian 09, revision B.01; Gaussian, Inc.:
Wallingford, CT, 2009.
11 A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev. 1988,
88, 899.
12 We considered 3b (with a similar reactivity as 3f) to reduce
the computational cost.
13 a) D. Seebach, U. Groselj, D. M. Badine, W. Bernd Schweizer
and A. K. Beck, Helvetica Chim. Acta, 2008, 91, 1999. b) Y.
Hayashi, D. Okamura, T. Yamazaki, Y. Ameda, H. Gotoh, S.
H
H
HO
O
N
3f
(20 mol%)
a
O
No TBAX
, 100% conv., >99% ee
TBAX (1 equiv.)
X = Cl, 84% conv., 88% eea
N
Ph
Ph
+
Toluene, 24 h, r.t.
then
Ph3P=CHCO2Me
n-Pr
a
CO2Me
X = Br
, 75% conv., 87% ee
n-Pr
a
X = I
, 46% conv., 92% ee
2a
1b
5a
Tsuzuki, T. Uchimaru and D. Seebach, Chem. Eur. J. 2014, 20
,
a
17077.
14 E. M. Arpa, M. Frías, C. Alvarado, J. Alemán and S. Díaz-
Tendero, J. Mol. Catal. A: Chem. 2016, 423, 308.
Scheme 4. Mechanistic tests performed under the influence of TBAX.
Conversion determined by 1H NMR and ee chiral-determined by SFC.
4 | J. Name., 2012, 00, 1-3
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