9706
X.-Y. Cao et al. / Tetrahedron 66 (2010) 9703e9707
local minima (with no imaginary frequency). The solvent effect of
the cyclohexanone itself was estimated using IEFPCM14 method
Yield: 73 mg (93%), syn/anti¼50/1, 94% ee, determined by HPLC
analysis (Chiralcel AS, i-PrOH/hexane¼10/90, 0.8 mL/min, 238 nm;
tr (minor)¼12.63 min, tr (major)¼18.01 min); 1H NMR (400 MHz,
(UAHF atomic radii) in acetone (3¼20.7) with the gas-phase opti-
mized structures. The difference of the reaction barrier between 1b
and 1c systems is expected to be very small (about 1.3 kcal/mol). It
is difficult to calculate the absolute reaction barrier accurately and
to compare the barriers of two different systems. Nevertheless, the
following discussion should be helpful to rationalize the experi-
mental observations.
CDCl3):
d
7.40 (d, J¼2.4 Hz, 1H), 7.26e7.16 (m, 2H), 4.89e4.87 (m,
2H), 4.25e4.23 (m, 1H), 2.81e2.90 (m, 1H), 2.49e2.37 (m, 2H),
2.13e2.09 (m, 1H), 1.85e1.81 (m, 1H), 1.74e1.70 (m, 2H), 1.67e1.58
(m, 1H), 1.35e1.25 (m, 1H).
Acknowledgements
Models Int-2H/TS-2H, and Int-HBn/TS-HBn are used in the cal-
culation for 1b and 1c systems, respectively. The optimized struc-
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20821002 and
20932008), the Major State Basic Research Development Program
(Grant No. 2009CB825300), the Chinese Academy of Sciences, and
the Science and Technology Commission of Shanghai Municipality
(No. 10ZR1437000).
tures are shown in Fig. 3. The distortion energy
the energies required to distort the intermediates into the transi-
tion state geometries.7m,15 The contribution of
S to S,
G (ꢁT
T¼273.15 K), and the relative free energies including solvent effect
DEdist are defined as
D
D
D
(DGsol, 273.15 K) are also given. The structures of Int-2H and TS-2H
were constructed based on the former studies.4 In Int-HBn and TS-
HBn, the initial conformation of the Bn group was kept the same as
that in N-Boc-protected catalyst 4c, which has been characterized
by X-ray crystallography.9
Supplementary data
Characterization data for all new compounds, full experimental
details, CIF file for 4c, and chiral HPLC spectra of 7. Supplementary
data related to this article can be found online at doi:10.1016/
Multi hydrogen bonds will benefit the activation of the nitro-
olefin and will stabilize the negative charges on the oxygen atom of
the nitro group in the transition state. These effects will lower the
reaction barrier. However, multi hydrogen bonds can also stabilize
the intermediate, which causes larger entropy loss and will require
References and notes
larger distortion energy (DEdist) to distort their geometries into the
transition states. These effects increase the reaction barrier. In Int-
HBn, there is only one hydrogen bond between one hydrogen atom
of the urea group and one oxygen atom of the nitro group. This
structure is flexible and the nitroolefin is parallel to the enamine,
indicating that the reaction center C2 approaches C1 easily.
Whereas in Int-2H, there are two strong hydrogen bonds and in this
rigid structure, the nitroolefin and the enamine are vertical to each
other. Therefore, compared with the 1c system, large distortion and
strain energy arosed when the reaction center approaches each
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experimental results very well.
3. Conclusion
In conclusion, we have synthesized several pyrrolidine-urea bi-
functional organocatalysts and found catalyst 1c with single hydro-
gen bond was superior to catalyst 1b, which contains two hydrogen
bonds in the asymmetric Michael addition of ketone with nitroolefin.
Theoretical study was performed to shed light on the origin of their
difference. The rigid structure formed between catalyst 1b with
nitroolefin via double hydrogen bonding retarded the approach of
nucleophilic enamine intermediate. These results provide valuable
insight into the function of hydrogen bonding and might be helpful in
the development of new and more efficient organocatalysts.
4. Experimental section
4.1. General
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Representative procedure for the Michael addition of cyclo-
hexanone 5a to nitroolefin 6a. Catalyst 1c (22.0 mg, 0.05 mmol) in
cyclohexanone (0.5 mL, 5.0 mmol) was stirred for 15 min at 0 ꢀC,
and then nitroolefin 6a (55.0 mg, 0.25 mmol) was added. The re-
action was stirred at 0 ꢀC until nitroolefin 6a was consumed
(monitored by TLC). The resulting mixture was concentrated under
reduced pressure and the residue was then subjected to flash
chromatography (petroleum/EtOAc¼1/4) to give the product 7a.
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