An organocatalytic asymmetric tandem reaction for the construction of bicyclic skeletons

Article abstract of DOI:10.1002/chem.200900696

Cyclic ketones react with (E)-2-nitroallylic acetates in the presence of catalytic pyrrolidine-thiourea, which affords bicyclic skeletons with four or five stereocenters in one single reaction with up to 98% ee in moderate to high yields. The cooperative

Full text of DOI:10.1002/chem.200900696

DOI: 10.1002/chem.200900696
An Organocatalytic Asymmetric Tandem Reaction for the Construction of
Bicyclic Skeletons
Chun-Li Cao, You-Yun Zhou, Jian Zhou, Xiu-Li Sun, Yong Tang,* Yu-Xue Li,*
Guang-Yu Li, and Jie Sun[a]
Abstract: Cyclic ketones react with (E)-2-nitroallylic acetates in the presence of
catalytic pyrrolidine-thiourea, which affords bicyclic skeletons with four or five ste-
reocenters in one single reaction with up to 98% ee in moderate to high yields.
The cooperative effects of both enamine and the Brønsted acid are found to be
crucial for the high reactivity and enantioselectivity of this cascade reaction, which
is demonstrated by both theoretical calculation and experimental data.
Keywords: bifunctional catalysts ·
density functional calculations
ketones · organocatalysis · tandem
·
reactions
Introduction
contiguous stereogenic centers.[5a] Very recently, they devel-
oped an organocatalytic asymmetric one-pot reaction to
create six stereocenters with excellent diastereo- and enan-
tioselectivity.[5c] The groups of Cꢀrdova[6b] and Hayashi[6c] in-
dependently developed organocatalytic cascade reactions
that generate four stereocenters in a simple operation. By
an organocatalytic desymmetrization reaction, Miller and
his co-worker reported a facile synthesis of d-myoinositol-1-
phosphate with six stereocenters.[6a] In spite of the afore-
mentioned achievements, the development of new organoca-
talytic cascade reactions that could install four or more ste-
reocenters in one reaction remains very challenging and val-
uable in asymmetric catalysis.
(E)-2-Nitroallylic acetates 1 could serve as multiple-cou-
pling reagents and install into the final product a nitro
group, which can then be easily transformed into other func-
tional groups. To the best of our knowledge, these particular
compounds have never been used for organocatalytic asym-
metric cascade reactions, although they have been combined
with chiral enamines for a formal [3+3] carbocyclization.[7]
We speculated that under the catalysis of suitable aminoca-
talysts, the combination of nitroallylic acetates 1 with cyclic
ketone 2 might spontaneously undergo Michael/elimination/
Michael reactions to give the bicycle [3.3.1] skeletons with
four or five chiral centers. In this paper, we wish to report
our efforts on this subject in detail.
The efficient construction of carbon–carbon bonds with the
control of multiple stereocenters in a single operation is of
fundamental interest in synthetic chemistry. In this field, a
modular combination of organocatalytic reactions into cas-
cades has emerged as a powerful strategy.[1] Secondary
amines and their salts have proven to be especially versatile
in organizing a cascade reaction by means of enamine or
iminium catalysis.[2,3] During the past several years, dozens
of elegant aminocatalyst-triggered tandem reactions have
been reported to furnish a product with more than one ste-
reocenter.[3–6] However, only a few examples could afford
complex molecules with four or more stereogenic centers[4–6]
in one cascade reaction. Of the reactions developed, Enders
et al. achieved a three-component cascade reaction that af-
forded cyclohexene derivatives with four stereocenters,[4a]
which was applied to the diastereo- and enantioselective
synthesis of pure polyfunctionalized tricyclic frameworks.[4b]
Jørgensen et al. reported a domino Michael/aldol reaction
of b-ketoesters and a,b-unsaturated ketones forming four
[a] Dr. C.-L. Cao, Y.-Y. Zhou, Dr. J. Zhou, Dr. X.-L. Sun,
Prof. Dr. Y. Tang, Dr. Y.-X. Li, Dr. G.-Y. Li, J. Sun
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032, China
Fax : (+86)21-54925078
E-mail: tangy@mail.sioc.ac.cn
Results and Discussion
liyuxue@mail.sioc.ac.cn
(E)-2-Nitroallylic acetate 1a is readily available through a
Morita–Baylis–Hillman reaction (for details see the Sup-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900696.
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Chem. Eur. J. 2009, 15, 11384 – 11389

FULL PAPER
Table 2. Catalyst screening for the asymmetric tandem reaction.[a]
porting Information). We were pleased to find that when 1a
was treated with cyclohexanone in ethyl acetate, it afforded
the desired product 4a in 60% conversion with 95% ee in
the presence of 20 mol% pyrrolidine-thiourea (3a) in com-
bination with an equal amount of 4-methoxybenzoic acid as
a cocatalyst.[8a] To improve the conversion, several solvents
were screened. The results are summarized in Table 1. Tolu-
Entry
Catalyst
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3a
99 (75)[d]
60
<5
67
25
39
<5
<5
<5
<5
<5
99
<5
99
30
96
95
–
86
90
92
–
–
–
–
–
Table 1. Effects of solvents on the reaction of cyclohexanone 2a and
1a.[a]
9
10
11
12
13[e]
14
15[f]
Entry[a]
Solvent
Conversion [%][b]
ee [%][c]
17
–
1
2
3
4
ethyl acetate
toluene
THF
CH2Cl2
CH3CN
iPrOH
60
<5
<5
<5
57
95
–
–
À8
95
–
[a] Catalyst (20 mol%) in neat 4-methoxybenzoic acid (20 mol%), 1a
(0.20 mmol), 2a (1 mL); reaction time: 48 h. [b] Determined by H NMR
spectroscopy. [c] Determined by chiral HPLC analysis. [d] Isolated yield.
[e] No 4-methoxybenzoic acid was added. [f] 10 mol% of 3a and
10 mol% of 4-methoxybenzoic acid; reaction time: 96 h.
5
95
95
96
1
6
77
99
7[d]
solvent-free
[a] Compounds 1a (0.20 mmol) and 2a (0.20 mL), solvent (1 mL), 3a
(20 mol%), and 4-methoxybenzoic acid (20% mol); reaction time: 48 h.
[b] Determined by 1H NMR spectroscopy. [c] Determined by chiral
HPLC analysis. [d] 1 mL of 2a.
dition of ketones to nitroolefins,[8c] promoted this reaction in
moderate conversion with up to 95% ee (Table 2, entry 2).
Pyrrolidine-thiourea (3a), which has a stronger hydrogen-
bond donor than 3b,[1f] afforded the product in 99% conver-
sion and 75% yield with 96% ee (entry 1). This result also
showed that the urea part of the catalyst plays an important
role in activating the nitroolefin, thereby suggesting that hy-
drogen bonding speeds up the reaction. An attempt to fur-
ther improve the reactivity by using catalyst 3c with a more
acidic hydrogen-bonding donor failed (entry 3), probably
due to the effects of the amide on the formation of the en-
amine intermediate. Although it is known that catalyst 3d[3d]
gave better ee values in the reaction of ketones with alkyl-
ene, THF, and CH2Cl2 were not as good as ethyl acetate,
and only very low conversions were obtained (Table 1, en-
tries 2–4). CH3CN and isopropanol gave moderate to good
conversions with excellent enantiomeric excess values (en-
tries 5 and 6). The optimal reaction condition is solvent-free
(entry 7). In this case, 99% conversion and 96% ee were
achieved.
Using nitroolefin 1a as a model substrate, a series of sec-
ondary amine catalysts were also investigated (Scheme 1).
As shown in Table 2, pyrrolidine-urea (3b)[8] with an equal
amount of 4-methoxybenzoic acid as a cocatalyst, which we
recently identified as an excellent catalyst for a Michael ad-
AHCTUNGTRENNUNG
idene malonates than 3a,[8b] compound 3d afforded lower
enantiomeric excess and conversion in the present reaction
than 3a. Both catalysts 3e and 3 f also delivered high enan-
tioselectivity, but the conversion is not satisfactory. Proline
3l and (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (3n)
gave very high conversion with low ee values (Table 2, en-
tries 12 and 14). Other secondary amines 3g–k and 3m[2]
were almost inactive (entries 7–11 and 13). These results
demonstrated that the high reactivity of catalyst 3a resulted
from the cooperative effects of both the enamine and
Brønsted acid catalysis. Under all conditions screened, only
one diastereomer was observed through 1H NMR spectro-
scopic analysis of the crude product. When the loading of
3a was reduced from 20 to 10 mol%, although the enantio-
meric excess was almost maintained, only 30% conversion
was obtained, even when the reaction time was prolonged
from 48 to 96 h (entry 15). One of the reasons for the cata-
Scheme 1. Catalysts screened.
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11385

Y. Tang, Y.-X. Li et al.
lyst deactivation is probably the addition of 3a to nitroolefin
1a, which led to the consumption of the catalyst.
compounds with four stereocenters. In the case of cyclopen-
tanone and tetrahydropyran-4-one, 3d gave better yields
than 3a. By using 3d as a catalyst, for example, cyclopenta-
none was also a suitable ketone and afforded the product
with 93% ee in 94% yield (entry 10). Both cycloheptenone
and acetone did not work in the current catalytic reaction
(entries 11 and 12). Since Seebach et al. have reported that
the enamine of either cycloheptenone or acetone can react
with nitroolefin very well to afford the corresponding prod-
uct,[7] these results suggested that the formation of the en-
amines from both cycloheptenone and acetone can be slug-
gish. Aliphatic nitroolefin was less active than aromatic ni-
troolefin in the current reaction. Thus, the reaction of ali-
phatic nitroolefin is quite slow.
Under optimal conditions, the generality of this reaction
was examined by investigating a variety of cyclic ketones (2)
and nitroolefins (1). As shown in Table 3, aryl nitroolefins 1
reacted smoothly with cyclic ketones in good yields with ex-
cellent enantioselectivities and diastereoselectivities. Gener-
ally, substituents on aryl groups had little effect on both
enantioselectivities and yields (entries 1–7). The enantiomer-
ic excesses were all above 94%, with some reaching 98%.
Heterocyclohexanone could also give the desired products
with good to high enantioselectivities (entries 8 and 9),
thereby providing easy access to optically active heterocyclic
Table 3. Asymmetric tandem reaction.[a]
For example, only
a
trace
amount of the desired product
was observed when (E)-4-
methyl-2-nitropent-2-enyl ace-
tate was employed as a sub-
strate (entry 12). Noticeably,
the optically pure product 4d
(>99% ee) could be obtained
by recrystallization from diethyl
ether. Both the relative and ab-
solute configurations of product
4d were determined by X-ray
diffraction analysis (Figure 1).[9]
The nitro group and the aryl
group are located in the trans
position. The carbonyl group is
oriented trans to the aryl group.
The absolute configuration of
compound 4d is assigned as
1S,2R,3S,5R (Figure 1). This ste-
reochemical outcome is consis-
tent with the proposed mecha-
nism (Scheme 2) as well as the
DFT calculations (Scheme 3).
This tandem transformation
could also be applied in making
a bicyclic compound with five
stereocenters. As shown in
Scheme 4, for example, we
found that the reaction took
place smoothly to afford two
isomers, 6a (92% ee) and 6b
(77% ee), with a moderate se-
lectivity (2.4:1) when com-
pound 5 was employed. The rel-
ative configurations of products
6a and 6b were determined by
Entry
1
Product
Yield[b]/ee[c] [%]
Entry
8
Product
Yield[b]/ee[c] [%]
75/96
27/97
2
3
4
73/94
9[d]
10[d]
11
77/77
94/93
trace
75/96
77/96 (>99)
5
56/98
74/95
12
13
trace
6[e]
0
7[e]
78/98
X-ray
diffraction
analysis
(Scheme 4).[9]
The reaction mechanism of
enamine derived from cyclic ke-
tones with nitroallylic carbonyl
compounds has been well stud-
[a] Catalyst (20 mol%) in neat 4-methoxybenzoic acid (20 mol%), 1 (0.20 mmol), 2 (1 mL), reaction time:
48 h. [b] Isolated yield. [c] Estimated by chiral GC or HPLC analysis. [d] Compound 3d as the catalyst
(30 mol%). [e] Isolated as atropisomers. For details, see the Supporting Information.
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Bicyclic Skeletons
FULL PAPER
Figure 1. X-ray crystal structure of compound 4d.
Scheme 4. The reaction of cyclohexanone 2a with compound 5.
undergoes an intramolecular Michael addition reaction, thus
affording the desired product 4 and regenerating the catalyst
to finish the catalytic cycle.
To find the origin of the high diastereoselectivity and
enantioselectivity of this reaction, density functional
theory[10] studies using the Gaussian 03 program[11] and the
B3LYP[12] method were performed. In this tandem reaction,
Scheme 2. A proposed mechanism for the formal [3+3] annulation reac-
tion.
À
we concentrated on the transition states of the first C C
bond-forming step that involves the formation of the first
two chiral centers (Scheme 3). The transition state (TS) is
composed of the (E)-2-nitroallylic acetates and the enamine
that formed from the ketones and catalyst 3a.
There should be many possible conformational isomers
for the transition state due to its flexibility. Based on a sys-
tematic conformational search (see the Supporting Informa-
tion), four thiourea-based models were constructed and
fully optimized at the B3LYP/6-31G** level (Figure 2). For
each structure, harmonic vibration frequency calculations
were carried out and thermal corrections were made, there-
by demonstrating that all of the four structures are transi-
tion states. The solvent effect of the cyclohexanone itself
was estimated using IEFPCM[13] with the gas-phase opti-
mized structures.
Of the four transition states, double strong hydrogen
bonds form between the two hydrogen atoms of the thio-
AHCTUNGTREGuNNUN rea group and the two oxygen atoms of the nitro group in
TS-SR or TS-SS, whereas only one oxygen atom of the nitro
group form hydrogen bonds in TS-RS or TS-RR. Therefore,
TS-SR and TS-SS are much more stable than TS-RS and
TS-RR. In addition, the conformations of the enamines in
TS-SR, TS-RS, and TS-RR are similar, in which the dihedral
angles D1234 are À55.78, À57.88, and À32.18, respectively
(the definition of the dihedral angle D1234 is shown in
Figure 2). In these transition-state structures, the thiourea
group is far away from the cyclohexenyl group. In TS-SS,
however, D1234 =62.88; the thiourea group is to some extent
eclipsed by the cyclohexenyl group, which will cause steric
À
Scheme 3. The first C C bond-forming step.
ied by Seebach et al.[7] On the basis of the mechanistic in-
sight, the aforementioned asymmetric tandem reaction can
be explained as outlined in Scheme 2. The formation of in-
termediate A by means of enamine catalysis facilitates the
first Michael addition, followed by an elimination of acetate
to afford B. Intermediate B is then isomerized to C, which
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11387

Y. Tang, Y.-X. Li et al.
Experimental Section
Typical procedure for the tandem re-
action (using 4a as an example):[14]
A
mixture of 3a (14.8 mg, 0.04 mmol,
20 mol%) and 4-methoxybenzoic acid
(6.0 mg, 0.04 mmol, 20 mol%) in cy-
clohexanone (1 mL) was stirred for
10 min at 258C and then nitroolefin 1a
(44.2 mg, 0.2 mmol) was added. After
the reaction was complete (monitored
by TLC), the excess of cyclohexanone
was removed under reduced pressure
and the residue was purified by flash
chromatography (petroleum/EtOAc=
1:7) to give product 6a (75%,
38.6 mg). Enantiomeric excess was de-
termined by HPLC analysis (Chiralcel
AD-H,
iPrOH/hexane=2:98,
214 nm; RA(minor)=
(major)=40.35 min) and
was found to be 96% ee. [a]2D0 =+82.4
(c=0.657 in CHCl3);
1H NMR
0.6 mLminÀ1
,
t CHTUNGTRENNUNG
37.97 min, tRACTHNGUTERNNUG
(300 MHz, [D]CDCl3, TMS): d=7.34–
7.23 (m, 3H), 7.16 (d, J=7.8 Hz, 2H),
4.59 (dt, J=5.1, 12.6 Hz, 1H), 3.78
(dd, J=3.0, 12.0 Hz, 1H), 2.80–2.67
(m, 3H), 2.58–2.50 (m, 1H), 2.38–1.86
(m, 5H), 1.76–1.68 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=215.8,
140.7, 129.1, 127.9, 127.4, 86.2, 53.0,
51.2, 43.0, 35.5, 35.1, 32.6, 15.6 ppm;
IR (film): 2941, 2859, 1724, 1553, 1455,
Figure 2. The optimized transition states with selected bond lengths [ꢃ]. The relative free energies in the gas
phase DGgas (in bold text) and the relative free energies including the solvent effect DGsol (in italic text) are in
kcalmolÀ1 (298 K, calculated at B3LYP/6-31G** level).
1371, 764, 701 cmÀ1
.
Compound 4j:[14] Procedure and scale
are the same as those for the prepara-
tion of 4a except 3d (14.0 mg,
0.06 mmol, 30 mol%) was used as the catalyst. Yield: 61.5 mg (94%).
Enantiomeric excess was determined by HPLC analysis (Chiralcel AD-
RA
(major)=37.54 min) and was found to be 93% ee. [a]2D0 =+83.2 (c=0.653
AHCTUNGTRENNUNG
strain. Furthermore, the larger dipole moment of TS-SR
(13.95 debye) over that of TS-SS (12.88 debye) increase
their energy difference to 2.0 kcalmolÀ1 by means of the sol-
vent effect. Thus, the most stable transition structure is TS-
SR and the enamine favors attacking the nitroolefin from
the Re face. This result is consistent with the experimental
observations.
H, iPrOH/hexane=5:95, 0.6 mLminÀ1, 230 nm; t
CHTUNGTREN(NUGN minor)=34.88 min, tR-
in CHCl3); m.p. 1348C; 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=
8.7 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 5.35–5.26 (m, 1H), 4.05–4.03 (m,
1H), 3.00 (t, J=12.3 Hz, 1H), 2.57–2.41 (m, 3H), 2.29–2.08 (m, 2H),
2.06–1.98 (m, 1H), 1.93–1.84 ppm (m, 1H); 13C NMR (75 MHz, CDCl3):
d=214.6, 135.1, 131.9, 129.9, 122.5, 79.8, 55.2, 47.8, 41.2, 34.3, 22.7,
21.4 ppm; IR (film): n˜ =2964, 2874, 1751, 1547, 1491, 1459, 1377,
1011 cmÀ1; MS (EI): m/z (%): 44 (100), 55 (83), 116 (82), 115 (73), 169
(48), 41 (48), 128 (46), 171 (45); exact mass calcd for C14H15BrNO3:
324.0325; found: 324.0229.
Conclusion
In conclusion, we have developed a novel organocatalytic
tandem reaction to construct bicyclic compounds with four
or five stereocenters in a single reaction. This is also the
first time that nitroallylic acetate has been applied in asym-
metric organocatalytic cascade reactions. The combination
of urea catalyst and enamine catalyst was essential for the
high reactivity, diastereoselectivity, and enantioselectivity of
this transformation, which was demonstrated by both experi-
mental data and theoretical calculations. The extension of
the application of nitroallylic acetate in other organocatalyt-
ic asymmetric transformations is now in progress in our lab-
oratory.
Acknowledgements
We are grateful for the financial support from the Natural Sciences Foun-
dation of China (grant nos. 20821002 and 20672131), the Major State
Basic Research Development Program (grant no. 2009CB825300), and
the Chinese Academy of Sciences.
[1] For selected reviews on organocatalytic domino reactions, see: a) D.
Tejedor, D. Gonzalez-Cruz, A. Santos-Exposito, J. J. Marrero-Tella-
do, P. de Armas, F. Garcia-Tellado, Chem. Eur. J. 2005, 11, 3502–
3510; b) H.-C. Guo, J.-A. Ma, Angew. Chem. 2006, 118, 362–375;
Angew. Chem. Int. Ed. 2006, 45, 354–366; d) D. Enders, C. Grondal,
M. R. M. Hꢂttl, Angew. Chem. 2007, 119, 1590–1601; Angew. Chem.
Int. Ed. 2007, 46, 1570–1581; c) J. Chapman, C. G. Frost, Synthesis
11388
www.chemeurj.org
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Chem. Eur. J. 2009, 15, 11384 – 11389

Bicyclic Skeletons
FULL PAPER
2007, 1–21; e) D. Enders, A. A. Narine, J. Org. Chem. 2008, 73,
7857–7870.
[6] a) B. R. Sculimbrene, S. J. Miller, J. Am. Chem. Soc. 2001, 123,
10125–10126; b) J. Casas, M. Engqvist, I. Ibrahem, B. Kaynak, A.
Cꢀrdova, Angew. Chem. 2005, 117, 1367–1369; Angew. Chem. Int.
Ed. 2005, 44, 1343–1345; c) Y. Hayashi, T. Okano, S. Aratake, D.
Hazelard, Angew. Chem. 2007, 119, 5010–5013; Angew. Chem. Int.
Ed. 2007, 46, 4922–4925; d) B. Tan, Z.-G. Shi, P.-J. Chua, G.-F.
Zhong, Org. Lett. 2008, 10, 3425–3428; e) B. Tan, P.-J. Chua, X.-F.
Zeng, M. Lu, G.-F. Zhong, Org. Lett. 2008, 10, 3489–3492.
[7] D. Seebach, M. Missbach, G. Calderari, M. Eberle, J. Am. Chem.
Soc. 1990, 112, 7625–7638.
[8] a) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901–
2904; b) C.-L. Cao, X.-L. Sun, J.-L. Zhou, Y. Tang, J. Org. Chem.
2007, 72, 4073–4076; c) C.-L. Cao, X.-L. Sun, Y.-B. Kang, Y. Tang,
Org. Lett. 2007, 9, 4151–4154.
[9] CCDC-714774 (4d), 714771 (6a) and 714772 (6b) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] a) P. Hohenberg, W. Kohn, Phys. Rev. 1964, 136, B864–B871; b) W.
Kohn, L. J. Sham, Phys. Rev. 1965, 140, A1133–A1138.
[2] For selected reviews on secondary amines and their salt catalyzed
asymmetric reactions, see: a) P. I. Dalko, L. Moisan, Angew. Chem.
2004, 116, 5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175;
b) B. List, Chem. Commun. 2006, 819–824; c) M. Marigo, K. A. Jør-
gensen, Chem. Commun. 2006, 2001–2011; d) G. Lelais, D. W. C.
MacMillan, Aldrichimica Acta 2006, 39, 79–87; e) C. Palomo, A.
Mielgo, Angew. Chem. 2006, 118, 8042–8046; Angew. Chem. Int.
Ed. 2006, 45, 7876–7880; f) A. Erkkilꢄ, I. Majander, P. M. Pihko,
Chem. Rev. 2007, 107, 5416–5470; g) S. Mukherjee, J. W. Yang, S.
Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569.
[3] For selected examples of secondary amines and their salt-catalyzed
asymmetric reactions, see: a) W. Yang, M. T. H. Fonseca, B. List, J.
Am. Chem. Soc. 2005, 127, 15036–15037; b) Y. Huang, A. M. Walji,
C. H. Larsen, D. W. C. Macmillan, J. Am. Chem. Soc. 2005, 127,
15051–15053; c) M. Marigo, T. Schulte, J. Franzꢅn, K. A. Jørgensen,
J. Am. Chem. Soc. 2005, 127, 15710–15711; d) W. Wang, J. Wang, H.
Li, Angew. Chem. 2005, 117, 1393; Angew. Chem. Int. Ed. 2005, 44,
1369; e) W. Wang, H. Li, J. Wang, L.-S. Zu, J. Am. Chem. Soc. 2006,
128, 10354–10355; f) S. Brandau, E. Maerten, K. A. Jørgensen, J.
Am. Chem. Soc. 2006, 128, 14986–14991; g) M. Marigo, S. Bertelsen,
A. Landa, K. A. Jørgensen, J. Am. Chem. Soc. 2006, 128, 5475–
5479; h) L.-S. Zu, J. Wang, H. Li, H.-X. Xie, W. Jiang, W. Wang, J.
Am. Chem. Soc. 2007, 129, 1036–1037; i) A. Carlone, S. Cabrera, M.
Marigo, K. A. Jørgensen, Angew. Chem. 2007, 119, 1119–1122.;
Angew. Chem. Int. Ed. 2007, 46, 1101–1104; j) D.-Q. Xu, Y.-F.
Wang, S.-P. Luo, S. Zhang, A.-G. Zhong, H. Chen, Z.-Y. Xu, Adv.
Synth. Catal. 2008, 350, 2610–2616; k) D. Enders, M. R. M. Hꢂttl, G.
Raabe, J. W. Bats, Adv. Synth. Catal. 2008, 350, 267–279; l) D. B.
Ramachary, Y. V. Reddy, B. V. Prakash, Org. Biomol. Chem. 2008, 6,
719–726; m) I. Ibrahem, G.-L. Zhao, R. Rios, J. Vesely, H. Sunden,
P. Dziedzic, A. Cꢀrdova, Chem. Eur. J. 2008, 14, 7867–7879; n) D.
Zhu, M. Lu, J. Chua, B. Tan, F. Wang, X.-H. Yang, G.-F. Zhong,
Org. Lett. 2008, 10, 4585–4588; o) J. Xin, L. Chang, Z. Hou, D.
Shang, X. Liu, X. Feng, Chem. Eur. J. 2008, 14, 3177–3181; p) M.-K.
Zhu, Q. Wei, L. Z. Gong, Adv. Synth. Catal. 2008, 350, 1281–1285.
[4] a) D. Enders, M. R. M. Hꢂttl, C. Grondal, G. Raabe, Nature 2006,
441, 861–863; b) D. Enders, M. R. M. Hꢂttl, J. Runsink, G. Raabe,
B. Wendt, Angew. Chem. 2007, 119, 471–473; Angew. Chem. Int.
Ed. 2007, 46, 467–469.
[11] Gaussian 03, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
AHCTUNGTREGeNNUN ry, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004..
[12] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[13] a) M. T. Cancꢆs, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107,
3032–3041; b) M. Cossi, V. Barone, B. Mennucci, J. Tomasi, Chem.
Phys. Lett. 1998, 286, 253–263. UAHF atomic radii method in ace-
tone (e=20.7).
[5] a) N. Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2004,
116, 1292–1297; Angew. Chem. Int. Ed. 2004, 43, 1272–1277; b) E.
Reyes, H. Jiang, A. Milelli, P. Elsner, R. G. Hazell, K. A. Jørgensen,
Angew. Chem. 2007, 119, 9362–9365; Angew. Chem. Int. Ed. 2007,
46, 9202–9205; c) S. Bertelsen, R. L. Johansen, K. A. Jørgensen,
Chem. Commun. 2008, 3016–3018.
[14] For more examples, please see the Supporting Information.
Received: March 18, 2009
Published online: September 16, 2009
Chem. Eur. J. 2009, 15, 11384 – 11389
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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