Enantioselective conjugate addition of malononitrile to chalcones promoted by α,α-L-diaryl prolinols: Noncovalent versus covalent catalysis?

Article abstract of DOI:10.1002/ejoc.201001466

The enantioselective conjugate addition of malononitrile to trans-chalcones has been investigated as a case study using easily available α,α-L-diaryl prolinols as promoters. Both experimental and computational results are consistent with a bifunctional no

Full text of DOI:10.1002/ejoc.201001466

FULL PAPER
DOI: 10.1002/ejoc.201001466
Enantioselective Conjugate Addition of Malononitrile to Chalcones Promoted
by α,α- -Diaryl Prolinols: Noncovalent versus Covalent Catalysis?
L
Alessio Russo,[a] Amedeo Capobianco,[b] Alessandra Perfetto,[a] Alessandra Lattanzi,*[a] and
Andrea Peluso*[a]
Keywords: Organocatalysis / Michael addition / Asymmetric catalysis / Enones / Computational chemistry
The enantioselective conjugate addition of malononitrile to
trans-chalcones has been investigated as a case study using
easily available α,α-L-diaryl prolinols as promoters. Both ex-
perimental and computational results are consistent with a
bifunctional noncovalent mode of activation of the reactive
partners, provided by the secondary amine and hydroxyl
groups of the promoter as general base and acid catalysis.
This most energetically affordable pathway predicts pre-
dominant formation of the R-configured adducts, which is in
agreement with the experimental findings. The present study
addresses, for the first time, the ability of proline derivatives
to assist product formation through noncovalent catalysis, in
analogy to the mode of action typically recognized for Cin-
chona alkaloids.
acceleration of the process. The excellent level of the
enantioselectivity and the sense of asymmetric induction
achieved in a wide array of transformations reported so far,
have been explained by invoking steric control. Indeed, ste-
ric hindrance of the diaryl carbinol unit of the secondary
amine catalyst forces the nucleophile to approach the lower
face of the carbon–carbon double bond of the iminium ion
(Figure 1).
Introduction
Asymmetric conjugate additions are probably the most
exploited transformations in organic synthesis for carbon–
carbon and carbon–heteroatom bond forming reactions.[1]
Research on this topic has gained considerable attention in
the last years and, thanks to a manifold of possible combi-
nations of the reactive partners, a variety of synthetically
useful adducts have been produced. Indeed, several nucleo-
philes, such as malonate esters,[2] diketones,[3] keto esters[4]
and nitroalkanes[5] have been widely used for the enantiose-
lective conjugate addition to different electron-poor al-
kenes.
Over the last years, we focused our interest on enantiose-
lective Michael additions promoted by α,α-l-diaryl prolin-
ols as catalysts.[6] Enones and nitro alkenes have been used
as acceptors, whereas oxygen and carbon-centred com-
pounds were used as nucleophiles.[7]
To the best of our knowledge, bifunctional proline and
its derivatives activate aliphatic aldehydes and ketones
through covalent formation of enamines and α,β-unsatu-
rated aldehydes with the generation of iminium ion interme-
diates.[8] In particular O-protected α,α-diaryl prolinols have
been suggested to provide iminium activation of α,β-unsat-
urated aldehydes in several Michael-type β-functionaliza-
tions.[9] The generation of a reactive iminium ion lowers the
LUMO of the electrophile and results in a significant rate
Figure 1. Steric control model in conjugate additions through imin-
ium ion activation of enals with O-protected diaryl prolinols (TMS
= trimethylsilyl).
Whereas the above mechanism is well-tested for α,β-un-
saturated aldehydes,[10] the case of chalcones deserves fur-
ther attention. Although some examples of activation of
trans-chalcones by chiral primary amines through iminium
ion formation have been reported,[8c,8d] chalcones are steri-
cally hindered carbonyl compounds that experience an in-
herent difficulty in forming iminium ions. Indeed, even in
the case of organocatalytic, highly enantioselective conju-
gate addition of malononitrile to enones in the presence of
9-amino-9-deoxyepiquinidine and trifluoroacetic acid
(TFA) as co-catalyst,[11a] chalcones were found to be less
effective substrates than other enones because formation of
the iminium ion, the key intermediate between the primary
amine catalyst and the sterically encumbered aromatic
ketone, is unfavourable.
[a] Dipartimento di Chimica, Università di Salerno,
Via Ponte don Melillo, 84084, Fisciano, Italy
Fax: +39-089-969603
[b] Dipartimento di Fisica, Università di Salerno,
Via Ponte don Melillo, 84084, Fisciano, Italy
E-mail: lattanzi@unisa.it; apeluso@unisa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001466.
All these considerations suggest that a different acti-
vation mode can be operating, at least for reactions with
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Conjugate Addition of Malononitrile to Chalcones
secondary amines. The activation model proposed for Cin-
chona alkaloids and for chiral thioureas is quite appealing
in our case because of the structural similarity between Cin-
chona alkaloids and prolinols (Figure 2). These bifunc-
tional promoters are capable of synergic noncovalent acti-
vation of pronucleophiles by the tertiary amine (general
base catalysis) and of electrophiles by the acidic group (hy-
drogen-bonding interactions).[12]
Figure 3. α,α-l-Diaryl prolinols screened in this study.
Table 1. Solvent and acid additive screen in the Michael addition
of malononitrile to trans-chalcone 1a mediated by diaryl prolinol
3a at room temperature.[a]
Entry Additive
Solvent
t [h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
hexane
CH3CN
THF
24
27
22
23
24
24
23
48
24
48
24
63
24
87
98
48
57
80
85
73
–
64
–
Ͻ10
Ͻ10
78
19
rac
4
32
36
39
36
–
28
–
n.d.
n.d.
11
CHCl3
toluene
p-xylene
m-xylene
toluene
toluene
toluene
toluene
toluene
Figure 2. Bifunctional noncovalent activation of the reagents pro-
vided by Cinchona alkaloids, α,α-diaryl prolinols and Takemoto’s
catalyst.
PTSA[d]
PTSA[e]
TFA[d]
TFA[e]
PhCO2H[d]
9
Several organocatalytic Michael addition reactions are
based on the use of Cinchona alkaloids, their thiourea de-
rivatives, and chiral thioureas exemplified by the Takemoto
catalyst (Figure 2).[13,3b–3c]
10
11
12
13
4-NO2C6H4OH[d] toluene
In analogy to the catalytic core of natural Cinchona al-
kaloids Ϫ the mode of action of which is now well-under-
stood Ϫ prolinols also bear an amine and a hydroxyl group
(Figure 2).[14]
[a] Reaction conditions: 1a (0.2 mmol),
2 (0.24 mmol), 3
(0.06 mmol), solvent (400 mL). [b] Isolated yield after flash
chromatography. [c] Determined by chiral HPLC analysis accord-
ing to the literature.[11a,11b] [d] 30 mol-% of additive was used. [e]
15 mol-% of additive was used.
In previous works,[6,7] we suggested that unprotected α,α-
diaryl prolinols could behave as bifunctional organocata-
lysts capable of noncovalent activation of both reagents,
acting in strict analogy to Cinchona alkaloids (Figure 2).
In this paper, the behaviour of diaryl prolinols is investi-
gated from both experimental and computational points of
view; the Michael addition of malononitrile and trans-chal-
cones was chosen as a case study. Our goal was not the
development of a highly efficient and enantioselective pro-
cess,[11] but, rather, to clarify whether the conjugate ad-
dition reaction mediated by diaryl prolinols proceeds
through a noncovalent or a covalent mechanism. Our re-
sults provide evidence that favours the noncovalent mecha-
nism.
Compound 3a, employed in hexane at room temperature,
exhibited good catalytic activity, although the product
showed only 19% ee (Table 1, entry 1). More polar solvents
led to product formation in satisfactory yield, but in race-
mic form (Table 1, entries 2 and 3). A screen of low polarity
solvents improved results in terms of yield and enantio-
selectivity (Table 1, entries 4–7). Toluene was chosen as the
best reaction medium. Acid additives of different pKa val-
ues were then investigated. In the presence of strong p-tol-
uensulfonic acid (PTSA), in amounts comparable with cata-
lyst 3a, no product was observed even after prolonged reac-
tion time (Table 1, entry 8). This result contrasts with litera-
ture precedents that invoke an iminium ion as intermediate,
because the presence of acid has been demonstrated to ac-
celerate the entire process by facilitating iminium ion for-
mation.[8]
Results and Discussion
Initially, a set of reactions were carried out to establish
When half the amount of PTSA (15 mol-%) was used,
the efficiency of α,α-l-diaryl prolinol 3a (Figure 3) in the the process still occurred, although slightly lower yield and
model reaction between malononitrile and trans-chalcone ee values were observed with respect to the use of catalyst
1a, either in the absence or in the presence of acidic addi- 3a (Table 1, entry 9 vs. 5). This result might be explained by
tives (Table 1).
considering that a low amount of the unprotonated amino
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A. Lattanzi, A. Peluso et al.
FULL PAPER
alcohol 3a, still present in solution, catalysed the reaction. Table 2. Catalyst screening for the Michael addition of malono-
nitrile to trans-chalcone 1a mediated by diaryl prolinols 3 at room
When additives such as TFA and benzoic acid were used,
the formation of the adduct was not observed (Table 1, en-
temperature in toluene.[a]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
tries 10–12). Finally, in the presence of p-nitrophenol at
30 mol-% loading, the product was isolated in comparable
yield but with a low ee value (Table 1, entry 13 vs. 5). As-
suming a noncovalent activation model, the least acidic ad-
ditive Ϫ p-nitrophenol Ϫ would be expected to behave as
an external hydrogen-bonding donor for the carbonyl group
of compound 1a, in competition with the catalyst hydroxyl
group, thus leading to an unselective conjugate addition
pathway.
Pfaltz and co-authors recently developed a fast and use-
ful new method for screening chiral catalysts, based on
mass-labelled quasi-enantiomeric substrates and electro-
spray mass spectrometry (ESI-MS).[15] This method allows
facile detection of catalytic intermediates in homogeneous
solution, such as iminium ions derived from the condensa-
tion of α,β-unsaturated aldehydes and O-protected α,α-l-
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3e
3e
24
18
21
24
21
20
24
43
91
165
80
92
89
89
83
73
67
17
57
80
36
34
26
39
53
–9
rac
6
9[d]
10[e]
61
67
[a] Reaction conditions: 1a (0.2 mmol),
2
(0.24 mmol), 3
(0.06 mmol), solvent (400 mL). [b] Isolated yield after flash
chromatography. [c] Determined by chiral HPLC analysis. [d] Reac-
tion performed at –8 °C using 700 μL of solvent. [e] Reaction per-
formed at –18 °C using 700 μL of solvent.
diaryl prolinols.[16] On the basis of these reports, and with addition reactions of enals, in terms of conversion and en-
the aim of detecting possible iminium ion intermediates, un- antiocontrol.[19] This finding has been justified by consider-
der reaction conditions similar to those reported in Table 1, ing the formation of iminium ions as illustrated in Figure 1.
trans-chalcone 1a was reacted in toluene with a preformed The ineffectiveness of 3a as a promoter has been ascribed
simple pyrrolidinium perchlorate salt at room temperature to the generation of relatively stable and unreactive N,O-
(Scheme 1).[17] After a reaction time of 20 h, ESI-MS analy- acetal species with aldehydes that would entrap catalyst 3a,
sis of the reaction mixture showed only the signal of the removing it from the catalytic cycle. In contrast, in our case,
pyrrolidinium ion (m/z 72), indicating the absence of any 3a was the most effective catalyst.
iminium ion.
The tertiary N-methylated diphenyl prolinol 3h proved
to be a poor catalyst (Table 2, entry 8). In a noncovalent
mechanistic framework, this result could be rationalized by
invoking the involvement of the N–H bond in the establish-
ment of an effective hydrogen-bonding network with the
reagents (see below). Finally, conducting the reaction with
the most efficient catalyst 3e at lower temperatures (Table 2,
entries 9 and 10) enabled the isolation of the adduct with
Scheme 1. Initial trial indicated the absence of any iminium ion.
1H and 13C NMR analyses of chalcone 1a with one an improved 67% ee at –18 °C. The absolute configuration
equivalent of the most effective catalyst 3b, mixed either in for the major enantiomer of compound 4a was established
CDCl3 or C6D6, were conducted at different times up to to be R by comparison of the optical rotation value and
24 h. The resonances of compounds 1a and 3b were exclu- HPLC retention times with those reported in the litera-
sively observed.[18]
ture.[11] A variety of trans-enones were then reacted under
These data reinforce literature precedent on the inherent the optimised conditions, namely 30 mol-% catalyst 3e in
difficulties involved in generating iminium ions from aro- toluene at –18 °C (Table 3).
matic ketones with secondary amines, and further supports
The electronic nature of the substituents in the phenyl
our proposal that the conjugate addition of malononitrile ring slightly influenced the level of enantioselectivity
to enones is likely to proceed through an alternative path- (Table 3, entries 2–5), with the electron-withdrawing groups
way. A range of substituted α,α-l-diaryl prolinols were then displaying a positive influence (up to 75% ee). The para-
assessed in toluene at room temperature under the same cyano-substituted derivative 3f proved to be almost insolu-
conditions (Figure 3, Table 2).
ble under the above mentioned conditions (Table 3, entry
The reactions showed comparable performance except 6), however, pleasingly, both the conversion and the asym-
with commercially available α,α-bis(2-naphthyl)prolinol metric induction could be significantly increased by work-
(3e), which furnished product 4a with significantly higher ing at 4 °C (Table 3, entry 7). A variety of benzoyl-substi-
ee (Table 2, entry 5). The O-methylated diphenyl prolinol tuted chalcones were converted into the products with
3f, employed under the same conditions, gave the product somewhat lower enantioselectivities (Table 3, entries 8–10).
with poor ee values and opposite absolute configuration, Enones bearing a β-alkyl group were also suitable com-
and the O-silylated derivative 3g afforded a racemic adduct pounds, affording the adducts in good yield with moderate
(Table 2, entries 6 and 7 vs. entry 1). According to previous ee values (Table 3, entries 11–13). As expected on the basis
results, O-protected derivatives such as compounds 3f and of our previous reports,[6,7] the experimental findings on the
3g were far more effective than compound 3a in Michael enantioselective Michael addition of malononitrile to chal-
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Conjugate Addition of Malononitrile to Chalcones
Table 3. Asymmetric Michael addition of malononitrile to trans- not operative in this case. This hypothesis was supported
enones 1 organocatalyzed by α,α-bis(2-naphthyl)prolinol (3e).[a]
by theoretical investigations that showed that the energy of
the first reaction intermediate along the covalent pathway
(i.e., the most stable (S,S)-hemiaminal A formed between
trans-chalcone and 3a) was found to be about 18.3 kcal/mol
above that of the reactants (Figure 4).
Entry
R1
R2
4
Yield [%][b] ee [%][c]
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
80
50
50
63
71
40
98
75
60
87
30
70
66
67
51
75
62
66
59
65
50
53
57
49
39
55
pMeC6H4
pClC6H4
pBrC6H4
pCF3C6H4
pCNC6H4
pCNC6H4
7[d]
8
9
4f
Figure 4. Hemiaminals formed between catalyst 3a and trans-chal-
cone (A), trans-cinnamaldehyde (B).
pMeOC6H4 Ph
mMeC6H4 Ph
m,pCl2C6H3 Ph
Ph
Ph
Ph
4g
4h
4i
4j
4j
10[d]
11
12[d]
13[d]
This energy is significantly higher than those of the inter-
mediates and the transition states of the alternative nonco-
valent mechanism proposed below (Figure 5).
Me
Me
cyclohexyl
4k
As expected,[9] the most stable (R,S)-hemiaminal B, ob-
tained from trans-cinnamaldehyde and catalyst 3a, was cal-
culated to be considerably more stable: 6.3 kcal/mol above
the reactants.
[a] Reaction conditions: 1a (0.2 mmol),
2
(0.24 mmol), 3
(0.06 mmol), solvent (600 mL). [b] Isolated yield after flash
chromatography. [c] Determined by chiral HPLC analysis. [d] Reac-
tion performed at 4 °C.
Previous studies on Michael additions and Henry reac-
tions showed that, in the case of bifunctional thioureas
bearing a tertiary amine group, the reaction proceeds
through formation of a zwitterionic complex between the
protonated thiourea and the nucleophile.[14b,14d] Following
this line of reasoning, we first analyzed the hypothetical
formation of a binary hydrogen-bonded complex between
malononitrile and prolinol, and calculated its possible evol-
ution into a zwitterionic adduct. The optimized structure
of the neutral hydrogen-bonded complex between prolinol
cones catalysed by diaryl prolinols 3 are in agreement with
a noncovalent activation of the reagents as depicted in Fig-
ure 2. DFT calculations on model compound 4a and ma-
lononitrile with catalysts 3a and 3e were then performed to
elucidate the most energetically favourable pathway for this
reaction and to unravel the origin of the enantioselectivity.
The Reaction Path
The reaction path for the Michael addition of malonon- and malononitrile (intermediate I), is shown in Figure 6. In
itrile to trans-chalcone 1a, both in the presence of 3a and this intermediate the substrate forms a C–H···N bond and
in the presence of the most selective catalyst 3e, was investi- a C–H···π bond with the phenyl moiety of the catalyst. The
gated by using DFT computations. Experimental results more basic site Ϫ the nitrogen of pyrrolidine Ϫ is suitably
provided evidence that iminium ions are not involved in the positioned in proximity to one of the malononitrile hydro-
reaction, suggesting that the usual covalent mechanism is gens to give the zwitterionic complex.
Figure 5. Schematic reaction energy profiles with catalyst 3a. (Dotted bars) pathway A; (grey bars) pathway B; (black bars) stationary
points common to both pathways. Energies include solvent contributions.
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A. Lattanzi, A. Peluso et al.
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bars). The binding energy of the binary hydrogen-bonded
complex between prolinol 3a and trans-chalcone (interme-
diate IV, Figure 7) is, –1.1 kcal/mol. The structure of IV
shows that chalcone is bound to the catalyst by a stronger
O–H···O hydrogen bond and by a weaker interaction in-
volving the N–H hydrogen of prolinol. Nevertheless, the
most relevant feature of IV is that its “bottom face” is not
sterically hindered, so that the basic nitrogen of the catalyst
can interact with an acidic hydrogen atom of malononitrile,
leading to the formation of the neutral ternary complex V.
The latter exhibits extra stability (–6.9 kcal/mol, Figure 5)
compared with I and IV, which can be ascribed to coopera-
tive effects; the negative charge of the basic nitrogen in-
creases (from –0.7 to –0.8) when malononitrile interacts
with IV, giving rise to a stronger interaction between chal-
cone and prolinol.
In the ternary complex V, proton transfer from malonon-
itrile to prolinol yielding the zwitterionic intermediate VI
(Figure 8) is a more energetically affordable process, requir-
ing only 2.1 kcal/mol rather than 6.2 kcal/mol needed for
transferring the proton in I (see Figure 5). The hydrogen-
bonding network established in the zwitterionic complex VI
is the key motif assuring catalyst efficiency. The N-methyl
derivative 3h is a poor catalyst (Table 2, entry 8) because
the presence of the methyl group on the nitrogen disrupts
the hydrogen-bond network necessary for the noncovalent
activation mechanism.
Figure 6. Neutral (I) and zwitterionic (III) forms of the hydrogen-
bonded complex between malononitrile and prolinol 3a, and the
related transition state (II). Distances are in Å.
However, proton transfer from malononitrile to prolinol
in the neutral complex I, leading to the ion pair III via
transition state II, is predicted to be endoergic in toluene
by 6.2 kcal/mol, both because of the low solvent polarity
and because of the modest acidity of malononitrile.
The same conclusion also holds for catalyst 3e (see the
Supporting Information). The direct protonation of proli-
nol by malononitrile is not feasible for the binary complex
I, but it could take place in a ternary complex involving
both of the reactants and the catalyst, where a hydrogen
bond between prolinol and chalcone could enhance the ba-
sicity of the amine group (pathway B in Figure 5, grey
The zwitterionic complex VI is the precursor of the C–C
bond-forming step, because it evolves into the transition
state VII (Figure 8) where the C–C bond-formation takes
place. In VII, the hydrogen bonds holding together the chal-
cone and the protonated catalyst are considerably shorter
than those in VI; a negative charge is growing on the car-
bonyl oxygen and a positive charge is growing on the reac-
tive carbon of chalcone (from +0.7 of VI to +1.3 of VII).
In summary, when chalcone assumes the enolate form,
the binding energy between the malononitrile anion and the
protonated catalyst is reduced, whereas the interaction be-
tween chalcone and the malononitrile anion increases. As a
consequence, the C–C distance for the forming bond de-
creases from 5.11 to 2.11 Å, bringing the reactive carbon of
chalcone and the central carbon of the malononitrile anion
Figure 7. Structures of the intermediates found for the initial steps
of pathway B. IV: Chalcone coordinated to prolinol. V: Neutral
complex with both substrates coordinated to the catalyst.
Figure 8. Stationary points for the C–C bond-forming step. VI: Malononitrile anion and chalcone coordinated to the protonated catalyst.
VII: Transition state for the C–C bond formation. VIII: Enolate coordinated to the protonated catalyst.
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Conjugate Addition of Malononitrile to Chalcones
into close contact. The total activation energy for the C–C
bond formation is 13.7 kcal/mol (Figure 5), indicating that
C–C bond formation is the rate-determining step and, as
shown below, also the enantioselectivity determining step
of the reaction.
Following the intrinsic reaction coordinate, the transition
state VII evolves from one side to its precursor VI and from
the other side to the zwitterionic complex VIII (Figure 8).
Complex VIII is characterized by a short hydrogen bond
length (1.54 Å) between the carbonyl oxygen of the enolate
and the proton on the prolinol nitrogen. Thus, a proton
transfer from the cationic amine moiety of the catalyst to
the oxygen of the enolate in VIII can easily take place, lead-
ing to the formation of the reaction product in the enol
form, hydrogen-bonded to the catalyst. The binding energy
holding together the resulting enol and the catalyst (see the
Supporting Information) is very low when compared with
the stabilized final product, which is predicted to be
–9.0 kcal/mol (Figure 5). Therefore, the reaction product in
the ketonic form is readily obtained from VIII and the cata-
lyst is quickly regenerated in the last step of the reaction.
Figure 9. The energetically most accessible transition states ob-
tained by catalysts 3a and 3e. Newman projections refer to the
forming C–C bond. Peripherals hydrogen atoms are omitted for
clarity. CPCM (conductor-like polarizable continuum model) rela-
tive energies [kcal/mol] are given in the labels; gas phase energies
in parentheses. For subscript and superscript labels see text.
Enantioselectivity and Solvent Effects
Both catalysts 3a and 3e lead to products with ee values
in favour of the (R)-4a product. Catalyst 3e is significantly
more enantioselective than 3a, likely due to steric effects of
the different aromatic moieties. However, steric hindrance
is not expected to be the only factor governing the ste-
reocontrol; enantiomeric excesses observed in toluene and
xylene, solvents that can better solvate both catalysts and preferred staggered conformations of the reacting mole-
chalcone molecules by stacking interactions, are higher cules. Another difference between the pro-R and the pro-S
than those observed for solvents of similar polarity such as transition states is in the relative orientations of the phenyl
hexane (Table 1).
substituents of chalcone and the aryl moieties on the cata-
The relative energies of the lowest energy transition states lyst. In pro-S-type transition states the benzoyl portion of
leading to R and S products with catalysts 3a and 3e are chalcone points in the direction of the aryl group of the
given in Figure 9. The transition states leading to the R catalyst; this unfavourable contact disappears in pro-R tran-
product are the lowest energy both for 3a and 3e, in agree- sition states, which adopt a more open configuration. Al-
ment with experimental findings. Furthermore, the energy though the above interaction does not represent severe ste-
differences between activated states leading to different ric hindrance, it plays a role in determining the slightly
enantiomers are higher for 3e than for 3a, so that the for- higher selectivity observed for catalyst 3e.
mer is predicted to be more selective than the latter, again,
The different structures of the pro-R and pro-S transition
in line with the experimental findings (see Table 2). The four states can also provide useful hints for understanding the
lowest energy transition states have very similar hydrogen- observed solvent dependence on enantiomeric excess. In-
bond patterns and, therefore, transition states leading to R deed, stacking interactions with solvent molecules stabilize
and S products are close in energy. There are, however, dif- the pro-R transition states by a larger amount than the pro-
ferences in the relative orientations of the malononitrile S transition states, because their open structures ensure a
anion with respect to the chalcone moiety upon the forma- larger number of contacts with the molecules of solvent.
tion of the two enantiomeric compounds, which hold for Thus, regardless of dielectric effects (hexane and toluene are
both catalysts. In transition states yielding the R product both nonpolar solvents with similar dielectric constants),
[R1(3a), R1ct(3e), Figure 9] the malononitrile anion is aligned solvents that give rise to stacking interactions with the cata-
in a near-staggered conformation along the new C–C bond. lyst, such as toluene and xylene, can stabilize the pro-R
This favourable orientation cannot be adopted in S1(3a) transition states better than the pro-S transition states. For
and S1ct(3e) because a terminal nitrogen atom of the ma- both catalysts, two possible rotamers for each enantiomer
lononitrile anion is engaged in a hydrogen bond, and the are possible; they are denoted with subscripts 1 and 2 in
C–C bond formation can only take place by compromising Figure 10 (a), and correspond to different conformations of
the hydrogen-bond catalyst–substrate interaction and the the new C–C bond.
Eur. J. Org. Chem. 2011, 1922–1931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1927

A. Lattanzi, A. Peluso et al.
FULL PAPER
Table 4. Relative energies [kcal/mol] of the transition states for the
C–C bond-forming step for 3e and 3a in toluene. Gas phase values
are given in parentheses. Subscripts refer to the conformation
about the forming C–C bond (see Figure 9). For superscript labels,
see text and Figures 10 and 11.
TS
3e
3a
R1ct
R1tt
R1cc
R1tc
R1ct
R2tt
R2cc
R2tc
S1ct
S1tt
0.0 (0.0)
0.5 (0.5)
0.9 (1.1)
1.2 (1.4)
1.2 (1.7)
1.6 (2.3)
1.2 (1.3)
1.9 (1.8)
0.8 (1.5)
1.4 (1.9)
1.4 (2.2)
2.0 (2.6)
2.0 (3.1)
2.9 (3.5)
3.2 (4.3)
3.7 (4.8)
0.0 (0.0)
–
–
–
0.4 (0.6)
–
–
–
0.4 (0.7)
–
–
–
S1cc
S1tc
S2ct
S2tt
2.2 (2.8)
–
–
–
S2cc
S2tc
Table 5. Computed free-activation energies ΔGTS [kcal/mol] and ee
values (%) for 4a at 298 K. Values at 255 K are given in parenthe-
Figure 10. Transition states for catalyst 3e showing the most rel-
evant conformations. Peripheral hydrogen atoms are omitted for
clarity. CPCM relative energies [kcal/mol] are given in the labels;
gas-phase energies in parentheses.
ses.
Calcd. (gas)
Calcd. (toluene)
ΔGTS
ee
Exp.[a]
ee
cat
ΔGTS
ee
3a
3e
–0.9(–0.8) 61(66)
–1.4(–1.4) 83(89)
–0.6(–0.5) 45(49)
–0.8(–0.8) 61(67)
36(–)
53(67)
[a] See Tables 1 and 2.
For catalyst 3e, additional conformations are possible
that involve rotations about the bond between the carbinol
carbon of prolinol and the naphthyl group; this gives rise
to two nonequivalent conformations per bond, labelled as
c and t (Figure 11).
Conclusions
The asymmetric conjugate addition of malononitrile to
trans-chalcones mediated by α,α-l-diaryl prolinols affords
the products in good yield and moderate enantioselectivity.
Further study of the reaction revealed that it does not pro-
ceed in the presence of acids as co-catalysts. ESI-MS analy-
sis of the reaction mixture composed of chalcone and a sim-
ple pyrrolidinium perchlorate salt did not provide any evi-
dence for the presence of any iminium ion intermediate, nei-
ther did NMR analysis of the mixture of chalcone and stoi-
chiometric loading of the most effective catalyst 3b. These
findings, together with the results of the DFT calculations,
suggest that the covalent mechanism, proceeding through
Figure 11. Non equivalent conformers of catalyst 3e.
The relative energies of all the transition states are given iminium ion formation, is not operative in this case. Ac-
in Table 4 and the ee values obtained from Table 4 are re- cording to DFT computations, a more energetically afford-
ported in Table 5.
able pathway would involve a bifunctional noncovalent ca-
Although quantitative assessments must be made with talysis provided by the promoter. The establishment of an
caution because of the very small energy differences in- effective network of hydrogen bonds would lead to the for-
volved, the computed ee values for product 4a are in rea- mation of a ternary neutral complex between the reactants
sonable agreement with the experimental values, especially and catalyst. That species evolves into a zwitterionic com-
at lower temperatures where entropic effects, partially ne- plex, which, as in Michael additions catalyzed by bifunc-
glected by our computations, play a minor role. In the gas tional thioureas, leads to carbon–carbon bond formation.
phase, the ee values are overestimated, which is in line with The latter is found to be the rate- and enantioselectivity-
the recent findings of Friesner and co-workers.[20]
determining step of the process. Computed ee values are in
1928
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1922–1931

Conjugate Addition of Malononitrile to Chalcones
tional in conjunction with the 6-311+G* basis set was used for the
computation of the reaction path of catalyst 3a both for the R and
S products.
reasonable agreement with the experimental values. More-
over, the analysis of the transition states provides a ration-
ale for the preferential formation of the R-enantiomer of
the adducts.
The potential of bifunctional l-proline derivatives that
are able to activate carbonyl compounds also through non-
covalent catalysis deserves further consideration. Work is in
progress along these lines.
For catalyst 3e, the reaction path was studied by using the smaller
6-31G* basis set. This basis set performs as well as the larger 6-
311+G* basis set in the case of catalyst 3a (see the Supporting
Information). To provide an easier comparison between the two
catalysts, the 6-31G* results were used in the analysis of enantio-
meric excesses for both catalysts.
Solvent effects were modelled by the CPCM method using the stan-
dard parameters for toluene, as implemented in Gaussian.[23]
Experimental Section
The nature of all stationary points (both in vacuum and in the
solution phase) were verified by computing the eigenvalues of the
Hessian matrix; all the computed transition states exhibit only one
large negative eigenvalue, whereas all the minimum energy struc-
tures have only positive eigenvalues.
All reactions requiring anhydrous or inert conditions were con-
ducted in flame-dried glassware under a positive pressure of nitro-
gen. CHCl3 was freshly distilled before use from CaH2. Reactions
were monitored by thin-layer chromatography (TLC) on Merck sil-
ica gel plates (0.25 mm), and visualized by UV light or I2 vapour.
Flash chromatography was performed on Merck silica gel 60 (par-
Enantiomeric excesses were computed by the formula
1
ticle size: 0.040–0.063 mm). H NMR and 13C NMR spectra were
recorded with a Bruker DRX 400 spectrometer at room tempera-
ture in CDCl3 as solvent. Chemical shifts for protons are reported
using residual CHCl3 as internal reference (δ = 7.26 ppm). 13C
NMR shifts were referenced to the shift of the C signal of CHCl3
(δ = 77.0 ppm). Optical rotation measurements were performed
with a Jasco Dip-1000 digital polarimeter using the Na lamp. FTIR
spectra were recorded as thin films on KBr plates with a Bruker
Vertex 70 spectrometer; absorption maxima wavenumbers are re-
ported in cm–1. ESI-MS was performed with a Bio-Q triple quadru-
pole mass spectrometer (Micromass, Manchester, UK) equipped
with an electrospray ion source. Melting points were measured with
a digital Electrothermal 9100 apparatus. Anhydrous p-xylene, m-
xylene and toluene were purchased from Aldrich. Petroleum ether
(PE) had a boiling range of 40–60 °C. Catalysts 3a, 3b, 3e and 3f–
h are commercially available compounds; they were purchased from
Aldrich and used as received. Catalysts 3c and 3d were prepared
according to the procedures reported in literature.[21] Compounds
4 are known, except 4i (see the Supporting Information and ref.[11]).
Enantiomeric excesses of compounds 4 were determined by HPLC
(Waters-Breeze 2487; UV dual λ absorbance detector and 1525 Bi-
nary HPLC Pump) using Daicel Chiralpak AD, AD-H and AS-H
columns.
where ΔGTS is the Gibbs free energy difference between the transi-
tion state leading to the favoured enantiomer and the transition
state leading to the disfavoured one. ΔGTS was approximated as
ΔATS, with A being the Helmholtz free energy given by:
Aj = –RTInZj
where the index j refers to the transition states leading to the R or
S enantiomers,
and the summation runs over all the transition states k leading to
j. All the energies, except where otherwise specified, include zero-
point vibrational corrections and the solvent polarization contri-
bution. Atomic charges were computed according to an approach
that makes use of atomic polar tensors (APT).[24]
A quantitative mechanistic description of a reaction path should
be based on the calculations of Gibbs free energies in solution.
However, this is not an affordable approach because of the well-
known difficulty of estimating entropy variations in solution. En-
tropy contributions estimated in the gas phase cannot be used for
discussing association and dissociation processes in solution. For
instance, the TΔS contribution to ΔG for the formation of the Wat-
son–Crick hydrogen-bonded complex between adenine and thy-
mine is about 3.5 kcal/mol at 25 °C in solution,[25] whereas the ideal
gas model yields a contribution as large as 20 kcal/mol. Interest-
ingly, nearly the same value was estimated for the binary complex
IV (Figure 7). Because of this, discussion of the reaction paths has
only been based on electronic energies, which include solvent polar-
ization effects. Entropic contributions are expected to significantly
affect only association and dissociation steps. In particular, the for-
mation of a ternary complex is expected to be entropically disfav-
oured; however, in the present case, the computed association en-
ergy for the ternary complex is only slightly lower than that com-
puted for the thiourea-substituted cinchona alkaloid-catalyzed
Michael addition of 1,3-dicarbonyl compounds to nitroalkenes,[14d]
for which the dual activation model proposed by Takemoto is
widely accepted.[3b,3c]
General Procedure for the Synthesis of Racemic Compounds 4: En-
one (0.20 mmol) and racemic piperidinemethanol (7.0 mg,
0.060 mmol) were dissolved in anhydrous toluene (0.5 mL). Ma-
lononitrile (16 mg, 0.24 mmol) was added and reaction was stirred
at room temperature. After completion of the reaction (monitored
by TLC; PE/EtOAc, 80:20), the mixture was directly purified by
flash chromatography (PE/Et2O, 90:10 to CHCl3) to give racemic
product 4 (68–97% yield).
General Procedure for the Asymmetric Michael Addition of Ma-
lononitrile to Enones: Enone (0.20 mmol) and catalyst 3e (21 mg,
0.060 mmol) were dissolved in anhydrous toluene (0.6 mL). Ma-
lononitrile (16 mg, 0.24 mmol) was added and the reaction was
stirred at –18 °C. After completion of the reaction (monitored by
TLC), the mixture was directly purified by flash chromatography
(PE/Et2O, 90:10 to CHCl3) to give product 4.
Computational Methods: All the calculations were carried out by
using the Gaussian 09 package.[22] Minimum energy nuclear config-
urations, transition states and vibrational frequencies were com-
puted by using density functional theory. The hybrid B3LYP func-
Eur. J. Org. Chem. 2011, 1922–1931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1929

A. Lattanzi, A. Peluso et al.
FULL PAPER
K. N. Houk, H. J. Martin, B. List, J. Am. Chem. Soc. 2003,
125, 2475–2479; c) C. Allemann, R. Gordillo, F. R. Clemente,
P. H.-Y. Cheong, K. N. Houk, Acc. Chem. Res. 2004, 37, 558–
569; d) A. Fu, B. List, W. Thiel, J. Org. Chem. 2006, 71, 320–
326; e) R. Gordillo, K. N. Houk, J. Am. Chem. Soc. 2006, 128,
3543–3553; f) K. N. Houk, P. H.-Y. Cheong, Nature 2008, 455,
309–313; g) I. Ibrahem, P. Hammar, J. Vesely, R. Rios, L. Eriks-
son, A. Cordova, Adv. Synth. Catal. 2008, 350, 1875–1884.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization of unknown compounds, further computa-
tional details, DFT coordinates and stick-and-ball representations;
coloured versions of Figures 6, 7, and 8.
Acknowledgments
[11]
For organocatalytic enantioselective conjugate addition of ma-
lononitrile to enones, see: a) X. Li, L. Cun, C. Lian, L. Zhong,
Y. Chen, J. Liao, J. Zhu, J. Deng, Org. Biomol. Chem. 2008, 6,
349–353; b) L. Yue, W. Du, Y.-K. Li, Y.-C. Chen, Tetrahedron
Lett. 2008, 49, 3881–3884; c) A. Russo, A. Perfetto, A. Lat-
tanzi, Adv. Synth. Catal. 2009, 351, 3067–3071.
The Ministero Italiano dell’Università e Ricerca (MIUR) and the
University of Salerno are acknowledged for financial support.
[1] For reviews and books, see: a) M. Shibasaki, N. Yoshikawa,
Chem. Rev. 2002, 102, 2187–2209; b) T. Ikariya, K. Murata, R.
Noyori, Org. Biomol. Chem. 2006, 4, 393–406; c) D. Almasi,
D. A. Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18,
299–365; d) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007,
2065–2092; e) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–
1716; f) S. Sulzer-Mossé, A. Alexakis, Chem. Commun. 2007,
3123–3135; g) A. Cordova (Ed.), Catalytic Asymmetric Conju-
gate Reactions, Wiley-VCH, Weinheim, Germany, 2010.
[2] For selected examples, see: a) N. Halland, P. S. Aburel, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2003, 42, 661–665; b) H. Li,
Y. Wang, T. Tang, L. Deng, J. Am. Chem. Soc. 2004, 126, 9906–
9907; c) S. H. McCooey, S. J. Connon, Angew. Chem. Int. Ed.
2005, 44, 6367–6370; d) J. Ye, D. J. Dixon, P. S. Hynes, Chem.
Commun. 2005, 4481–4483; e) T. Ooi, D. Ohara, K. Fukumoto,
K. Maruoka, Org. Lett. 2005, 7, 3195–3197; f) K. R. Knudsen,
C. E. T. Mitchell, S. V. Ley, Chem. Commun. 2006, 66–68; g)
J. M. Andres, R. Manzano, R. Pedrosa, Chem. Eur. J. 2008, 14,
5116–5119.
[3] For selected examples, see: a) J. Wang, H. Li, W. Duan, L. Zu,
W. Wa n g , Org. Lett. 2005, 7, 4713–4716; b) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672–
12673; c) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takem-
oto, J. Am. Chem. Soc. 2005, 127, 119–125; d) M. Terada, H.
Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006, 128, 1454–1455; e)
D. A. Evans, S. Mito, D. Seidel, J. Am. Chem. Soc. 2007, 129,
11583–11592; f) J. P. Malerich, K. Hagihara, V. H. Rawal, J.
Am. Chem. Soc. 2008, 130, 14416–14417.
[12]
[13]
a) H. Hiemstra, H. Wynberg, J. Am. Chem. Soc. 1981, 103,
417–430; b) H. Wynberg, Top. Stereochem. 1986, 16, 87–129.
For reviews, see: a) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P.
McDaid, L. Deng, Acc. Chem. Res. 2004, 37, 621–631; b) T.
Marcelli, J. H. van Maarseveen, H. Hiemstra, Angew. Chem.
Int. Ed. 2006, 45, 7496–7504; c) C. Palomo, M. Oirabide, R.
López, Chem. Soc. Rev. 2009, 38, 632–653; d) T. Marcelli, H.
Hiemstra, Synthesis 2010, 1229. For reviews on bifunctional
thioureas, see: e) Y. Takemoto, Org. Biomol. Chem. 2005, 3,
4299–4306; f) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007,
107, 5713–5743; g) S. J. Connon, Chem. Commun. 2008, 2499–
2510.
a) G. Vayner, K. N. Houk, Y.-K. Sun, J. Am. Chem. Soc. 2004,
126, 199–203; b) P. Hammar, T. Marcelli, H. Hiemstra, F.
Himo, Adv. Synth. Catal. 2007, 349, 2537–2548; c) C. S. Cucin-
otta, M. Kosa, P. Melchiorre, A. Cavalli, F. L. Gervasio, Chem.
Eur. J. 2009, 15, 7913–7921. For DFT studies on bifunctional
thiourea catalyzed Michael additions, see: d) A. Hamza, G.
Schubert, T. Soós, P. I, J. Am. Chem. Soc. 2006, 128, 13151–
13160.
a) C. Markert, A. Pfaltz, Angew. Chem. Int. Ed. 2004, 43, 2498–
2500; b) C. A. Müller, A. Pfaltz, Angew. Chem. Int. Ed. 2008,
47, 3363–3366; c) A. Teichert, A. Pfaltz, Angew. Chem. Int.
Ed. 2008, 47, 3360–3362. For further applications of ESI-MS
techniques to identify enamine/iminium intermediates of car-
bonyl compounds, see: d) C. Marquez, J. O. Metzger, Chem.
Commun. 2006, 1539–1541; e) D. Gryko, M. Zimnicka, R. Lip-
in´ski, J. Org. Chem. 2007, 72, 964–970; f) Z.-J. Wu, S.-W. Luo,
J.-W. Xie, X.-Y. Xu, D.-M. Fang, G.-L. Zhang, J. Am. Soc.
Mass Spectrom. 2007, 18, 2074–2080; g) G. Guillena, M. Hita,
C. Nájera, S. F. Viózquez, J. Org. Chem. 2008, 73, 5933–5943;
h) W. Schrader, P. P. Handayani, J. Zhou, B. List, Angew. Chem.
Int. Ed. 2009, 48, 1463–1466.
[14]
[15]
[4] For selected examples, see: a) D. A. Evans, D. Seidel, J. Am.
Chem. Soc. 2005, 127, 9958–9959; b) F. Wu, H. Li, R. Hong,
L. Deng, Angew. Chem. Int. Ed. 2006, 45, 947–950.
[5] For selected examples, see: a) S. Hanessian, V. Pham, Org. Lett.
2000, 2, 2975–2978; b) E. J. Corey, F.-Y. Zhang, Org. Lett.
2000, 2, 4257–4259; c) N. Halland, R. G. Hazell, K. A.
Jørgensen, J. Org. Chem. 2002, 67, 8331–8338; d) T. Ooi, S.
Fujioka, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 11790–
11791; e) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett.
2005, 7, 1967–1969; f) A. Prieto, N. Halland, K. A. Jørgensen,
Org. Lett. 2005, 7, 3897–3900; g) T. Marcelli, R. N. S.
van der Haas, J. H. van Maarseveen, H. Hiemstra, Angew.
Chem. Int. Ed. 2006, 45, 929–931.
[16]
[17]
I. Fleischer, A. Pfaltz, Chem. Eur. J. 2010, 16, 95–99.
The generation of the pyrrolidinium/perchlorate salt was per-
formed according to Pfaltz procedure reported in ref.[16]
.
[18]
For NMR characterization, X-ray analysis of enamine and im-
inium ion intermediates formed with aliphatic and α,β-unsatu-
rated aldehydes with different O-protected α,α-l-diaryl prolin-
ols, see: U. Grosˇelj, D. Seebach, D. M. Badine, W. B. Schweizer,
A. K. Beck, I. Krossing, P. Klose, Y. Hayashi, T. Uchimaru,
Helv. Chim. Acta 2009, 92, 1225–1259.
For selected examples, see: a) Y. Okuyama, H. Nakan, H.
Hongo, Tetrahedron: Asymmetry 2000, 11, 1193–1198; b) S.
Karlsson, H.-E. Högberg, Tetrahedron: Asymmetry 2002, 13,
923–926; c) J. Franzén, M. Marigo, D. Fielenbach, T. C. Wab-
nitz, A. Kjærsgaard, K. A. Jørgensen, J. Am. Chem. Soc. 2005,
127, 18296–18304; d) Y. Chi, S. H. Gellman, Org. Lett. 2005,
7, 4253–4256; e) H. Gotoh, R. Masui, H. Ogino, M. Shoji,
Y. Hayashi, Angew. Chem. Int. Ed. 2006, 45, 6853–6856; f) I.
Ibrahem, R. Rios, J. Vesely, G.-L. Zhao, A. Córdova, Chem.
Commun. 2007, 849–851; g) I. Ibrahem, R. Rios, J. Vesely, A.
Córdova, Tetrahedron Lett. 2007, 48, 6252–6257; h) J. Vesely,
G.-L. Zhao, A. Bartoszewicz, A. Córdova, Tetrahedron Lett.
2008, 49, 4209–4212.
[6] For a review, see: A. Lattanzi, Chem. Commun. 2009, 1452–
1463.
[7] a) A. Lattanzi, Org. Lett. 2005, 7, 2579–2582; b) A. Lattanzi,
Tetrahedron: Asymmetry 2006, 17, 837–841; c) A. Russo, A.
Lattanzi, Adv. Synth. Catal. 2008, 350, 1991–1995; d) A. Russo,
A. Lattanzi, Org. Biomol. Chem. 2010, 8, 2633–2638.
[8] For reviews, see: a) G. Lelais, D. W. C. MacMillan, Aldrichim-
ica Acta 2006, 39, 79–87; b) A. Erkkilä, I. Majander, P. M.
Pihko, Chem. Rev. 2007, 107, 5416–5470; c) G. Bartoli, P. Mel-
chiorre, Synlett 2008, 1759–1772; d) L.-W. Xu, J. Luo, Y. Lu,
Chem. Commun. 2009, 1807–1821; e) J. Seayad, B. List, Org.
Biomol. Chem. 2005, 3, 719–724; f) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569.
[9] For reviews, see: a) C. Palomo, A. Mielgo, Angew. Chem. Int.
Ed. 2006, 45, 7876; b) A. Mielgo, C. Palomo, Chem. Asian J.
2008, 3, 922.
[19]
[10] For selected examples, see: a) S. Bahmanyar, K. N. Houk, J.
Am. Chem. Soc. 2001, 123, 11273–11283; b) S. Bahmanyar,
1930
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1922–1931

Conjugate Addition of Malononitrile to Chalcones
[20] S. T. Schneebeli, M. L. Hall, R. Breslow, R. Friesner, J. Am.
Chem. Soc. 2009, 131, 3965–3973.
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09 Re-
vision A.02, Gaussian Inc. Wallingford CT 2009.
[21] a) D. J. Mature, T. K. Jones, L. C. Xavier, T. J. Blacklock, R. A.
Reamer, J. J. Mohan, E. T. Turner Jones, K. Hoogsteen, M. W.
Baum, E. J. J. Grabowski, J. Org. Chem. 1991, 56, 751–762; b)
A. Lattanzi, A. Russo, Tetrahedron 2006, 62, 12264–12269.
[22] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
[23] V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995–2001.
[24] J. Cioslowski, J. Am. Chem. Soc. 1989, 111, 8333–8336.
[25] T. Caruso, A. Capobianco, A. Peluso, J. Am. Chem. Soc. 2007,
129, 15347–15353.
Received: October 28, 2010
Published Online: February 25, 2011
Eur. J. Org. Chem. 2011, 1922–1931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1931