Density functional theory study of the Cinchona thiourea-catalyzed Henry reaction: Mechanism and enantioselectivity

Article abstract of DOI:10.1002/adsc.200700367

We report a density functional theory investigation of the enantioselective Cinchona thiourea-catalyzed Henry reaction of aromatic aldehydes with nitromethane. We show that two pathways (differing in the binding modes of the reactants to the catalyst) are

Full text of DOI:10.1002/adsc.200700367

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DOI: 10.1002/adsc.200700367
Density Functional Theory Study of the Cinchona Thiourea-
Catalyzed Henry Reaction: Mechanism and Enantioselectivity
Peter Hammar,a Tommaso Marcelli,b Henk Hiemstra,b and Fahmi Himoa,*
a
Department of Theoretical Chemistry, School of Biotechnology, Royal Institute of Technology, SE-106 91 Stockholm,
Sweden
Fax : (+46)-8-5537-8590; e-mail: himo@theochem.kth.se
Van’t Hoff Institute of Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam,
b
The Netherlands
Received: July 26, 2007; Published online: November 27, 2007
Dedicated to Professor Jan Bäckvall on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: We report a density functional theory in- ers. The enantioselectivity is investigated, and our re-
vestigation of the enantioselective Cinchona thiour- sults are in agreement with the experimentally ob-
ea-catalyzed Henry reaction of aromatic aldehydes served solvent dependence of the reaction.
with nitromethane. We show that two pathways (dif-
fering in the binding modes of the reactants to the Keywords: Cinchona alkaloids; density functional
À
catalyst) are possible for the formation of the C C theory; enantioselectivity; nitroaldol reaction; orga-
bond, and that they have comparable reaction barri- nocatalysis
Introduction
thiourea[7] led to a dramatic improvement in both
scope and enantioselectivity: organocatalyst 1 was
The reaction between an enolizable nitroalkane and a shown to promote the addition of nitromethane to ar-
carbonyl compound, known as the Henry or nitroal- omatic and heteroaromatic aldehydes in consistently
dol reaction, is a very important synthetic tool for the high yields and enantiomeric excesses (Scheme 1).[8]
creation of a carbon-carbon bond and up to two con-
tiguous stereogenic centers.[1] Traditionally, like the
aldol reaction, this reaction was mainly carried out in
the presence of strong bases, leading to dehydration
with concomitant formation of a nitroolefin. The in-
terest in asymmetric versions of this reaction started
growing after the groundbreaking work of Shibasaki
and co-workers on the use of chiral bimetallic lithi-
um-lanthanum catalysts.[2] In the last two decades
many other asymmetric metal catalysts have been de-
veloped: nowadays, aldehydes or a-keto esters can be
converted to the corresponding nitroalcohols with
mostly excellent enantio- and diastereoselectivity.[3]
On the other hand, the number of efficient asym-
metric organocatalysts for the Henry reaction is con-
siderably lower.[4] Our interest in this reaction started
with the observation that Cinchona alkaloids bearing
a phenol on the C-6’ position (cupreines)[5] are moder-
ately enantioselective bifunctional organocatalysts for
the addition of nitromethane to activated aromatic al-
dehydes.[6] Replacement of the phenol with a better
Scheme 1. Cinchona thiourea-catalyzed enantioselective
hydrogen bonding moiety such as an electron-poor Henry reaction.
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In the same period, Nagasawa and co-workers devel- Computational Details
oped a guanidine-thiourea catalyst giving excellent re-
sults in the Henry reaction of aliphatic aldehydes[9] All calculations were performed using the hybrid den-
and Deng and co-workers showed that simple cu- sity functional theory method B3LYP as implemented
preines are highly enantioselective catalysts for the in the Gaussian03 program package.[16] Geometries
addition of nitromethane to a-keto esters.[10] More re- were optimized with the 6-31G
ACHTRE(UNG d,p) basis set, and
cently, Griengl and co-workers obtained high stereo- characterized by frequency calculations. Final ener-
selectivities using the hydroxynitrile lyase extracted gies were calculated using a larger basis set, 6-311+
from Hevea brasiliensis as biocatalyst for the Henry
reaction of selected aldehydes with nitromethane and fects obtained from the frequency calculations.
nitroethane.[11]
The effect of solvation was calculated as single
GACHTRE(UNG 2d,2p), and corrected for zero-point vibrational ef-
Despite the impressive advancement of asymmetric point energies using the CPCM polarizable continu-
organocatalysis in these last years,[12] the mechanisms um model[17] with THF (e=7.58) as solvent, and was
of most organocatalytic transformations have not added as a correction to the final energies.
been investigated in detail. While considerable efforts
have been applied to the understanding of amino
acid-catalyzed reactions, mechanistic studies on Cin- Results and Discussion
chona-derived organocatalysts are scarce.[13]
In this paper we report a theoretical study of the Model Catalyst
Cinchona thiourea-catalyzed Henry reaction, aimed
at the elucidation of the mode of action of this cata- In order to reduce the computational costs for the cal-
lyst and the origins of the enantioselection. We culations described below, we decided to employ a
employ the density functional theory (DFT) of slightly simplified catalyst. We envisaged that the ben-
B3LYP,[14] which has become the method of choice for zyloxy substituent on C-9 could be replaced by a me-
this kind of studies, as it yields accurate geometries thoxy group and that removal of the trifluoromethyl
and energies. Accordingly, it has been used in a groups on the thiourea part would have provided a
number of investigations of organocatalytic reac- catalyst leading to still considerable asymmetric in-
tions.[15]
duction. To corroborate this, we synthesized thiourea
The reaction we considered in the present study is 4 (Figure 1). Its use in the Henry reaction of benzal-
the addition of nitromethane to benzaldehyde (2), dehyde with nitromethane provided nitroalcohol 3 in
yielding nitroalcohol 3 (Scheme 2).
73% ee. Although this enantiomeric excess is slightly
lower compared to that obtained with thiourea 1
(89%), this result is sufficient to justify removal of
both a phenyl ring and two trifluoromethyl groups to
model the asymmetric Henry reaction.
Thiourea 1 and its pseudoenantiomeric quinine-de-
rived counterpart show nearly perfect enantiomeric
behaviour.[8] Therefore, we also removed from our
model the vinyl fragment of the quinuclidine, assum-
ing no specific role in the enantioselection process.
Scheme 2. Henry reaction of benzaldehyde with nitrome-
thane considered in the present paper.
Figure 1. Structures of the catalysts considered in this study.
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Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry Reaction
with the quinuclidine nitrogen pointing in the oppo-
site direction with respect to the thiourea moiety
(syn-open) as it would not have been productive
À
during the C C bond forming step assuming simulta-
neous coordination of both reactants.
Mechanism
Figure 2. The open and closed conformations of quinidine.
The generally accepted mechanism for the Henry re-
action involves deprotonation of nitromethane, and
À
Compound 5 (59 atoms) was therefore chosen as the the subsequent C C bond formation, which is fol-
main computational model for thiourea 1 in the study lowed by protonation of the product and the regener-
of the reaction mechanism and stereoselectivity. At a ation of the catalyst.
later stage, we introduced back the trifluoromethyl
À
substituents and recalculated a number of the C C
bond forming transition states, to investigate their Step 1: Deprotonation
role on the enantioselection. Compound 6 (65 atoms)
was accordingly used in those calculations.
The first step of the reaction is the deprotonation of
Cinchona alkaloids exist in solution as a mixture of nitromethane by the quinuclidine nitrogen, the most
rapidly interconverting conformers.[18] One issue that basic site in the catalyst. The enthalpic gain for bring-
has to be considered when modeling reactions cata- ing together nitromethane and the catalyst (complex
lyzed by this class of compounds is the determination I, Figure 3) is calculated to be 6.8 kcalmolÀ1 in the gas
of which conformation is adopted by the catalyst phase, which is reduced to only 1.1 kcalmolÀ1 when
(Figure 2).
solvation is considered, in the form of a dielectric
Due to its tricyclic structure, catalyst 7[19] cannot continuum with a dielectric constant of e=7.58, corre-
adopt closed conformations. Reaction of benzalde- sponding to THF. We note that the nitro group coor-
hyde catalyzed by 10 mol% thiourea 7 proceeded dinates to the thiourea moiety of the catalyst in a bi-
with moderate yet considerable asymmetric induction dentate fashion and the a-protons are suitably posi-
(65% ee). We judged this result in agreement with tioned in proximity of the quinuclidine nitrogen.
the catalyst being in an open conformation. Similar From there, the barrier for the proton transfer is cal-
arguments were used by Deng et al. to justify the pro- culated to be 14.7 kcalmolÀ1 in gas phase and
posal of an open arrangement in the transition state 10.8 kcalmolÀ1 in solvent. The optimized transition
of the cupreidine-catalyzed addition of substituted b- state (II) structure is shown in Figure 3. At the TS, an
dicarbonyl compounds to nitroalkenes.[20]
In the density functional calculations described ated. The critical C H bond distance is 1.64 Š and
below we did not consider the open conformation the N H bond distance is 1.16 Š. Due to the high
ion pair (nitromethide and protonated catalyst) is cre-
À
À
Figure 3. Optimized structures of the stationary points for the proton transfer from the nitromethane to the quinuclidine of
the catalyst. Nitromethane bidentately coordinated to the thiourea of the catalyst (I); the transition state for the proton
transfer (II); nitromethide coordinated to the quinuclidinium and the thiourea (III).
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À
Figure 4. Structures of the stationary points for the C C bond forming step of Pathway A. Both substrates coordinated to
the catalyst (IV), the transition state for C C bond formation (V), the intermediate coordinated to the protonated catalyst
(VI).
À
degree of charge separation at the TS, it is likely that
Pathway A: When benzaldehyde is bound to the
geometry optimization of the TS in solution will yield ion pair complex III in the fashion shown in Figure 4
somewhat different distances, but this is assumed not (IV, Pathway A) a small enthalpic gain is calculated
to affect the calculated energetics. The negative in the gas phase (1.1 kcalmolÀ1). However, when the
charge that is developing on the nitromethane causes solvation effects are included, this becomes an en-
the hydrogen bonds between the nitro group and thio- thalpic penalty of 3.6 kcalmolÀ1. As seen from
urea to be shorter, 1.96 and 2.10 Š, compared to 2.12 Figure 4, the nitro group of the nitromethide forms
and 2.24 Š.
hydrogen bonds to both the quinuclidinium proton
The reaction step is found to be slightly exothermic and one of the thiourea hydrogens, while the alde-
(1.7 kcalmolÀ1) when solvation is considered, but en- hyde oxygen forms a hydrogen bond to the other ni-
dothermic by 2.4 kcalmolÀ1 in the gas phase, due to trogen.
the poor stabilization of the resulting ion pair in the
gas phase. These results demonstrate that the first sition states (6 in total) for the formation of the C C
step is energetically feasible.
For Pathway A we have calculated all possible tran-
À
bond: these are discussed in detail in the stereochem-
It is instructive here to consider the relative pKa istry subsection below. The TS with the lowest energy
values of the species involved in the reaction step. Ex- leads to the S-product and is depicted in Figure 4 (V).
perimentally, nitromethane has a pKa value of 17.2, Compared to complex IV, it has a calculated barrier
while the pKa of quinuclidinium is 9.8.[21] The differ- of 11.2 kcalmolÀ1 in the gas phase, and 8.9 kcalmolÀ1
ence is thus 7.4 units, which corresponds to a reaction in solution, which, added to the 3.6 kcalmolÀ1 en-
energy of ca +10 kcalmolÀ1. The complexation of the thalpic penalty of binding, results in a total barrier of
ion pair (nitromethide and the protonated catalyst) is 12.5 kcalmolÀ1 including solvation. Kinetic analysis of
thus quite strong, leading to a slightly exothermic re- the reaction of p-trifluoromethylbenzaldehyde with
action step.
nitromethane catalyzed by 1 showed first-order in
both substrates and catalyst (see Supporting Informa-
À
tion), in agreement with C C bond formation being
À
Step 2: C CBond Formation
the rate-limiting step.
À
At the transition state, the critical C C bond dis-
As demonstrated by Papai and co-workers for conju- tance is 1.93 Š, and the interaction between the nitro-
gate additions, in tertiary amine/thiourea organocatal- methide and the thiourea is lost in favour of a double
ysis two distinct modes of binding of the electrophile hydrogen bond between the thiourea and the alde-
and nucleophile to the catalyst leading to two distinct hyde carbonyl, to better stabilize the developing
[22]
À
routes to C C bond formation can be envisioned.
In the first, called Pathway A, the nucleophilic ni-
anion.
The resulting intermediate (VI) is only
tromethide anion is coordinated to the positively- 0.3 kcalmolÀ1 lower than the TS in the gas phase and
charged trialkylammonium, while the aldehyde elec- 1.5 kcalmolÀ1 when solvation is considered. This coor-
trophile is coordinated to the thiourea moiety dination does not allow any proton transfer but, due
(Figure 4). In the second binding mode, called Path- to the high basicity of the alkoxide compared to the
way B, the opposite coordination pattern is found other species present, protonation is assumed to be a
(Figure 5).
fast event once the product is released from the cata-
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À
Figure 5. Structures of the stationary points for the C C bond forming step of Pathway B. Both substrates coordinated to
the catalyst (VII), the transition state for C C bond formation (VIII), the protonated product coordinated to the regenerat-
ed catalyst (IX).
À
lyst. The protonated product (which is the same for to be almost thermoneutral (À0.7 kcalmolÀ1 in the
Pathways A and B, see Figure 5) is 13.8 kcalmolÀ1 gas phase and +1.2 kcalmolÀ1 when solvent is consid-
lower than the unprotonated intermediate VI in sol- ered), in good agreement with the well-known rever-
vent, and 19.5 kcalmolÀ1 in the gas phase.
sibility of the Henry reaction. This means that the
Pathway B: Considering the corresponding station- protonated product IX is bound to the catalyst by
ary points leading to the S-product for Pathway B, it 6.7 kcalmolÀ1 in solvent (13.5 kcalmolÀ1 in the gas
can be noted that the binding of benzaldehyde to the phase).
ion pair complex III in the fashion shown in Figure 5
Scheme 3 summarizes the two mechanistic path-
(VII, Pathway B) results in a larger enthalpic penalty, ways, and Figure 6 summarizes the energies obtained
calculated to 9.6 kcalmolÀ1 in the gas phase and from the calculations.
10.5 kcalmolÀ1 when solvent is considered. Clearly,
this binding mode is unfavoured compared to com-
plex IV, which has a strong interaction between the Stereoselectivity of C CBond Formation
À
positive and negative charges.
À
On the other hand, the barrier for the C C bond Experimentally, it was previously found that the enan-
formation starting from this structure is quite low, cal- tiomeric excess of Henry product 3 is strongly depen-
culated to 1.6 kcalmolÀ1 in the gas phase and dent on the reaction medium.[8] This is not an uncom-
3.6 kcalmolÀ1 in solution for the S-product (stereo- mon phenomenon in organocatalysis. However, in
chemistry discussed below). The total barrier (11.2 most cases such an effect can be readily rationalized
and 14.1 kcalmolÀ1 in the gas phase and solution, re- in terms of solvent polarity. For the asymmetric
spectively) is thus only 1.6 kcalmolÀ1 higher than for Henry reaction, such a correlation was not possible.
Pathway A, indicating that both pathways are quite For instance, THF and dichloromethane are both
viable.
aprotic solvents having similar dielectric constants yet
À
At the transition state (VIII), the critical C C bond their use in the Henry reaction at room temperature
distance is 2.35 Š, considerably longer than for Path- led to the formation of 5 in 62% and 6% ee, respec-
way A. As a result of the charge development on the tively. On the other hand, enantiomeric excesses
aldehyde oxygen atom, the hydrogen bond to the qui- roughly correlate with the Lewis basicity of the sol-
nuclidinium is shorter, 1.57 Š compared to 1.71 Š in vent, according to the experimental scale compiled by
reactant VII. The hydrogen bonds of the nitro group Maria and Gal, using boron trifluoride as the refer-
to the thiourea moiety, on the other hand, are slightly ence Lewis acid (Figure 7).[23] The Lewis basicity for
longer (1.94 and 2.02 Š compared to 1.89 and toluene (5% ee) is not available but it is reasonable
1.90 Š).
to assume a very low basicity since its donor number
For this reaction step, no intermediate could be lo- (DN, the Lewis basicity determined using SbCl5 as the
cated in gas phase. Instead the proton was found to reference Lewis acid) is small: DN for toluene is
transfer to the alkoxide at the same transition state, 0.1 kcalmolÀ1 compared to 2.7 kcalmolÀ1 for nitrome-
resulting in the protonated product IX.
thane and 20.0 kcalmolÀ1 for THF.[24] Methanol is also
The overall reaction between nitromethane and not included in this scale because it is a protic solvent.
benzaldehyde yielding nitroalcohol 3, was calculated As seen from Figure 7, it is clear that solvents of
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Scheme 3. Proposed mechanisms for the Cinchona thiourea-catalyzed Henry reaction.
higher Lewis basicity than nitromethane lead to con- solvent properties can thus induce large changes in
siderable asymmetric induction. The exact reason for the ee.
this still remains to be uncovered.
In the present study, we have located the transition
Overall, the high solvent sensitivity of the enantio- states leading to both enantiomers for the two path-
selectivity indicates the energies of the transition ways. In the case of Pathway A, we can envision three
states leading to the S and R stereomers of the prod- TS rotamers for each enantiomer (Figure 8, TSS1–
uct are very close. Seemingly small differences in the TSR3), corresponding to the different Newman projec-
À
tions for C C bond formation. For Pathway B, the
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À
geometry around the forming C C bond compared to
TSS1: the C C bond distance is 1.93 Š and q3 is 608.
À
Also the hydrogen bond distances to the catalyst are
very similar, within 0.05 Š. The difference lies rather
in the orientation of the phenyl ring of benzaldehyde.
For TSS1, it points in the direction of the phenyl of
the thiourea, whereas in TSR1 the aldehyde substitu-
ent points in direction of the methyl ether of the cata-
lyst. None of these interactions represent severe ster-
ics, but these observations might be enough to explain
the small energy difference between the two transi-
tion states, in agreement with the observed selectivity.
The two torsional angles q1 and q2 as defined in
Figure 8 can function as good indicators of the strain
imposed on the catalyst at the transition states. In the
free catalyst in the open conformation, these angles
are calculated to be 1528 and 1008, respectively, in
agreement to those found by Burgi and Baiker for
Figure 6. Calculated reaction energy profile (including solva-
tion) for the two pathways.
conformational restriction imposed by the bidentate cinchonidine (1548 and 1018).[18c]
hydrogen bonds between the thiourea and the nitro
We note that the conformational change of the cat-
group of the nitromethide allows only for one TS for alyst is quite small in all the calculated transition
each enantiomer (Figure 8, TSS4 and TSR4), both states: q1 is 58–158 larger than in the free catalyst indi-
having the phenyl group of benzaldehyde and the cating that the catalyst has to open up a little more to
nitro group of nitromethide anion in a trans-arrange- afford beneficial hydrogen bonding to the quinuclidi-
ment.
nium. The deviation for q2 is smaller, À18–78.
We first note that the TS with the lowest energy
The transition states TSS2 and TSR2 have higher en-
(TSS1) corresponds to the S-product, in agreement ergies compared to TSS1 (+3.7 and +3.9 kcalmolÀ1,
with the experimental findings. The calculated energy respectively). One reason for this is that they have to
difference to the lowest TS corresponding to the R- adopt a less staggered conformation about the form-
product is quite small, only 1.1 kcalmolÀ1 (TSR1), also ing C C bond. q3 is 428 and 508 for the two transition
À
À
in good agreement with the experiments and with the states, respectively. The critical C C bond distance is
general conclusions from the solvent studies, namely longer than for TSS1 (2.03 Š vs. 1.93 Š) and the hy-
that the energies of the transition states leading to the drogen bond distances to the thiourea are slightly
different products must be close.
longer, indicating a lower transition state stabiliza-
At the preferred transition state (TSS1) the forming tion.
À
C C bond has a distance of 1.93 Š, and the confor-
The energies of the anti conformation (TSS3 and
mation of the substrates is staggered, the dihedral TSR3) are significantly higher than for the other tran-
angle of the substituents on the two carbons (q3, see sition states (+6.8 and +7.3 kcalmolÀ1, respectively,
Figure 8) is 598. Transition state TSR1 has very similar compared to TSS1). This is mainly due to the arrange-
Figure 7. Enantiomeric excess of nitroalcohol 3 vs. dielectric constant and Lewis basicity of the solvent.
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Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry Reaction
Table 1. Summary of calculated relative transition state en-
ergies (kcalmol ) for the C C bond forming step. Values
include solvation effects (gas phase values in parentheses).
ment of the substrates being far from the optimal
staggered conformation. Moreover, the enforced ge-
ometry of the hydrogen bonding between the nega-
tively charged nitro group and the quinuclidinium is
poor.
À1
À
Catalyst 5
Catalyst 6
Pathway A
For the transition states of Pathway B (TSS4 and
TSR4), the nitro group forms two hydrogen bonds to
the thiourea moiety, while the developing negative
charge at the aldehyde is interacting with the positive
charge of the quinuclidinium. This arrangement re-
sults in an almost eclipsed conformation about the
S1
S2
S3
R1
R2
R3
0.0 (0.0)
3.7 (1.4)
6.8 (7.9)
1.1 (1.3)
3.9 (1.0)
7.3 (8.5)
0.0 (0.0)
1.8 (1.6)
-
0.0 (0.6)
5.3 (0.8)
-
À
forming C C bond, which yields higher transition
Pathway B
state energies (+1.6 and +3.1 kcalmolÀ1, respectively,
compared to TSS1).
S4
R4
1.6 (1.1)
3.1 (1.2)
3.3 (0.8)
4.6 (1.1)
For the six lowest-lying transition states (TSS1,
TSR1, TSS2, TSR2, TSS4, and TSR4), we have reopti-
mized the structures using catalyst 6, which has addi-
tional trifluoromethyl substituents at the thiourea ate. The geometries of these two transition states are
part. The energetic results are reported in Table 1.
As expected, the overall geometries of the transi-
shown in Figure 9.
These results are still consistent with the experi-
tion states are very similar to the ones without the tri- mental findings in that the energies of the transition
fluoromethyl substituents. However, a non-negligible states leading to the opposite enantiomers must be
effect on the calculated energies can be detected. close, such that different solvents can significantly
Most significantly, adding these two CF3 groups to the alter the difference.
catalyst increases somewhat the steric interactions be-
It should be mentioned here that adding a benzyl-
tween the two phenyls in TSfS1, whereas TSfR1 is unaf- oxy substituent on C-9 to catalyst 6 (originally present
fected. As a result of this, the energy difference be- in 1) did not affect the calculated energetics signifi-
tween these two lowest-lying transition states drops cantly. The difference between TSS1 and TSR1 be-
from 1.1 to 0.0 kcalmolÀ1, i.e., they become degener- comes now 0.2 kcalmolÀ1 (compared to 0.0 kcalmolÀ1
for catalyst 6), verifying the initial assumption that
the C-9 ether does not play any major role in the ster-
eoselection.
Figure 8. Optimized transition states for Pathway A (TS –
b
S1
TSR3) and Pathway B (TSS4 and TSR4). Distances in Šng-
À
strçm for the forming C C bond and the three hydrogen
bonds between the catalyst and the substrates. Insets show
Conclusions
À
the corresponding Newman projection along the forming C
In the present paper, we have used DFT calculations
to study the reaction mechanism and the enantiose-
C bond. Framed insets define the dihedral angles specified.
Relative energies (kcalmolÀ1) including solvation correction
are given in the labels (gas phase values in parentheses).
Figure 9. The energetically most accessible transition states using catalyst 6.
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was added dropwise. Stirring was continued overnight, the
reaction was quenched with brine (10 mL) and the mixture
was extracted with EtOAc (2”20 mL). The combined or-
ganic layers were washed with brine (3”5 mL), dried on
MgSO4 and concentrated under vacuum. Purification by
column chromatography (EtOAc/MeOH, 9:1) afforded the
title compound (yield: 1.75 g, 84%) as a pale yellow oil with
spectral data matching those reported in the literature.[25]
1H NMR (CDCl3): d=8.74 (d, J=4.5 Hz, 1H), 8.02 (d, J=
9.2 Hz, 1H), 7.42 (d, J=4.5 Hz, 1H), 7.37 (dd, J=9.2,
2.6 Hz, 1H), 7.27 (m, 1H), 6.09 (m, 1H), 5.10–5.05 (m, 3H),
3.92 (s, 3H), 3.32 (s, 3H), 3.30 (m, 1H), 3.00–2.77 (m, 4H),
2.24 (m, 1H), 2.03 (m, 1H), 1.72 (bs, 1H), 1.47 (m, 2H),
1.21 (m, 1H).
lectivity of the reaction of benzaldehyde (2) with ni-
tromethane catalyzed by Cinchona thiourea 5.
Our results support the proposed reaction mecha-
nism in which nitromethane deprotonation and alde-
À
hyde complexation are followed by a C C bond for-
mation step and subsequent protonation of the result-
À
ing alkoxide. Two possible routes to C C bond forma-
tion (Pathway A and B in Scheme 3) involving oppo-
site coordination patterns of the hydrogen bond
donors (quinuclidinium and thiourea) and acceptors
(nitromethide anion and aldehyde) were found. Path-
way A is slightly preferred over Pathway B.
Table 1 summarizes the calculated energies for the
À
different transition states of the C C bond formation
Methyl Cupreidine (MeCPD)
step. In both pathways we see a slight preference for
the S enantiomer, in agreement with the experimental
findings. The calculated magnitude of the energy dif-
ference between the lowest-lying transition states
leading to the opposite enantiomers is very small (or
non-existing), which is consistent with the previously
discussed solvent effect. Slight differences in the inter-
action of the solvent with the pro-R and pro-S transi-
tion states can thus affect this small energy difference
resulting in changes in the enantioselectivity. It is
worth pointing out that the CPCM model we em-
ployed in this computational study can only account
for dielectric effects of the solvent in an averaged
way. Therefore, the experimentally determined sol-
vent dependence of the enantioselectivity cannot be
satisfactorily explained with such an implicit model.
To a solution of MeQD (1.74 g, 5.2 mmol) in DMF (30 mL),
sodium ethanethiolate (1.73 g, 20.6 mmol) was added. The
mixture was warmed to 1108C and stirring was continued
for 20 h. After cooling, the reaction was quenched with satd.
NH4Cl (35 mL) and water (30 mL). The resulting mixture
was extracted with EtOAc (2”150 mL) and the combined
organic layers were washed with brine (3”30 mL), dried on
MgSO4 and concentrated under vacuum. Purification by
flash chromatography (EtOAc/MeOH, 9:1+1% Et3N) af-
forded the title compound as a yellow foam; yield: 1.08 g
Experimental Section
General Remarks
1
NMR spectra (1H and 13C) were measured using a Bruker
ARX 400 MHz spectrometer. High-resolution mass spectra
were recorded on a JEOL JMS-SX/SX 102A tandem mass
spectrometer. Infrared spectra were performed on a Bruker
IFS 28 FT spectrometer. Thiourea 7 was prepared according
to Deng et al.[19]
(64%). H NMR (CDCl3): d=8.70 (d, J=4.5 Hz, 1H0, 8.03
(d, J=9.1 Hz, 1H), 7.94 (bs, 1H), 7.82 (d, J=2.5 Hz, 1H),
7.39 (d, J=4.5 Hz, 1H), 7.37 (dd, J=9.1, 2.5 Hz, 1H), 6.12
(m, 1H), 5.30 (bs, 1H), 5.16–5.11 (m, 2H), 3.60 (m, 1H),
3.21 (s, 3H), 3.12–2.87 (m, 4H), 2.35 (m, 1H), 2.25 (m, 1H),
1.80 (bs, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.12 (m, 1H);
13C NMR (CDCl3): d=156.73, 146.49, 143.54, 143.04, 139.83,
131.27, 127.73, 123.16, 117.88, 115.02, 106.43, 81.04, 58.76,
56.84, 49.54, 49.11, 39.58, 28.02, 25.68, 19.82; IR (NaCl):
nmax =3072, 2938, 2876, 1618, 1509, 1468, 1242, 1120, 1067,
Methyl Quinidine (MeQD)
To a solution of quinidine (2 g, 6.2 mmol) in DMF (20 mL),
sodium hydride (60% suspension in mineral oil, 618 mg,
15.5 mmol) was added portionwise. The resulting mixture
was stirred for 1 h then methyl iodide (423 mL, 6.8 mmol)
912, 831 cmÀ1
;
HR-MS (FAB):m/z=325.1921 (M+H+),
calcd. for [C20H25N2O2]+: 325.1911.
Aryl Triflate (8)
To a solution of MeCPD (1.10 g, 3.42 mmol) in CH2Cl2
(25 mL), N-phenyl-bis(trifluoromethanesulfonimide) (1.22 g,
3.42 mmol)
and
4-dimethylaminopyridine
(50 mg,
0.41 mmol) were added and the resulting mixture was stirred
overnight. The solvent was then evaporated and the residue
was diluted with EtOAc (100 mL), extracted with saturated
Na2CO3 (3”50 mL), dried on MgSO4 and concentrated
under vacuum. Purification by flash chromatography (0–5%
MeOH in EtOAc) afforded the title compound as a pale
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Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry Reaction
1H), 7.30 (d, J=4.5 Hz, 1H), 7.06 (m, 2H), 6.11–6.02 (m,
1H), 5.05–4.96 (m, 3H), 4.19 (bs, 2H), 3.28 (m, 1H), 3.25 (s,
3H), 2.92–2.86 (m, 3H), 2.72 (m, 1H), 2.19 (m, 1H), 2.06
(m, 1H), 1.68 (bs, 1H), 1.46–1.39 (m, 2H), 1.08 (m, 1H);
13C NMR (CDCl3): d=146.01, 144.91, 143.23, 142.92, 140.78,
131.27, 127.68, 120.83, 118.27, 114.20, 102.60, 83.01, 59.15,
56.94, 49.87, 49.40, 40.13, 28.14, 26.36, 20.75; IR (NaCl):
nmax =3335, 3208, 2937, 2874, 1622, 1513, 1119, 1067, 910,
828 cmÀ1; HR-MS (FAB): m/z=324.2086 (M+H+), calcd.
for [C20H26N3O]+: 324.2070.
1
yellow oil; yield: 1.01 g (65%). H NMR (CDCl3): d=8.96
(d, J=4.5 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H), 8.18 (d, J=
2.6 Hz, 1H), 7.60 (dd, J=9.3, 2.6 Hz, 1H), 7.52 (d, J=
4.5 Hz, 1H), 6.05 (m, 1H), 5.12–5.07 (m, 2H), 4.91 (d, J=
5.7 Hz, 1H), 3.31 (s, 3H), 3.12–3.06 (m, 2H), 2.95 (m, 1H),
2.75 (m, 2H), 2.27 (m, 1H), 1.97 (m, 1H), 1.78 (bs, 1H),
1.53 (m, 2H), 1.39 (m, 1H); 13C NMR (CDCl3): d=151.07,
147.29, 146.85, 146.64, 140.15, 132.96, 126.53, 122.52, 120.41,
118.73 (q, J=321 Hz), 115.96, 114.54, 83.71, 60.43, 57.30,
Thiourea (5)
To a solution of amine 9 (64 mg, 0.2 mmol) in THF (5 mL)
was added phenyl isothiocyanate (24 mL, 0.2 mmol) and the
49.66, 48.99, 39.61, 27.78, 26.11, 22.77; IR (NaCl): nmax
=
2937, 1508, 1423, 1213, 1140, 928, 846, 829 cmÀ1; HR-MS
(FAB):
m/z=325.1921
(M+H+),
calcd.
for
[C21H24F3N2O4S]+: 457.1403.
Aminoquinoline (9)
To a warm (668C) solution of triflate 8 (0.96 g, 2.09 mmol)
in THF (20 mL) were added Pd(OAc)2 (27 mg, 0.12 mmol),
AHCTREUNG
(Æ)-BINAP (118 mg, 0.19 mmol), Cs2CO3 (955 mg,
mixture was stirred for 24 h at room temperature. The THF
was removed under reduced pressure and the crude product
was purified by flash chromatography (EtOAc/MeOH,
95:5+0.5% Et3N), affording a pale yellow foam; yield:
40 mg (45%). 1H NMR (CDCl3): d=8.85 (d, J=4.5 Hz,
1H), 8.22 (d, J=1.6 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.91
(dd, J=9.1, 2.1 Hz, 1H), 7.45 (d, J=4.5 Hz, 1H), 7.39 (m,
3H), 7.26 (m, 1H), 6.10–6.01 (m, 1H), 5.09 (m, 3H), 3.23 (s,
3H + m, 1H), 3.07 (m, 1H), 2.91–2.85 (m, 2H), 2.65 (m,
1H), 2.22 (m, 1H), 2.05 (m, 1H), 1.73 (bs, 1H), 1.45 (m,
2H), 1.26 (m, 1H); 13C NMR (CDCl3): d=79.88, 149.69,
146.42, 145.59, 140.43, 136.91, 136.11, 130.82, 129.54, 126.91,
126.69, 126.39, 125.14, 118.92, 117.55, 114.47, 82.82, 59.74,
57.12, 50.32, 49.73, 49.30, 39.88, 27.96, 26.09, 21.31; IR
(CHCl3): nmax =3332, 2921, 2360, 1593, 1121 cmÀ1; [a]D22:
+151.4 (c 1.00, CHCl3); HR-MS (FAB): m/z=459.2217,
(M+H+), calcd. for [C27H31N4OS]+: 459.2213.
2.93 mmol) and benzophenone imine (421 mL, 2.51 mmol).
The mixture was stirred for 24 h then was allowed to cool to
room temperature, filtered over a short pad of Celite and
eluted with CH2Cl2. The filtrate was concentrated under
vacuum and the residue was redissolved in THF (10 mL)
and 10% acqueous citric acid (20 mL). The mixture was
stirred at room temperature for 24 h then EtOAc (100 mL)
and satd. Na2CO3 (100 mL) were added. The layers were
separated and the water layer was washed with EtOAc
(50 mL). The combined organic layers were extracted with
1N HCl (2”75 mL). The combined acidic water layers were
washed with CH2Cl2 (3”50 mL). Ethyl acetate (100 mL)
was added and the mixture was made alkaline by the addi-
tion of saturated Na2CO3 (~150 mL) and extracted. The
water layer was then further extracted with EtOAc (3”
100 mL). The combined organic layers were washed with
brine (2”50 mL), dried on MgSO4 and concentrated under
vacuum. Purification by flash chromatography (EtOAc/
MeOH, 9:1+1% ammonium hydroxide) afforded the title
Supporting Information
Complete citation for ref.[16] Kinetic profiles for catalyst 1.
Cartesian coordinates of the reported transition state struc-
tures.
Acknowledgements
1
compound as a white foam; yield: 230 mg (34%). H NMR
(CDCl3): d=8.58 (d, J=4.5 Hz, 1H), 7.88 (d, J=9.6 Hz,
Jan Geenevasen is gratefully acknowledged for his precious
help with the kinetic measurements. Dr. Enrico Burello is ac-
Adv. Synth. Catal. 2007, 349, 2537 – 2548
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DEDICATED CLUSTER
FULL PAPERS
Peter Hammar et al.
knowledged for stimulating discussions about the solvent ef-
fects. T.M. gratefully acknowledges the National Research
School Combination Catalysis (NRSC-C) for financial sup-
port. F.H. gratefully acknowledges financial support from:
The Swedish National Research Council, The Wenner-Gren
Foundations, The Carl Trygger Foundation, and The Magn
Bergvall Foundation.
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ric Organocatalysis, Wiley-VCH, Weinheim, 2005;
f) Enantioselective Organocatalysis, (Ed.: P. I. Dalko),
Wiley-VCH, Weinheim, 2007.
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Adv. Synth. Catal. 2007, 349, 2537 – 2548