Enantioselective Michael addition of aldehydes to maleimides organocatalysed by chiral 1,2-diamines: An experimental and theoretical study

Article abstract of DOI:10.1016/j.tetasy.2013.10.001

Simple and commercially available chiral 1,2-diamines were used as organocatalysts for the enantioselective conjugate addition of aldehydes, including α,α-disubstituted, to maleimides. The reaction was carried out in the presence of hexanedioic acid as an

Full text of DOI:10.1016/j.tetasy.2013.10.001

Tetrahedron: Asymmetry 24 (2013) 1531–1535
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Michael addition of aldehydes to maleimides
organocatalysed by chiral 1,2-diamines: an experimental and
theoretical study
b
a,
Angel Avila a, Rafael Chinchilla a, , Enrique Gómez-Bengoa , Carmen Nájera
⇑
⇑
a Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
b Departamento de Química Orgánica I, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastíán, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and commercially available chiral 1,2-diamines were used as organocatalysts for the enantiose-
Received 23 September 2013
Accepted 4 October 2013
Available online 4 November 2013
lective conjugate addition of aldehydes, including
a,a-disubstituted, to maleimides. The reaction was
carried out in the presence of hexanedioic acid as an additive in aqueous solvents at room temperature.
By employing (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine as organocatalysts, the corresponding
Michael adducts bearing new stereocenters were obtained in high or quantitative yields with enantiose-
lectivities of up to 92%, whereas the use of (1S,2S)-1,2-diphenylethane-1,2-diamine gave a much lower
ee. Theoretical calculations were used to justify the observed sense of the stereoinduction.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
a,a-disubstituted aldehydes as pro-nucleophiles resulted in much
lower enantioselectivities.
Maleimides have been successfully used in different asymmet-
ric organocatalytic transformations.1 Among the compounds that
can be prepared by the organocatalytic functionalization of malei-
mides, succinimides are one of the most important, since the suc-
cinimide moiety is present in natural products and some clinical
drug candidates.2 Moreover, succinimides can be transformed into
CF3
CF3
Ph
S
S
Ph
N
H
N
H
CF3
N
H
N
H
CF3
NH2
NH2
other interesting compounds such as c
-lactams,3 which are impor-
2
1
tant in the treatment of epilepsy,4 HIV,5 neurodegenerative disease
and depression.6
The most direct and simple way of preparing enantioenriched
succinimides is by the organocatalytic enantioselective Michael
addition of carbon nucleophiles to maleimides.1 These carbon
Me
CF3
S
Ph
Me
S
N
H
N
H
NH2
N
N
H
CF3
nucleophiles are usually generated by
a-deprotonation of
H
NH2
pro-nucleophiles by means of chiral bifunctional organocatalysts
bearing both an acidic moiety and a tertiary amine.1 The subse-
quent formation of a transition state involving the co-ordination
of the maleimide and the enolate generated after deprotonation
by the tertiary amine, leads to an enantioselective process.
However, when the aldehydes are used as pro-nucleophiles, the
corresponding succinimides can be obtained using primary
amine-bearing organocatalysts amenable to create transition
states after formation of a transient enamine with the reacting
aldehyde. Thus, the first enantioselective conjugate addition of
EtO2C Me
3
4
NiPr
N
H
NHiPr
NH2
5
Since then, several bifunctional primary amine organocatalysts
have been developed and applied to the enantioselective Michael
aliphatic aldehydes to N-aryl-maleimides used a,a-phenylprolinol
addition of
a,a-disubstituted aldehydes to maleimides giving
silyl ether as an organocatalyst.7 However, the use of
excellent results,8 such as the trifluoromethylated primary amine
thioureas 1,8a,b 28a,b and 3,8e the beyerane-containing thiourea
4,8f a primary amine guanidine 5,9 and a cinchonidine-derived pri-
mary amine.10
⇑
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: chinchilla@ua.es (R. Chinchilla), cnajera@ua.es (C. Nájera).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.001

1532
A. Avila et al. / Tetrahedron: Asymmetry 24 (2013) 1531–1535
As observed, chiral 1,2-diamines, mainly cyclohexane-1,2-
a,a-disubstituted aldehydes. In addition, DFT calculations were
diamines, are used as a source of chirality for the preparation of
several of these organocatalysts. Therefore, it would be interesting
to see if these untransformed simple starting diamines could
themselves act as chiral organocatalysts. The literature shows a
few recent examples confirming this assertion. Thus, chiral cyclo-
hexane-1,2-diamines, such as 6a and its enantiomer ent-6a, have
been used as very effective organocatalysts in an enantioselective
vinylogous Michael addition reaction of cyclopentanone11 or
used to explain the observed enantioselectivity.
2. Results and discussion
We chose the most commonly employed (1S,2S)-cyclohexane-
1,2-diamine 6a as the initial organocatalyst in the model Michael
conjugate addition of isobutyraldehyde to N-phenylmaleimide
under different reaction conditions (Table 1).
c
-butenolides12 to chalcones, as well as in aldol reactions of ke-
tones to aromatic aldehydes13 or cyclohexanone to isatins.14 In
addition, other chiral 1,2-diamines such as (1R,2R)-1,2-diphenyl-
1,2-ethanediamine ent-6b, have been used as organocatalysts in
the enantioselective Michael addition reactions of aryl methyl
ketones with 2-furanones,15 or in the enantioselective synthesis
of 3,4-dihydropyran derivatives via organocatalytic Michael
NH2
NH2
Ph
NH2
NH2
NH2
NH2
Ph
6a
ent-
6a
6b
Thus, the use of a 20 mol % loading of 6a in toluene as the sol-
vent gave rise to an almost quantitative yield of succinimide (R)-
9aa with 48% ee (Table 1, entry 1). The absolute configuration
was determined according to the order of elution of the corre-
sponding enantiomers in chiral HPLC (see Section 4).8b Changing
the solvent to dichloromethane gave a good yield for 9aa but in a
racemic form, whereas the use of other solvents such as acetone,
tert-butyl methyl ether (TBME), nitromethane or DMF gave lower
yields and low enantioselectivities for (R)-9aa (Table 1, entries
3–6). However, when neat water was used as solvent, a good yield
of (R)-9aa with 60% ee was observed (Table 1, entry 7). When a
mixture of DMF/water (1:1) was employed (R)-9aa was isolated
quantitatively in 71% ee. In addition, changing the DMF/water ratio
reactions of
a
,b-unsaturated enones.16 However, relatively low to
moderate enantioselectivity was observed when chiral (1R,2R)-
cyclohexane-1,2-diamine ent-6a or (1R,2R)-1,2-diphenyl-1,2-eth-
anediamine ent-6b were employed as organocatalysts for the
enantioselective Michael addition of isobutyraldehyde to N-phen-
ylmaleimide, respectively, with the reaction being performed in
the presence of benzoic acid as the additive and in dichlorometh-
ane as the solvent.8a
Herein we report how the use of appropriate reaction condi-
tions allows the use of simple and commercially available chiral
1,2-diamines as organocatalysts for the direct enantioselective
reaction of aldehydes to maleimides, particularly using the difficult
Table 1
Screening and optimization of the reaction conditions for the enantioselective Michael addition
O
O
cat.
additive
O
O
N
Ph
+
N
Ph
H
solvent, T
H
*
O
O
7a
9aa
8a
Entry
Catalyst (mol %)
Additivea (mol %)
Solvent
T (°C)
t (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (10)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6b (20)
ent-6a (20)
—
—
—
—
—
—
—
—
PhMe
CH2Cl2
Acetone
TBME
MeNO2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
2
2
2
2
2
2
2
2
2
2
4
1
1
1
1
1
5
1
97
90
60
40
35
80
90
99
99
99
99
99
99
99
99
99
50
99
48 (R)
0
34 (R)
35 (R)
6 (R)
DMF
H2O
28 (R)
60 (R)
71 (R)
85 (R)
80 (R)
85 (R)
85 (R)
75 (R)
77 (R)
91 (R)
85 (R)
50 (S)
92 (S)
DMF/H2Od
DMF/H2Oe
DMF/H2Of
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
9
—
—
—
10
11
12
13
14
15
16
17
18
Imidazole (20)
PhCO2H (20)
MeCO2H (20)
HDA (20)
HDA (20)
HDA (20)
HDA (20)
25
25
a
b
c
d
e
f
HDA: hexanedioic acid.
Isolated yield after flash chromatography.
Enantioselectivities and absolute stereochemistry determined by chiral HPLC.8b
1/1, v/v.
2/1, v/v.
4/1, v/v.

A. Avila et al. / Tetrahedron: Asymmetry 24 (2013) 1531–1535
1533
allowed us to increase the enantioselectivity of the process. Thus,
the use of a 2:1 DMF/water ratio increased the enantioselectivity
for (R)-9aa up to 85%, although the use of a 4:1 ratio lowered it
down to 80% (Table 1, entries 9 and 10). Finally, we diminished
the organocatalyst loading down to 10 mol %, obtaining (R)-9aa
quantitatively with 85% ee, although the reaction time doubled
(Table 1, entry 11).
Next, we considered the influence of the addition of additives to
the model reaction. Thus, the addition of imidazole (20 mol %), in-
creased the enantioselectivity of this reaction when using primary
amine–guanidine as an organocatalyst,9b increased the reaction
rate considerably but kept the enantioselectivity for (R)-9aa at
85% (Table 1, entry 12). The addition of some acid additives, such
as benzoic or acetic acids, which has proven to be effective in
increasing the enantioselectivity of this process,8a also increased
the reaction rate, probably facilitating the formation of the initial
enamine, but gave lower enantioselectivity (Table 1, entries 13
and 14). However, the addition of hexanedioic acid (HDA,
20 mol %), an additive, that has been very effective in chiral cyclo-
hexane-1,2-diamine-catalysed transformations,11–14 also acceler-
ated the reaction, giving rise quantitatively to (R)-9aa in 91% ee
(Table 1, entry 15). Lowering the reaction temperature to 0 °C did
not improve the enantioselectivity of the process (Table 1, entry
16).
We also explored the use of (1S,2S)-1,2-diphenylethane-1,2-
diamine 6b as an organocatalyst for the model addition reaction
under more effective reaction conditions [DMF/water 2:1, HDA
(20 mol %), rt], but the reaction was very slow, yielding only a
50% yield of the corresponding Michael adduct in 50% ee after 5d
(Table 1, entry 17). However, it is noteworthy that in this case
the reaction was biased towards the opposite (S)-9aa, although
the configuration of 1,2-diamines 6a and 6b is ‘similar’. This con-
trary enantioselection has recently been observed in a Michael
addition of aryl methyl ketones with 2-furanones organocatalysed
by ent-6a and ent-6b.15 In addition, expecting to achieve an oppo-
site enantioselection for 9aa using the enantiomer of 6a, that is,
ent-6a, as an organocatalyst, we performed the reaction under
the best reaction conditions, obtaining the expected adduct (S)-
9aa with 92% ee (Table 1, entry 18).
Once the most effective organocatalyst and reaction conditions
were established [6a (20 mol %), DMF/water 2:1, HDA (20 mol %),
rt] we extended the application of this organocatalytic methodol-
ogy to other aldehydes and maleimides (Table 2). As in the case
of the model reaction, the absolute configuration of the known suc-
cinimides was assigned according to the elution order of their
enantiomers in chiral HPLC when compared to the literature (see
Section 4).
Thus, when isobutyraldehyde was reacted with N-phenylmalei-
mides bearing halogens on the phenyl ring, such as a chloro atom
at the 3- and 4-position 8b and 8c or a bromo atom at the 4-posi-
tion 8d, the enantioselectivities for the obtained succinimides
(R)-9ab, (R)-9ac and (R)-9ad were 72%, 59% and 80%, respectively
(Table 2, entries 2–4). In addition, when methoxy or acetoxy
groups were present on the phenyl ring of the maleimide, as in
the case of 8e and 8f, the enantioselectivities for the corresponding
succinimides (R)-9ae and (R)-9af were 74% and 75%, respectively
(Table 2, entries 5 and 6).
Non-N-arylated maleimides were also used for the conjugate
addition with isobutyraldehyde. Thus, N-benzylmaleimide 8g
quantitatively afforded the corresponding succinimide (R)-9ag
with 75% ee, whereas N-methylmaleimide 8h gave adduct
(R)-9ah also quantitatively in 70% ee (Table 2, entries 7 and 8).
The simple maleimide 8i was also explored, yielding quantitatively
the succinimide (R)-9ai with an enantioselectivity of 68% (Table 2,
entry 9).
Other
a,a-disubstituted aldehydes were employed for the
organocatalysed Michael addition reaction to N-phenylmaleimide.
Thus, 2-ethylbutanal 7b afforded succinimide (R)-9ba in 77% ee,
with cyclopentane-7c and cyclohexane carbaldehyde 7d gave suc-
cinimides (R)-9ca and (R)-9da in 78% with 67% ee, and in 96% and
93% yield, respectively (Table 2, entries 11 and 12). In addition, the
use of
a-monosubstituted aldehydes such as propanal 7e and
3-phenylpropanal 7f afforded the Michael adducts (S,R)/(R,R)-9ea
and (S,R)/(R,R)-9fa, respectively, as mixtures of diastereomers with
Table 2
Enantioselective Michael addition of aldehydes to maleimides organocatalysed by 1,2-diamine 6a
O
O
6a
(20 mol%)
O
O
HDA (20 mol%)
DMF/H2O 2/1 (v/v)
rt
R1
N
R3
+
N
R3
H
H
R2
R1 R2
O
O
7
8
9
Entry
Aldehyde
R2
Maleimide
t (d)
Adduct No.
Yielda (%)
eeb,c (%)
R1
No.
R3
No.
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
–(CH2)4–
–(CH2)5–
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
Ph
3-ClC6H4
4-ClC6H4
4-BrC6H4
2-MeOC6H4
4-AcOC6H4
Bn
Me
H
Ph
Ph
Ph
Ph
Ph
8a
8b
8c
8d
8e
8f
8g
8h
8i
8a
8a
8a
8a
8a
1
1
1
1
1
1
1
1
1
2
1
2
1
1
(R)-9aa
(R)-9ab
(R)-9ac
(R)-9ad
(R)-9ae
(R)-9af
(R)-9ag
(R)-9ah
(R)-9ai
(R)-9ba
(R)-9ca
(R)-9da
(S,R)/(R,R)-9ea
(S,R)/(R,R)-9fa
99
95
98
94
91
90
99
99
99
92
96
93
97d
90e
91
72
59
80
75
74
75
70
68
77
78
67
79/82
69/63
9
10
11
12
13
14
Me
Bn
H
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC.
Absolute configuration assigned by the order of elution of the enantiomers in chiral HPLC (see Section 4).
Mixture of diastereomers 1.2/1 determined by 1H NMR (300 MHz) in the reaction crude.
Mixture of diastereomers 1.9/1 determined by 1H NMR (300 MHz) in the reaction crude.
d
e

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A. Avila et al. / Tetrahedron: Asymmetry 24 (2013) 1531–1535
enantioselectivities of up to 82% and 69%, respectively, for the ma-
jor isomer [Table 2, entries 13 and 14, see footnotes (d) and (e)].
Concerning the sense of the enantioinduction achieved in this
organocatalysed reaction by using these chiral 1,2-diamines, sev-
eral doubts arose. Thus the observed (R)-stereochemistry in all
the formed succinimides 9, which was achieved employing organ-
ocatalyst 6a, is the same as that observed when using primary
amine-thiourea organocatalysts prepared from enantiomeric ent-
6a.8b This suggests that a different transition state is operating in
this addition reaction when 1,2-diamine 6a is the organocatalyst.
In addition, the opposite (S)-stereochemistry observed for 9aa
when employing 6b as the organocatalyst (see Table 1), indicates
different mechanistic behaviour for 1,2-diamines 6a and 6b.
In order to gain further insight into the origin of the observed
enantioselectivity, we carried out DFT theoretical calculations at
the B3LYP/6-311+G⁄⁄(IEFPCM, water) computational level. Based
on our own previous experience,9b the sense of induction achieved
with catalyst 6a was unexpected. First, we located the most stable
transition states with 6a, finding that the two lowest in energy
(TS1-S and TS1-R) proceed through a synclinal conformation, with
the formation of a weak H-bond between one of the O atoms of the
maleimide and the NH2 moiety of the diamine (TS1-S). The com-
parison of their energies would anticipate the preferential forma-
tion of the (S)-enantiomer, in contrast to the experimental
observations. When we broke the H-bonding interaction, and com-
puted the open transition structures TS2-S and TS2-R, the activa-
tion energies increased (DDGà = 1.2 and 5.0 kcal/mol higher than
TS1-S) due to the lack of stabilization of the negative charge that
develops in the maleimide portion during the transition state.
The new lowest in energy transition state is TS4-R, 1.5 kcal/mol
lower than TS4-S, predicting ca. 10:1 enantioselectivity in favour of
the (R)-enantiomer. The activation of the maleimide and stabiliza-
tion of the developing charge were achieved by hydrogen-bonding
with a water molecule,17 which bridges the oxygen atom and the
NH2 moiety.
We next applied this concept to the study of the reaction cat-
alysed by (1S,2S)-1,2-diphenylethane-1,2-diamine 6b, and again
found an agreement between the experimental and computa-
tional results. The operative transition state in the presence of
6b is TS6-S, leading to the formation of the (S)-enantiomer. With
regard to the computed structures, we do not have a complete
explanation for the opposite enantioinduction observed with 6a
and 6b, but it seems to be related to the higher flexibility of
the latter, and the relative disposition of the two phenyl rings.
In any case, the flexibility of 6b also results in a measurable
decrease in the energy differences between transition states
TS5-S, TS6-S and TS6-R (0.7, 0, and 0.6 kcal/mol relative ener-
gies), which is in accordance with the worse performance of
6b as a catalyst, leading to a modest 50% ee.
H
H
H
H
H
H
NH2
NH
NH2
NH
N
N
H
H
O
NH
O
NH
O
O
H
H
H
Ph N
H
Ph N
NPh
NPh
w
H
w
H
w
H
H
O
O
w
O
O
N
Ph
Ph
N
Ph
Ph
Ph
Ph
Ph
Ph
N
N
w
w
O
H
H
H
w
TS1-S
TS1-R
TS2-S
TS2-R
H
ΔΔG‡ = 0
ΔΔG‡ = 1.5
ΔΔG‡ = 5.0
ΔΔG‡ = 1.2
w
O
NH
O
NH
O
NH
NH
Ph N
O
Ph N
O
The relative activation energies of TS2-S (+5.0 kcal/mol) and
TS2-R (+1.5 kcal/mol) would be in accordance with the experimen-
tal formation of the (R)-enantiomer, if we could surpass their lack
of stabilization. In this regard, gas-phase computational methods
are especially inefficient in dealing with developing charges, and
solvent stabilization is required in order to obtain accurate results.
We thought that the introduction of some explicit water molecules
in conjunction with computation in a solvent model would help us
to compare more accurately the TS1 and TS2-type transition struc-
tures. Gratifyingly, TS3 and TS4-type transition structures, which
contain two molecules of water (identified as w in the Figure) in
each case, fairly reproduce the experimental sense of induction.
NPh
NPh
O
O
TS5-S
TS6-R
ΔΔG‡ = 0.6
TS5-R
ΔΔG‡ = 3.8
TS6-S
ΔΔG‡ = 0
ΔΔG‡ = 0.7
3. Conclusion
It can be concluded that commercial, enantiomerically pure
1,2-diamines can be used as organocatalysts in enantioselective
conjugate additions of aldehydes, mainly
a,a-disubstituted, to
different maleimides in an aqueous solvent. The enantioselectivi-
ties obtained when chiral trans-cyclohexane-1,2-diamines are
employed as organocatalysts are much higher than those obtained
when chiral 1,2-diphenyl-1,2-ethanediamine is used, a contrary
sense of enantioselectivity for both 1,2-diamines being observed.
The sense of enantioinduction has been explained by theoretical
calculations, which reveal the participation of an open transition
state, in which the maleimide is hydrogen-bond activated by the
surrounding water molecules. One of these molecules acts as a
bridge between the oxygen atom of the maleimide and the NH2
moiety of the catalyst.
w
H
H
H
H
w
w
w
H
H
H
H
H
H
N
N
N
N
w
H
H
H
H
w
w
O
w
O
NH
O
NH
O
NH
NH
H
Ph N
H
Ph N
NPh
NPh
O
O
O
O
TS3-S
TS3-R
TS4-S
TS4-R
ΔΔG‡ = 1.6
ΔΔG‡ = 3.1
ΔΔG‡ = 1.5
ΔΔG‡ = 0

A. Avila et al. / Tetrahedron: Asymmetry 24 (2013) 1531–1535
1535
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To a solution of 6a, ent-6a or 6b (0.04 mmol), the maleimide
(0.2 mmol) and hexanedioic acid (0.04 mmol) in DMF/H2O (2:1,
v/v) (0.5 mL) was added the aldehyde (0.4 mmol) and the mixture
was stirred at room temperature until reaction completion (TLC).
The reaction was then quenched with HCl 2 M (10 mL) and the
mixture was extracted with AcOEt (3 Â 10 mL). The organic phase
was washed with a saturated solution of NaHCO3 (10 mL) and H2O
(10 mL), dried over MgSO4, and the filtrate was concentrated to
give a crude product, which was purified by silica gel chromatog-
raphy (n-hexane/AcOEt).
The already reported adducts 9 were identified by comparison
of their spectroscopic data with those in the literature.9 Their
enantiomeric excesses and absolute configurations were deter-
mined by chiral HPLC.9b
7. Zhao, G.-L.; Xu, Y.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Chem.
Commun. 2007, 734–735.
8. (a) Yu, Y.; Jin, Z.; Huang, H.; Ye, T.; Liang, X.; Ye, J. Org. Biomol. Chem. 2010, 8,
4767–4774; (b) Bai, J.-F.; Peng, L.; Wang, L.-l.; Wang, L. X.; Xu, X.-Y. Tetrahedron
2010, 66, 8928–8932; (c) Xue, F.; Liu, L.; Zhang, S.; Duan, W.; Wang, W. Chem.
Eur. J. 2010, 16, 7979–7982; (d) Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh,
A. Tetrahedron Lett. 2011, 52, 4158–4160; (e) Miura, T.; Masuda, A.; Ina, M.;
Nakashima, K.; Nishida, S.; Tada, N.; Itoh, A. Tetrahedron: Asymmetry 2011, 22,
1605–1609; (f) Ma, Z.-w.; Liu, Y.-x.; Li, P.-l.; Ren, H.; Zhu, Y.; Tao, J.-c.
Tetrahedron: Asymmetry 2011, 22, 1740–1748; (g) Ma, Z.-W.; Liu, Y.-X.; Zhang,
W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Eur. J. Org. Chem. 2011, 6747–6754.
9. (a) Avila, A.; Chinchilla, R.; Nájera, C. Tetrahedron: Asymmetry 2012, 23, 1625–
1627; (b) Avila, A.; Chinchilla, R.; Gómez-Bengoa, E.; Nájera, C. Eur. J. Org. Chem.
2013, 5085–5092.
4.2. Calculations
All structures were optimized using the functional B3LYP18 and
the 6-31G⁄ basis set as implemented in GAUSSIAN 09
,
and the ener-
19
gies were single-point refined in a solvent model at B3LYP/6-
311G++ level on the previously optimized structures, including
polarization functions for better description of hydrogen bonds in-
volved in the reaction. The solvation factors were introduced with
the IEF-PCM method,20 using water as the solvent. The stationary
points were characterized by frequency calculations in order to
verify that they have the right number of imaginary frequencies.
The intrinsic reaction coordinates (IRC)21 were followed to verify
the energy profiles connecting each TS to the correct associated lo-
cal minima.
10. Yang, W.; Jiang, K.-Z.; Lu, X.; Yang, H.-M.; Li, L.; Lu, Y.; Xu, L.-W. Chem. Asian. J.
2013, 8, 1182–1190.
11. Wang, J.; Wang, X.; Ge, Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 1751–1753.
12. Wang, J.; Qi, C.; Ge, Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 2124–2126.
13. Liu, Y.; Wang, J.; Sun, Q.; Li, R. Tetrahedron Lett. 2011, 52, 3584–3587.
14. Liu, Y.; Gao, P.; Wang, J.; Sun, Q.; Ge, Z.; Li, R. Synlett 2012, 1031–1034.
15. Wang, W.; Wang, J.; Zhou, S.; Sun, Q.; Ge, Z.; Wang, X.; Li, R. Chem. Commun.
2013, 1333–1335.
16. Liu, Y.; Liu, X.; Wang, M.; He, P.; Lin, L.; Feng, X. J. Org. Chem. 2012, 77, 4136–
4142.
17. Comparison of the H-X distances in the different structures clearly reveals that
the hydrogen bonds are generally much tighter with the water molecules (1.68
Å in TS4-R) than with the NH2 groups (2.10 Å in TS1-S).
Acknowledgments
18. (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789; (b) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648–5652; (c) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys.
Chem. 1996, 100, 12974–12980.
We thank the financial support from the Spanish Ministerio de
Economía y Competitividad (projects CTQ2010-20387, CTQ2010-
21263-C02 and Consolider Ingenio 2010, CSD2007-00006), FEDER,
the COST Action CM0905 ‘Organocatalysis’, the Generalitat
Valenciana (Prometeo/2009/039), the Basque Government (GV
Grant IT-291-07) and the Universities of Alicante and the Basque
Country. We also thank SGI/IZO-SGIker UPV/EHU for allocation of
computational resources.
19. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Menucci, B., Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrewski, V. G.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02,
Gaussian Inc., Wallingford CT, 2009.
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