Pyrimidine-derived prolinamides as recoverable bifunctional organocatalysts for enantioselective inter- and intramolecular aldol reactions under solvent-free conditions

Article abstract of DOI:10.1002/ejoc.201500007

Chiral L-prolinamides 2 containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6-hexanedioic acid as a co-catalyst under solvent-free conditions. The intermolecular reaction between ketone-aldehyde and aldehyde-aldehyde must be performed under wet conditions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols with high regio-, diastereo-, and enantioselectivities. For the Hajos-Parrish-Eder-Sauer-Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland-Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H-bonding networks occurring with catalysts 2a and 2b. The intermolecular ketone-aldehyde and aldehyde-aldehyde aldol reactions and the Hajos-Parrish-Eder-Sauer-Wiechert versions with the employment of chiral L-prolinamides containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are successfully performed under solvent-free conditions; WMK = Wieland-Miescher ketone.

Full text of DOI:10.1002/ejoc.201500007

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FULL PAPER
DOI: 10.1002/ejoc.201500007
Pyrimidine-Derived Prolinamides as Recoverable Bifunctional Organocatalysts
for Enantioselective Inter- and Intramolecular Aldol Reactions under Solvent-
Free Conditions
Pascuala Vizcaíno-Milla,[a] José M. Sansano,[a] Carmen Nájera,*[a] Béla Fiser,[b] and
Enrique Gómez-Bengoa*[b]
Dedicated to Professor J. Elguero on the occasion of his 80th birthday
Keywords: Organocatalysis / Aldol reactions / Nitrogen heterocycles / Solvent-free process
Chiral
L
-prolinamides 2 containing the (R,R)- and (S,S)-trans-
stereomers of catalyst 2 give similar results at room tempera-
ture in the absence of water to give the corresponding Wie-
land–Miescher ketone and derivatives. Both types of reac-
tions were scaled up to 1 g, and the organocatalysts were
recovered by extractive workup and reused without any ap-
preciable loss in activity. DFT calculations support the stereo-
chemical results of the intermolecular process and the bi-
functional role played by the organocatalyst by providing a
computational comparison of the H-bonding networks occur-
ring with catalysts 2a and 2b.
cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit
are synthesized and used as general organocatalysts for
intermolecular and intramolecular aldol reactions with 1,6-
hexanedioic acid as a co-catalyst under solvent-free condi-
tions. The intermolecular reaction between ketone–aldehyde
and aldehyde–aldehyde must be performed under wet condi-
tions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols
with high regio-, diastereo-, and enantioselectivities. For the
Hajos–Parrish–Eder–Sauer–Wiechert reaction, both dia-
times but also with only a slight excess amount of the carb-
onyl compound acting as a nucleophile and a lower loading
of catalyst.[4] To increase the stereoselective efficiency of
proline-based organocatalysts, they have been bonded to
chiral scaffolds to form match and mismatch combinations.
C2-Symmetric chiral diamines such as 1,2-diphenylethane-
diamine, trans-cyclohexane-1,2-diamine, and 1,1Ј-bi-
naphthyl-3,3Ј-diamine (binam) allow organocatalysts bear-
ing two prolinamide units to be designed.[2] Another strat-
egy for the preparation of bifunctional organocatalysts is to
bond a prolinamide in one of the amino groups and to add
an extra hydrogen-bond-donating motif in the other amino
group. Our group has described that chiral binam-derived
prolinamides of type 1a and 1b bearing a sulfonamide unit
can be used as general organocatalysts for inter- and intra-
molecular aldol reactions under solvent-free conditions un-
der conventional magnetic stirring (Figure 1).[5] However,
Introduction
Enamine catalysis constitutes an important branch of
asymmetric organocatalysis mainly for aldol, Mannich, and
Michael reactions and for the α-functionalization of carb-
onyl compounds.[1] A plethora of organocatalysts have been
successfully designed for this activation mode; pyrrolidine-
containing systems such as proline and its derivatives are
the most efficient catalysts, especially for aldol reactions.[2]
Prolinamide derivatives bearing an additional functionality
able to form one or two hydrogen bonds allow for extra
interactions and provide a more bulky environment.[3] In
addition, a higher solubility of prolinamides in organic sol-
vents enhances the reaction rate and the stereoselectivity.
Moreover, they are also suitable for solvent-free aldol pro-
cesses, which can be performed not only in shorter reaction
[a] Departamento de Química Orgánica, Facultad de Ciencias,
and Centro de Innovación en Química Avanzada (ORFEO- for the recovery of these types of bifunctional catalysts it
CINQA), Universidad de Alicante,
was necessary to anchor the sulfonamide unit to a silica gel
Apdo. 99, 03080 Alicante, Spain
support by means of gel–sol techniques.[6] We envisaged
E-mail: cnajera@ua.es
http://www.ua.es/
that trans-cyclohexane-1,2-diamines, commercially access-
ible in both enantiomeric forms, could be a more flexible
skeleton to anchor the prolinamide that is able to form the
enamine intermediates and a 2-aminopyrimidine group to
form extra hydrogen bonds with the carbonyl acceptor. We
found that systems 2a and 2b are simple, recoverable, and
[b] Departamento de Química Orgánica I, Facultad de Química,
Universidad del País Vasco,
Apdo. 1072, 20080 San Sebastián, Spain
E-mail: enrique.gomez@ehu.es
http://www.ehu.eus/es/web/quimicaorganica1/atalak
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500007.
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C. Nájera, E. Gómez-Bengoa et al.
FULL PAPER
reusable bifunctional organocatalysts for inter- and intra- of 2:1 to 3:1 and enantiomeric excess (ee) values of 11 and
molecular aldol reactions under solvent-free conditions 69%, respectively (Table 1, entries 1 and 2). The addition of
(Figure 1).
10 mol-% of 1,6-hexanedioic acid (HDA) gave similar re-
sults, but the addition of water (1 mL) increased the ee val-
ues notably and also the diastereoselectivity (Table 1, en-
tries 3–6). On the other hand, reducing the amount of water
to 12 equiv. mainly increased the reaction rate (Table 1, en-
tries 7 and 8). Finally, just by lowering the temperature to
10 °C a notable increase in the anti/syn ratios to 19:1 and
24:1 was observed for catalysts 2a and 2b, respectively, and
the ee values increased to 90 and 97%, respectively (Table 1,
entries 9 and 10). The recovery of catalyst 2b was under-
taken by performing the reaction between cyclohexanone
(6a) of 4-nitrobenzaldehyde (7a) on a 1 g scale. The reaction
took place in 36 h with a higher 51:1dr; the pure anti-aldol
was obtained after recrystallization in 83% yield, and anti-
8aa was obtained with 95%ee. The catalyst was recovered
in 87% yield after extractive acid–basic workup (see the
Supporting Information). After a second run, the aldol
product was obtained in 70% yield with the same diastereo-
selectivity and enantioselectivity, and the catalyst was reco-
vered in 72% yield.
Figure 1. Bifunctional prolinamides derived from binam and trans-
1,2-cyclohexanediamine.
Table 1. Optimization of the intermolecular aldol reaction.[a]
Results and Discussion
Diastereomeric catalyst 2a was prepared starting from
mono-tert-butoxycarbonyl (Boc)-protected (R,R)-cyclo-
hexane-1,2-diamine (3) and N-Boc-l-Pro (4)[7] (Scheme 1).
The reaction of 3[8] with 2-chloropyrimidine in 2-propanol
heated at reflux in the presence of triethylamine for 36 h
followed by Boc deprotection with trifluoroacetic acid
(TFA) afforded 2-aminopyrimidine (R,R)-5 in 79% overall
yield. Then, N-Boc-l-Pro (4) was allowed to react with ethyl
chloroformate in the presence of triethylamine, which was
followed by in situ addition of (R,R)-5. Finally, TFA-medi-
ated Boc deprotection allowed the synthesis of 2a in 54%
overall yield. Similarly, diastereomer 2b was prepared start-
ing from (S,S)-cyclohexane-1,2-diamine.
Entry
2
Additive H2O T [°C] t [h] Conv. [%][b] anti/syn[c] ee [%][d]
(mol-%)
1
2
3
4
5
6
7
8
9
10
2a
2b
–
–
–
–
–
–
25
25
25
25
25
25
24
20
24
20
24
24
19
17
24
24
100
100
100
100
89
2:1
3:1
2:1
2.5:1
10:1
8:1
4:1
7:1
19:1
25:1
11
69
20
62
83
90
85
90
90
97[e]
2a HDA(10)
2b HDA(10)
2a HDA (10) 1 mL
2b HDA (10) 1 mL
2a HDA (10) 12 equiv. 25
2b HDA (10) 12 equiv. 25
2a HDA (10) 12 equiv. 10
2b HDA (10) 12 equiv. 10
64
100
100
100
100
[a] Reaction conditions: A mixture of cyclohexanone (1.2 mmol), p-
nitrobenzaldehyde (0.3 mmol), 2 (10 mol-%), additive (see column),
and H2O (see column) was magnetically stirred at the temperature
and time indicated. [b] Conversion based on aldehyde 7a
(1H NMR, 300 MHz). [c] Determined by 1H NMR spectroscopy.
[d] Determined by HPLC on a chiral stationary phase. [e] The reac-
tion took place over 36 h to provide the product in 83% yield with
51:1dr and a 95%ee if it was performed on a 1 g scale.
The scope of the intermolecular aldol reaction was
studied under the last reaction conditions, that is, catalyst
2b (10 mol-%), HDA (10 mol-%), and water (12 equiv.) at
10 °C (Table 2). Cyclohexanone (6a) was allowed to react
Scheme 1. Synthesis of organocatalyst 2a.
For the optimization reaction studies, the aldol reaction with aromatic aldehydes 7a–e to afford corresponding anti-
between cyclohexanone (6a) and p-nitrobenzaldehyde (7a) aldols 8aa–8ae in good yields (56–94%) with good dia-
was performed with pyrimidine–prolinamides 2 under sol- stereoselectivities (90:10 to 96:4) and enantioselectivities (8
vent-free conditions (Table 1). With a 10 mol-% loading of to Ͼ99%; Table 2, entries 1–5). Aliphatic aldehydes such as
catalyst 2a or 2b in the absence of any additive, the aldol 2,2-dimethoxyacetaldehyde and ethyl glyoxylate were also
reaction took place at room temperature with full conver- assayed as acceptors with cyclohexanone. The reaction with
sion to give product 8aa with anti/syn diastereomeric ratios an aqueous solution of 2,2-dimethoxyacetaldehyde (60wt.-
2
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Recoverable Bifunctional Organocatalysts
Table 2. Solvent-free intermolecular aldol reaction of ketones with aldehydes organocatalyzed by 2b.[a]
[a] Reaction conditions: Catalyst 2b (10 mol-%), ketone (1.2 mmol), aldehyde (0.3 mmol), water (6 mmol), and HDA (10 mol-%) with
magnetic stirring at 10 °C. [b] Yield of isolated product after column chromatography based on aldehyde 7. [c] Determined by analysis
of the crude product by 1H NMR spectroscopy (300 MHz). [d] Determined by HPLC on a chiral stationary phase for the anti dia-
stereomer. [e] For the anti isomer. [f] 60wt.-% aqueous solution. In this case, external water was not added. [g] 50% in toluene. [h] Deter-
mined from its benzoate by HPLC on a chiral stationary phase. [i] 91%ee for the anti diastereomer. [j] Acetone: 20 equiv. [k] A 2:1 mixture
of regioisomers 8fa and iso-8faЈ was obtained. [l] A 83:17 mixture of regioisomers 8ga and iso-8gaЈ was obtained.
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%) was performed without adding water, which gave aldols
Catalyst 2b (30 mol-%), in the presence of 1,6-hexane-
8af[8] in 75% yield as a 6:1 mixture of diastereomers and dioic acid (30 mol-%) and water (12 equiv.), promoted the
anti-8af with 97%ee (Table 2, entry 6). Upon using a 50% cross-aldol reaction between propanal (7h, 5 equiv.) and p-
toluene solution of ethyl glyoxylate as the acceptor, α- nitrobenzaldehyde (7a) at 0 °C under solvent-free condi-
hydroxy ester 8ag was obtained as a 32:1 mixture of anti/syn tions over 3 d. After subsequent reduction with NaBH4 in
diastereomers in 80% yield with 93%ee for the anti-aldol MeOH, corresponding diol 9ha was isolated in 52% overall
(Table 2, entry 7).
yield as a 3:1 mixture of anti/syn diastereomers; the anti-
By reaction with p-nitrobenzaldehyde, other cyclohexan- diol was obtained with 90%ee (Scheme 2).
one derivatives such as 4-oxacyclohexanone (6b) gave anti-
diastereomer 8ba with 97:3dr and 93%ee (Table 2, entry 8).
The protected 1,3-dihydroxyacetone 2,2-dimethyl-1,3-di-
oxan-5-one (6c) reacted with 2,2-dimethoxyacetaldehyde
(7f) to afford 8cf as a 95:5 mixture of anti/syn diastereomers
in 68% yield. Protected d-erythro-pentos-4-ulose (8cf) was
obtained with 89%ee (Table 2, entry 9). For comparison, l-
Pro (30 mol-%)[9] gave, after a reaction time of 13 h, 8cf in Scheme 2. Solvent-free aldehyde–aldehyde cross-aldol reaction.
47% yield with 90%de and 83%ee under the same solvent-
free conditions. Cyclopentanone (6d) reacted with p-nitro-
Next, the intramolecular Hajos–Parrish–Eder–Sauer–
benzaldehyde (7a) to give mainly syn-aldol 8da according to Wiechert (HPESW)[10] aldol reaction was assayed with tri-
the general behavior of cyclopentanone under prolinamide ketone 10a by using both catalysts 2a and 2b under solvent-
catalysis. Compound 8da was obtained as a 1:3 anti/syn free conditions (Table 3). In this case, the use of wet condi-
mixture in 76% yield with 91 and 30%ee, respectively tions at room temperature with prolinamide 2a produced
(Table 2, entry 10).
Mischler–Wieland ketone 11a in a lower ee at a longer reac-
On the other hand, upon using acyclic ketones such as tion time (Table 3, compare entries 1 and 2). Upon using 2b
acetone, butanone, and methoxyacetone in the aldol reac- as the organocatalyst, the reaction needed 20 h instead of
tion with p-nitrobenzaldehyde, products 8ea–ga were ob- 10 h and 11a was obtained in slightly lower 86%ee instead
tained. In the case of acetone, a large excess of 20 equiv. of 89%ee (Table 3, compare entries 2 and 3). Upon lower-
was needed to achieve a good conversion and a high 99%ee ing the reaction temperature to 10 °C, 11a was obtained in
(Table 2, entry 11). In the case of butanone, a 2:1 regioisom- 87 and 88%ee by using catalysts 2a and 2b, respectively
eric mixture of anti/syn-8fa and iso-8faЈ aldols was obtained (Table 3, entries 4 and 5). Therefore, it was preferable to
in 81% yield (Table 2, entry 12). anti/syn-Aldols 8fa were perform the reaction at room temperature regardless of the
isolated as a 91:9 diastereomeric mixture, and the major organocatalyst (Table 3, entries 2 and 3). For allyl-substi-
diastereomer was obtained with 86%ee. Similarly, meth- tuted triketone 10b and by using catalyst 2a, bicyclic alk-
oxyacetone gave an 83:17 mixture of regioisomers 8ga and enone 11b, a precursor of (–)-anominine,[11] was obtained
iso-8gaЈ (Table 2, entry 13). Aldols 8ga were isolated as an in 77% yield with 84%ee (Table 3, entry 6). In the case of
82:18 mixture of anti/syn diastereomers, and the anti-aldol triketone 10c, corresponding alkenone 11c was obtained in
was obtained with 84%ee.
53% yield with moderate 77%ee (Table 3, entry 7). Cyclo-
Table 3. Solvent-free intramolecular aldol HPESW reaction of triketones organocatalyzed by 2a and 2b.[a]
Entry
R
n
10
2
H2O
T [°C]
t [h]
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
2
2
2
2
2
2
2
1
1
10a
10a
10a
10a
10a
10b
10c
10d
10d
2a
2a
2b
2a
2b
2a
2a
2a
2b
12 equiv.
25
25
25
10
10
25
25
25
25
20
10
20
17
17
16
16
16
16
11a
11a
11a
11a
11a
11b
11c
11d
11d
(99)
92
(99)
(99)
(99)
77
53
80
(99)
75
89
86
87
88
84
77
79
68
–
–
–
–
–
–
–
–
Me
allyl
benzyl
Me
Me
[a] Reaction conditions: Catalyst 2 (10 mol-%), ketone (0.3 mmol), HDA (10 mol-%) with magnetic stirring. [b] Yield of isolated product
1
after column chromatography; conversions determined by H NMR spectroscopy are given in parentheses. [c] Determined by HPLC on
a chiral stationary phase.
4
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Recoverable Bifunctional Organocatalysts
pentanedione derivative 10d gave aldol condensation prod- Hb is severely hindered by geometrical restrictions. Indeed,
uct 11d in better ee upon using prolinamide 2a instead of Hb points away from the reaction center in the most stable
prolinamide 2b as the organocatalyst (Table 3, compare en- conformations. The energy difference between TSA-anti
tries 8 and 9). The recovery of catalyst 2a was undertaken and TSA-syn is 0.7 or 2.7 kcalmol–1, depending on the
by performing the synthesis of Wieland–Miescher ketone computational model used, and this is enough to explain
(11a) on a 1 g scale. The reaction took place over 4 h and the anti selectivity provided by 2a under the experimental
provided the product in 81% yield with 89%ee. The catalyst conditions.
was recovered in 79% yield after extractive acid–basic
workup (see the Supporting Information). After a second
run, 11a was obtained with the same ee in 79% yield and
the catalyst was recovered in 74% yield.
To obtain further insight into the mechanism of the cata-
lyst activity and the origin of the enantioselectivity for the
intermolecular aldol reaction, DFT calculations[12] were
performed. We were especially interested in analyzing the
H-bonding network responsible for the efficiency of the cat-
alyst. Geometry optimizations were done at the B3LYP/6-
31+G** level[13] of theory in a solvent model system
Figure 3. Transition states for the reaction between enamine A and
(CPCM, water as solvent).[14] Single-point energies were ob-
p-nitrobenzaldehyde. Gibbs Free energies computed at the M06-
2X/6-311+G** level. Value in parentheses corresponds to the
B3LYP energy.
tained for the optimized structures at the M06–2X/6-
311+G** (CPCM, water) level[15] to better account for the
The computed Ha–O and Hc–O bond lengths (ca. 1.8
and 1.6 Å, respectively) are very similar in both structures
and do not determine the preference for the formation of
the anti transition state, which instead is related to the space
available to accommodate the phenyl ring of p-nitrobenz-
aldehyde around the forming C–C bond. This effect is com-
mon in other related prolinamide systems. Thus, approach-
ing p-nitrobenzaldehyde prefers to position its aromatic ring
on the outer-most position (to the left of our view in Fig-
ure 4), which avoids steric interactions with the cyclohexane
and cyclohexanone rings. However, as suggested by qualita-
tive analysis of the 3D structure (Figure 4), there is still
enough space available in the inner area to accommodate
the aryl ring, and this is in line with the low–medium energy
difference (1–3 kcalmol–1) between the anti and syn dia-
stereoisomers with this catalyst.
polarization of the H-bonds, the developing charges, and
the dispersion effects of such large molecules. Although at
a high computational cost, we decided to compute the exact
structures used in the experimental studies (enamines A and
B, Figure 2). These enamines are formed in the reaction be-
tween p-nitrobenzaldehyde and catalysts 2a and 2b, respec-
tively, and owing to the presence of an acidic cocatalyst,
they are assumed to be protonated to a great extent under
the experimental conditions. Furthermore, the protonated
species are predicted to be much more active and are able to
form stronger H-bonds than the neutral species. The most
intriguing data to be explained is the similar enantio-
selectivity achieved with diastereomeric catalysts 2a/2b,
which implies that the stereogenic center of the pyrrolidine
ring dictates the selectivity of the reaction.
Figure 2. Species computed in this study.
In all the located transition structures, p-nitrobenzalde-
hyde is consistently activated by H-bonding with two of the
three available NH moieties present in enamines A and B;
consequently, many combinations exist, depending on
which NH groups are involved in the activation. After an
extensive conformational search, the most feasible struc-
tures for each diastereomer are TSA-anti and TSA-syn (Fig-
ure 3), which interestingly, contain a similar H-bonding ac-
tivation pattern. In both cases, the amidic (Ha) and pyrim-
idinium (Hc) NH groups are correctly positioned to activate
Figure 4. Front view of the TSA-anti transition structure. The
forming C–C bond appears eclipsed in the center of the figure in a
the carbonylic oxygen atom, whereas the participation of Newman projection.
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Figure 5. Transition states for the reaction between enamine B and p-nitrobenzaldehyde. Gibbs Free energies computed at the M06–2X/
6-311+G** level. Value in parentheses corresponds to the B3LYP energy.
On the other hand, the different configuration in en- able to weaken intramolecular H-bonds, which makes the
amine B induces a profound change in the orientation of transition states less rigid, loosens the internal restrictions,
the NH groups, especially Hb and Hc, which point in oppo- and lowers the final diastereoselectivities. We believe that
site directions with respect to enamine A. As a result, Hb is even the use of a solvent model system in these types of
better suited for carbonyl activation (Figure 5), whereas Hc calculations is not able to reliably mimic the effect of the
points away from the reaction center. As before, the com- bulk water in terms of absolute energy values. Nevertheless,
puted Ha–O and Hb–O bond lengths (ca. 1.8 and 1.6 Å, the computational results are in good agreement with the
respectively) are very similar in both structures. Interest- experimental data and show the right reactivity/selectivity
ingly, the energy difference is significantly increased in this trend. The computed transition structures are also informa-
case to 4.4 kcalmol–1 (7.7 kcalmol–1 at B3LYP level), which tive about the H-bonding pattern responsible for the reac-
justifies the good selectivity obtained with catalyst 2b.
tivity, which can help to develop new and improved cata-
The main reason for the higher computed selectivity can lysts.
be seen in the 3D representation of TSB-anti (Figure 6).
The involvement of Hb, in the catalyst approach of the pyr-
imidinyl ring to the reaction center, in blocking the space Conclusions
available to accommodate the phenyl ring in the syn ap-
We showed that pyrimidine-derived prolinamides are
proach appears in the comparison between Figure 4 and
Figure 6. Thus, the computational results show a better per-
formance for 2b than for 2a, in agreement with the experi-
mental data. However, the experimental difference between
both catalysts and the diastereoselectivity, in general, is
lower than that predicted by the computational results. In
this regard, water is present in a large amount in the reac-
tion media, and it is well known that water molecules are
useful recoverable catalysts for inter- and intramolecular
aldol reactions under solvent-free conditions in the presence
of 1,6-hexanedioic acid as a co-catalyst. The use of water
(12 equiv.) has a notable influence on the diastereo- and
enantioselectivity only in the intermolecular processes for
ketone–aldehyde and aldehyde–aldehyde aldol reactions.
DFT calculations showed that the activation of the alde-
hyde is attained by double H-bonding with the NH groups
of catalysts 2a and 2b, which explains the preferential for-
mation of the anti diastereoisomer in both cases.
Experimental Section
Synthesis of Catalyst 2: A mixture of 3[7] (3.27 g, 15.25 mmol), tri-
ethylamine (2.53 mL, 18.31 mmol), and 2-chloropyrimidine (2.09 g,
18.31 mmol) in 2-propanol was stirred for 36 h at 80 °C under an
argon atmosphere. The mixture was concentrated in vacuo, and the
residue was dissolved in CH2Cl2 (10 mL) and washed with H2O
(3ϫ 20 mL). After removal of the solvent under reduced pressure,
the resulting residue was purified by flash chromatography (hexane/
ethyl acetate) to give Boc-protected 5 (3.52 g, 72%). The resulting
solid residue was dissolved in dichloromethane (110 mL) and tri-
fluoroacetic acid (9.08 mL, 120 mmol) was added at 0 °C. The re-
sulting mixture was stirred for 4 h at r.t. Then, the solvents were
removed under reduced pressure, and the residue was dissolved in
CH2Cl2 (30 mL) and extracted with H2O (3ϫ 30 mL). The aqueous
layer was treated with 2 n NaOH until basic pH and was then
Figure 6. Front view of the TSB-anti transition structure. The
forming C–C bond appears eclipsed in the center of the figure in a
Newman projection.
6
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Recoverable Bifunctional Organocatalysts
extracted with CH2Cl2 (3ϫ 60 mL). The organic layer was dried
with MgSO4, filtered, and concentrated under reduced pressure to
yield 5 (2.64 g, 90% yield).
(1 mL) and NaBH4 (12 mg, 0.3 mmol) was added at 0 °C. The mix-
ture was stirred for 1 h and then the solvent was evaporated. The
resulting residue was purified by flash chromatography (hexane/
EtOAc, 4:1) to give pure diol 9ha in 52% overall yield.
Ethyl chloroformate (1.72 mL, 18.13 mmol) was added dropwise to
a solution of Boc-l-proline (4; 3.24 g, 13.74 mmol) and triethyl-
amine (2.1 mL, 15.11 mmol) in dry CH2Cl2 (30 mL) at 0 °C. After
stirring the resulting solution for 30 min at 0 °C, a solution of 5
General Procedure for Intramolecular Aldol Reactions: Triketone 10
(0.3 mmol) was added to a mixture of catalyst 2b (8.6 mg,
0.03 mmol) and hexanedioic acid (4.38 mg, 0.03 mmol) at 25 °C.
(2.64 g, 13.74 mmol) dissolved in dry CH2Cl2 (15 mL) was added The mixture was stirred for the time required (monitored by TLC,
over 15 min, and stirring was continued overnight at room tem-
perature under an argon atmosphere. The mixture was washed with
saturated aqueous solutions of KHSO4 (2ϫ 30 mL) and NaHCO3
(2ϫ 30 mL) and finally with brine (2ϫ 30 mL). The organic layer
was dried with MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy (hexane/ethyl acetate) to afford Boc-protected 2 (3.42 g,
64%). The resulting solid was dissolved in CH2Cl2 (82 mL) and
trifluoroacetic acid (6.85 mL, 89.1 mmol) was added. The mixture
was stirred for 4 h, and the solvents were removed under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL) and ex-
tracted with H2O (3ϫ 20 mL). The aqueous layer was treated with
2 n NaOH until basic pH and was then extracted with CH2Cl2
(3ϫ 60 mL). The organic layer was dried with MgSO4, filtered,
and concentrated under reduced pressure to give 2 (84%).
see Table 3). The residue was purified by flash chromatography
(hexane/ethyl acetate) to yield pure aldol product 11.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, copies of the 1H NMR and 13C NMR spec-
tra and HPLC chromatograms for all compounds, and DFT calcu-
lation results.
Acknowledgments
The Spanish Ministerio de Ciencia e Innovación (MICINN) (pro-
jects CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-
00006), the Spanish Ministerio de Economia y Competitividad
(MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-
REDC), Fondos Europeos para el Desarrollo Regional (FEDER),
Generalitat Valenciana (PROMETEO 2009/039 and PROMET-
EOII/2014/017), the Basque Government (GV Grant IT-291-07),
the European Commission, FP7 Marie Curie Actions through the
ITN ECHONET network (MCITN-2012-316379), the University
of Alicante, and the University of the Basque Country are grate-
fully acknowledged for financial support. The authors also thank
SGIker (UPV-EHU) for allocation of computational resources.
(R)-N-[(1R,2R)-2-(Pyrimidin-2-ylamino)cyclohexyl]pyrrolidine-2-
carboxamide (2a): Yield 54%. [α]2D6 = +34.90 (c = 1, CHCl3). White
1
solid, m.p. 141 °C. H NMR: δ = 8.23 (d, J = 4.7 Hz, 2 H), 7.85
(d, J = 8.1 Hz, 1 H), 6.47 (t, J = 4.8 Hz, 1 H), 5.39 (d, J = 8.0 Hz,
1 H), 3.92–3.81 (m, 1 H), 3.72 (ddd, J = 19.7, 10.9, 3.9 Hz, 1 H),
3.63 (dd, J = 9.2, 5.1 Hz, 1 H), 2.79 (dt, J = 10.0, 6.9 Hz, 1 H),
2.45 (dt, J = 10.1, 6.3 Hz, 1 H), 2.19–2.01 (m, 3 H), 2.01–1.91 (m,
1 H), 1.85–1.71 (m, 2 H), 1.61 (td, J = 12.9, 5.6 Hz, 1 H), 1.50–
1.26 (m, 5 H), 1.24–1.14 (m, 1 H) ppm. 13C NMR: δ = 175.72
(C=O), 162.49 (ArC), 158.05 (ArCH), 110.31 (ArCH), 60.48 (CH),
54.64 (CH), 53.63 (CH), 47.09 (CH2), 33.09 (CH2), 32.70 (CH2),
[1] B. List (Ed.), Science of Synthesis: Asymmetric Organocatalysis
1, Lewis Base and Acid Catalysts, Thieme, Stuttgart, Germany,
2012.
[2] For the first proline-catalyzed intermolecular aldol reaction,
see: a) X. H. Liu, L. L. Lin, X.-M. Feng, Chem. Commun. 2009,
48, 6145–6158; b) B. List, R. A. Lerner, C. F. Barbas III, J. Am.
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Soc. Rev. 2010, 39, 1600–1632; b) P. M. Pihko, I. E. Majander,
A. Erkkilä, Top. Curr. Chem. 2010, 291, 29–75; c) X.-H. Chen,
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Organocatalyzed Reactions (Ed.: R. Mahrwald), Springer, Hei-
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[4] For recent reviews on the use of solvent-free conditions for
enantioselective aldol reactions, see: a) J. G. Hernández, E. Jua-
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ballero, G. Guillena, C. Nájera, Mini-Rev. Org. Chem. 2014,
11, 118–128.
[5] a) G. Guillena, C. Nájera, S. F. Viózquez, Synlett 2008, 3031–
3035; b) B. Bradshaw, G. Etxebarria-Jardí, J. Bonjoch, S. F.
Viózquez, G. Guillena, C. Nájera, Adv. Synth. Catal. 2009, 351,
2482–2490; c) S. F. Viózquez, G. Guillena, C. Nájera, B. Brad-
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Viózquez, G. Guillena, C. Nájera, Org. Synth. 2011, 88, 330–
341; e) A. Bañón-Caballero, G. Guillena, C. Nájera, Green
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30.83 (CH ), 25.77 (CH ), 25.15 (CH ), 24.95 (CH ) ppm. IR: ν =
˜
2
2
2
2
3311, 1644, 1582, 1561, 1511, 1450, 1413 cm–1. HRMS (ESI): calcd.
forC15H24N5O [M+H]+ 290.1981; found 290.1967.
(R)-N-[(1S,2S)-2-(Pyrimidin-2-ylamino)cyclohexyl]pyrrolidine-2-
carboxamide (2b): Yield 54%. [α]2D6 = +52.70 (c = 1.1, CHCl3). Yel-
1
low oil. Rf = 0.75 (EtOAc/MeOH, 9:1). H NMR: δ = 8.24 (d, J =
4.8 Hz, 2 H), 7.76 (d, J = 7.3 Hz, 1 H), 6.48 (t, J = 4.8 Hz, 1 H),
5.51 (d, J = 7.6 Hz, 1 H), 3.88–3.65 (m, 2 H), 3.51 (dd, J = 9.1,
5.4 Hz, 1 H), 2.88 (qt, J = 10.1, 6.5 Hz, 2 H), 2.27–2.11 (m, 1 H),
2.07–1.97 (m, 2 H), 1.93 (br., 2 H), 1.85–1.70 (m, 3 H), 1.70–1.58
(m, 2 H), 1.45–1.22 (m, 4 H) ppm. 13C NMR: δ = 175.46 (C=O),
162.55 (ArC), 158.01 (ArCH), 110.34 (ArCH), 60.52 (CH), 54.91
(CH), 53.79 (CH), 47.20 (CH2), 32.75 (CH2), 32.72 (CH2), 30.74
(CH ), 26.07 (CH ), 24.98 (CH ), 24.90 (CH ) ppm. IR: ν = 3271,
˜
2
2
2
2
1648, 1585, 1564, 1516, 1449, 1416 cm–1. HRMS (EI+): calcd. for
C15H23N5O [M]+ 289.1903; found 289.1908.
General Procedure for Intermolecular Aldol Reactions: The ketone
(1.2 mmol) was added to a mixture of the corresponding aromatic
aldehyde (0.3 mmol), catalyst 2b (8.6 mg, 0.03 mmol), hexanedioic
acid (4.38 mg, 0.03 mmol), and water (64.8 μL, 3.6 mmol) at 10 °C.
The mixture was stirred until the aldehyde was consumed (moni-
tored by TLC). Then, the crude product was diluted with EtOAc
and washed with NH4Cl saturated solution, dried with anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate) to yield the
pure aldol product. In the case of the reaction between propanal
and p-nitrobenzaldehyde, an excess of 5 equiv. of propanal was
used. After the same workup, the residue was dissolved in MeOH
Eur. J. Org. Chem. 0000, 0–0
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Pages: 9
C. Nájera, E. Gómez-Bengoa et al.
FULL PAPER
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Received: January 5, 2015
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50007
/KAP1
Date: 05-03-15 13:18:05
Pages: 9
Recoverable Bifunctional Organocatalysts
Bifunctional Organocatalysts
The intermolecular ketone–aldehyde and
aldehyde–aldehyde aldol reactions and the
Hajos–Parrish–Eder–Sauer–Wiechert ver-
sions with the employment of chiral
l-prolinamides containing the (R,R)- and
(S,S)-trans-cyclohexane-1,2-diamine scaf-
fold and a 2-pyrimidinyl unit are success-
fully performed under solvent-free con-
ditions; WMK = Wieland–Miescher ket-
one.
P. Vizcaíno-Milla, J. M. Sansano,
C. Nájera,* B. Fiser,
E. Gómez-Bengoa* ........................... 1–9
Pyrimidine-Derived Prolinamides as Re-
coverable Bifunctional Organocatalysts for
Enantioselective Inter- and Intramolecular
Aldol Reactions under Solvent-Free Con-
ditions
Keywords: Organocatalysis / Aldol reac-
tions / Nitrogen heterocycles / Solvent-free
process
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