2-aminoimidazolyl and 2-aminopyridyl (S)-prolinamides as versatile multifunctional organic catalysts for aldol, Michael, and Diels-Alder reactions

Article abstract of DOI:10.1002/ejoc.201201643

The synthesis of multifunctional organocatalysts, easily obtained by the condensation of (S)-proline with 2-aminopyridine, 2,6-diaminopyridine, or 2-aminoimidazole, is reported. These chiral prolinamides promoted the aldol condensation between cyclohexano

Full text of DOI:10.1002/ejoc.201201643

FULL PAPER
DOI: 10.1002/ejoc.201201643
2-Aminoimidazolyl and 2-Aminopyridyl (S)-Prolinamides as Versatile
Multifunctional Organic Catalysts for Aldol, Michael, and Diels–Alder
Reactions
Manuel Orlandi,[a] Maurizio Benaglia,*[a] Laura Raimondi,*[a] and Giuseppe Celentano[b]
Keywords: Organocatalysis / Aldol reactions / Enantioselectivity / Prolinamides
The synthesis of multifunctional organocatalysts, easily ob-
tained by the condensation of (S)-proline with 2-aminopyr-
idine, 2,6-diaminopyridine, or 2-aminoimidazole, is reported.
These chiral prolinamides promoted the aldol condensation
between cyclohexanone and different aromatic aldehydes
with moderate to very high enantioselectivities (up to 98%
ee), depending on the nature of the substituents on the aryl
ring. Computational studies were performed to clarify the
stereochemical behaviour of the two different types of cata-
lysts and to understand the role of the different structural
components of the chiral prolinamides in the recognition pro-
cesses between the catalysts and the reactants. In prelimi-
nary experiments, trifluoroacetate salts of the chiral prolin-
amides have been used for the first time as catalysts in Diels–
Alder reactions between cyclopentadiene and cinnamal-
dehyde and in Michael reactions.
actions of the pyridylprolinamide with an appropriate addi-
tive,[6] and this may give unexpected and unknown proper-
ties to the catalytic systems. Indeed, prolinamides are one
of the most popular classes of compounds that have been
developed to overcome some of the limitations of proline
itself (such as high catalyst loading, excess of nucleophile,
long reaction times, and low solubility of catalyst in organic
media).[7] Advantages of these systems include: (i) their easy
preparation from (S)-proline; (ii) their high stability, due to
the robust amide linkage , which means that in some cases,
they can be recovered and reused without detrimental ef-
fects; and (iii) the acidity of the NH proton, which can acti-
vate electrophiles by hydrogen bonding.
Following our interest in the development of readily
available chiral organocatalysts,[8] we decided to investigate
further the behavior of 2-aminopyridine-[9] and 2-amino-
imidazole-derived prolinamides as catalysts with potential
applications in different stereoselective carbon–carbon
bond-forming reactions, such as aldol, Mannich, and
Michael reactions, but also in cycloadditions. We decided
to synthesize differently substituted 2-pyridylprolinamides
and a 2-imidazolylprolinamide to undertake a preliminary
study of their behavior in the aldol reaction between cyclo-
hexanone and different aldehydes and, for the first time, in
Michael and Diels–Alder reactions (Figure 1).
Introduction
The use of molecular recognition processes between the
catalyst and the reactants may open new possibilities in the
almost unexplored field of supramolecular self-assembled
organocatalysts. The addition of achiral compounds to a
chiral organocatalyst host can transform an unselective cat-
alyst into a highly selective one through a self-assembly pro-
cess that leads to the generation of a new catalytically active
entity.[1] The utilization of hydrogen-bonding networks be-
tween chiral (pre)catalysts and a library of achiral additives
may offer the opportunity to tune and modify the steric
environment presented by the newly generated supramolec-
ular catalyst.[2] The use of additives along with proline has
also opened new avenues in the field of flow chemistry.
Based on the recent discovery that urea additives increase
the rate of various proline-catalysed reactions,[3] it has re-
cently been observed[4] that a urea tethered to a tertiary
amine increases the rate of a number of batch reactions,
including the α-aminoxylation reaction.[5]
In this context, further possibilities to increase the struc-
tural complexity of catalysts may come from the insertion
of heterocyclic moieties into the structure. The introduction
of a pyridine moiety might open new opportunities for the
assembly of supramolecular adducts arising from the inter-
[a] Dipartimento di Chimica, Università degli Studi di Milano,
via Golgi 19, 20133 Milano, Italy
Fax: +39-025031-4159
E-mail: maurizio.benaglia@unimi.it
Homepage: http://users.unimi.it/Benagliagroup/
[b] Dipartimento di Scienze Farmaceutiche,
Università degli Studi di Milano,
Results and Discussion
The straightforward condensation of (S)-Boc-proline
with differently substituted 2-aminopyridines gave the cor-
responding prolinamides in good yields (Scheme 1). Bis-
Via Mangiagalli 25, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201643
2346
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Multifunctional Organic Catalysts
the corresponding proline derivatives was accomplished by
treating 6–9 with a 1:1 mixture of CH2Cl2/TFA (trifluoro-
acetic acid) at 25 °C for 1 h.
Finally, the condensation of the acyl chloride derived
from N-Cbz-(S)-proline with the commercially available
sulfate salt of 2-aminoimidazole gave, after palladium-cata-
lysed deprotective hydrogenolysis, the desired 2-imidazolyl-
(S)-prolinamide (i.e., 5) in 25% overall yield and with only
a single chromatographic purification (Scheme 2).
Figure 1. Catalysts 1–5 used in this work.
Scheme 2. Synthesis of imidazole-derived prolinamide 5, DIPEA =
diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine.
Boc derivative 6, the precursor of catalyst 2b, was synthe-
sized in 63% yield by condensation of an excess of (S)-Boc-
proline with 2,6-diaminopyridine. However, simply by using
a different stoichiometric ratio between the reactants
(2 equiv. proline to 1 equiv. pyridine), the monosubstituted
product (i.e., 7) was isolated after chromatographic purifi-
cation as the major product in 71% yield. Starting from
intermediate 7, it was possible to prepare the N-trifluo-
roacetamide 8, the immediate precursor of catalyst 3, by
reaction with trifluoroacetic anhydride in 57% non-opti-
mized yield. Analogously, the condensation of 7 with 4-tol-
uenesulfonyl chloride gave the corresponding sulfonamide
(i.e., 9). For the sake of comparison, the 2-pyridyl amide of
(S)-Boc-proline was also prepared, and was converted into
At the beginning of our study, 2-pyridylprolinamide de-
rivatives 2a and 2b were tested in the aldol condensation
between cyclohexanone and 4-nitrobenzaldehyde under dif-
ferent conditions (Scheme 3, R = 4-nitrophenyl).[10] After a
preliminary screening, chloroform was selected as the sol-
vent for this study.[11] Typically the reaction was performed
at 25 °C by treating 3 equiv. cyclohexanone and 1 equiv. al-
Scheme 3. Aldol reaction of cyclohexanone with differently substi-
catalyst 1. The deprotection of the Boc derivatives to give tuted aldehydes.
Scheme 1. Synthesis of chiral 2-pyridylprolinamides; DCM = dichloromethane, EDC = ethyl(dimethylaminopropyl)carbodiimide, TEA
= triethylamine.
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M. Orlandi, M. Benaglia, L. Raimondi, G. Celentano
FULL PAPER
dehyde with 20 mol-% of the catalyst. The behaviour of the Table 2. Aldol reactions of cyclohexanone with different aldehydes
catalysed by prolinamide 2a.
catalysts was also investigated in the presence of acid addi-
Entry
R
Yield[a] [%]
dr[b] [%]
ee[c] [%]
tives. A few selected results are collected in Table 1.
1
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
4-OMeC6H4
Ph-CH=CH
C6H11
4-ClC6H4
4-CF3C6H4
C6F5
3-NO2C6H4
2-NO2C6H4
3-FC6H4
75
47
45
55
70
n.r.
n.r.
n.r.
75
87
41
33
85
15
47
90:10
55:45
53:47
92:8
70:30
–
95
55 (28)
60 (14)
91
70
–
Table 1. Enantioselective aldol reaction in CHCl3 promoted by
organocatalysts 2a and 2b.
2[d]
3[e]
4[f]
5
Entry Acid additive Catalyst Yield[a] dr[b] anti/syn
ee[c]
[%]
[%]
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
6
7
–
TFA
HCl
PhCOOH
–
TFA
PhCOOH
2a
2a
2a
2a
2b
2b
2b
51
75
5
71
19
25
27
80:20
90:10
96:4
60:40
97:3
Ͼ 99:1
98:2
47
95
n.d.
91
33
71
–
–
–
–
82:18
57:43
Ͼ 99:1
90:10
90:10
90:10
55:45
61
47 (13)
93
33
55
31
37 (15)
55
[a] Yields determined after chromatographic purification. [b] Dia-
stereoisomeric ratio determined by NMR spectroscopy and con-
firmed by HPLC analysis. [c] Enantiomeric excess of the anti iso-
mer determined by HPLC on chiral stationary phase.
2-FC6H4
[a] Yields determined after chromatographic purification. Reaction
conditions: cyclohexanone (0.6 mmol), catalyst (0.04 mmol), alde-
hyde (0.2 mmol), 25 °C in CHCl3. [b] Diastereoisomeric ratio deter-
mined by NMR spectroscopy and confirmed by HPLC analysis.
[c] Enantiomeric excess of the anti isomer determined by HPLC on
chiral stationary phase. [d] Reaction run in hexanes. [e] Reaction
run in toluene. [f] Reaction run with 5 mol-% catalyst.
Catalyst 2a promoted the reaction to give the product
in 51% yield and with a 47% ee for the anti isomer. The
performance of the catalyst was greatly improved from the
points of view of both yield and stereoselectivity by adding
an additive. The addition of benzoic acid was beneficial to
the enantioselectivity (91% ee) but detrimental to the dias-
teoreselectivity (entry 4). The best results were obtained
when the trifluoroacetic acid salt of prolinamide 2a was
used. In this case, a high anti selectivity was observed, and
enantioselectivity increased to 95% (entry 2). The same
trend was found for bis-prolinamide catalyst 2b, although
in this case, the aldol product was isolated with a lower
enantioselectivity and in a much lower yield.
Next, the catalytic activity of the trifluoroacetate salt of
2a was tested in the reaction of cyclohexanone with dif-
ferent aldehydes (Scheme 3). The data are reported in
Table 2. Catalyst 2a was able to promote the aldol reaction
to give reasonable yields of the products only with aromatic
aldehydes bearing electron-withdrawing groups. Under
these conditions, aldehydes without activating groups or ali-
phatic aldehydes did not react. Differently substituted com-
pounds were tested, but substituents in the ortho position
adversely affected the enantioselectivity. For most of the al-
dehydes that reacted, the enantioselectivity ranged between
50 and 65% ee. Two special cases are represented by 4-ni-
trobenzaldehyde and pentafluorobenzaldehyde, which gave
enantioselectivities higher than 93%.
The behavior of the chiral prolinamides in the aldol reac-
tion was also studied using computational methods. Only
theoretical studies can provide a rationale for the observed
diastereo- and enantioselectivities, but, more interestingly,
they can also enable the prediction of the stereochemical
outcome of reactions. This last aspect, by far the more at-
tractive for the organic chemist, remains elusive at present
in most cases, but it is actually the ultimate goal in this
field. The idenification of all of the accessible diastereoiso-
meric transition-state structures should allow an unambigu-
ous prediction of the stereoselectivity of a reaction. How-
ever, an extensive computational study of a given reaction
need for time-consuming quantum mechanical methods in
order to locate all the transition-state structures that are,
in principle, accessible for the reactants. In the field of the
organocatalysis, the main causes of stereoselectivity are
often non-bonding interactions, which are not well mod-
elled with standard methods and basis sets, and which re-
quire the time-consuming use of more sophisticated func-
tionals, or at least the introduction of polarization func-
tions.[12] Despite these drawbacks, we undertook the study
of the aldol reaction of cyclohexanone with aromatic alde-
hydes in the presence of protonated catalyst 2a.
Location of transition-state structures, however, is not al-
ways a simple task, because of the flatness of those regions
of potential energy surfaces. Because of the size of our
problem, we adopted a stepwise approach. A preliminary
study of the potential energy surface by semiempirical
methods was used to quickly locate all eight transition-state
structures for the reaction of cyclohexanone with 4-ni-
trobenzaldehyde. The enamine formed by the reaction of
cyclohexanone with protonated catalyst 2a can adopt two
different conformations when coordinated with the alde-
hyde; the two adducts are shown in Figure 2. In type 1 ad-
ducts, the oxygen of the amide and the protonated pyridine
are hydrogen bonded, and the aldehyde is coordinated to
Figure 2. The two different conformations of the adduct between
within transition-state theory is seriously hampered by the catalyst-bound enamine and aldehyde.
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Multifunctional Organic Catalysts
the amidic NH only; in type 2 adducts, the aldehyde is
bridged between the two NH moieties.
Moreover, for both type 1 and type 2 transition states,
four diastereoisomeric structures are possible, giving a total
of eight transition-state structures. These eight structures
were fully optimized, and characterized as such by vi-
brational analysis, with the PM6 Hamiltonian. These eight
PM6 transition-state structures were subsequently used as
starting structures for higher level calculations. In this way,
we were able to locate at the B3LYP/6-31G(d,p) level eight
transition-state structures that were fully optimized (all
structures are shown in Figure 3), and were characterized
as such by vibrational analysis.
Finally, free energies were calculated also at the B3LYP/
6-311+G(2d,p) level on the eight B3LYP/6-31G(d,p) geo-
metries, in order to better account for non-bonding interac-
tions that are likely to play a significant role in the origin of
the stereoselectivity in organocatalysis. Relative free-energy
values ΔΔG‡ for PM6, B3LYP/6-31G(d,p), and B3LYP/6-
311+G(2d,p)//B3LYP/6-31G(d,p) transition-state structures
are reported in Table 3. Interestingly enough, in all cases,
the formation of the new C–C bond and the proton transfer
from the amidic NH to the aldehyde oxygen are concerted
processes. Also, in type 2 transition-state structures, the am-
idic proton, and not the one from the protonated pyridine,
is transferred selectively. Calculated stereoselectivities are
reported in Table 4.
Table 3. Free-energy differences for the transition-state structures
for the reaction of 4-nitrobenzaldehyde with cyclohexanone in the
presence of protonated catalyst 2a.[a]
PM6
B3LYP/6-
31G(d,p)
B3LYP/6-
311+G(2d,p) //
B3LYP/6-31G(d,p)
Ty1–2S,1ЈS
Ty1–2R,1ЈR 7.39 (1.77)
Ty1–2S,1ЈR 0.00
6.34 (1.52)
23.59 (5.64)
45.34 (10.84)
0.00
23.16 (5.53)
45.51 (10.88)
0.00
Ty1–2R,1ЈS 10.87 (2.60) 32.54 (7.78)
Ty2–2S,1ЈS 11.44 (2.73) 27.20 (6.50)
Ty2–2R,1ЈR 11.54 (2.76) 41.24 (9.86)
33.36 (7.97)
25.94 (6.20)
40.50 (9.68)
16.61 (3.97)
32.22 (7.70)
Ty2–2S,1ЈR 2.11 (0.50)
Ty2–2R,1ЈS 6.03 (1.44)
18.05 (4.31)
25.70 (8.53)
[a] All energies are in kJ/mol (kcal/mol) and are ZPE (zero-point
energy) corrected.
Table 4. Calculated stereoselectivities (T = 298.15 K), expressed as
a percentage of the total product formed for the reaction of 4-
nitrobenzaldehyde with cyclohexanone in the presence of proton-
ated catalyst 2a.
PM6
B3LYP/6-31G(d,p) B3LYP/6-
311+G(2d,p) //
B3LYP/6-31G(d,p)
2S,1ЈS
2R,1ЈR
2S,1ЈR
2R,1ЈS
5.22
3.60
85.20
5.98
0.01
0
99.99
0
0.01
0
99.99
0
Inspection of the data collected in Table 3 suggests some
interesting ideas. Generally, type 1 transition-state struc-
tures are clearly preferred over the corresponding type 2
structures. This is also true in PM6 calculations, but it is a
Figure 3. B3LYP/6-31g(d,p) transition-state structures for the reac-
tion of 4-nitrobenzaldehyde with cyclohexanone in the presence of
protonated catalyst 2a; Ty1 = type 1; Ty2 = type 2.
Eur. J. Org. Chem. 2013, 2346–2354
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M. Orlandi, M. Benaglia, L. Raimondi, G. Celentano
FULL PAPER
particularly dramatic effect for the DFT (density functional
theory) derived structures. Type 1 transition-state structures
are characterized by an enhanced rigidity of the catalyst
moiety (due to the intramolecular hydrogen-bond), an intri-
guing feature if one needs to tailor the catalyst towards a
specific substrate.
The correct diastereoisomer was always predicted at each
of the levels of theory investigated in this study. Also at the
PM6 level, the calculated syn/anti ratio (9:91) agrees nicely
with the experimental result (Table 4 vs. Table 5). In our
case, B3LYP/6-31G(d,p) calculations seem to be adequate
to model the reaction, and increasing the basis set does not
appear to be essential to achieve reliable results.
Figure 5. Comparison of catalyst 2a and imidazole-derived prolin-
amide 5.
As for the origin of the stereoselectivity in this reaction,
the B3LYP/6-31G(d,p) type 1 transition-state structure
leading to the 2S,1ЈR diastereoisomer is shown in Figure 4.
From this orientation it can clearly be seen that a perfectly
staggered conformation around the forming C–C bond is
achieved, and that repulsion between the aromatic ring and
the cyclohexyl ring is avoided. In all of the other transition-
state structures, one or both of these features are lacking.
The aldol reaction between cyclohexanone and 4-ni-
trobenzaldehyde proceeded smoothly in the presence of cat-
alyst 5 in different solvents, usually with very high enantio-
selectivities for the major anti isomer, up to 98% ee in the
best case (Table 5). In DMF, 2-imidazolylprolinamide cata-
lysed the reaction to give the product in quantitative yield
and with 97% ee for the major stereoisomer (anti/syn ratio:
81:19). Catalyst 5 efficiently promoted the reactions with or
without TFA as additive. In the presence of an acidic addi-
tive, protonated species D (Figure 5) may be assumed to be
the catalytically active species, and without TFA, neutral
compound C will be the promoter of the reaction. In this
last case, the increased reactivity of catalyst 5 compared to
catalyst 2a could be explained as being due to the increased
acidity of amidic NH group, which in turn is due to the
intramolecular coordination of the imidazole NH proton to
the carboxyamide moiety.
Figure 4. B3LYP/6-31g(d,p) Ty1-2S,1ЈR transition-state structure –
staggered view along the forming C–C bond.
Table 5. Aldol reactions of cyclohexanone with 4-nitrobenzalde-
hyde catalysed by prolinamide 5.
It is interesting that a simple method such as PM6 seems
to offer some qualitatively reliable results. Synthetic organic
chemists are in need of reliable, non-time-consuming meth-
ods that can predict reaction stereoselectivities without
committing to high-level calculations in preliminary studies.
In this case, a qualitative prediction of the stereoselectivity
of an organocatalytic reaction appears to be possible also
with semi-empirical Hamiltonians.
However it is evident that catalyst 2a suffers from a lim-
ited reactivity, since only aromatic aldehydes bearing elec-
tron-withdrawing groups react smoothly. This can be due
in part to the presence of the two conformations shown in
Figure 5. In structure A, which is more stable than structure
B by 6 kcal/mol [at the B3LYP/6-311G(2d,p)//B3LYP/6-
31G(d,p) level of theory], the hydrogen-bonding network
formed by the NH of the amide group and the NH+ of the
protonated pyridine ring, which is necessary for the molecu-
Entry
Acid additive Solvent
Yield[a] dr[b] anti/syn ee[c]
[%]
[%]
1
2
3
4
5
6
7
TFA
–
TFA
–
TFA
–
–
CHCl3
DMF
DMF
MeOH
MeOH
H2O
25
95
98
55
65
21
99
66:34
80:20
81:19
86:14
82:18
70:30
87:13
67
94
97
98
93
75
96
–
[a] Yields determined after chromatographic purification. Reaction
conditions: cyclohexanone (0.6 mmol), catalyst (0.04 mmol), alde-
hyde (0.2 mmol), 25 °C in CHCl3. [b] Diastereoisomeric ratio deter-
mined by NMR spectroscopy and confirmed by HPLC analysis.
[c] Enantiomeric excess of the anti isomer determined by HPLC on
chiral stationary phase.
Some interesting results came from the investigation of
lar recognition processes of the reactants, is lost. In order the methodology with other aromatic aldehydes (Table 6).
to retain a heterocyclic NH group available for substrate With reagents bearing electron-withdrawing groups, catalyst
activation through hydrogen bonding, 2-imidazolylprolin- 5 always gave very good enantioselectivity, usually higher
amide 5 was synthesized and tested in aldol reactions.
than that obtained with catalyst 2b.
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Multifunctional Organic Catalysts
Table 6. Aldol reactions of cyclohexanone with different aldehydes
catalysed by prolinamide 5.
Table 7. Enantioselective Diels–Alder reaction promoted by
organocatalysts 1–5.
Entry
R
Solvent
Yield[a]
[%]
dr[b] [%]
ee[c]
[%]
Entry Catalyst
Yield[a]
[%]
dr[b]
exo/endo
ee[c] [%],
exo
ee[c] [%],
endo
1[d]
2
3
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CF3C6H4
C6F5
4-ClC6H4
4-ClC6H4
Ph
DMF
–
–
–
98
75
35
65
97
57
55
41
65
23
35
81:19
96:4
97:3
94:6
96:4
75:25
77:23
76:24
80:20
77:23
60:40
97
91
91
87
97
57
87
81
67
67
51
1
1
71
85
45
75
35
77
99
75:25
77:23
78:22
70:30
69:31
68:32
75:25
15
55
57
38
27
23
35
23
47
50
48
37
21
23
2
2a
2a
2b
3
3[d]
4
4
5
–
5
6
7
6[d]
7
DMF
–
DMF
–
4
5
8
9
[a] Yields determined after chromatographic purification. Reaction
conditions: cyclohexanone (0.6 mmol), catalyst (0.04 mmol), alde-
hyde (0.2 mmol), 25 °C, 48 h. [b] Diastereoisomeric ratio deter-
mined by NMR spectroscopy and confirmed by HPLC analysis.
[c] Enantiomeric excess of the anti isomer determined by HPLC on
chiral stationary phase. [d] Reaction run at 0 °C for 72 h.
Ph
10
4-OMeC6H4
3-OH-C6H4
–
11[d]
DMF
[a] Yields determined after chromatographic purification. Reaction
conditions: cyclohexanone (0.6 mmol), catalyst (0.04 mmol), alde-
hyde (0.2 mmol), 25 °C in CHCl3. [b] Diastereoisomeric ratio deter-
mined by NMR spectroscopy and confirmed by HPLC analysis.
[c] Enantiomeric excess of the anti isomer determined by HPLC on
chiral stationary phase. [d] TFA was added.
Also with less reactive substrates like benzaldehyde, it
was possible to isolate the product in reasonable yield and
with an enantioselectivity of up to 86% ee. Finally, even
aldehydes bearing electron-donating groups, which were
completely unreactive with catalyst 2b, gave the aldol prod-
ucts in the presence of 5, albeit in low yields and with mod-
est stereoselectivities.
Scheme 4. Stereoselective organocatalytic Diels–Alder cycload-
ditions and Michael reactions.
The trifluoroacetate salts of compounds 1–5 were also
tested as catalysts in Diels–Alder reactions. It has recently
been recognized that the use of hydrogen bonding to acti-
vate an appropriately functionalized substrate may repre-
sent a viable alternative to the traditional methodology that
relies upon Lewis acid catalysis.[12] However, hydrogen-
bond-activation of substrates for Diels–Alder cycload-
ditions is still a relatively underexplored field.[13] We have
recently demonstrated that trifluoroacetate salts of enantio-
merically pure bis-amines[14] and bis-imines[15] may be used
to catalyse the stereoselective Diels–Alder cycloaddition of
cyclopentadiene to cinnamaldehyde and crotonaldehyde to
give the products with good exo stereoselectivities and
enantioselectivities of up to 71%.
Following our studies in this area, the trifluoroacetate
salts of compounds 1–5 were used in the enantioselective
Diels–Alder reaction between cyclopentadiene and cinnam-
aldehyde [Table 7; Equation (a) in Scheme 4]. Typically the
reaction was run for 72 h at 25 °C, in the presence of
5 equiv. cyclopentadiene for 1 equiv. aldehyde. Yields and
diastereoisomeric ratios were determined on the purified re-
action products.
in terms of diastereoselectivity and enantioselectivity. Cata-
lyst 1, which lacks the amino group at the 6-position,
showed almost no stereoselectivity. The other catalysts were
either less reactive (catalyst 3) or less stereoselective (2b and
4). Catalyst 5 showed excellent reactivity, but poor stereodi-
recting properties. Although the results are too preliminary
for any type of speculation, it is safe to say that even with
cinnamaldehyde, which is not a “specially designed” sub-
strate, , modification of the functionalization of the hetero-
cyclic ring of the prolinamide plays a role in controlling the
stereochemical outcome of the reaction.
Catalyst 5 was also preliminarily tested in the Michael
addition of cyclohexanone to nitrostyrene. In the presence
of 20 mol-% organocatalyst and 30 mol-% trifluoroacetic
acid, the addition product was isolated in 55% yield as a
single stereoisomer with 51% ee [Equation (b) in Scheme 4].
For sake of comparison, it should be mentioned that no
reaction occurred with catalysts 2a or 2b.
Conclusions
Trifluoroacetate salts of 2-pyridylprolinamides were in-
deed able to promote the cycloaddition reaction between
2-Pyridyl- and 2-imidazolyl-derived prolinamides have
cyclopentadiene and cinnamaldehyde, and the product was been studied as organocatalysts able to promote stereoselec-
formed in good yields, usually with exo stereoselectivity. tive C–C bond-forming reactions. The aldol condensation
The level of enantioselectivity of this process was unsatis- between cyclohexanone and different aromatic aldehydes
factory, since a maximum of 57% ee was reached. However, gave the products with moderate to very high enantio-
it is interesting to compare the results from the different selectivities (up to 98% ee), depending on the nature of the
catalysts bearing in mind the groups at the 6-position of substituents at the aryl ring. In preliminary experiments tri-
their pyridine rings. Catalyst 2a gave the best performance fluoroacetate salts of the chiral prolinamides were also used
Eur. J. Org. Chem. 2013, 2346–2354
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2351

M. Orlandi, M. Benaglia, L. Raimondi, G. Celentano
FULL PAPER
80 °C. [α]2D3 = –107.5 (c = 0.33 in CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 9.10 (br. s, 1 H, NH), 7.87 (br. d, 2 H, Py-H), 7.65
(br. t, 1 H, Py-H), 4.25 (m, 2 H, CHN), 3.50 (m, 4 H, CH2N),
2.40–1.90 (m, 8 H, CH2CH2), 1.40 [s, 18 H, C(CH3)3] ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.2, 158.6, 149.0, 140.5, 109.3, 80.8,
61.0, 47.1, 30.8, 29.4, 24.2 ppm.
for the first time as catalysts in Diels–Alder reactions be-
tween cyclopentadiene and cinnamaldehyde. A Michael re-
action was also successfully catalysed by the 2-imidazolyl-
derived prolinamide. Computational studies have been per-
formed to clarify the stereochemical behaviour of the cata-
lysts and to understand the role of the different structural
components of the chiral prolinamides in the interactions
between the catalyst and the reactants. The straightforward
synthesis of the new organocatalysts and a deep insight into
the transition-state structures of the reactions achieved by
PM6 calculations are further advantages of the reported
methodology. These studies represent a starting point for
the development of designed chiral compounds where mo-
lecular recognition processes between catalyst and reactants
may lead to the generation of supramolecular self-as-
sembled organocatalysts with new catalytic properties.
(S)-N-(6-Aminopyridin-2-yl)pyrrolidine-2-carboxamide (2a): White
solid, m.p. 55–59 °C. [α]2D3 = –35.5 (c = 0.27 in CH2Cl2). H NMR
1
(300 MHz, CDCl3): δ = 9.80 (br. s, 1 H, NH), 7.56 (d, 1 H, Py-H),
7.41 (t, 1 H, Py-H), 6.22 (d, 1 H, Py-H), 4.30 (br., 2 H, NH2), 3.85
(m, 1 H, CHN), 3.00 (m, 2 H, CH2N), 2.20–2.00 (m, 2 H,
CH2CH2), 1.95–1.85 (m, 2 H, CH2CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.5, 157.0, 149.0, 140.7, 128.7, 104.1, 103.1, 67.5,
61.0, 47.2, 31.1, 24.3 ppm.
(2S,2ЈS)-2,2Ј-[Pyridine-2,6-diylbis(azanediyl)]bis(pyrrolidine-2-
carboxamide) (2b): White solid, m.p. 115–117 °C. [α]2D3 = –117.5 (c
1
= 0.11 in CH2Cl2). H NMR (300 MHz, CDCl3): δ = 9.70 (br. s, 1
H, NH), 7.66 (br. d, 2 H, Py-H), 7.55 (br. t, 1 H, Py-H), 3.95 (m,
2 H, CHN), 3.10 (m, 4 H, CH2N), 2.20–2.05 (m, 2 H, CH2CH2),
1.90–1.75 (m, 2 H, CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.5, 157.5, 149.0, 108.1, 68.5, 61.9, 49.2, 32.1 ppm.
Experimental Section
General Methods: TLC was performed on Merck silica gel 60 TLC
plates F254 and visualized using UV light or phosphomolybdic
acid. Flash chromatography was carried out on silica gel (230–
400 mesh). 1H NMR spectra were recorded at 300 MHz and 13C
NMR spectra were obtained at 75 MHz. Chemical shifts were cal-
ibrated using tetramethylsilane (for 1H) or residual solvent peaks
(for 13C). Optical rotations were obtained with a Perkin–Elmer 241
polarimeter at 589 nm. HPLC for ee determination was performed
with an Agilent 1100 instrument under the conditions reported be-
low. Semiempirical and DFT calculations were performed with
Gaussian09.[16–17] Frequency calculations allowed the characteriza-
tion of transition-state structures and the calculation of ZPE-cor-
rected free energies.
(S)-tert-Butyl 2-[6-(2,2,2-Trifluoroacetamido)pyridin-2-ylcarb-
1
amoyl]pyrrolidine-1-carboxylate (8): H NMR (300 MHz, CDCl3):
δ = 9.55 (br. s, 1 H, NH), 8.20 (br. s, 1 H, NH), 8.00 (d, 1 H, Py-
H), 7.86 (d, 1 H, Py-H), 7.75 (t, 1 H, Py-H), 4.45 (br. m, 1 H,
CHN), 3.48 (br. m, 2 H, CH2N), 2.27 (br. m, 2 H, CH2CH2), 1.96
(m, 2 H, CH2CH2), 1.47 [s, 9 H, C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.79, 155.55, 154.54, 150.08, 147.11,
141.10, 111.45, 109.84, 81.18, 60.88, 47.29, 28.36, 24.44 ppm. 19F
NMR (282.1 MHz, CDCl3): δ = –77.75 ppm.
(S)-tert-Butyl 2-[6-(4-Methylphenylsulfonamido)pyridin-2-ylcarb-
1
amoyl]pyrrolidine-1-carboxylate (9): H NMR (300 MHz, CDCl3):
δ = 9.30 (br. s, 1 H, NH), 8.75 (br. s, 1 H, NH), 7.86 (br. d, 1 H,
Py-H), 7.73 (d, 2 H, Ph-H), 7.59 (br. t, 1 H, Py-H), 7.23 (d, 2 H,
Ph-H), 7.06 (br. d, 1 H, Py-H), 4.35 (br. m, 1 H, CHN), 3.50 (br.
m, 2 H, CH2N), 2.38 (s, 3 H, PhCH3), 2.16 (br. m, 2 H, CH2CH2),
2.16 (m, 2 H, CH2CH2), 1.91 [s, 9 H, C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.72, 155.77, 154.22, 150.24, 148.78,
144.28, 140.90, 136.28, 129.77, 127.28, 109.67, 108.41, 80.62, 61.57,
47.11, 28.30, 24.35, 21.54 ppm.
Synthesis of Catalysts 2a and 2b, General Procedure: The synthesis
of catalyst 2a is reported as an example. 2,6-Diaminopyridine
(1.1 mmol) was added to a stirred mixture of (S)-Boc-proline
(1 mmol), EDC (3 mmol), and HOBt (hydroxybenzotriazole;
1 mmol) in DCM (3 mL) at room temperature. After 48 h, the mix-
ture was diluted with CH2Cl2 (7 mL), washed with HCl (3.7% aq.;
3ϫ 10 mL), and dried with Na2SO4. A concentrated solution ob-
tained under reduced pressure was purified by flash chromatog-
raphy on silica gel (hexane/ethyl acetate) to give the precursor of
2a, compound 7 (65%). To synthesise catalyst 2b, the condensation
of (S)-Boc-proline (2 equiv.) and 2,6-diaminopyridine (1 equiv.)
gave the precursor of 2b, compound 6 (61%), along with com-
pound 7 (27%). To obtain unprotected catalysts 2a or 2b, Boc de-
rivatives 6 or 7 were treated with a 1:1 TFA/CH2Cl2 solution for
30 min at room temp. Then CH2Cl2 was added to the reaction mix-
ture, the resulting solution was washed three times with NaHCO3
(sat. aq.), the organic extracts were dried, and the solvents were
evaporated under vacuum to give catalyst 2a or 2b (quantitative).
Synthesis of Catalyst 5: Oxalyl choride (4.8 mmol) was added to a
solution of Cbz-proline (1 g, 4 mmol) in CH2Cl2 under an inert
atmosphere. The reaction mixture was stirred at 40 °C for 4 h. After
this time, the solution of crude Cbz-proline chloride was concen-
trated under reduced pressure and the residue was dissolved in
DMF to give solution A. A mixture of 2-imidazolamine hydrogen
sulfate (2 mmol), DIPEA (16 mmol), and a catalytic amount of
DMAP (100 mg) in DMF was prepared (solution B). Solution A
was slowly added to solution B at 0 °C under a nitrogen atmo-
sphere. The resulting reaction mixture was allowed to warm to
room temp., and then it was stirred for 12 h. The reaction mixture
was concentrated under reduced pressure, and the residue was puri-
fied by flash chromatography on silica gel (CH2Cl2/MeOH) to give
Cbz-5 (30%).
(S)-tert-Butyl 2-(6-Aminopyridin-2-ylcarbamoyl)pyrrolidine-1-carb-
oxylate (7): Waxy solid. [α]2D3 = –67.5 (c = 0.23 in CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 9.20 (br. s, 1 H, NH), 7.80 (br. d, 1
H, Py-H), 7.45 (br. t, 1 H, Py-H), 6.32 (br. d, 1 H, Py-H), 4.40 (br.,
2 H, NH2), 4.35 (m, 1 H, CHN), 3.50 (m, 2 H, CH2N), 2.20–1.90
(m, 4 H, CH2CH2), 1.38 [s, 9 H, C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.5, 158.0, 151.0, 139.7, 128.4, 110.1,
108.7, 81.8, 61.2, 48.7, 30.7, 29.1, 24.0 ppm. HRMS (ESI+): calcd.
for C15H22N4O3Na [M + Na]+ 329.1590; found 329.15824.
Catalyst 5 was obtained in quantitative yield by hydrogenation of
Cbz-5 over Pd/C (10 %) in MeOH. Catalyst 5 was purified by
crystallization from chloroform before use.
(S)-Benzyl 2-[(1H-Imidazol-2-yl)carbamoyl]pyrrolidine-1-carboxyl-
ate (Cbz-5): White solid, [α]2D3 = –93.8 (c = 0.28 in CHCl3). 1H
(2S,2ЈS)-Di-tert-butyl
(carbonyl)}bis(pyrrolidine-1 carboxylate) (6): White solid, m.p. 77–
2,2Ј-{[Pyridine-2,6-diylbis(azanediyl)]bis- NMR (300 MHz, CDCl3): δ = 6.89 (s, 2 H, Im-H), 4.27 (br. m, 1
H, CHN), 3.38 (m, 2 H, CH2N), 2.41 (m, 1 H, CH2CH2), 2.16 (m,
2352
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2346–2354

Multifunctional Organic Catalysts
3 H, CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.29,
155.48, 154.76, 142.52, 139.07, 136.46, 128.46, 128.23, 127.93,
117.61, 105.92, 67.28, 60.54, 60.26, 47.36, 46.97, 40.24, 31.55,
29.97, 24.46, 23.72 ppm. ESI-MS: m/z = 337.12683 [M + Na]+,
315.14521 [M + H]+.
[4]
[5]
[6]
[7]
S. M. Opalka, J. L. Steinbacher, B. A. Lambiris, D. T.
McQuade, J. Org. Chem. 2011, 76, 6503.
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(S)-N-(1H-Imidazol-2-yl)pyrrolidine-2-carboxamide (5): 1H NMR
(300 MHz, CDCl3): δ = 6.89 (s, 2 H, Im-H), 4.27 (br. m, 1 H,
CHN), 3.38 (m, 2 H, CH2N), 2.41 (m, 1 H, CH2CH2), 2.16 (m, 3
H, CH2CH2) ppm.
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2011, 52, 3298, and references cited therein.
Under these conditions, catalysts 3 and 4, and known catalyst
1, gave modest results, with reactivities comparable with or
lower than catalyst 2a. The introduction of protons of different
acidities (trifluoroacetamide and p-toluenesulfonamide groups)
did not significantly alter the reactivity of the catalysts, and
apparently neither did it modify the substrate-recognition pro-
cess. However, all catalysts 1–5 were tested in the Diels–Alder
reaction (see below).
In view of the fact that these catalysts have been used in as-
sembly or molecular recognition phenomena, mainly through
hydrogen bonding, non-polar solvents were selected. However,
it should be mentioned that the reaction of cyclohexanone with
4-nitrobenzaldehyde and benzaldehyde in DMF gave the corre-
sponding aldol products in 15 and 12% yields, respectively,
with modest anti selectivity and low enantioselectivity.
Reviews: a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289; b)
P. M. Pihko, Angew. Chem. 2004, 116, 2110; Angew. Chem. Int.
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Aldol Reaction. Typical Procedure: Cyclohexanone (0.6 mmol) was
added to a solution of catalyst (0.04 mmol) and the appropriate
aldehyde (0.2 mmol) in chloroform (0.3 mL). The mixture was
stirred for 72 h at room temperature. After this time, the reaction
mixture was concentrated under reduced pressure, and the residue
was purified on silica gel, eluting with mixtures of hexane/ethyl
acetate.
[8]
[9]
Diels–Alder Reaction. Typical Procedure: Aldehyde (0.3 mmol) was
added to a stirred solution of catalyst (0.03 mmol) in CHCl3
(0.3 mL) under an inert atmosphere. After 5 min, cyclopentadiene
(1.5 mmol) was added, and the reaction mixture was allowed to stir
for 72 h at 25 °C. The reaction mixture was concentrated to dryness
under reduced pressure, and the residue was analysed by NMR
spectroscopy. The yield and diastereoisomeric ratio were confirmed
after isolation of the product by flash chromatography on a short
silica gel column, eluting with mixtures of ethyl acetate/hexanes.
The ee values were determined by HPLC analysis of the alcohols
obtained by NaBH4 reduction of the cycloadducts [for the exo iso-
mer: Chiralpak OJ-H column, hexane/2-propanol (7:3); flow rate
0.8 mL/min; λ 225 nm: tmajor = 38.7 min, tminor = 51.8 min].
[10]
[11]
Michael Reaction. Typical Procedure: A mixture of cyclohexanone
(300 μL) and catalyst (0.04 mmol) was stirred for 10 min. After this
time, nitrostyrene (0.2 mmol) was added, and the reaction mixture
was stirred for 72 h at room temperature. The reaction was then
purified on silica gel, eluting with mixtures of hexane/ethyl acetate.
[12]
[13]
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of catalysts 2a and 5 and descriptions of their
synthesis, selected HPLC traces of the aldol products, coordinates
of all B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p) transition-state struc-
tures.
Acknowledgments
Financial support by Ministero dell’Università e della Ricerca
(MIUR-PRIN, Rome) within the national project Nuovi metodi
catalitici stereoselettivi e sintesi stereoselettiva di molecole funzion-
ali is gratefully acknowledged. M. B. thanks the European Union
(COST Action CM0905-Organocatalysis). Special thanks go to Dr.
Michele Ceotto for his invaluable help in discussing the computa-
tional studies.
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[17]
Eur. J. Org. Chem. 2013, 2346–2354
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2353

M. Orlandi, M. Benaglia, L. Raimondi, G. Celentano
FULL PAPER
Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Mil-
lam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
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Received: December 5, 2012
Published Online: February 28, 2013
2354
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Eur. J. Org. Chem. 2013, 2346–2354