Prolinamides of Aminouracils, Organocatalyst Modifiable by Complementary Modules

Article abstract of DOI:10.1002/ejoc.201800886

We report the synthesis and evaluation of prolinamide organocatalysts that incorporate aminouracils. The features of these catalysts are enhanced NH acidity of the amide because of the electron-withdrawing nature of the heterocycle, an additional hydrogen-bond donor at the α or β positions of this functional group (using 6-aminouracil or 5,6-diaminouracil respectively), and it can be recovered due to its low solubility and used again without decreasing the enantioselectivity. A unique feature of these systems is the self-assembly capability with complementary modules by Watson–Crick interactions. These supramolecular adducts behave differently from the catalyst alone, some of them have lower performance but others improve the selectivity of the product. Therefore, this approach avoids the synthesis of many catalysts.

Full text of DOI:10.1002/ejoc.201800886

A Journal of
Accepted Article
Title: Prolinamides of aminouracils, organocatalyst modifiable by
complementary modules
Authors: Karen M. Ruíz-Pérez, Beatriz Quiroz-García, and Marcos
Hernández-Rodríguez
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800886
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10.1002/ejoc.201800886
European Journal of Organic Chemistry
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Prolinamides of aminouracils, organocatalyst modifiable by
complementary modules
Karen M. Ruíz-Pérez[a], Beatriz Quiroz-García[a], Marcos Hernández Rodríguez*[a]
Abstract: We report the synthesis and evaluation of prolinamide
organocatalysts that incorporate aminouracils. The features of these
catalysts are enhanced NH acidity of the amide because of the
electron withdrawing nature of the heterocycle, additional hydrogen
bond donor at the α or β positions of this functional group (using 6-
aminouracil or 5,6-diaminouracil respectively), and it can be recovered
due to its low solubility and used again without losing
enantioselectivity. A unique feature of these systems is that the self-
assembly capability with complementary modules by Watson-Crick
interactions. These supramolecular adducts behave differently from
the catalyst alone, some of them have lower performance but others
improve the selectivity of the product. Therefore, this approach avoids
the synthesis of many catalysts.
the potential to improve the stereoselectivity.[7,8] This approach
opens the option of a tunable system that avoids the synthesis of
many catalysts[9] (Figure 1).
Introduction
Organocatalysis is an established toolkit to build chiral
molecules.[1] Among these methods, aminocatalysis is used to
activate aldehydes or ketones by primary or secondary amines
trough enamine or iminium species.[2] Prolinamide aminocatalysts
induce enantioselectivity through the cyclic Houk-List model.
Consequently, the hydrogen bonding properties of the NH donor
of the amide is crucial in this TS.[3] The substitution of the
carboxylic functional group of proline A to amide B allows a higher
solubility of the catalyst, lower catalyst loading, avoid stationary
resting states and overall higher selectivity.
Studies with
prolinamides have found that higher NH acidity or another
hydrogen bond (HB) donor group, C and D respectively, enhance
the selectivity of the catalyst.[4] In this manuscript, we studied
prolinamides of aminouracils[5] under the hypothesis that the
electron withdrawing properties of the uracil in aminocatalyst 1
would provide good HB donor properties to the NH moiety.
Besides, the substitution pattern in the uracil allows the possibility
of an additional hydrogen bond donor as shown in structures 2
and 3 at a different distance from the aforementioned NH. Another
interesting feature of the proposed aminocatalyst (AC) is the
possibility to self-assemble to other molecules by HB to form
supramolecular adducts E. The different scaffolds that have been
developed to pair with uracil[6] can be exploited to create with the
developed systems diverse supramolecules. In principle, each
adduct can be a catalyst with a different steric environment with
Figure 1. Hypothesis for the catalyst in this work.
Results and Discussion
Besides catalyst 1 and 2 mentioned above, we studied diamino
uracil 3a and the dimethylated analog 3b. Other systems that are
not prolinamides but incorporate uracil or guanine, 4 and 5
respectively, were also aimed in this study and the phenylalanine
amide 6 (Figure 2).
[a]
Instituto de Química, Universidad Nacional Autónoma de México.
Circuito Exterior, Ciudad Universitaria, Del. Coyoacán, C.P. 04510
México, Cd. Mx., México.
E-mail: marcoshr@unam.mx
https://www.iquimica.unam.mx/departamentos/qorg/95-deps/qo/138-
drmarcoshernandeziq-alias
Supporting information for this article are available on the WWW
under https://doi.org/
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Scheme 1. Synthesis of AC 1.
The 6-aminouracil showed lower reactivity and scarce solubility,
so the prolinamide couldn’t be obtained by a variety of activating
agents and conditions. We solved this issue employing an oxygen
protected analog (4-amino-2,6-dibenzyloxypyrimidine, 10) which
reacted with the activated proline and after removal of protecting
groups of 11 AC 2 was obtained. The 5,6-diaminouracil it is
reported to be prone to dimerize by oxidation by air exposure.[10]
Therefore, we used the same strategy employing pyrimidine 10 as
starting material. The amino group was introduced by nitrosation
and further reduced to the desired compound 12. The coupling of
diaminopyrimidine 12 with N-Boc-proline yielded 13 and the
removal of protecting groups led us to catalyst 3a. With
commercially available 1,3-dimethyl-5,6-diaminouracil 14 was
synthesized 3b using the same conditions. In both cases, the
connectivity to the 5-amino group was correlated through NMR
experiments (Scheme 2).
Figure 2. New catalyst examined in this work.
The overall synthetic approach to obtain the ACs was to couple N-
Boc protected proline 7 activated by isobutyl chloroformate (IBCF)
and add the corresponding commercially available aminouracil.
With this method, 5-aminouracil was attached and obtained 8,
which after removal of the protecting group afforded 1 (Scheme 1).
Compound 6 was made by the same procedure employing N-Cbz-
phenylalanine as starting material (not shown).
Scheme 2. Synthesis of AC 2, 3a-b.
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Scheme 3. Synthesis of AC 4 and 5.
To study catalysts without the NH of the amide, we considered
other ACs with uracil and guanine 4 and 5 respectively. We
reduced the carboxyl group of proline and transformed to the
bromoalkyl compound 16. This compound reacted with N3-Bz
uracil 17 to obtain compound 18 in 33 % along with the N3-Bz
analog in 48 %. The removal of the Boc group, afforded AC 4.
The direct nucleophilic substitution of 16 with guanine failed. We
employed chloropurine 19 as a substrate, and not only it was
successfully attached, but also the desired regioisomer 20 was
the major product. The acidic hydrolysis led to AC 5 (Scheme 3).
examined very polar solvents in which the catalyst was
completely soluble. In DMF or DMSO (Table 1, entries 8-9) the
aldol compound can be obtained. Particularly, in DMF a good
yield and acceptable 85:15 enantiomeric ratio (70 % ee) was
attained. With a mixture DMF/chloroform or NMP the product
was obtained but lower yield compared to pure DMF (Table 1,
entries 10-11). Other conditions for the reaction optimization can
be found in the ESI.
Table 1. Screening of solvents of the model aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde with catalyst 1.[ a]
The aldol reaction between ketones and aldehydes is the
archetypical reaction to study the new ACs.[11] We chose
cyclohexanone and 4-nitrobenzaldehyde as reactants to
examine the performance of these compounds (Scheme 4).
Entry
Solvent
Yield (%)[b]
d.r.
anti/syn
ee
(%)[c]
1
CHCl3
Traces
9
-
-
2
THF
84/16
84/16
92/8
50
56
92
88
84
34
70
70
72
78
3
Dioxane
11
4
MeOH
19
5
Neat
12
83/17
88/12
55/45
83/17
84/16
91/9
Scheme 4. Aldol reaction between cyclohexanone and 4-nitrobenzaldehyde.
6
CHCl3/MeOH 2:1
CHCl3/MeOH 2:1 50 C
DMF[d]
30
7
54
Catalyst 1 was studied in common organic solvents. We
observed that in non-polar media, such as chloroform, no
product was found whereas increasing the polarity of the solvent
some aldol compound was formed (Table 1, entries 1-4). If the
reaction was done without solvent a similar result in yield was
obtained (Table 1, entry 5). The reason for this low activity is the
low solubility of the catalyst in common solvents. A mixture
chloroform/methanol at room temperature slightly increased the
yield and at higher temperature moderate yield with loss of
selectivity was the outcome (Table 1, entries 6-7). Next, we
8
82
9
DMSO[d]
59
10
11
DMF/CHCl3 1:2[d]
NMP[d]
24
59
81/19
[a] Reaction conditions: cyclohexanone (1.5 mmol), 4-nitrobenzaldehyde (0.3
mmol) and catalyst (5 mol%), 0.5 M, room temperature, 72 h. [b] Isolated yield.
[c] Determined by chiral HPLC analysis. [d] Concentration 0.88 M.
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Table 2. Evaluation of the new AC in the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde.[a] It is shown yield, d.r. and ee in parenthesis for each
experiment.
[a] Reaction conditions: cyclohexanone (1.5 mmol), 4-nitrobenzaldehyde (0.3 mmol) and catalyst (5 mol%), DMF, 0.88 M, 72 h. [b] It was studied the free amino and
the TFA salt, on both experiments little product was found.
We choose DMF as the solvent to study all the catalysts so the
solubility would not be an issue and therefore a clear evaluation
of their features can be achieved. Table 2 shows the results with
the synthesized catalysts. The 6-aminouracil in system 2 was
the most stereoselective. Diaminouracils 3a and 3b with the
hydrogen bond donor in β position presented lower selectivity
compared to 1 or 2. It was not surprising that compound 4 could
not get good diastereo or enantioselectivity due to the lack of the
hydrogen bond donor. The ACs with guanine 5 or phenylalanine
6 instead of proline did not promote the reaction.
Table 3. Substrate scope of aldehydes with catalysts 1 and 2.[a] It is shown yield, d.r. and ee in parenthesis for each experiment.
[a] Reaction conditions: cyclohexanone (1.5 mmol), aldehyde (0.3 mmol) and catalyst (5 mol%), DMF, 0.88 M, 120 h.
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A further comparison between catalyst 1 and 2 with different
aldehydes showed a better performance of the latter over the
former. The reaction showed a strong dependence on the
electrophilic character of the aldehyde. It was obtained good yield
and selectivity with aromatic aldehydes with electron withdrawing
groups (Table 3, 21b-g). Benzaldehyde, 1-naphthaldehyde and p-
tolualdehyde showed moderate to low yield and selectivity (Table
3, 21h-j). Aromatic aldehydes with electron donating groups no
reactivity was found (Table 3, 21k-l). Aldehydes attached to
heterocyclic rings have also a dependency on the ring character.
Therefore, the aldehyde containing electron rich furan a low
reactivity was found whereas with pyridine a similar behavior as
the phenyl with electronwithdrawing groups was obtained (Table 3,
21m-n). It was found that employing acyclic ketones the reaction
was sluggish and with enolizable aldehydes further condensation
of the product prevents isolation in good yield like in the aldol 23.
Table 4. Substrate scope of cyclic ketones.a It is shown yield, d.r. and ee in parenthesis for each experiment.
[a] Reaction conditions: cyclohexanone (1.5 mmol), aldehyde (0.3 mmol) and catalyst (5 mol%), DMF, 0.88 M, 120 h.
Other cyclic ketones were studied as pronucleophiles in the
aldol reaction. Again, in all experiments compound
Next, we studied the effect of the complementary modules in the
model reaction between cyclohexanone and 4-
2
outperforms catalyst 1. Four and five-membered ring ketones
favor the syn diastereomer, whereas six and seven-membered
cyclic ketones the anti diastereomer was obtained with high ee
employing catalyst 2 (Table 4).
nitrobenzaldehyde. We first employed catalyst 1 due to the
possibility to improve the moderate selectivity of this system.
The examined complementary modules that bind to uracil by
Watson-Crick pairing, some are commercially available or
already reported the synthesis.
Figure 3. Effect of the complementary modules in the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde with catalyst 1. It is shown yield, d.r. (ee) of
each experiment. *With i-Pr at N9. Reaction conditions: cyclohexanone (1.5 mmol), aldehyde (0.3 mmol), 5 % 1, 5% module, DMF, 0.88 M, 120 h.
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The 2,6-diaminopyridines (Py), 2,4-diaminopyrimidines (PyMD),
2,6-diaminopurines (DP) and adenine (A) were modified in the
amino group with acyl derivatives to enhance the NH hydrogen
bond donor properties and with benzyl and phenyl to provide a
different steric environment of the module. Comparing the results
with and without additive we found the designed effect. Some of
the examined molecules diminished the ee (acyl derivatives)
whereas the unsubstituted diaminopyridine (Py-a) notably
improved the outcome of the reaction being almost as selective as
catalyst 2.[12] We also observed that unsubstituted diaminopurine
and adenine increased the selectivity of the reaction (Figure 3).
We also explored the effect of Py-a on the performance of catalyst
2 through the Watson-Crick pairing between these compounds
(green, Figure 4). It was found that in all cases the supramolecular
adduct showed a positive effect on the yield and selectivity of the
reaction compared to the result with catalyst 2 solely.
Scheme 5. Effect of two different complementary modules on the performance of
catalyst 2. It is shown yield, d.r. (ee) of each experiment. Reaction conditions:
cyclohexanone (1.5 mmol), aldehyde (0.3 mmol), 5 % 1, 5% module, DMF, 0.88
M, 120 h.
We used cytosine to test the importance of the NH in the
prolinamide on the reaction to obtain 21g. The self-assemble
hinders the prolinamide NH (together with N1H and C2=O) and as
expected a drop in the yield and selectivity (31 % yield) was found.
This drop in yield was more pronounced with aldol 25 where no
reaction occurs. The addition of cytosine could be a strategy to
change the amino catalyst from a hydrogen bond donor to only
steric effect on the reaction without planning a new synthesis
(Scheme 5).
We further provide insights on the binding between 5-aminouracil
and Py-a by studying the stoichiometry and the binding between
these compounds in a polar media with H-Bond acceptor capacity.
The stoichiometry was addressed by Job’s continuous variation
method[13] using compound 8 and Py-a showed the expected 1:1
ratio between these species (Figure 5). We also used DOSY
experiments in DMSO-d6 to study the hydrodynamic radius (rH) of
these compounds and mixtures 8/Py-a (1:1 and 1:2) (See Figures
S3-S6 in the ESI). The experiment showed that there is
dissociated species in equilibrium with associated species with an
increment of the rH of the catalyst in the mixture of compounds.
Figure 4. Effect of the complementary modules in the aldol reaction employing
catalyst 2 (1st row, black) and 2 + Py-a (2nd row, green). It is shown yield, d.r.
(ee) of each experiment. Reaction conditions: cyclohexanone (1.5 mmol),
aldehyde (0.3 mmol), 5 % 1, 5 % module, DMF, 0.88 M, 120 h.
Figure 5. Job’s plot analysis between 8 and Py-a.
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1H NMR (300 MHz, DMSO-d6, mixture of rotamers):  11.45 (br, 1H, Ura-
NH3), 10.61 (br, 1H, Ura-NH1), 9.06 (s, 1H, CONH), 8.06 (s, 1H, Ura-H6),
4.40 (br, 1H, C*H), 3.41-3.24 (m, 2H, CH2N), 2.17-1.68 (m, 4H, CH2CH2),
1.39-1.29 (m, 9H, ((CH3)3) ppm. 13C NMR (75 MHz, DMSO-d6, mixture of
On the other hand, the low solubility of catalyst 2 can be an
advantage. In a 1.5 mmol scale of the model aldol reaction the
catalyst can be precipitated with EtOAc at the end, recovered and
used in another reaction. It was found that indeed the recovered
catalyst can be used and recovered in two further experiments
without loss in the enantioselectivity, albeit some erosion of the
yield (Scheme 6).
rotamers):

171.76/171.07 (CONH), 160.52 (Ura-C4), 153.85/153.20
(CO2C(CH3)3), 149.53(Ura-C2), 128.78/128.33 (Ura-C6), 113.18 (Ura-C5),
78.88/78.64 (C(CH3)3), 59.62 (C*H), 46.75/46.55 (CH2N), 30.87/28.76
(CH2C*HNH), 28.09/27.92 ((CH3)3), 23.89/23.30 (NCH2CH2) ppm. IR (KBr):
ṽ = 3283, 2829, 1680, 1656, 1244, 1201, 1173, 1128, 833, 717, 555, 520,
435 cm-1. MS-DART (positive): m/z (%) 325 (25) [M + H]+, 225(100), 269
(50). HRMS (DART/TOF): m/z [M+H]+ calcd for C14H21N4O5 325.1506;
found 325.1510.
(S)-1-tert-Butoxycarbonyl-2-((2,6-bisbenzyloxypyrimidyl-4-
yl)carbamoyl)pyrrolidine (11):
A small modification of the general
procedure. Pyrimidine 10 was dissolved in CH2Cl2 instead of DMF. Purified
by column chromatography (Hexane/EtOAc 4:1). Obtained (538 mg, 46 %)
of 11 as a white solid, mp 53 – 55 °C, [α]D25 = -33.2 (c 0.34, MeOH), Rf =
0.32 (Hexane/EtOAc 4:1 x2). 1H NMR (300 MHz, CDCl3 mixture of
rotamers):  9.38 (br, 0.5H, CONH), 8.39 (br, 0.5H, CONH), 7.45-7.30 (m,
11H, Ph-H, PyMD-H5), 5.40 (s, 2H, OCH2Ph), 5.36 (s, 2H, OCH2Ph), 4.63-
4.17 (m, 1H, C*H), 3.71-3.22 (m, 2H, CH2N), 2.49-1.87 (m, 4H, CH2CH2),
1.47 (m, 9H, (CH3)3). 13C NMR (75 MHz, CDCl3 mixture of rotamers): 
172.82 (PyMD-C2), 172.02/171.52 (CONH), 163.82 (PyMD-C6), 158.77
(PyMD-C4), 156.25/154.50 (CO2C(CH3)3), 136.48 (ipso-Ph), 136.34 (ipso-
Ph), 128.64 (Ph), 128.56 (Ph), 128.18 (Ph), 127.98 (Ph), 89.40 (PyMD-C5),
81.26 (C(CH3)3), 69.30 (OCH2Ph), 68.64 (OCH2Ph), 62.11/61.20 (C*H),
47.33 (CH2N), 30.97/29.81 (CH2C*HN), 28.44 ((CH3)3), 24.59/24.10
(NCH2CH2) ppm. IR (KBr): ṽ = 3332-2879, 1670, 1574, 1511, 1397, 1333,
1161, 1117, 736, 695 cm-1. MS-DART (positive): m/z (%) 505 (48) [M + H]+,
(308) 100. HRMS (DART/TOF): m/z [M+H]+ calcd for C28H33N4O5
505.2445; found 505.2456.
Scheme 6. Scale up and recycling of catalyst 2. It is shown yield, d.r. (ee) of
each experiment.
Conclusion
We found that aminocatalysts that incorporate aminouracils can
promote the aldol reaction in polar media. Among them, catalyst 2
with 6-aminouracil was very selective with aldehydes with
electronwithdrawing groups. It was also shown the possibility to
have a variety of catalyst by the assembly of complementary
modules in solution through Watson-Crick pairing being the result
with system 1+Py-a almost as selective as catalyst 2. Besides, the
low solubility of the catalysts makes the recovery and recycle of
the catalyst for 3 consecutive reactions.
(S)-1-tert-Butoxycarbonyl-2-((4-amino-2,6-bisbenzyloxypyrimidyl-5-
yl)carbamoyl)pyrrolidine (13):
A small modification of the general
procedure. Pyrimidine 12 was dissolved in CH2Cl2 instead of DMF. Purified
by column chromatography (CH2Cl2/MeOH, 97:3). Obtained (1000 mg,
25
83 %) of 13 as a pale yellow solid, mp 64 - 65 °C, [α]D = -47.4 (c 0.27,
MeOH), Rf = 0.4 (CH2Cl2/MeOH, 95:5). 1H NMR (300 MHz, CDCl3 mixture
of rotamers):  7.57-7.25 (m, 10H, Ph-H), 5.40-5.28 (m, 4H, OCH2-Ph),
4.35-4.24(m, 1H, C*H), 3.45-3.34 (m, 2H, CH2N), 2.26-1.56 (m, 4H,
CH2CH2), 1.42 (s, 9H, (CH3)3) ppm. 13C NMR (75 MHz, CDCl3 mixture of
Experimental section
General: All starting materials were purchased from Aldrich and used as
received. THF, toluene, diethyl ether were distilled from sodium
benzophenone ketyl. Flash column chromatography was carried out with
silica gel 60 (70-230 mesh, 63-200 m), TLC was performed with silica gel
F254 plates. Melting points are uncorrected. 1H and 13C NMR were
recorded at 300 MHz and 75 MHz respectively. Chemical shifts (δ) were
reported in ppm downfield from TMS, and coupling constants were
reported in Hertz. Mass spectra and HRMS (DART) were measured with a
quadrupole and TOF mass spectrometers. CSP-HPLC analyses were
performed using the indicated chiral column and UV detector. With hexane
HPLC Fermont, EtOH-HPLC Fermont and isopropanol-HPLC Fermont.
rotamers):

171.75 (CONH), 165.24 (PyMD-C2), 162.13 (PyMD-C6),
161.76 (PyMD-C4), 155.86 (CO2C(CH3)3), 137.03 (ipso-Ph), 128.52 (Ph),
128.43 (Ph), 128.07 (Ph), 127.89 (Ph), 93.92 (PyMD-C5), 80.89 (C(CH3)3),
68.96/68.37 (OCH2Ph), 60.77 (C*H), 47.31(CH2N), 29.79/29.30 (CH2C*HN),
28.45 ((CH3)3), 24.70 (NCH2CH2) ppm. IR (KBr): ṽ = 3435, 3291, 3148,
2958, 1692, 1640, 1577, 1514, 1419, 1350, 1240, 1138, 1042, 961, 727,
692, 438 cm-1. MS-DART (Positive): m/z (%) 520 (100) [M + H]+. HRMS
(DART/TOF): m/z [M+H]+ calcd for C28H34N5O5 520.2554; found 520.2552.
(S)-1-tert-Butoxycarbonyl-2-((2,4-dioxo-1,3-dimethyl-1,2,3,4-
tetrahydro-pyrimidin-5-yl)carbamoyl)pyrrolidine (15): Purified by
column chromatography (CH2Cl2/MeOH, 100-0 to 97:3). Obtained (367 mg,
43 %) of 15 as a pale yellow foam, mp 130 - 133 °C, [α]D25 = -0.73 (c 0.27,
CHCl3), Rf = 0.5 (CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3):  7.44 (s,
1H, CONH), 5.75 (s, 2H, Ura-NH2), 4.24-4.20 (m, 1H, C*H), 3.58-3.48(m,
2H, CH2N), 3.41 (s, 3H, Ura-N1CH3), 3.28 (s, 3H, Ura-N3CH3), 2.31-1.82 (m,
4H, CH2CH2), 1.43 (s, 9H, (CH3)3) ppm. 13C NMR (75 MHz, CDCl3): 
172.78 (CONH), 160.58 (Ura-C4), 155.68 (CO2C(CH3)3), 151.33 (Ura-C6),
150.90 (Ura-C2), 88.37(Ura-C5), 80.84(C(CH3)3), 61.20 (C*H), 47.54
(CH2N), 30.22 (CH2C*HN), 29.66 (Ura-N1CH3), 28.53((CH3)3), 28.27 (Ura-
N3CH3), 24.77 (NCH2CH2) ppm. IR (KBr): ṽ = 3324-2881, 1622, 1588, 1504,
1403, 1160, 755, 495 cm-1. MS-DART (Positive): m/z (%) 368 (100) [M +
H]+. HRMS (DART/TOF): m/z [M+H]+ calcd for C16H26N5O5 368.1928; found
368.1938.
General procedure for coupling of N-Boc-L-proline with aminouracils
and aminopyrimidines. Synthesis of compounds 8, 11, 13, 15: N-Boc-
L-proline (500 mg, 2.32 mmol, 1.0 equiv) was dissolved in 15 mL of CH2Cl2
under N2 atmosphere. It was cooled to 0 °C and added N-methylmorpholine
(NMM) (0.33 mL, 3.0 mmol, 1.3 equiv) and after
5 min, isobutyl
chloroformate (0.4 mL, 2.8 mmol, 1.2 equiv) was slowly added. The
reaction mixture was stirred 1 h at 0 °C, then NMM (0.33 mL, 3.0 mmol, 1.3
equiv) and a suspension of the corresponding aminouracil (2.32 mmol, 1.0
equiv) in 10 ml of DMF were added. The reaction was kept at 0°C for 2 h
and at room temperature overnight. The solvent was evaporated and the
residue purified by column chromatography with a mixture of solvents
indicated in each compound.
(S)-1-tert-Butoxycarbonyl-2-((2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-
yl)carbamoyl)pyrrolidine (8): Purified by column chromatography
(CH2Cl2/MeOH, 97:3). Obtained (557 mg, 74 %) of 8 as a white solid, mp
145 - 150 °C, [α]D25 = -74.8 (c 0.22, MeOH), Rf = 0.48 (CH2Cl2/MeOH, 9:1).
General procedure for the Boc removal. Catalysts 1, 3b and 4: N-Boc-
proline derivative (2.36 mmol, 1.0 equiv) was dissolved in 4 mL of CH2Cl2
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and added 2.3 mL (30.1 mmol, 13 equiv) of trifluoroacetic acid. The
reaction was stirred for 2 - 3 h. The reaction mixture was concentrated and
the solid washed with EtOAc to obtain the pure catalysts 1, 3b, 4.
225 (100) [M + H]+. HRMS (DART/TOF): m/z [M+H]+ calcd for C9H13N4O3
225.0982; found 225.0987.
(S)-2-((2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-
(S)-N-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-prolinamide
yl)carbamoyl)pyrrolidine trifluoroacetate (3a): Obtained (799 mg, 95 %)
of a 3a as a white solid, mp 220°C decom., [α]D25 = +1.11 (c 0.27, MeOH),
Rf = 0.2 (MeOH/i-PrOH/NH4OH, 3:7:1). 1H NMR (300 MHz, DMSO-d6): 
10.51 (br, 1H, NH), 10.37 (s, 1H, NH), 9.20 (br, 1H,NH), 8.91 (s, 1H, NH),
6.40 (s, 1H, CONH), 4.28-4.23 (m, 1H, C*H), 3.24-3.20 (m, 2H, CH2NH),
2.39-2.28 (m, 1H, CH2C*HNH), 2.07-1.82 (m, 3H, CH2CH2) ppm. 13C NMR
(75 MHz, DMSO-d6):  168.85 (CONH), 161.18 (Ura-C4), 151.88 (Ura-C6),
149.82 (Ura-C2), 85.41 (Ura-C5), 59.24 (C*H), 45.86 (CH2NH), 29.45
(CH2C*HNH), 23.64 (NHCH2CH2) ppm. IR (KBr): ṽ = 3174-2984, 1671,
1607, 1196, 1130, 798, 763, 720, 531 cm-1. MS-DART (Positive): m/z (%)
240 (90) [M + H]+, 116 (100), 89 (60). HRMS (DART/TOF): m/z [M+H]+
calcd for C9H14N5O3 240.1091; found 240.1099.
trifluoroacetate (1): Obtained (776 mg, 97 %) of 1 as a white solid, mp
25
230 - 234 °C, [α]D = -33.3 (c 0.20, MeOH), Rf = 0.39 (MeOH/i-
1
PrOH/NH4OH (3:7:1). H NMR (300 MHz, DMSO-d6):  11.49 (s, 1H, Ura-
NH3), 10.88 (br, 1H, Ura-NH1), 9.90 (s, 1H, CONH), 9.18 (br, 2H, N+H2),
8.04 (s, 1H, Ura-H6) 4.49-4.45 (m, 1H, C*H), 3.28-3.18 (m, 2H, CH2NH),
2.37-2,29 (m, 1H, CH2C*HNH), 1.98-1.72 (m, 3H, CH2CH2) ppm. 13C NMR
(75 MHz, DMSO-d6):  167.49 (CONH), 160.57 (Ura-C4), 158.56 (q, J =
31.3 Hz, F3CCO), 149.76 (Ura-C2), 131.41 (Ura-C6), 117.21 (q, J =299.2
Hz, F3C), 112.33 (Ura-C5), 59.20 (C*H), 45.87 (CH2NH), 29.90
(CH2C*HNH), 23.58 (NHCH2CH2) ppm. IR (KBr): ṽ = 3283-2829, 1651,
1556, 1201, 1173, 1128, 833, 717, 555, 520, 435 cm-1. MS-DART
(positive): m/z (%) 225 (35) [M + H]+, 115 (100), 116 (40). HRMS
(DART/TOF): m/z [M+H]+ calcd for C9H13N4O3 225.0982; found 225.0988.
Synthesis of pyrimidines 10 and 12. 4-amino-2,6-dibenzyloxy-
pyrimidine (10): A suspension of 460 mg (11.6 mmol, 4.5 equiv) of sodium
hydride (60% wt, previously washed with anhydrous Et2O) in 30 mL of
anhydrous toluene was slowly added 2 mL (19.0 mmol, 7.3 equiv) of benzyl
alcohol. When the hydrogen evolution stopped, it was added 800 mg (2.6
mmol, 1.0 equiv) of 6-amino-2,4-dichloropyrimidine (9). The reaction
mixture was refluxed for 16 h under nitrogen atmosphere. It was cooled to
room temperature, neutralized with AcOH and the solvent was evaporated.
The product was purified by column chromatography (Hexane/EtOAc 4:1).
A white solid was obtained (995 mg, 66%), mp 95 - 96, lit. [14] 74 - 76 °C, Rf
= 0.23 (Hexane/EtOAc 4:1 x2). 1H NMR (300 MHz, CDCl3):  7.47-7.31 (m,
10H, Ph-H), 5.51 (s, 1H, PyMD-H5), 5.37-5.36 (m, 4H, OCH2Ph), 5.05 (br,
2H, NH2) ppm. 13C NMR (75 MHz, CDCl3):  171.32 (PyMD-C2), 166.05
(PyMD-C6), 164.59 (PyMD-C4), 136.97 (ipso-Ph), 136.75 (ipso-Ph), 128.46
(Ph-H), 128.33 (Ph-H), 127.95 (Ph-H), 127.90 (Ph-H), 127.89 (Ph-H),
127.77 (Ph-H), 81.44 (PyMD-C5), 68.51 (OCH2Ph), 67.81 (OCH2Ph) ppm.
IR (KBr): ṽ = 3480, 3291, 3156, 1629, 1566, 1407, 1344, 1202, 796, 739,
690 cm-1. MS-DART (positive): m/z (%) 308 (100) [M + H]+. HRMS
(DART/TOF): m/z [M+H]+ calcd for C18H18N3O2 308.1393; found 308.1399.
(S)-2-((2,4-Dioxo-1,3-dimethyl-1,2,3,4-tetrahydro-pyrimidin-5-
yl)carbamoyl)pyrrolidine trifluoroacetate (3b): Obtained (873 mg, 97%)
of 3b as a beige solid, mp 144 - 146 °C, [α]D25 = +1.21 (c 0.66, MeOH), Rf
= 0.3 (MeOH/i-PrOH/NH4OH (3:7:1). 1H NMR (300 MHz, DMSO-d6):  9.04
(s, 2H, NH), 6.82 (s, 1H, CONH), 4.35-4.31 (m, 1H, C*H), 3.32 (s, 3H, Ura-
N1CH3), 3.26-3.22 (m, 2H, CH2NH), 3.11 (s, 3H, Ura-N3CH3), 2.38-2.29 (m,
1H, CH2C*HNH), 2.10-1.90 (m, 3H, CH2CH2) ppm. 13C NMR (75 MHz,
DMSO-d6):  169.34 (CONH), 159.02 (Ura-C4), 152.28 (Ura-C6), 150.59
(Ura-C2), 86.02 (Ura-C5), 59.25 (C*H), 45.92 (CH2NH), 30.08 (Ura-N1CH3),
29.58 (CH2C*HNH), 27.52 (Ura-N3CH3), 23.62 (NHCH2CH2) ppm. IR (KBr):
ṽ = 3195, 1672, 1589, 1507, 1196, 1176, 1125, 833, 799, 757, 719, 496
cm-1.
MS-DART (Positive): m/z (%) 268 (100) [M +
H]+. HRMS
(DART/TOF): m/z [M+H]+ calcd for C11H18N5O3 268.1404; found 268.1409.
(S)-1-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-1-yl)methylpyrrolidine
trifluoroacetate (4): Obtained (864 mg, 96 %) of 4 as a white solid mp 180
25
-182 °C, [α]D = -9.6 (c 0.23, MeOH), Rf = 0.3 (MeOH/i-PrOH/NH4OH
(3:7:1). 1H NMR (300 MHz, MeOH-d4):  7.60 (d, J = 7.9Hz, 1H, Ura-C6),
5.69 (d, J = 7.9 Hz, Ura-C5), 4.17 (dd, J = 15.1, 8.8 Hz, 1H, C*HCH2N),
4.01 (dd, J = 15.1, 3.5 Hz, 1H, C*HCH2N), 3.85-3.76 (m, 1H, C*H), 3.45-
3.36 (m, 1H, CH2NH), 3.30-3.21 (m, 1H, CH2NH), 2.30-2.20 (m, 1H,
CH2C*H), 2.13-1.97(m, 2H, CH2CH2C*H), 1.83-1.70 (m, 1H, CH2C*H). 13C
NMR (75 MHz, MeOH-d4):  166.42 (Ura-C4), 153.68 (Ura-C2), 146.87
(Ura-C6), 103.16 (Ura-C5), 61.75 (C*H), 50.31 (C*HCH2N), 46.62 (CH2NH),
28.51 (CH2C*HNH), 23.48 (NHCH2CH2). IR (KBr): ṽ = 3029, 1689, 1662,
1179, 1135, 834, 800, 719, 521, 423 cm-1. MS-DART (positive): m/z (%)
196 (100) [M + H]+. HRMS (DART/TOF): m/z [M+H]+ calcd for C9H14N3O2
196.1080; found 196.1085.
4,5-diamino-2,6-bis(benzyloxy)pyrimidine (12): Pyrimidine 10 (500 mg,
1.63 mmol, 1.0 equiv) was dissolved in DMSO (4 mL) and isoamyl nitrite[15]
(230 mg, 1.95 mmol, 1.2 equiv) was added. The reaction mixture was
stirred for 4 h. Water (8 mL) was added and the suspension was stirred for
a further 2 h. The blue solid was filtered and washed with water. It was
dissolved in CH2Cl2, dried over Na2SO4, and concentrated to dryness. The
4-amino-2,6-bisbenzyloxy-5-nitrosopyrimidine was purified by column
chromatography (CH2Cl2). A blue solid was obtained (435 mg, 79%), mp
136 - 138 °C, lit.[16] 140 - 142 °C, Rf = 0.5 (CH2Cl2/MeOH 97:3). 1H NMR
(300 MHz, CDCl3):  10.13 (br, 1H, NH2), 7.55-7.32 (m, 10H, Ph-H), 6.04
(br, 1H, NH2), 5.76 (s, 2H, OCH2Ph), 5.45 (s, 2H, OCH2Ph) ppm. 13C NMR
(75 MHz, CDCl3):  173.30 (PyMD-C2), 165.90 (PyMD-C6), 149.76 (PyMD-
C4), 140.82 (PyMD-C5), 135.54 (ipso-Ph), 135.49 (ipso-Ph), 128.77 (Ph),
128.63 (Ph), 128.58 (Ph), 128.36 (Ph), 128.29 (Ph), 70.53 (CH2), 70.10
(CH2) ppm. IR (KBr): ṽ = 3359-2956, 1625, 1522, 1353, 1307, 1202, 1157,
955, 794, 744, 693, 661 cm-1. MS-DART (Positive): m/z (%) 337 (100) [M +
H]+. HRMS (DART/TOF): m/z [M+H]+ calcd for C18H17N4O3 337.1295; found
General procedure for the Boc and OBn removal. Catalysts 2 and 3a:
Prolinamide (2.38 mmol, 1 equiv) was dissolved in CH2Cl2 (4.5 mL).
Trifluoroacetic acid (26.18 mmol, 11 equiv) was added and the reaction
was stirred for 2 h. The solvent was evaporated, and the solid was
dissolved in MeOH (30 mL). It was added Pd/C (10%) and the reaction was
stirred for 3 h under H2 atmosphere. The reaction mixture was filtered
through Celite, washed with CH2Cl2-MeOH 1:1 (150 mL) and the solvent
was evaporated. The product was washed with EtOAc to obtain the pure
catalysts 2, 3a.
337.1305. The nitroso compound was reduced adapting
a literature
procedure.[17] Zinc powder (193.4 mg, 2.95 mmol, 5.0 equiv) was added to
a solution of 4-amino-2,6-bisbenzyloxy-5-nitrosopyrimidine (200 mg, 0.59
mmol, 1.0 equiv) in acetic acid (4 mL), the suspension was stirred for 20
min. A change in color from blue to yellow was observed. The reaction
mixture was filtered over Celite and washed with EtOAc (20 mL). The
product was concentrated to dryness and purified by column
chromatography (CH2Cl2/MeOH 95:5). A yellow solid was obtained (175
mg, 91%), mp 78 - 80 °C, Rf = 0.39 (CH2Cl2/MeOH 97:3). 1H NMR (300
MHz, CDCl3):  7.43-7-25 (m, 10H, Ph-H), 5.36 (s, 2H, CH2), 5.29 (s, 2H,
CH2) ppm. 13C NMR (75 MHz, CDCl3):  160.75 (PyMD-C2), 158.50
(PyMD-C6), 158.40 (PyMD-C4), 137.43 (ipso-Ph), 137.04 (ipso-Ph), 128.61
(Ph), 128.41 (Ph), 128.15 (Ph), 127.98 (Ph), 127.78 (Ph), 102.53 (PyMD-
C5), 68.63 (CH2), 68.30 (CH2) ppm. IR (KBr): ṽ = 3325, 3174, 1654, 1582,
1451, 1405, 1340, 1322, 1200, 1030, 880, 739, 689, 589 cm-1. MS-DART
(S)-N-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-6-yl)-prolinamide
trifluoroacetate (2): Obtained (745 mg, 92 %) of a 2 as a white solid, mp
25
260 °C decomp., [α]D
=
-16.1 (c 0.23, MeOH), Rf
=
0.5
(MeOH/iPrOH/NH4OH 3:7:1 x2). 1H NMR (300 MHz, DMSO-d6):  10.31 (br,
5H, NH), 5.84(s, 1H, Ura-C5), 4.37-4.32 (m, 1H, C*H), 3.25-3.20 (m, 2H,
CH2NH), 2.37-2.28 (m, 1H, CH2C*HNH), 2.01-1.87 (m, 3H, CH2CH2) ppm.
13C NMR (75 MHz, DMSO-d6):  169.27 (CONH), 164.53 (Ura-C4), 158.56
(q, J = 31.3 Hz, F3CCO), 150.32 (Ura-C2), 147.09 (Ura-C6), 117.21 (q, J =
299.2 Hz, F3C), 86.35 (Ura-C5), 60.01 (C*H), 46.00 (CH2NH), 29.20
(CH2C*HNH), 23.61 (NHCH2CH2) ppm. IR (KBr): ṽ = 2966-2794, 1660,
1569, 1200, 1132, 832, 720, 535, 417 cm-1. MS-DART (positive): m/z (%)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800886
European Journal of Organic Chemistry
FULL PAPER
(Positive): m/z (%) 323 (100) [M + H]+. HRMS (DART/TOF): m/z [M+H]+
Synthesis of AC 5. (S)-1-tert-Butoxycarbonyl-2-(2-amino-6-chloro-
purine-9-yl) methylpyrrolidine (20): The bromopyrrolidine 16 (947 mg,
3.6 mmol, 2 equiv) was dissolved in anhydrous DMF (30 mL). It was added
2-amino-6-chloropurine 19 (300 mg, 1.8 mmol, 1 equiv) and K2CO3 (746
mg, 5.4 mmol, 3 equiv). The reaction mixture was stirred at 70-80 ° C for 6
h. The reaction crude was concentrate to dryness and was dissolved in
DCM (100 mL), washed with water (40 mL), dried over Na2SO4 and
concentrated. The product was purified by column chromatography
(CH2Cl2/MeOH 100:0 to 99:1). A white solid was obtained (318 mg, 50 %),
mp 75 - 78 °C, [α]D25 = -85.2 (c, 0.27, DCM), Rf = 0.48 (CH2Cl2/MeOH 97:3
x2). 1H NMR (300 MHz, CDCl3 mixture of rotamers):  7.69 (s, 1H, Pur-H8),
5.25 (br, 2H, NH2), 4.41-4.09 (m, 3H, C*H, PurN9-CH2), 3.29-3.18 (m, 2H,
CH2N), 1.97-1.59 (m, 4H, CH2CH2), 1.45 (s, 9H, (CH3)3) ppm. 13C NMR (75
MHz, CDCl3 mixture of rotamers):  159.29 (Pur-C2), 155.01 (CO), 154.40
(Pur-C6), 151.40 (Pur-C4), 143.17/142.70 (Pur-C8), 125.19 (Pur-C5), 80.23
(C(CH3)3), 57.25 (C*H), 47.15/46.43 (NCH2), 45.16 (PurN9-CH2), 29.21
(C*HCH2), 28.53 (CH3)3), 23.67/22.92 (NCH2CH2) ppm. IR (KBr): ṽ =3325,
3208, 2972-2881, 1679, 1608, 1558, 1392, 1159, 1102, 908, 771 cm-1. MS-
DART (positive): m/z (%) 353 (100) [M + H]+. HRMS (DART/TOF): m/z
[M+H]+ calcd for C15H22ClN6O2 353.1487; found 353.1497.
calcd for C18H19N4O2 323.1502; found 323.1510.
Synthesis of precursor 18. (S)-1-tert-Butoxycarbonyl-2-bromomethyl-
pyrrolidine. (16): N-Boc-OTs prolinol (7.1 g, 20 mmol, 1 equiv) and LiBr
(5.16 g, 30 mmol, 3.0 equiv) were dissolved in 40 mL of acetone. The
reaction mixture was refluxed for 6 h (it was observed the formation of a
precipitate). It was cooled and concentrated. The residue was dissolved in
40 mL of DCM and 40 mL of water and the aqueous phase was washed
with DCM (30 mL x 2) The combined organic layers were washed with
brine (30 mL), dried (Na2SO4 anh) and concentrated. The product was
purified by column chromatography by a mixture Hexane/EtOAc 9:1
obtaining 5.0 g (95 % yield) of a colorless oil, [α]D25 = -35.3 (c 0.32, DCM),
lit.[18] [α]D25 = -40.5 (c 0.80, CHCl3), Rf = 0.66 (Hexane/EtOAc, 4:1). 1H NMR
(300 MHz, CDCl3 mixture of rotamers):  4.03-3.96 (m, 1H, C*H), 3.65-3.52
(m, 1H, CH2N), 3.43-3.23 (m, 3H, CH2N, CH2Br), 1.98-1.77 (m, 4H,
CH2CH2), 1.45 (s, 9H, (CH3)3) ppm. 13C NMR (75 MHz, CDCl3 mixture of
rotamers):  154.59 (NCO2C(CH3)3), 80.02/79.71 (C(CH3)3), 58.01/57.88
(C*H), 47.45/46.99 (CH2N), 34.95 (CH2Br), 30.15/29.43 (CH2C*HN), 28.58
((CH3)3), 23.65/22.87 (NCH2CH2) ppm. IR (KBr): ṽ = 2973, 1757, 1689,
1386, 1167, 110, 771, 649, 549 cm-1. MS-DART (positive): m/z (%) 264
(54) [M + H]+, 266 (53), 206 (100), 207 (99). HRMS (DART/TOF): m/z
[M+H]+ calcd for C10H19BrNO2 264.0593; found 264.0595.
(S)-2-(2-amino-6-oxo-1H-purin-6(1H)-one-9-yl)methylpyrrolidine
hydrochloride (5): Compound 20 (300 mg, 0.8 mmol, 1.0 equiv) was
dissolved in 6 M HCl (1.5 mL) and heated to 70-80 °C with stirring for 2 h.
The solvent was evaporated and the residue was washed with EtOAc. The
hydrochloride salt was obtained as a white solid (204 mg, 83 %), mp 203 -
3-Benzoyluracil (17): Uracil (500 mg, 4.46 mmol, 1 equiv), benzoyl
chloride (1.2 ml, 10.3 mmol, 2.3 equiv), dry acetonitrile (4.5 mL, 86 mmol,
19.3 equiv) y dry pyridine (1.78 mL, 22.1 mmol, 5.0 equiv) were stirred
together at room temperature. After 24h, the solvent was evaporated and
the residue was dissolved in CH2Cl2 (25 mL) and water (25 mL) was added.
The organic layer was separated and evaporated. The residue was
dissolved in a mixture of aqueous K2CO3 (0.5 M, 5 mL) and dioxane (10
mL). After 30 min, the pH is adjusted to 5 with addition of acetic acid. The
solvent was evaporated and the residue was allowed to stir with saturated
solution NaHCO3 (25 mL). After 1 h, the product was filtered and washed
with cold water (2.5 mL x 3). The product was recrystallized from water-
acetone. A white solid was obtained (645 mg, 70 %), mp 174 - 176 °C,
25
207 °C, [α]D = +31.9 (c 0.37, MeOH), Rf = 0.33 (MeOH/iPrOH/NH4OH
1
3:7:1 x 2). H NMR (300 MHz, DMSO-d6):  11.91 (br, 1H, Pur-H1), 10.83
(br, 1H), 9.96 (br, 2H, N+H2), 9.22 (s, 1H, Pur-H8), 7.49 (br, 2H, NH2), 4.73-
4.65 (m, 1H, NCH2C*H), 4.49-4.43 (m, 1H, CH2C*H), 3.98 (m, 1H, C*H),
3.26-3.13 (m, 2H, CH2NH), 2.14-1.66 (m, 4H, CH2CH2) ppm. 13C NMR (75
MHz, DMSO-d6): .155.69 (Pur-C6), 153.48 (Pur-C2), 149.90 (Pur-C4),
137.19 (Pur-C8), 108.29 (Pur-C5), 57.72 (C*H), 44.86 (C*HCH2N), 44.42
(CH2N), 27.57 (C*HCH2), 22.84 (NCH2CH2) ppm. IR (KBr): ṽ = 3335-2491,
1680, 1629, 1596, 1360, 1176, 1064, 843, 663, 543, 501 cm-1. MS-DART
(positive): m/z (%) 235 (100) [M + H]+. HRMS (DART/TOF): m/z [M+H]+
calcd for C10H15N6O 235.1301; found 235.1306.
lit.[19] 173.5 - 175.8 °C, Rf = 0.46 (CH2Cl2/MeOH, 9:1). H NMR (300 MHz,
1
DMSO-d6):  11.63 (br, 1H, Ura-NH), 7.97 (m, 2H, Ph-H, Ura-C6), 7.78 (m,
1H, Ph-H) 7.67-7.58 (m, 3H, Ph-H), 5.74 (d, J = 7.7 Hz, 1H, Ura-C5) ppm.
13C NMR (75 MHz, DMSO-d6):  169.99 (COPh), 162.91 (Ura-C4), 150.05
(Ura-C2), 143.28 (Ura-C6), 135.36 (Ph), 131.33 (ipso-Ph), 130.17 (Ph),
129.47 (Ph), 100.07 (Ura-C5) ppm. IR (KBr): ṽ = 3271-2965, 1745, 1702,
1649, 1595, 1413, 1229, 1180, 932, 783, 677, 531, 450 cm-1. MS-DART
(positive): m/z (%) 217 (72) [M + H]+, 105 (100), 218 (10) HRMS
(DART/TOF): m/z [M+H]+ calcd for C11H9N2O3 217.0607; found 217.0612.
Synthesis of AC 6. (S)-N-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-
2-amino-3-phenylpropionamide (6): N-Cbz-L-phenylalanine (1.0 g, 3.34
mmol, 1.0 equiv) was dissolved in CH2Cl2 (30 ml) at 0°C under N2
atmosphere. NMM (0.5 mL, 4.35 mmol, 1.3 equiv) was added, and after 5
min, isobutyl chroroformate (0.52 mL, 4.0 mmol, 1.2 equiv) was slowly
added. The reaction mixture was stirred for 1 h at 0 °C. Again, NMM (0.6
mL, 5.3 mmol, 1.6 equiv) and a suspension of uracil (427 mg, 3.34 mmol,
1.0 equiv) in DMF (10 mL) were added. The reaction was stirred at 0 °C for
2 h and at room temperature overnight. The solvent was evaporated and
filtered through a short silica column with CH2Cl2/MeOH (8:2). The fraction
with Rf = 0.34 (CH2Cl2/ MeOH 97:3 x2) was concentrated and used in the
next reaction. The coupled product was dissolved in MeOH-DMF 1:1 (40
ml), 10 percent Pd/C (98 mg) was added. The reaction was stirred at room
temperature under hydrogen atmosphere. After 24h, the reaction mixture
was filtered through Celite, washed with CH2Cl2/MeOH 1:1 (30 mL), and
concentrated under vacuum. The product was recrystallized of
EtOH/MeOH. A beige solid was obtained (68 %, 448 mg), mp > 270 °C,
(S)-1-tert-Butoxycarbonyl-2-((2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-1-
yl)methyl)pyrrolidine (18): It was adapted from a literature procedure.[20]
Pyrrolidine 16 (1186 mg, 4.48 mmol, 0.8 equiv), uracil 17 (1213 mg, 5.61
mmol, 1.0 equiv), K2CO3 (775.3 mg, 5.61 mmol, 1.0 equiv) and TBAI (207
mg, 0.56 mmol, 0.1 equiv) were dissolved in dry DMF (15 mL). The
reaction mixture was allowed to stir at 70-80 °C for 24 h. The reaction
crude was concentrate to dryness. The product was purified by two column
chromatographies (CH2Cl2/MeOH, 95:5 and Hexane/EtOAc, 1:1). The
unprotected product 18 (440 mg, 33 %) and the protected product 30 (859
25
[α]D = +66.3 (c 0.19, MeOH), Rf = 0.55 (MeOH). 1H NMR (300 MHz,
25
mg, 48 %) were obtained as white solid. mp 95 - 96 °C, [α]D = + 90.8 (c
DMSO-d6):  11.46 (br, 1H, Ura-NH6), 10.89 (br, 1H, Ura-NH1), 9.82 (s, 1H,
CONH), 8.48 (br, 2H, NH2), 8.02 (s, 1H, Ura-H6), 7.32-7.24 (m, 5H, Ph-H),
4.43-4.39 (m, 1H, C*H), 3.16-3.02 (m, 2H, PhCH2) ppm. 13C NMR (75 MHz,
DMSO-d6):  167.23 (CONH), 160.38 (Ura-C4), 149.55 (Ura-C2), 134.88
(ipso-Ph), 130.39 (Ura-C6), 129.57 (Ph), 128.45 (Ph), 127.12 (Ph), 112.36
(Ura-C5), 53.29 (C*H), 37.03 (PhCH2) ppm. IR (KBr) ṽ = 3320-2912, 1722,
1670, 1542, 1454, 1236, 833, 750, 702, 539 cm-1. MS-DART (positive): m/z
(%) 275 (100) [M + H]+, HRMS (DART/TOF): m/z [M+H]+ calcd for
C13H15N4O3 275.1138; found 275.1147.
0.25, MeOH) Rf = 0.6 (CH2Cl2/MeOH, 95:5 x2) or 0.33 (EtOAc). 1H NMR
(300 MHz, DMSO-d6 mixture of rotamers):  11.18 (br, 1H, Ura-NH), 7.50-
7.44 (m, 1H, Ura-H6), 5.52-5.42 (m, 1H, Ura-H5), 4.10 (m, 1H, C*H), 3.83-
3.75 (m, 1H, CH2N), 3.43-3.36 (m, 1H, CH2N), 3.26-3.25 (m, 2H,
C*HCH2N), 1.98-1.55 (m, 4H, CH2CH2) 1.31-1.29 (m, 9H, C(CH3)3) ppm.
13C NMR (75 MHz, DMSO-d6 mixture of rotamers):  163.99 (Ura-C4),
153.97/153.70 (CO2C(CH3)3), 151.30/151.13 (Ura-C2), 146.16/145.72 (Ura-
C6), 100.31 (Ura-C5), 78.61/78.46 (C(CH3)3), 55.05/54.35 (C*H), 50.55
(CH2N), 45.95/45.36 (C*HCH2N), 28.05/27.91 ((CH3)3), 27.35 (C*HCH2),
23.05/22.00 (NCH2CH2) ppm. IR (KBr): ṽ = 3176-2879, 1749, 1669, 1389,
1168, 764, 548, 422 cm-1. MS-DART (positive): m/z (%) 296 (15) [M + H]+,
240 (38), 88 (50), 196 (100). HRMS (DART/TOF): m/z [M+H]+ calcd for
C14H22N3O4; 296.3416 found 296.1604.
General procedures for the aldol reaction: In a screw-thread vial
catalyst (0.015 mmol, 0.05 equiv) was disolved in DMF (0.19 mL). It was
added cyclohexanone (0.15 mL, 1.5 mmol, 5 equiv) and stirred 5 min.
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10.1002/ejoc.201800886
European Journal of Organic Chemistry
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Aldehyde (0.3 mmol, 1.0 equiv) was added and the reaction mixture was
stirred 72 h (Tables 1-2, Figure 3 and Scheme 6) or 120 h (Tables 3-4,
Figure 4 and Scheme 5) at room temperature. It was concentrated to
dryness and purified by column chromatography Hexane/EtOAc (8:2). For
the complementary modules evaluation it was added the
diaminocompound Py, PyMD, Pur or A (0.015 mmol, 0.05 equiv) and
stirred 1h prior the addition of the aldehyde.
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Acknowledgments
We thank DGAPA-UNAM (grant IN207318) and CONACyT (grant
254014) for financial support. K. M. R.-P. gratefully acknowledge
CONACyT/México for Ph.D. scholarship (No. 273441). We also
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Keywords: Organocatalysis • Self-assembly • Aldol reaction •
Supramolecular catalyst • Pyrimidines.
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10.1002/ejoc.201800886
European Journal of Organic Chemistry
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Supramolecular catalyst
Karen M. Ruíz-Pérez, Beatriz Quiroz-
García, Marcos Hernández Rodríguez*
Page No. – Page No.
Prolinamides of aminouracils,
organocatalyst modifiable by
complementary modules.
Prolinamide organocatalysts with aminouracils have the features of enhanced
NH acidity, additional hydrogen bond donor and the self-assembly with
complementary modules by Watson-Crick pairing. Each module affects the
selectivity on the reaction and particularly 2,6-diaminopyridine is beneficial to
the selectivity in the reaction.
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