Synthesis of dihydrouracils spiro-fused to pyrrolidines: Druglike molecules based on the 2-arylethyl amine scaffold

Article abstract of DOI:10.3390/molecules15042269

The synthesis of a small library of dihydrouracils spiro-fused to pyrrolidines is described. These compounds are synthesized from ss-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. The ss-aryl pyrrolidines are synthesized through a three-step methodology that includes a Knoevenagel condensation reaction, a 1,3-dipolar cycloaddition reaction, and a nitrile reduction. Copyright

Full text of DOI:10.3390/molecules15042269

Molecules 2010, 15, 2269-2301; doi:10.3390/molecules15042269
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Dihydrouracils Spiro-Fused to Pyrrolidines:
Druglike Molecules Based on the 2-Arylethyl Amine Scaffold
Daniel Blanco-Ania 1, Carolina Valderas-Cortina 1, Pedro H.H. Hermkens 2, Leo A.J.M.
Sliedregt 3, Hans W. Scheeren 1and Floris P.J.T. Rutjes 1,*
1
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525
AJ Nijmegen, The Netherlands
2
MSD Research Laboratories, P.O. Box 20, 5340 BH Oss, The Netherlands
3
Solvay Pharmaceuticals, Sector Discovery Weesp, P.O. Box 900, 1380 DA Weesp, The
Netherlands
∗ Author to whom correspondence should be addressed; E-Mail: f.rutjes@science.ru.nl.
Received: 5 February 2010; in revised form: 26 March 2010 / Accepted: 30 March 2010 /
Published: 30 March 2010
Abstract: The synthesis of a small library of dihydrouracils spiro-fused to pyrrolidines is
described. These compounds are synthesized from β-aryl pyrrolidines, providing products
with the 2-arylethyl amine moiety, a structural feature often encountered in compounds
active in the central nervous system. The β-aryl pyrrolidines are synthesized through a
three-step methodology that includes a Knoevenagel condensation reaction, a 1,3-dipolar
cycloaddition reaction, and a nitrile reduction.
Keywords: Knoevenagel condensation; 1,3-dipolar cycloaddition; azomethine ylide;
parallel synthesis; spiro dihydrouracils
1. Introduction
The 2-arylethyl amine moiety 1 (Figure 1) is an important privileged structure, which is
encountered in numerous compounds active in the central nervous system (CNS). This privileged
structure is present in neurotransmitters such as dopamine, epinephrine, norepinephrine, and serotonin
[1]. Salmeterol [2,3] and venlafaxine [4–6], two of the ten best-selling prescription drugs in 2006 [7],

Molecules 2010, 15
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also contain this moiety. In addition, the 2-arylethyl amine unit occurs in many hallucinogenic drugs,
such as LSD, MDMA (ecstasy), mescaline, and psilocybin (magic mushrooms) [8,9].
Figure 1. 2-Arylethyl amine (1), uracil (2), thymine (3), and zidovudine (AZT, 4).
H
O
N
O
H
N
H
N
N
O
O
O
O
O
Me
NH2
HO
Ar
NH
NH
Me
N3
1
2
3
4
On the other hand, pyrimidine-2,4-diones are a class of bioactive heterocyclic molecules, the most
famous examples being uracil (2) and thymine (3, Figure 1), which form part of the nucleotides of
RNA and DNA, respectively [10]. Pyrimidine-2,4-diones have attracted considerable attention in the
pharmaceutical industry as anti-inflammatory agents [11], dopamine receptor agonists [12], serotonin
uptake inhibitors [13], and antiepileptic agents [14]. A good example of a pyrimidine-2,4-dione
derivative with a medicinal application is zidovudine (AZT, 4, Figure 1), used as an anti-AIDS agent
[15]. This moiety is also the core structural element of some fungicides [16] and herbicides [17].
It is known that the difference in activity and receptor selectivity of drugs might be explained by the
conformation of the contained privileged structure. Generation of semi-rigid drugs facilitates the study
of their interactions with the receptors, may lead to more selective interactions with fewer side effects,
and permits the rational design of more potent and selective drugs in the future [18,19]. Herein we
present the parallel synthesis of a library comprised of compounds combining all the above features
(Scheme 1). First, these compounds possess a β-aryl pyrrolidine with a conformationally constrained
2-arylethyl amine. Second, they are semirigid structures because of the spiro fusion to a dihydrouracil.
It is known that the combination of privileged structures can lead to new chemical entities that may
have pharmacological relevance [20,21] and increase the structural diversity.
Scheme 1. Combination of two privileged structures to generate a product with increased rigidity.
R
O
N
O
NH
1 +
2
HN
Ar
possible new
biological activity
2. Results and Discussion
We envisioned that a suitable strategy to synthesize these compounds may proceed as shown
retrosynthetically in Scheme 2. The spiro dihydrouracils 5 could be synthesized by an annulation
reaction of α-aminomethyl esters 6 and an isocyanate. The aminomethyl group of compounds 6 could
be derived from a masked amino function, such as a cyano group, by reduction. Compounds 7 possess
two electron-withdrawing groups at the carbon in the 3-position of the pyrrolidine, rendering it a
perfect pattern for preparation by a 1,3-cycloaddition reaction of an azomethine ylide and an electron-

Molecules 2010, 15
2271
deficient alkene. This would leave the 3-aryl-2-cyanoacrylates 8 as starting materials, which could be
obtained by the Knoevenagel condensation reaction of methyl 2-cyanoacetate (9) and an aromatic
aldehyde.
Scheme 2. Retrosynthetic analysis for the synthesis of spiro dihydrouracils 5.
R
O
N
O
CO2Me
NH2
CO2Me
CN
NC
Ar
CO2Me
NC
CO2Me
NH
MeN
MeN
MeN
Ar
Ar
Ar
5
6
7
8
9
2.1. Knoevenagel condensation reaction
The synthesis of compound class 5 commenced with the condensation reaction of methyl 2-
cyanoacetate (9) and aromatic aldehydes 10. Twelve aldehydes 10{1–12} (electron-rich aromatic,
electron-rich heteroaromatic, and electron-poor heteroaromatic aldehydes; Figure 2) were selected for
the formation of the scaffolds.
Figure 2. Aromatic aldehydes 10{1–12} used for the Knoevenagel reaction.
MeO
CHO
CHO
CHO
CHO
CHO
CHO
O
O
CHO
CHO
N
N
Me
MeO
Me
OMe
1
3
2
4
5
6
N
CHO
CHO
CHO
N
CHO
S
N
N
H
H
N
7
9
8
10
11
12
The reaction conditions for the Knoevenagel condensation reaction are critically dependent on the
electron-withdrawing groups bound to the activated methylene [22] and need to be optimized in every
case. Initially, these reactions were performed using EtOH as solvent, but transesterification (up to
3%) was observed and the resulting mixture of methyl and ethyl esters was impossible to separate.
These reactions also took place in THF (see entry 8, Table 1), but required a longer reaction time.
Finally, treatment of 9 with a catalytic amount of piperidine in MeOH (except for entry 8 because of
the low solubility of 10{8} in MeOH) at room temperature produced the desired acrylates 8{1–12} in
excellent yields (Table 1). All these compounds are only sparingly soluble in MeOH, allowing the pure
crystalline products to be easily collected by filtration. These products can also be recrystallized from
MeOH yielding crystals of >99.5% purity. The reaction was completely stereoselective in all cases
13
[23], only the E alkenes were observed as could be inferred from the C-NMR coupling constants
between the olefinic proton and the carbon atoms of the ester and the nitrile [24,25]. These values are
3
3J = 6.6–6.9 Hz for the carbonyl group and J = 13.6–13.9 Hz for the cyano group. The Knoevenagel
adducts are stable at room temperature and unreactive towards the regular atmosphere, therefore
remain unchanged for months.

Molecules 2010, 15
Table 1. Knoevenagel condensation reaction to form the 2-cyanoacrylates 8{1–12}.
2272
ArCHO
10{1–12}, piperidine
NC
CO2Me
NC
CO2Me
MeOH, 21 °C
Ar
9
8{1–12}
Time
(min)
30
30
40
Yield
(%)
99
94
99
99
95
96
99
99
94
99
93
Entry ArCHO Product
1
2
10{1}
10{2}
10{3}
10{4}
10{5}
10{6}
10{7}
10{8}
10{9}
10{10}
10{11}
10{12}
8{1}
8{2}
8{3}
8{4}
8{5}
8{6}
8{7}
8{8}
8{9}
8{10}
8{11}
8{12}
3
4
5
6
7
8
9
60
120
120
30
480a
30
10
11
12
30
90
25
99
a THF was used as solvent.
2.2. 1,3-Dipolar cycloaddition reaction
The next step in the synthesis was the formation of the pyrrolidine-core structures by a 1,3-dipolar
cycloaddition reaction using an azomethine ylide. This reaction is an important method for the
formation of pyrrolidines [26] and has been used in the synthesis of natural products [27,28]. Among
the vast number of procedures for making azomethine ylides [29–41], the decarboxylative
condensation of α-amino acids with aldehydes, typically heated in toluene or DMF, was chosen [42].
Thus, the reaction of paraformaldehyde and sarcosine (N-methylglycine) in refluxing toluene in the
presence of the 2-cyanoacrylates 8 cleanly provided the desired pyrrolidines 7, containing the 2-
arylethyl amine motif (Table 2). The reaction was clean to such an extent that in some cases an
extraction (H2O/Et2O) was all the purification needed (or just a short column chromatography). The
reaction was totally stereospecific in most cases (entries 1–6 and 8), highly stereospecific for 8{9}
(entry 9), and partially stereospecific for the electron-poor heteroaryls 8{10–12} (entries 10–12) [43].
The mixtures of diastereoisomers that arose could not be separated by column chromatography. The
reaction did not take place with compound 8{7} (entry 7); after 4 h only some minor unidentified
compounds were formed and most of the substrate was recovered, but there was no trace of compound
7{7}. The reaction of substrate 8{5} did form the product 7{5}, but with a lower yield compared to all
the others. The reaction of substrate 8{8} formed the expected cycloadduct, but the indolic nitrogen
was (dimethylamino)methylated during the reaction.

Molecules 2010, 15
Table 2. 1,3-Dipolar cycloaddition reaction to form the pyrrolidine-core structures 7.
2273
CO2Me
CN
NC
CO2Me
MeNHCH2CO2H
MeN
(CH2O)n, PhMe, Δ
Ar
Ar
7{1–6,9–13}
8{1–12}
Time
(min)
20
75
80
80
120
80
Yield
(%)
94
99
95
99
52
95
–
Entry
Acrylate
Product(s)a
1
2
3
4
5
6
7
8{1}
8{2}
8{3}
8{4}
8{5}
8{6}
8{7}
7{1}
7{2}
7{3}
7{4}
7{5}
7{6}
7{7}
CO2Me
240
CN
MeN
8
8{8}
150
85
N
NMe2
7{13}
CO2Me
CN
MeN
9
8{9}
7{9} +
80
45
87b
90c
S
11{9}
CO2Me
CN
MeN
7{10}
N
10
8{10}
+
11{10}
CO2Me
CN
MeN
7{11}
11
8{11}
25
72d
85e
+
N
11{11}
CO2Me
CN
MeN
7{12}
12
8{12}
45
N
+
11{12}
a
Ratio calculated by integration of the 1H-NMR signals of the crude reaction mixture;
b 7{9}/11{9} = 70:1; c 7{10}/11{10} = 6.5:1; d 7{11}/11{11} = 6.6:1; e 7{12}/11{12} = 5:1
After analysis of the results obtained so far, it was decided to continue the research only with the
diastereomerically pure compounds 7{1–6} for the construction of the library scaffolds.
2.3. Reduction
The chemoselective reduction of the nitrile was best achieved by a heterogeneous catalytic
hydrogenation using Raney nickel under a hydrogen atmosphere at room temperature (Table 3) [44].
We found that the addition of NH3 or Et3N was crucial for the reaction to go to completion [45].
Eventually, Et3N was used since with NH3 amide 12 (Figure 3) was formed alongside the product.

Molecules 2010, 15
2274
Figure 3. Amide 12 formed.
CONH2
CN
MeN
Ar
12
Thus, compounds 7{1–6} were reacted under these conditions to complete the synthesis of the
library scaffolds. After elimination of Raney nickel by filtration through diatomaceous earth and
evaporation of MeOH and Et3N, the reaction cleanly gave the α-aminomethyl esters 6{1–6}.
Table 3. Reduction of the cyano group from the α-cyano esters 7.
CO2Me
CN
CO2Me
NH2
H2, Ra-Ni, Et3N
MeN
MeN
MeOH, 21 °C, 15 h
Ar
Ar
6{1–6}
7{1–6}
Entry Substrate
Product
6{1}
6{2}
6{3}
6{4}
Yield (%)
1
2
3
4
5
6
7{1}
7{2}
7{3}
7{4}
7{5}
7{6}
95
95
89
85
73
95
6{5}
6{6}
2.4. Parallel synthesis of spiro dihydrouracils
The procedure followed for the formation of the spiro dihydrouracils was formation of a urea by
addition of an isocyanate and subsequent cyclization by reaction with a base. The conversion of
chemset 6 into chemset 5 was accomplished using reagent chemset 13. Eight isocyanates 13{1–8}
(alkyl, electron-rich aryl, electron-poor aryl, and heteroaryl isocyanates; Figure 4) were selected for
the generation of a 48-compound library.
Figure 4. Isocyanates 13{1–8} used for the reaction of scaffolds 6{1–6}.
NCO
Ph
EtO2C
NC
NCO
NCO
NCO
NCO
1
3
2
4
NCO
NCO
NCO
EtO
F3C
N
5
7
6
8
The reactions for the formation of the α-ureidomethyl esters were run in either CH2Cl2 or DMF
depending on reagent solubility and reactivity. Thus, the reactions of 6{1–6} and 13{1,3–5} in CH2Cl2
for 15 h at room temperature afforded the corresponding α-ureidomethyl esters. In order to reach full
conversion to the α-ureidomethyl esters using isocyanates 13{2,6–8}, DMF at 80 °C for 15 h had to be

Molecules 2010, 15
2275
used. After evaporation of the solvent, the crude mixture was dissolved in THF and 1 M KOBut in
THF (1 equiv) was added [46,47]. The reactions were stirred at room temperature for 15 h and the
solvent was evaporated. Liquid–liquid extraction afforded two different types of compounds,
depending on the isocyanate used: (1) the alkyl isocyanates 13{1–3} gave the expected 4-aryl-
spiro[dihydrouracil-5,3′-pyrrolidines] 5{1–6,1–3} with yields ranging from 49 to 80% (61% average)
and with purities ranging from 60 to 99% (83% average; Scheme 3 and Table 4) according to LC-MS
analysis (also confirmed by 1H-NMR spectroscopy) and (2) the aryl isocyanates 13{4–8} gave mostly
the unexpected α-ureidomethyl acids 14{1–6,4–8} with yields ranging from 45 to 79% (64% average)
and with purities ranging from 0 to >99% (82% average; Scheme 4 and Table 5) according to LC-MS
analysis (also confirmed by 1H-NMR spectroscopy).
Scheme 3. Spiro dihydrouracil formation from scaffolds 6{1–6}.
R
1. RNCO 13{1,3}, CH2Cl2
O
N
O
CO2Me
NH2
21 °C, 15 h or
NH
MeN
MeN
RNCO 13{2}, DMF
80 °C, 15 h
Ar
6{1–6}
Ar
5{1–6,1–3}
2. KOBut, THF, 21 °C, 15 h
R = Et, PhCH2CH2, EtO2CCH2CH2
Scheme 4. α-Ureidomethyl acid formation from scaffolds 6{1–6}.
1. RNCO 13{4,5}, CH2Cl2
O
CO2Me
NH2
CO2H
21 °C, 15 h or
R
N
N
MeN
MeN
H
H
RNCO 13{6–8}, DMF
80 °C, 15 h
Ar
6{1–6}
Ar
14{1–6,4–8}
2. KOBut, THF, 21 °C, 15 h
R = Ph, 4-CF3C6H4, 4-EtOC6H4, 3-NCC6H4, 3-Py
The reactions carried out with reagent 13{1} resulted in high purities (89% average) for the
formation of the spiro dihydrouracils, due to lack of competing reactions. The purities of the products
from the reactions run in DMF (reagent 13{2}) were in the range 60 to 92% (70% average). These
lower purities could be due to partial decomposition of the isocyanates at the temperature used for the
reactions in DMF. The reactions carried out with reagent 13{3} gave a mixture of the expected ethyl
esters 5{1–6,3}, the methyl esters 5{1–6,9} (from transesterification of the ethyl ester on the R group
by methoxide, formed in the cyclization), the acids 5{1–6,10} (from hydrolysis of the esters), and the
deorganylated compounds 5{1–6,11} (Figure 5 and Table 4). The overall cyclization reaction worked
well, since products 5{1–6,9}, 5{1–6,10}, and 5{1–6,11} were formed from 5{1–6,3}. Shorter
reaction times should thus be used to avoid these side reactions.

Molecules 2010, 15
2276
Figure 5. Products formed from the reaction with reagent 13{3}.
CO2Et
CO2Me
CO2H
H
N
O
N
O
O
N
O
O
N
O
O
O
NH
NH
NH
NH
MeN
MeN
MeN
MeN
Ar
Ar
Ar
Ar
5{1–6,3}
5{1–6,9}
5{1–6,10}
5{1–6,11}
The above-mentioned deorganylation side reaction could have taken place through an E1cB
mechanism (Scheme 5). The substrate 5{1–6,3} (or 5{1–6,9}) is deprotonated to form the enolate
5{1–6,12}, which undergoes an elimination reaction to afford 5{1–6,11} after work-up.
Scheme 5. Formation of compounds 5{1–6,11}.
CO2Et
CO2Et
H
N
O
N
O
O
N
O
O
N
O
O
O
base
work-up
NH
NH
NH
NH
MeN
MeN
MeN
MeN
Ar
Ar
Ar
Ar
5{1–6,3}
5{1–6,12}
5{1–6,11}
The aryl-substituted dihydrouracils underwent hydrolysis (and not the alkyl-substituted
dihydrouracils) because the electrophilicity of the ureide carbonyls is enhanced (with respect to the
alkyl group) due to the conjugation of the imide-type nitrogen with the aryl group. Thus, residual H2O
from KOBut could have hydrolyzed the ureide to the ureido acid [48].
Table 4. Parallel synthesis of spiro dihydrouracil library 5{1–6,1–3}a,b.
Ph
R
O
N
O
O
N
O
O
N
O
NH
NH
NH
MeN
MeN
MeN
5{1,1}
51% (89%)
5{1,2}
63% (70%)
5{1,3}
80% (91%)c
Ph
R
O
N
O
O
N
O
O
N
O
NH
NH
NH
MeN
MeN
MeN
OMe
OMe
OMe
5{2,1}
60% (93%)
5{2,2}
64% (60%)
5{2,3}
49% (88%)c

Molecules 2010, 15
2277
Table 4. Cont.
Ph
R
N
O
N
O
O
N
O
O
O
NH
NH
NH
MeN
MeN
MeN
OMe
OMe
OMe
OMe
OMe
OMe
5{3,1}
66% (90%)
5{3,2}
60% (68%)
5{3,3}
54% (95%)c
Ph
R
O
N
O
O
N
O
O
N
O
NH
NH
NH
MeN
MeN
MeN
O
O
O
O
O
O
5{4,1}
63% (95%)
5{4,2}
64% (68%)
5{4,3}
61% (98%)c
Ph
R
O
N
O
O
N
O
O
N
O
NH
NH
NH
MeN
MeN
MeN
N
N
N
Me
Me
Me
5{5,1}
61% (99%)
5{5,2}
54% (92%)
5{5,3}
66% (79%)c
Ph
R
O
N
O
O
N
O
O
N
O
NH
NH
NH
MeN
MeN
MeN
N
N
N
Me
Me
Me
5{6,1}
69% (69%)
5{6,2}
5{6,3}
62% (86%)c
68% (62%)
a
b
% = Crude yield based on mass recovery; (%) = Purity determined by LC-MS at 215 nm;
c Mixture of compounds, R = CH2CH2CO2Et, CH2CH2CO2Me, CH2CH2CO2H, and H.
Table 5. Parallel synthesis of α-ureidomethyl acid library 14{1–6,4–8}a,b.
CF3
OEt
N
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
N
N
N
N
N
N
N
N
N
CN
MeN
MeN
MeN
MeN
MeN
H
H
H
H
H
H
H
H
H
H
14{1,4}
14{1,5}
14{1,6}
14{1,7}
14{1,8}
49% (>99%)
75% (97%)
48% (>99%)
54% (>99%)
49% (79%)
CF3
OEt
N
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
N
H
N
N
H
N
N
H
N
N
H
CN
N
N
H
MeN
MeN
MeN
MeN
MeN
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
14{2,4}
14{2,5}
14{2,6}
14{2,7}
14{2,8}
60% (99%)
65% (98%)
70% (>99%)
60% (96%)
45% (76%)

Molecules 2010, 15
2278
Table 5. Cont.
OEt
CF3
N
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
H
N
N
N
N
N
N
N
CN
N
N
MeN
MeN
MeN
MeN
MeN
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
14{3,4}
14{3,5}
14{3,6}
14{3,7}
14{3,8}
76% (97%)
63% (99%)
52% (99%)
58% (>99%)
48% (43%)
CF3
CF3
CF3
OEt
OEt
OEt
N
N
N
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
N
H
N
N
H
N
N
H
N
N
H
CN
N
N
H
O
MeN
MeN
MeN
MeN
MeN
MeN
MeN
MeN
MeN
H
H
H
H
H
O
O
O
O
O
O
O
O
O
14{4,4}
14{4,5}
14{4,6}
61% (77%)c
14{4,7}
14{4,8}
74% (>99%)
68% (>99%)
62% (99%)
54% (71%)
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
N
N
N
N
N
N
N
CN
N
N
MeN
MeN
MeN
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
Me
Me
Me
Me
Me
14{5,4}
58% (14%)d
14{5,5}
65% (79%)e
14{5,6}
62% (16%)f
14{5,7}
14{5,8}
56% (0%)g
61% (99%)
O
O
O
O
O
CO2H
CO2H
CO2H
CO2H
CO2H
N
N
N
N
N
N
CN
N
N
N
N
MeN
MeN
MeN
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
Me
Me
Me
Me
Me
14{6,4}
79% (97%)h
14{6,5}
14{6,6}
70% (94%)i
14{6,7}
14{6,8}
76% (>99%)
67% (99%)
71% (36%)
b
c
a % = Crude yield based on mass recovery; (%) = Purity determined by LC-MS at 215 nm; Plus
d
e
f
g
5{4,6} (21%). Plus 5{5,4} (77%); Plus 5{5,5} (18%). Plus 5{5,6} (81%); Plus 5{5,8} (54%);
h Plus 5{6,4} (2%); i Plus 5{6,6} (5%).
In order to find conditions for the exclusive formation of the spiro dihydrouracils using aryl
isocyanates, the α-ureidomethyl ester 15{1,4} was synthesized, isolated, and reacted with several
bases under different conditions for the formation of spiro dihydrouracil 5{1,4} (Table 6).
Firstly, the reaction was attempted with an easy-to-handle base because, if successful, it would
make the work-up of the reactions easy—an important factor in parallel synthesis. All the amines used
were found to have insufficient basicity for this transformation to take place (entries 1–5) [49–51]. The
amidine DBU gave promising results, but the separation of the product 5{1,4} from DBU (and
especially from the coreagent Bu4NBr, entry 8) was difficult and tedious, making these reaction
conditions unsuitable for parallel synthesis [52,53]. Potassium tert-butoxide was the only base that
caused >99% of the starting material to react [54], but it was the base that gave the largest amount of
hydrolyzed product 14{1,4} (entries 9–12). Heating only (entry 15) resulted in decomposition of the
starting material. To the best of our knowledge, there is no example in the literature of a dihydrouracil
ring with such a tendency toward hydrolysis under basic conditions. This cyclization can also take
place using acid catalysis [55-58], but this has not yet been attempted.

Molecules 2010, 15
Table 6. Optimization of the formation of spiro dihydrouracil 5{1,4}.
2279
Ph
N
O
O
O
O
CO2Me
CO2H
Ph
Ph
N
H
N
NH
N
N
+
MeN
MeN
MeN
H
H
H
Ph
Ph
Ph
15{1,4}
5{1,4}
14{1,4}
Productsa
15{1,4}/5{1,4}/14{1,4}
Entry
Conditions
Et3N (1.1 equiv), THF, Ar, reflux, 22 h
Proton sponge (0.2 equiv), THF, 21 °C, 5 h
Proton sponge (1 equiv), THF, 21 °C, 17 h
Proton sponge (1 equiv), THF, reflux, 7 h
DIPEA (1 equiv), DMF, 90 °C, 6 h
1
2
3
4
5
1:0:0
1:0:0
1:0:0
1:0:0
1:0:0
6
7
DBU (1 equiv), THF, Ar, 26 °C, 5 h
DBU (1 equiv), THF, Ar, reflux, 17 h
1:0:0
5:1:0
8
9
DBU (1 equiv), Bu4NBr, 4 Å MS, PhMe, Ar, reflux, 27 h
1:9:0
1:3:1
0:2:1
0:1:2
3:6:1
1:3:0
1:0:4
KOBut (1 equiv), THF, 29 °C, 30 min
10
11
12
13
14
15
KOBut (1 equiv), THF, 31 °C, 55 min
KOBut (1 equiv), THF, Ar, 21 °C, 2 h
KOBut (0.1 equiv), THF, Ar, 21 °C, 17 h
Phosphazene P2-t-Bu (0.1 equiv), THF, Ar, 21 °C, 5 h
Phosphazene P2-t-Bu (1 equiv), THF, Ar, 21 °C, 18 h
DMSO, 165 °C, 15 h
decomposition
a Ratio calculated by integration of the 1H-NMR signals of the crude reaction mixture.
The compounds 5{1–6,1–3}, 5{1,4}, 6{1–6}, 14{1–6,4–8}, and 15{1,4} were tested on different
CNS targets, but the results cannot be published because of the patent policy of the companies
involved in the project.
3. Experimental
3.1. General
Reagents were obtained from commercial suppliers and were used without purification. Solvents
were distilled from appropriate drying agents prior to use and were stored under nitrogen. Reactions
were followed, and RF values were obtained, using thin-layer chromatography (TLC) on silica gel-
coated plates (Merck 60 F254) with the indicated solvent mixture. Detection was performed with UV
light and/or by charring at ca. 150 °C after dipping into a solution of KMnO4 or ninhydrin. Column or
flash chromatography was carried out using ACROS silica gel (0.035–0.070 mm, pore diameter
ca. 6 nm). IR spectra were recorded on an ATI Mattson Genesis Series FTIR spectrometer. High-
resolution mass spectra were recorded on a JEOL AccuTOF (ESI) or a MAT900 (EI, CI, and ESI).
Low-resolution ESI mass spectra were recorded on a Thermo Finnigan LCQ Advantage Max Ion Trap
mass spectrometer. Elemental analyses were carried out using a Carlo Erba Instruments CHNS-O EA
1108 element analyzer. Melting points were analyzed with a Büchi melting point B-545 and are not

Molecules 2010, 15
2280
corrected. Gas chromatography (GC) was performed on a Hewlett Packard 5890, containing a HP1
column (25 m x 0.32 mm x 0.17 μm), FID detection, and equipped with a HP3393A integrator. NMR
spectra were recorded at 298 K on a Bruker DMX 300 (300 MHz) or a Varian 400 (400 MHz)
spectrometer in the solvent indicated. Chemical shifts are given in parts per million (ppm) with respect
1
to tetramethylsilane (0.00 ppm) or CD3SOCHD2 (2.50 ppm) as internal standard for H-NMR; and
13
CDCl3 (77.16 ppm) or CD3SOCD3 (39.52 ppm) as internal standard for C-NMR [59]. Coupling
constants are reported as J values in hertz (Hz). Multiplicity data are denoted by s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), b (broad), and app (apparent). Peak assignment in 13C spectra are
based on 2D gHSQC and gHMBC spectra, and DEPT 135 when needed. Chain numbering
corresponds to IUPAC nomenclature, so unprimed atoms belong to the principal chain, primed atoms
belong to the first named substituent, doubled-primed atoms to the second named substituent, etc. LC-
MS measurements were run on a Shimadzu LC-10A VP series liquid chromatography system,
equipped with an SPD-10A VP UV-vis detector and a LCMS-2010A mass spectrometer. The column
used for the LC analysis was an Agilent Zorbax Extend C18 (3.5 μm, 4.6 × 150 mm), and it was eluted
at 1 mL/min with a gradient made up of two solvent mixtures. Solvent A consisted of 0.1%
trifluoroacetic acid in water and solvent B consisted of 0.1% trifluoroacetic acid in acetonitrile. The
gradient was run as follows: t ) 0 min, 50% A; t ) 5 min, 5% A; t ) 10 min, 5% A; t ) 12.5 min, 50% A;
t ) 20 min, 50% A. A wavelength of 215 nm was selected for the analysis of purity.
3.2. General procedure for Knoevenagel condensation reaction
Piperidine (5 drops) was added to a solution of methyl 2-cyanoacetate (9) and the aldehyde 10
(1.0 equiv) in MeOH. The resulting reaction mixture was stirred at room temperature for the time
indicated in each case. The reaction mixture was filtered and the precipitate was recrystalized from
MeOH. The filtrate was concentrated under reduced pressure and purified by recrystalization from
MeOH.
Methyl (E)-2-cyano-3-phenylacrylate (8{1}): According to the general procedure, the reaction of
methyl 2-cyanoacetate (9, 7.940 g, 80.13 mmol) with benzaldehyde 10{1} (8.504 g, 80.13 mmol) over
30 min afforded 8{1} (14.910 g, 99%) as a white solid. 1H-NMR [400 MHz, δ (ppm), CDCl3]: 8.21 (s,
1 1H, 3-CH), 7.97–7.92 (m, 2 1H, 2′-CH + 6′-CH), 7.56–7.43 (m, 3 1H, 3′-CH + 4′-CH + 5′-CH), 3.90
1
13
(s, 3 H, OCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 162.5 (CO2), 154.9 (3-C), 133.1 (4′-C), 131.1
(1′-C), 130.8 (2′-C + 6′-C), 129.0 (3′-C + 5′-C), 115.2 (CN), 102.4 (2-C), 53.4 (OCH3). FTIR [ν (cm–
1), neat]: 3036, 2954, 2224, 1727, 1606, 1200, 767, 685. Elem. anal. calcd. for C11H9NO2: C 70.58%,
H 4.85%, N 7.48%; found C 70.39%, H 4.54%, N 7.43%. RF: 0.63 (heptane/AcOEt, 1:1). Mp: 87.9 °C
(from MeOH, colorless flake-like crystals). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(4-methoxyphenyl)acrylate (8{2}): According to the general procedure, the
reaction of methyl 2-cyanoacetate (9, 6.804 g, 68.66 mmol) with 4-methoxybenzaldehyde 10{2}
1
(9.349 g, 68.66 mmol) over 30 min afforded 8{2} (14.020 g, 94%) as a white solid. H-NMR [400
MHz, δ (ppm), CDCl3]: 8.14 (s, 1 1H, 3-CH), 8.00–7.95 (m, 2 1H, 2′-CH + 6′-CH), 7.01–6.95 (m, 2 1H,
3′-CH + 5′-CH), 3.91 (s, 3 1H, CO2CH3), 3.88 (s, 3 1H, OCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]:
163.8 (4′-C), 163.5 (CO2), 154.5 (3-C), 133.6 (2′-C + 6′-C), 124.2 (1′-C), 116.1 (CN), 114.7 (3′-C + 5′-

Molecules 2010, 15
2281
C), 98.8 (2-C), 55.6 (OCH3), 53.1 (CO2CH3). FTIR [ν (cm–1), neat]: 3084, 2954, 2846, 2215, 1714,
1580, 1264, 1174, 841. Elem. anal. calcd. for C12H11NO3: C 66.35%, H 5.10%, N 6.45%; found C
66.24%, H 4.98%, N 6.33%. RF: 0.58 (heptane/AcOEt, 1:1). Mp: 104.1 °C (from MeOH, off-white
small crystals). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(3,5-dimethoxyphenyl)acrylate (8{3}): According to the general procedure, the
reaction of methyl 2-cyanoacetate (9, 5.835 g, 58.89 mmol) with 3,5-dimethoxybenzaldehyde 10{3}
1
(9.785 g, 58.89 mmol) over 40 min afforded 8{3} (12.399 g, 99%) as a yellow solid. H-NMR [400
MHz, δ (ppm), CDCl3]: 8.17 (s, 1 1H, 3-CH), 7.15 (d, J = 2.4 Hz, 2 1H, 2′-CH + 6′-CH), 6.65 (t, J = 2.4
1
1
1
13
Hz, 1 H, 4′-CH), 3.94 (s, 3 H, CO2CH3), 3.84 (s, 6 H, 2 × OCH3). C-NMR [75 MHz, δ (ppm),
CDCl3]: 163.1 (CO2), 161.2 (3′-C + 5′-C), 155.6 (3-C), 133.1 (1′-C), 115.6 (CN), 108.7 (2′-C + 6′-C),
106.4 (4′-C), 103.0 (2-C), 55.8 (2 × OCH3), 53.6 (CO2CH3). FTIR [ν (cm–1), neat]: 3086, 2940, 2841,
2217, 1723, 1604, 1247, 1167, 840. Elem. anal. calcd for C13H13NO4: C 63.15%, H 5.30%, N 5.66%;
found C 63.22%, H 5.14%, N 5.53%. RF: 0.56 (heptane/AcOEt, 1:1). Mp: 121.5 °C (from MeOH, long
light yellow needles). Purity: >99.5% (GC).
Methyl (E)-3-(1,3-benzodioxol-5-yl)-2-cyanoacrylate (8{4}): According to the general procedure, the
reaction of methyl 2-cyanoacetate (9, 6.002 g, 60.57 mmol) with piperonal 10{4} (9.094 g, 60.57
1
mmol) over 60 min afforded 8{4} (13.836 g, 99%) as a light greenish solid. H-NMR [400 MHz, δ
(ppm), CDCl3]: 8.12 (s, 1 1H, 3-CH), 7.71 (d, J = 1.9 Hz, 1 1H, 4′-CH), 7.41 (ddd; J = 8.2, 1.9, 0.6 Hz;
1 1H, 6′-CH), 6.91 (d, J = 8.2 Hz, 1 1H, 7′-CH), 6.09 (s, 2 1H, 2′-CH2), 3.92 (s, 3 1H, OCH3). 13C-NMR
[75 MHz, δ (ppm), CDCl3]: 163.6 (CO2), 154.7 (3-C), 152.5 (7′a-C), 148.8 (3′a-C), 130.0 (6′-C), 126.1
(5′-C), 116.1 (CN), 109.1 (4′-C), 109.0 (7′-C), 102.5 (2′-C), 99.5 (2-C), 53.4 (OCH3). FTIR [ν (cm–1),
neat]: 3029, 2957, 2218, 1723, 1579, 1244, 1205, 1041, 922, 819. HRMS [EI (m/z)] calcd for
C12H9NO4 = 231.0532, found for [M+•] = 231.0532 (|Δ| = 0.0 ppm), peaks at (relative intensity): 231
(100), 200 (21), 170 (32), 142 (12), 114 (21). Elem. anal. calcd for C12H9NO4: C 62.34%, H 3.92%, N
6.06%; found C 62.24%, H 3.86%, N 6.00%. RF: 0.60 (heptane/AcOEt, 1:1). Mp: 169.6 °C (from
MeOH, light green cotton-like solid). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(1-methyl-1H-pyrrol-2-yl)acrylate (8{5}): According to the general procedure,
the reaction of methyl 2-cyanoacetate (9, 7.107 g, 71.72 mmol) with 1-methyl-1H-pyrrole-2-
carbaldehyde 10{5} (7.827 g, 71.72 mmol) over 120 min afforded 8{5} (12.932 g, 95%) as a yellow
1
1
1
solid. H-NMR [400 MHz, δ (ppm), CDCl3]: 8.08 (s, 1 H, 3-CH). 7.72 (d, J = 4.4 Hz, 1 H, 3′-CH),
1
1
1
1
7.01 (t, J = 1.8 Hz, 1 H, 5′-CH), 6.39–6.36 (m, 1 H, 4′-CH), 3.89 (s, 3 H, OCH3), 3.78 (s, 3 H,
13
NCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 164.8 (CO2), 139.6 (3-C), 131.7 (5′-C), 127.5 (2′-C),
120.0 (3′-C), 117.1(CN), 112.2 (4′-C), 92.8 (2-C), 53.0 (OCH3), 34.4 (NCH3). FTIR [ν (cm–1), neat]:
3120, 2957, 2899, 2210, 1717, 1591, 1243, 748. Elem. anal. calcd for C10H10N2O2: C 63.15%, H
5.30%, N 14.73%; found C 63.19%, H 5.09%, N 14.70%. RF: 0.29 (heptane/AcOEt, 1:1). Mp: 154.2
°C (from MeOH, yellow solid). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(1-methyl-1H-indol-3-yl)acrylate (8{6}): According to the general procedure,
the reaction of methyl 2-cyanoacetate (9, 6.011 g, 60.66 mmol) with 1-methyl-1H-indole-3-
carbaldehyde 10{6} (9.656 mg, 60.66 mmol) over 120 min afforded 8{6} (13.977 g, 96%) as a yellow

Molecules 2010, 15
2282
1
1
1
solid. H- NMR [400 MHz, δ (ppm), CDCl3]: 8.56 (s, 1 H, 3-CH), 8.49 (s, 1 H, 2′-CH), 7.84–7.80
(m, 1 1H, 4′-CH), 7.42–7.31 (m, 3 1H, 5′-CH + 6′-CH + 7′-CH), 3.91 (s, 3 1H, CO2CH3), 3.90 (s, 3 1H,
13
NCH3). C- NMR [75 MHz, δ (ppm), CDCl3]: 164.6 (CO2), 146.2 (3-C), 137.0 (7′a-C), 134.9 (2′-C),
128.5 (3′a-C), 124.1 (6′-C), 122.8 (5′-C), 118.6 (4′-C), 118.5 (CN), 110.6 (7′-C), 110.1 (3′-C), 93.3 (2-
C), 52.9 (OCH3), 34.2 (NCH3). FTIR [ν (cm–1), neat]: 3118, 3026, 2950, 2222, 1701, 1586, 1255, 751.
HRMS [EI (m/z)] calcd for C14H12N2O2 = 240.0899, found for [M+•] = 240.0895 (|Δ| = 1.6 ppm), peaks
at (relative intensity): 240 (100), 209 (53), 140 (18), 49 (12). Elem. anal. calcd for C14H12N2O2: C
69.99%, H 5.03%, N 11.66%; found C 69.69%, H 4.85%, N 11.42%. RF: 0.37 (heptane/AcOEt, 1:1).
Mp: 165.9 °C (from MeOH, yellow solid). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(1H-pyrrol-2-yl)acrylate (8{7}): According to the general procedure, the
reaction of methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with 1H-pyrrole-2-carbaldehyde 10{7}
1
(951 mg, 10.00 mmol) over 30 min afforded 8{7} (1.744 g, 99%) as a yellow solid. H-NMR [400
1
1
1
MHz, δ (ppm), CDCl3]: 9.92 (bs, 1 H, NH), 8.02 (s, 1 H, 3-CH), 7.26–7.23 (m, 1 H, 5′-CH), 6.98–
1
1
1
13
6.94 (m, 1 H, 3′-CH), 6.44 (dt; J = 3.9, 2.3 Hz; 1 H, 4′-CH), 3.89 (s, 3 H, OCH3). C-NMR [75
MHz, δ (ppm), CDCl3]: 164.2 (CO2), 142.8 (3-C), 128.4 (5′-C), 127.0 (2′-C), 124.7 (3′-C), 118.6 (CN),
112.7 (4′-C), 91.8 (2-C), 53.0 (OCH3). FTIR [ν (cm–1), neat]: 3300, 3032, 2950, 2215, 1692, 1593,
1221, 750. Elem. anal. calcd for C9H8N2O2: C 61.36%, H 4.58%, N 15.90%; found C 61.45%, H
4.58%, N 15.79%. RF: 0.37 (heptane/AcOEt, 1:1). Mp: 140.2 °C (from MeOH, small thin yellow
needles). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(1H-indol-3-yl)acrylate (8{8}): According to the general procedure, the reaction
of methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with 1H-indole-3-carbaldehyde 10{8} (1.452 g,
10.00 mmol) in THF (15 mL) over 480 min afforded 8{8} (2.239 g, 99%) as a yellow solid. 1H-NMR
1
1
1
[400 MHz, δ (ppm), CD3SOCD3]: 12.64 (bs, 1 H, NH), 8.64 (s, 1 H, 2′-CH), 8.63 (s, 1 H, 3-CH),
8.05–7.99 (m, 1 1H, 4′-CH), 7.67–7.63 (m, 1 1H, 7′-CH), 7.41–7.30 (m, 2 1H, 5′-CH + 6′-CH), 3.92 (s,
1
13
3 H, OCH3). C-NMR [75 MHz, δ (ppm), CD3SOCD3]: 163.3 (CO2), 146.3 (3-C), 135.9 (7′a-C),
132.4 (2′-C), 126.6 (3′a-C), 123.3 (6′-C),_121.9 (5′-C), 118.3 (4′-C), 117.8 (CN), 112.7 (7′-C), 109.7
(3′-C), 91.8 (2-C), 52.6 (OCH3). FTIR [ν (cm–1), neat]: 3266, 3132, 2989, 2943, 2212, 1695, 1589,
1241, 742. Elem. anal. calcd for C13H10N2O2: C 69.02%, H 4.46%, N 12.38%; found C 68.97%, H
4.38%, N 12.22%. RF: 0.80 (AcOEt). Mp: 189.5 °C (from MeOH, yellow needles). Purity: >99.5%
(GC).
Methyl (E)-2-cyano-3-(2-thienyl)acrylate (8{9}): According to the general procedure, the reaction of
methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with thiophene-2-carbaldehyde 10{9} (1.121 g, 10.00
mmol) over 30 min afforded 8{9} (1.816 g, 94%) as a light brown solid. 1H-NMR [400 MHz, δ (ppm),
CDCl3]: 8.36 (s, 1 1H, 3-CH), 7.84 (d, J = 3.9 Hz, 1 1H, 3′-CH), 7.80 (d, J = 4.9 Hz, 1 1H, 5′-CH), 7.24
(dd; J = 4.9, 3.9 Hz; 1 1H, 4′-CH), 3.92 (s, 3 1H, OCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 162.9
(CO2), 146.7 (3-C), 137.2 (3′-C), 135.8 (2′-C), 135.2 (5′-C), 128.6 (4′-C), 115.6 (CN), 98.8 (2-C), 53.4
_
(OCH3). FTIR [ν (cm–1), neat]: 3087, 3028, 2964, 2216, 1718, 1590, 1271, 1214, 729. Elem. anal.
calcd for C9H7NO2S: C 55.94%, H 3.65%, N 7.25%; found C 55.98%, H 3.63%, N 7.23%. RF: 0.61
(heptane/AcOEt, 1:1). Mp: 106.9 °C (from MeOH, light brown needles). Purity: >99.5% (GC).

Molecules 2010, 15
2283
Methyl (E)-2-cyano-3-(2-pyridyl)acrylate (8{10}): According to the general procedure, the reaction of
methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with pyridine-2-carbaldehyde 10{10} (1.071 g, 10.00
1
mmol) over 30 min afforded 8{10} (1.863 g, 99%) as a brown solid. H-NMR [400 MHz, δ (ppm),
1
1
CDCl3]: 8.83 (ddd; J = 4.8, 1.6, 1.0 Hz; 1 H, 6′-CH), 8.30 (s, 1 H, 3-CH), 7.89 (app dt; J = 7.8, 1.2
Hz; 1 1H, 3′-CH), 7.85 (app dt; J = 1.6, 7.8 Hz; 1 1H, 4′-CH), 7.44 (ddd; J = 7.3, 4.9, 1.5 Hz; 1 1H, 5′-
CH), 3.96 (s, 3 1H, OCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 162.6 (CO2), 153.7 (3-C), 150.7 (6′-
C), 150.0 (2′-C), 137.1 (4′-C), 126.8 (5′-C), 126.4 (3′-C), 114.8 (CN), 106.4 (2-C), 53.7 (OCH3). FTIR
[ν (cm–1), neat]: 3050, 2963, 2220, 1720, 1278, 1215, 781, 740. Elem. anal. calcd for C10H8N2O2: C
63.83%, H 4.28%, N 14.89%; found C 64.06%, H 4.26%, N 14.79%. RF: 0.34 (heptane/AcOEt, 1:1).
Mp: 131.7 °C (from MeOH, small brown needles). Purity: >99.5% (GC).
Methyl (E)-2-cyano-3-(3-pyridyl)acrylate (8{11}): According to the general procedure, the reaction of
methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with pyridine-3-carbaldehyde 10{11} (1.071 g, 10.00
1
mmol) over 90 min afforded 8{11} (1.750 g, 93%) as a light yellow dust. H-NMR [300 MHz, δ
1
1
(ppm), CDCl3]: 8.91 (d, J = 1.8 Hz, 1 H, 2′-CH), 8.74 (dd; J = 4.8, 1.8 Hz; 1 H, 6′-CH), 8.57–8.51
(m, 1 1H, 4′-CH), 8.26 (s, 1 H, 3-CH), 7.46 (dd; J = 7.8, 4.8 Hz; 1 1H, 5′-CH), 3.95 (s, 3 H, OCH3).
1
1
13C-NMR [75 MHz, δ (ppm), CDCl3]: 161.9 (CO2), 153.3 (3-C), 152.7 (6′-C), 151.3 (2′-C), 135.8 (4′-
_
C), 127.3 (3′-C), 123.9 (5′-C), 114.7 (CN), 105.1 (2-C), 53.8 (OCH3). FTIR [ν (cm–1), neat]: 3031,
2959, 2223, 1722, 1280, 697. RF: 0.13 (heptane/AcOEt, 1:1). Mp: 129.2 °C.
Methyl (E)-2-cyano-3-(4-pyridyl)acrylate (8{12}): According to the general procedure, the reaction of
methyl 2-cyanoacetate (9, 991 mg, 10.00 mmol) with pyridine-4-carbaldehyde 10{12} (1.071 g, 10.00
1
mmol) over 25 min afforded 8{12} (1.863 g, 99%) as a pink solid. H-NMR [400 MHz, δ (ppm),
1
1
1
CDCl3]: 8.86–8.80 (m, 2 H, 2′-CH + 6′-CH), 8.23 (s, 1 H, 3-CH), 7.80–7.74 (m, 2 H, 3′-CH + 5′-
CH), 3.97 (s, 3 1H, OCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 161.8 (CO2), 152.4 (3-C), 151.2 (2′-
_
C + 6′-C), 138.0 (4′-C), 123.3 (3′-C + 5′-C), 114.2 (CN), 107.8 (2-C), 53.8 (OCH3). FTIR [ν (cm–1),
neat]: 3033, 2955, 2225, 1726, 1236, 1198, 818. Elem. anal. calcd for C10H8N2O2: C 63.83%, H
4.28%, N 14.89%; found C 63.94%, H 4.25%, N 14.75%. RF: 0.12 (heptane/AcOEt, 1:1). Mp:
126.6 °C (from MeOH, small pink needles). Purity: >99.5% (GC).
3.3. General procedure for 1,3-dipolar cycloaddition reactions of 8
A round-bottomed flask fitted with a Dean–Stark apparatus, a reflux condenser, and a drying tube
containing calcium chloride was charged with 2-cyanoacrylate 8 and toluene (0.20–0.25 M). When the
mixture was under reflux, sarcosine (N-methylglycine; 1.2 equiv) and paraformaldehyde (3.6 equiv)
were added. This addition was repeated every 40 min until the substrate had completely reacted. Water
(20 mL) was then added and the layers were separated. The aqueous layer was extracted with Et2O
(3 × 30 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo.
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-phenylpyrrolidine-3-carboxylate (7{1}): According to the
general procedure, 2-cyanoacrylate 8{1} (5.342 g, 28.54 mmol) afforded 7{1} (6.524 g, 94%) as a
1
white solid, after column chromatography (heptane/AcOEt, 3:1→2:1). H-NMR [400 MHz, δ (ppm),

Molecules 2010, 15
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CDCl3]: 7.33–7.19 (m, 5 1H, Ph), 4.00 (app t, J = 7.8 Hz, 1 1H, 4-CH), 3.70 (s, 3 1H, OCH3), 3.25 (d, J
= 9.9 Hz, 1 1H, 2-CHH), 3.18 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.04 (dd; J = 9.6, 7.8 Hz; 1 1H, 5-CHH),
3.00 (dd; J = 9.6, 8.1 Hz; 1 1H, 5-CHH), 2.38 (s, 3 1H, NCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]:
167.6 (CO2), 136.6 (1′-C), 128.0 (2′-C + 6′-C), 127.9 (3′-C + 5′-C), 127.5 (4′-C), 117.2 (CN), 64.9 (2-
C), 60.2 (5-C), 54.4 (3-C), 53.5 (CO2CH3), 51.8 (4-C), 41.1 (NCH3). FTIR [ν (cm–1), neat]: 2950,
2846, 2790, 2241, 1740, 1247, 772, 699. MS [ESI (m/z)] calcd for (C14H16N2O2 + H)+ = 245, found
245. RF: 0.24 (heptane/AcOEt, 1:1). Mp: 53.3 °C (from heptane, colorless crystals). Purity: >99.5%
(GC).
(±)-Methyl
(3R,4R)-3-cyano-4-(4-methoxyphenyl)-1-methylpyrrolidine-3-carboxylate
(7{2}):
According to the general procedure, 2-cyanoacrylate 8{2} (6.162 g, 28.37 mmol) afforded 7{2} (7.688
1
1
g, 99%) as a yellow oil. H-NMR [400 MHz, δ (ppm), CDCl3]: 7.28–7.22 (m, 2 H, 2′-CH + 6′-CH),
6.87–6.82 (m, 2 1H, 3′-CH + 5′-CH), 3.98 (app t, J = 8.0 Hz, 1 1H, 4-CH), 3.80 (s, 3 1H, CO2CH3), 3.76
(s, 3 H, OCH3), 3.31 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.20 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.07 (dd; J =
1
1
1
1
13
9.6, 7.8 Hz; 1 H, 5-CHH), 3.02 (dd; J = 9.6, 8.1 Hz; 1 H, 5-CHH), 2.44 (s, 3 H, NCH3). C-NMR
[75 MHz, δ (ppm), CDCl3]: 168.1 (CO2), 159.1 (4′-C), 129.4 (2′-C + 6′-C), 128.6 (1′-C), 117.8 (CN),
113.8 (3′-C + 5′-C), 65.2 (2-C), 60.8 (5-C), 55.2 (OCH3), 54.9 (3-C), 53.9 (CO2CH3), 51.8 (4-C), 41.6
_
(NCH3). FTIR [ν (cm–1), neat]: 2951, 2836, 2788, 2243, 1740, 1247, 832. MS [ESI (m/z)] calcd for
(C15H18N2O3 + H)+ = 275, found 275. RF: 0.23 (heptane/AcOEt, 1:1). Purity: 98.9% (GC).
(±)-Methyl (3R,4R)-3-cyano-4-(3,5-dimethoxyphenyl)-1-methylpyrrolidine-3-carboxylate
(7{3}):
According to the general procedure, 2-cyanoacrylate 8{3} (9.745 g, 39.41 mmol) afforded 7{3}
1
(11.398 g, 95%) as a white solid, after column chromatography (heptane/AcOEt, 3:1→2:1). H-NMR
1
1
[400 MHz, δ (ppm), CDCl3]: 6.51 (d, J = 2.2 Hz, 2 H, 2′-CH + 6′-CH), 6.41 (t, J = 2.2 Hz, 1 H, 4′-
CH), 3.99 (app t, J = 7.9 Hz, 1 1H, 4-CH), 3.84 (s, 3 1H, CO2CH3), 3.78 (s, 6 1H, 2 × OCH3), 3.30 (d, J
= 9.9 Hz, 1 1H, 2-CHH), 3.24 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.09 (dd; J = 9.6, 7.8 Hz; 1 1H, 5-CHH),
3.06 (dd; J = 9.6, 8.0 Hz; 1 1H, 5-CHH), 2.47 (s, 3 1H, NCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]:
168.8 (CO2), 161.1 (3′-C + 5′-C), 139.4 (1′-C), 118.1 (CN), 107.0 (2′-C + 6′-C), 100.2 (4′-C), 65.7 (2-
_
C), 60.7 (5-C), 55.6 (2 × OCH3), 54.8 (3-C), 54.2 (CO2CH3), 52.6 (4-C), 41.8 (NCH3). FTIR [ν (cm–
1), neat]: 2948, 2837, 2790, 2243, 1743, 1595, 1203, 1155. HRMS [EI (m/z)] calcd for C16H20N2O4 =
304.1423, found for [M+•] = 304.1436 (|Δ| = 4.2 ppm), peaks at (relative intensity): 304 (16), 261 (18),
193 (11), 57 (100), 42 (20). Elem. anal. calcd for C16H20N2O4: C 63.14%, H 6.62%, N 9.20%; found C
63.33%, H 6.65%, N 9.19%. RF: 0.19 (heptane/AcOEt, 1:1). Mp: 94.7 °C (from heptane, colorless
crystals). Purity: >99.5% (GC).
(±)-Methyl
(3R,4R)-4-(1,3-benzodioxol-5-yl)-3-cyano-1-methylpyrrolidine-3-carboxylate
(7{4}):
According to the general procedure, 2-cyanoacrylate 8{4} (9.774 g, 42.27 mmol) afforded 7{4}
(12.041 g, 99%) as a white solid. 1H-NMR [400 MHz, δ (ppm), CDCl3]: 6.88 (d, J = 1.7 Hz, 1 1H, 4′-
CH), 6.81 (dd; J = 8.0, 1.7 Hz; 1 1H, 6′-CH), 6.77 (d, J = 8.0 Hz, 1 1H, 7′-CH), 5.95 (d, J = 1.6 Hz, 1
1
1
1
1H, 2′-CHH), 5.94 (d, J = 1.6 Hz, 1 H, 2′-CHH), 3.97 (t, J = 7.8 Hz, 1 H, 4-CH), 3.84 (s, 3 H,
1
1
OCH3), 3.28 (d, J = 9.9 Hz, 1 H, 2-CHH), 3.23 (d, J = 9.9 Hz, 1 H, 2-CHH), 3.06 (dd; J = 9.5, 7.8
Hz; 1 1H, 5-CHH), 3.01 (dd; J = 9.5, 7.8 Hz; 1 1H, 5-CHH), 2.45 (s, 3 1H, NCH3). 13C-NMR [75 MHz,
δ (ppm), CDCl3]: 168.5 (CO2), 147.9 (3′a-C), 147.5 (7′a-C), 130.8 (5′-C), 122.0 (6′-C), 117.9 (CN),

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108.8 (7′-C), 108.3 (4′-C), 101.2 (2′-C), 65.3 (2-C), 60.8 (5-C), 54.8 (3-C), 54.0 (OCH3), 52.1 (4-C),
_
41.5 (NCH3). FTIR [ ν (cm–1), neat]: 2965, 2900, 2788, 2242, 1740, 1249, 1036, 929. HRMS [EI
(m/z)] calcd for C15H16N2O4 = 288.1110, found for [M+•] = 288.1097 (|Δ| = 4.5 ppm), peaks at (relative
intensity): 288 (13), 57 (100), 42 (11). Elem. anal. calcd for C15H16N2O4: C 62.49%, H 5.59%, N
9.72%; found C 62.56%, H 5.61%, N 9.69%. RF: 0.22 (heptane/AcOEt, 1:1). Mp: 87.6 °C (from
heptane, colorless crystals). Purity: >99.5% (GC).
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(1-methyl-1H-pyrrol-2-yl)pyrrolidine-3-carboxylate (7{5}):
According to the general procedure, 2-cyanoacrylate 8{5} (1.132 g, 5.95 mmol) afforded 7{5} (765
1
mg, 52%) as a yellow oil, after column chromatography (heptane/AcOEt, 3:1→2:1). H-NMR [400
MHz, δ (ppm), CDCl3]: 6.62 (dd; J = 2.7, 1.7 Hz; 1 1H, 5′-CH), 6.28 (dd; J = 3.6, 1.7 Hz; 1 1H, 3′-CH),
6.14 (dd; J = 3.6, 2.7 Hz; 1 1H, 4′-CH), 4.25 (app t, J = 8.2 Hz, 1 1H, 4-CH), 3.87 (s, 3 1H, OCH3), 3.57
1
1
1
(s, 3 H, 1′-NCH3), 3.45 (d, J = 9.9 Hz, 1 H, 2-CHH), 3.26 (dd; J = 9.5, 7.6 Hz; 1 H, 5-CHH), 3.04
(d, J = 9.9 Hz, 1 1H, 2-CHH), 2.84 (app t, J = 9.1 Hz, 1 1H, 5-CHH), 2.44 (s, 3 1H, 1-NCH3). 13C-NMR
[75 MHz, δ (ppm), CDCl3]: 168.9 (CO2), 128.2 (2′-C), 123.5 (5′-C), 117.2 (CN), 108.7 (4′-C), 107.6
(3′-C), 65.2 (2-C), 61.3 (5-C), 54.2 (OCH3), 53.8 (3-C), 43.7 (4-C), 41.5 (1-NCH3), 34.0 (1′-NCH3).
FTIR [ ν (cm–1), neat]: 2951, 2888, 2791, 2242, 1741, 1241, 717. MS [ESI (m/z)] calcd for
(C13H17N3O2 + H)+ = 248, found 248. RF: 0.23 (heptane/AcOEt, 1:1). Purity: 98.2% (GC).
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrolidine-3-carboxylate (7{6}):
According to the general procedure, 2-cyanoacrylate 8{6} (9.241 g, 38.46 mmol) afforded 7{6}
(10.831 g, 95%) as a yellow solid, after column chromatography (heptane/AcOEt, 3:1→2:1). 1H-NMR
[400 MHz, δ (ppm), CDCl3]: 7.50 (dt; J = 8.1, 1.0 Hz; 1 1H, 4′-CH), 7.29 (dt; J = 8.3, 1.0 Hz; 1 1H, 7′-
1
1
CH), 7.22 (ddd; J = 8.3, 7.1, 1.0 Hz; 1 H, 6′-CH), 7.19 (s, 1 H, 2′-CH), 7.10 (ddd; J = 8.1, 7.0, 1.0
Hz; 1 1H, 5′-CH), 4.43 (dd; J = 9.6, 7.5 Hz; 1 1H, 4-CH), 3.76 (s, 3 1H, OCH3), 3.74 (s, 3 1H, 1′-NCH3),
1
1
3.51 (d, J = 10.2 Hz, 1 H, 2-CHH), 3.25 (d, J = 10.2 Hz, 1 H, 2-CHH), 3.23 (dd; J = 9.6, 7.5 Hz; 1
1H, 5-CHH), 3.08 (t, J = 9.6 Hz, 1 1H, 5-CHH), 2.51 (s, 3 1H, 1-NCH3). 13C-NMR [75 MHz, δ (ppm),
CDCl3]: 169.0 (CO2), 136.8 (7′a-C), 127.7 (3′a-C), 127.4 (2′-C), 122.1 (6′-C), 119.5 (5′-C), 118.7 (4′-
C), 118.5 (CN), 109.63 (3′-C), 109.58 (7′-C), 65.3 (2-C), 60.9 (5-C), 55.1 (3-C), 53.9 (OCH3), 45.2 (4-
C), 42.0 (1-NCH3), 33.0 (1′-NCH3). FTIR [ν (cm–1), neat]: 3045, 2948, 2842, 2786, 2243, 1741, 1474,
1243, 742. HRMS [EI (m/z)] calcd for C17H19N3O2 = 297.1477, found for [M+•] = 297.1467 (|Δ| = 3.5
ppm), peaks at (relative intensity): 297 (17), 144 (16), 57 (100), 42 (21). RF: 0.17 (heptane/AcOEt,
1:1). Mp: 92.6 °C. Purity: 98.8% (GC).
(±)-Methyl
(3R,4R)-3-cyano-4-{1-[(dimethylamino)methyl]-1H-indol-3-yl}-1-methylpyrrolidine-3-
carboxylate (7{13}): According to the general procedure, 2-cyanoacrylate 8{8} (1.512 g, 6.68 mmol)
1
afforded 7{13} (1.929 g, 85%) as a yellow solid. H-NMR [300 MHz, δ (ppm), CDCl3]: 7.45 (d, J =
7.8 Hz, 1 1H, 4′-CH), 7.36 (d, J = 8.1 Hz, 1 1H, 7′-CH), 7.24 (s, 1 1H, 2′-CH), 7.14 (ddd; J = 8.1, 6.9,
1
1
1
1.0 Hz; 1 H, 6′-CH), 7.05 (ddd; J = 7.8, 6.9, 1.0 Hz; 1 H, 5′-CH), 4.69 (d, J = 12.9 Hz, 1 H,
NCHHN), 4.58 (d, J = 12.9 Hz, 1 1H, NCHHN), 4.40 (dd; J = 9.3, 7.6 Hz; 1 1H, 4-CH), 3.67 (s, 3 1H,
OCH3), 3.43 (d, J = 10.0 Hz, 1 1H, 2-CHH), 3.17 (d, J = 10.0 Hz, 1 1H, 2-CHH), 3.16 (dd; J = 9.3, 7.6
Hz; 1 1H, 5-CHH), 3.04 (t, J = 9.3 Hz, 1 1H, 5-CHH), 2.42 (s, 3 1H, 1-NCH3), 2.23 (s, 6 1H, N(CH3)2).
13C-NMR [75 MHz, δ (ppm), CDCl3]: 168.5 (CO2), 136.7 (7′a-C), 127.5 (3′a-C), 126.9 (2′-C), 121.9

Molecules 2010, 15
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(6′-C), 119.4 (5′-C), 118.3 (4′-C), 118.0 (CN), 110.21 (3′-C), 110.17 (7′-C), 68.6 (NCH2N), 65.3 (2-C),
_
60.7 (5-C), 55.1 (3-C), 53.8 (OCH3), 44.8 (4-C), 42.7 (N(CH3)2), 41.8 (NCH3). FTIR [ν (cm–1), neat]:
3049, 2942, 2842, 2778, 2242, 1740, 1460, 1239, 729. Elem. anal. calcd for C19H24N4O2: C 67.04%, H
7.11%, N 16.46%; found C 66.98%, H 7.05%, N 16.18%. RF: 0.19 (AcOEt). Mp: 105.8 °C.
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(2-thienyl)pyrrolidine-3-carboxylate (7{9}): According to the
general procedure, 2-cyanoacrylate 8{9} (720 mg, 3.73 mmol) afforded 7{9} (814 mg; 87%, combined
1
yield including 11{9}) as a yellow oil, after column chromatography (heptane/AcOEt, 1:1). H-NMR
[300 MHz, δ (ppm), CDCl3]: 7.23 (dd; J = 5.1, 1.0 Hz; 1 1H, 5′-CH), 7.04 (dt; J = 3.6, 1.0 Hz; 1 1H, 3′-
1
1
1
CH), 6.98 (dd; J = 5.1, 3.6 Hz; 1 H, 4′-CH), 4.32 (app t, J = 7.8 Hz, 1 H, 4-CH), 3.85 (s, 3 H,
1
1
OCH3), 3.40 (d, J = 9.9 Hz, 1 H, 2-CHH), 3.24 (dd; J = 9.6, 7.2 Hz; 1 H, 5-CHH), 3.17 (d, J = 9.9
1
1
1
Hz, 1 H, 2-CHH), 3.00 (dd; J = 9.6, 8.4 Hz; 1 H, 5-CHH), 2.46 (s, 3 H, NCH3). MS [ESI (m/z)]
calcd for (C12H14N2O2S + H)+ = 251, found 251. RF: 0.31 (heptane/AcOEt, 1:1). Purity: 97.6% (GC).
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(2-pyridyl)pyrrolidine-3-carboxylate (7{10}): According to
the general procedure, 2-cyanoacrylate 8{10} (1.006 g, 5.35 mmol) afforded a 6.5:1 mixture of
7{10}/11{10} (1.182 g; 90%, combined yield) as a white solid, after column chromatography
1
(CH2Cl2/MeOH, 24:1). (Measured from a 6.5:1 mixture of 7{10}/11{10}) H-NMR [400 MHz, δ
(ppm), CDCl3]: 8.61 (d, J = 4.8 Hz, 1 1H, 6′-CH), 7.68 (app dt; J = 1.8, 7.6 Hz; 1 1H, 4′-CH), 7.30 (d, J
= 7.8 Hz, 1 1H, 3′-CH), 6.91 (ddd; J = 7.6, 4.8, 0.7 Hz; 1 1H, 5′-CH), 4.30 (t, J = 8.0 Hz, 1 1H, 4-CH),
3.88 (s, 3 1H, OCH3), 3.38 (d, J = 9.6 Hz, 1 1H, 2-CHH), 3.28 (dd; J = 9.3, 8.0 Hz; 1 1H, 5-CHH), 3.26
(d, J = 9.6 Hz, 1 1H, 2-CHH), 3.22 (dd; J = 9.3, 8.0 Hz; 1 1H, 5-CHH), 2.49 (s, 3 1H, NCH3). MS [ESI
(m/z)] calcd for (C13H15N3O2 + H)+ = 246, found 246. RF: 0.07 (heptane/AcOEt, 1:1).
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(3-pyridyl)pyrrolidine-3-carboxylate (7{11}): According to
the general procedure, 2-cyanoacrylate 8{11} (2.969 g, 15.78 mmol) afforded a 6.6:1 mixture of
7{11}/11{11} (2.782 g; 72%, combined yield) as a light yellow sticky solid, after column
1
chromatography (CH2Cl2/MeOH, 29:1). (Measured from a 6.6:1 mixture of 7{11}/11{11}) H-NMR
[400 MHz, δ (ppm), CDCl3]: 8.56 (dd; J = 4.9, 1.7 Hz; 1 1H, 6′-CH), 8.56–8.54 (m, 1 1H, 2′-CH), 7.81
(app dt; J = 8.0, 2.0 Hz; 1 1H, 4′-CH), 7.33 (ddd; J = 8.0, 4.9, 0.5 Hz; 1 1H, 5′-CH), 4.06 (app t, J = 7.7
Hz, 1 1H, 4-CH), 3.84 (s, 3 1H, OCH3), 3.32 (d, J = 10.0 Hz, 1 1H, 2-CHH), 3.28 (d, J = 10.0 Hz, 1 1H,
2-CHH), 3.09 (dd; J = 9.5, 7.8 Hz; 1 1H, 5-CHH), 3.06 (dd; J = 9.5, 7.6 Hz; 1 1H, 5-CHH), 2.47 (s, 3
1H, NCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 168.0 (CO2), 150.1 (2′-C), 149.65 (6′-C), 135.9 (4′-
C), 133.2 (3′-C), 123.5 (5′-C), 117.6 (CN), 65.1 (2-C), 60.6 (5-C), 54.4 (3-C), 54.1 (CO2CH3), 49.4 (4-
C), 41.3 (NCH3). MS [ESI (m/z)] calcd for (C13H15N3O2 + H)+ = 246, found 246. RF: 0.10
(heptane/AcOEt, 1:1).
(±)-Methyl (3R,4S)-3-cyano-1-methyl-4-(3-pyridyl)pyrrolidine-3-carboxylate (11{11}): According to
the general procedure, 2-cyanoacrylate 8{11} (2.969 g, 15.78 mmol) afforded a 6.6:1 mixture of
7{11}/11{11} (2.782 g; 72%, combined yield) as a light yellow sticky solid, after column
1
chromatography (CH2Cl2/MeOH, 29:1). (Measured from a 6.6:1 mixture of 7{11}/11{11}) H-NMR
[400 MHz, δ (ppm), CDCl3]: 8.56–8.54 (m, 1 1H, 2′-CH), 8.53 (dd; J = 4.9, 1.7 Hz; 1 1H, 6′-CH), 7.69
1
1
(app dt; J = 8.0, 2.0 Hz; 1 H, 4′-CH), 7.25 (ddd; J = 8.0, 4.9, 0.5 Hz; 1 H, 5′-CH), 4.07–4.04 (m, 1

Molecules 2010, 15
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1
1
1
1H, 4-CH), 3.40 (d, J = 10.2 Hz, 1 H, 2-CHH), 3.35 (d, J = 10.2 Hz, 1 H, 2-CHH), 3.27 (s, 3 H,
OCH3), 3.09 (dd; J = 9.3, 6.6 Hz; 1 1H, 5-CHH), 2.97 (dd; J = 9.3, 8.6 Hz; 1 1H, 5-CHH), 2.51 (s, 3 1H,
13
NCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 166.6 (CO2), 150.0 (2′-C), 149.60 (6′-C), 135.9 (4′-C),
131.9 (3′-C), 123.2 (5′-C), 120.2 (CN), 63.4 (2-C), 59.6 (5-C), 53.4 (4-C), 53.1 (CO2CH3), 52.4 (3-C),
41.2 (NCH3). RF: 0.10 (heptane/AcOEt, 1:1).
(±)-Methyl (3R,4R)-3-cyano-1-methyl-4-(4-pyridyl)pyrrolidine-3-carboxylate (7{12}): According to
the general procedure, 2-cyanoacrylate 8{12} (1.037 g, 5.51 mmol) afforded a 5:1 mixture of
7{12}/11{12} (1.145 g; 85%, combined yield) as a light yellow oil, after column chromatography
(CH2Cl2/MeOH, 24:1). (Measured from a 5:1 mixture of 7{12}/11{12}) 1H-NMR [400 MHz, δ (ppm),
CDCl3]: 8.62–8.58 (m, 2 1H, 2′-CH + 6′-CH), 7.32–7.28 (m, 2 1H, 3′-CH + 5′-CH), 4.03 (app t, J = 7.6
Hz, 1 1H, 4-CH), 3.86 (s, 3 1H, OCH3), 3.32 (d, J = 10.0 Hz, 1 1H, 2-CHH), 3.26 (d, J = 10.0 Hz, 1 1H,
2-CHH), 3.09 (dd; J = 9.8, 7.2 Hz; 1 1H, 5-CHH), 3.06 (dd; J = 9.8, 7.8 Hz; 1 1H, 5-CHH), 2.47 (s, 3
1H, NCH3). MS [ESI (m/z)] calcd for (C13H15N3O2 + H)+ = 246, found 246. RF: 0.06 (heptane/AcOEt,
1:1).
3.4. General procedure for reduction
An excess (7–8 heaped teaspoons) of freshly washed (with MeOH) Raney nickel was added to a
solution of α-cyano ester 7 with Et3N (ca. 1 equiv) in MeOH (0.25–0.30 M). The mixture was stirred
for 15 h at room temperature under a hydrogen atmosphere (1 atm). The catalyst was separated by
filtration with suction through a glass filter with a 0.5 cm layer of diatomaceous earth. The catalyst
was washed thoroughly with MeOH. The combined methanolic solutions were concentrated on a
rotary evaporator.
(±)-Methyl (3R,4S)-3-(aminomethyl)-1-methyl-4-phenylpyrrolidine-3-carboxylate (6{1}): According to
the general procedure, α-cyano ester 7{1} (5.040 g, 20.63 mmol) afforded 6{1} (4.858 g, 95%) as a
colorless oil. 1H-NMR [200 MHz, δ (ppm), CDCl3]: 7.36–7.21 (m, 5 1H, Ph), 3.93 (dd; J = 8.6, 7.3 Hz;
1 1H, 4-CH), 3.79 (s, 3 1H, OCH3), 3.35 (d, J = 9.6 Hz, 1 1H, 2-CHH), 3.08 (dd; J = 9.2, 7.3 Hz; 1 1H,
1
1
5-CHH), 2.77 (app t, J = 9.0 Hz, 1 H, 5-CHH), 2.62 (d, J = 13.0 Hz, 1 H, CHHNH2), 2.52 (d,
J = 13.0 Hz, 1 1H, CHHNH2), 2.48 (d, J = 9.6 Hz, 1 1H, 2-CHH), 2.41 (s, 3 1H, NCH3), 1.78 (bs, 2 1H,
NH2). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 175.9 (CO2), 138.4 (1′-C), 128.7 (2′-C + 6′-C), 127.9 (3′-
C + 5′-C), 126.6 (4′-C), 64.0 (2-C), 61.6 (5-C), 58.6 (3-C), 52.2 (CO2CH3), 49.9 (4-C), 46.7
(CH2NH2), 42.2 (NCH3). FTIR [ν (cm–1), neat]: 3386, 3028, 2946, 2781, 1727, 1601, 1455, 1174, 772,
703. HRMS [ESI (m/z)] calcd for (C14H20N2O2 + H)+ = 249.16030, found 249.15963 (|Δ| = 2.71 ppm).
RF: 0.30 (CH2Cl2/MeOH, 8:1). Purity: 99.1% (GC).
(±)-Methyl (3R,4S)-3-(aminomethyl)-4-(4-methoxyphenyl)-1-methylpyrrolidine-3-carboxylate (6{2}):
According to the general procedure, α-cyano ester 7{2} (6.997 g, 25.51 mmol) afforded 6{2} (6.731 g,
1
1
95%) as a colorless oil. H-NMR [400 MHz, δ (ppm), CDCl3]: 7.27–7.23 (m, 2 H, 2′-CH + 6′-CH),
6.86–6.82 (m, 2 1H, 3′-CH + 5′-CH), 3.88 (app t, J = 8.0 Hz, 1 1H, 4-CH), 3.79 (s, 3 1H, CO2CH3), 3.78
(s, 3 1H, OCH3), 3.33 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.06 (dd; J = 8.8, 7.8 Hz; 1 1H, 5-CHH), 2.71 (app
1
1
1
t, J = 8.9 Hz, 1 H, 5-CHH), 2.63 (d, J = 13.2 Hz, 1 H, CHHNH2), 2.52 (d, J = 13.2 Hz, 1 H,

Molecules 2010, 15
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1
1
1
13
CHHNH2), 2.46 (d, J = 9.9 Hz, 1 H, 2-CHH), 2.40 (s, 3 H, NCH3), 0.92 (bs, 2 H, NH2). C-NMR
[75 MHz, δ (ppm), CDCl3]: 176.1 (CO2), 158.2 (4′-C), 130.3 (1′-C), 129.7 (2′-C + 6′-C), 113.5 (3′-C +
5′-C), 64.1 (2-C), 61.8 (5-C), 58.6 (3-C), 55.2 (OCH3), 52.3 (CO2CH3), 49.2 (4-C), 46.8 (CH2NH2),
_
42.3 (NCH3). FTIR [ν (cm–1), neat]: 3383, 3222, 2947, 2834, 2779, 1724, 1247, 834. HRMS [ESI
(m/z)] calcd for (C15H22N2O3 + H)+ = 279.17087, found 279.17006 (|Δ| = 2.87 ppm). RF: 0.27
(CH2Cl2/MeOH, 8:1). Purity: 98.1% (GC).
(±)-Methyl
(3R,4S)-3-(aminomethyl)-4-(3,5-dimethoxyphenyl)-1-methylpyrrolidine-3-carboxylate
(6{3}): According to the general procedure, α-cyano ester 7{3} (7.452 g, 25.06 mmol) afforded 6{3}
1
(6.730 g, 89%) as a yellow oil, after column chromatography (CH2Cl2/MeOH, 9:1). H-NMR [400
1
1
MHz, δ (ppm), CDCl3]: 6.51 (d, J = 2.2 Hz, 2 H, 2′-CH + 6′-CH), 6.35 (t, J = 2.2 Hz, 1 H, 4′-CH),
3.87 (app t, J = 7.9 Hz, 1 1H, 4-CH), 3.80 (s, 3 1H, CO2CH3), 3.78 (s, 6 1H, 2 × OCH3), 3.31 (d, J = 9.8
1
1
1
Hz, 1 H, 2-CHH), 3.06 (dd; J = 9.0, 7.8 Hz; 1 H, 5-CHH), 2.72 (app t, J = 8.8 Hz, 1 H, 5-CHH),
2.71 (d, J = 13.0 Hz, 1 1H, CHHNH2), 2.58 (d, J = 13.0 Hz, 1 1H, CHHNH2), 2.48 (d, J = 9.8 Hz, 1 1H,
2-CHH), 2.40 (s, 3 H, NCH3), 1.45 (bs, 2 H, NH2). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 176.5
(CO2), 160.6 (3′-C + 5′-C), 141.2 (1′-C), 107.5 (2′-C + 6′-C), 98.6 (4′-C), 64.2 (2-C), 61.6 (5-C), 58.7
(3-C), 55.3 (2 × OCH3), 52.4 (CO2CH3), 50.0 (4-C), 46.6 (CH2NH2), 42.3 (NCH3). FTIR [ν (cm–1),
neat]: 3380, 3188, 2942, 2835, 2781, 1723, 1593, 1203, 1152. HRMS [ESI (m/z)] calcd for
(C16H24N2O4 + H)+ = 309.18143, found 309.18062 (|Δ| = 2.62 ppm). RF: 0.30 (CH2Cl2/MeOH, 8:1).
Purity: 98.2% (GC).
1
1
(±)-Methyl
(3R,4S)-3-(aminomethyl)-4-(1,3-benzodioxol-5-yl)-1-methylpyrrolidine-3-carboxylate
(6{4}): According to the general procedure, α-cyano ester 7{4} (7.009 g, 24.31 mmol) afforded 6{4}
1
(6.055 g, 85%) as a light yellow oil, after column chromatography (CH2Cl2/MeOH, 9:1). H-NMR
[400 MHz, δ (ppm), CDCl3]: 6.88 (d, J = 1.7 Hz, 1 1H, 4′-CH), 6.78 (dd; J = 8.1, 1.5 Hz; 1 1H, 6′-CH),
6.72 (d, J = 8.1 Hz, 1 1H, 7′-CH), 5.92 (s, 2 1H, 2′-CH2), 3.83 (app t, J = 7.7 Hz, 1 1H, 4-CH), 3.78 (s, 3
1H, OCH3), 3.27 (d, J = 9.9 Hz, 1 1H, 2-CHH), 3.01 (dd; J = 9.3, 7.6 Hz; 1 1H, 5-CHH), 2.67 (app t, J
= 8.7 Hz, 1 1H, 5-CHH), 2.66 (d, J = 12.9 Hz, 1 1H, CHHNH2), 2.53 (d, J = 12.9 Hz, 1 1H, CHHNH2),
13
2.48 (d, J = 9.9 Hz, 1 1H, 2-CHH), 2.38 (s, 3 1H, NCH3), 1.01 (bs, 2 1H, NH2). C-NMR [75 MHz, δ
(ppm), CDCl3]: 176.3 (CO2), 147.4 (3′a-C), 146.3 (7′a-C), 132.5 (5′-C), 122.0 (6′-C), 109.3 (4′-C),
107.8 (7′-C), 100.8 (2′-C), 63.8 (2-C), 61.8 (5-C), 58.6 (3-C), 52.1 (OCH3), 49.5 (4-C), 46.6
(CH2NH2), 42.0 (NCH3). FTIR [ν (cm–1), neat]: 3320, 3317, 2946, 2841, 2776, 1721, 1248, 1232,
1034, 929. HRMS [ESI (m/z)] calcd for (C15H20N2O4 + H)+ = 293.15013, found 293.14936 (|Δ| = 2.63
ppm). RF: 0.25 (CH2Cl2/MeOH, 8:1). Purity: 97.4% (GC).
(±)-Methyl (3R,4S)-3-(aminomethyl)-1-methyl-4-(1-methyl-1H-pyrrol-2-yl)pyrrolidine-3-carboxylate
(6{5}): According to the general procedure, α-cyano ester 7{5} (752 mg, 3.04 mmol) afforded 6{5}
1
(559 mg, 73%) as a light yellow oil, after column chromatography (CH2Cl2/MeOH, 9:1). H-NMR
1
1
[400 MHz, δ (ppm), CDCl3]: 6.54 (dd; J = 2.4, 1.8 Hz; 1 H, 5′-CH), 6.07 (dd; J = 3.6, 2.7 Hz; 1 H,
4′-CH), 6.04 (dd; J = 3.8, 1.7 Hz; 1 1H, 3′-CH), 4.10 (dd; J = 10.5, 7.2 Hz; 1 1H, 4-CH), 3.78 (s, 3 1H,
1
1
1
OCH3), 3.60 (s, 3 H, 1′-NCH3), 3.39 (d, J = 9.9 Hz, 1 H, 2-CHH), 3.19 (app t, J = 8.2 Hz, 1 H, 5-
1
1
CHH), 2.72 (d, J = 13.2 Hz, 1 H, CHHNH2), 2.62 (d, J = 13.2 Hz, 1 H, CHHNH2), 2.47 (app t,
J = 9.8 Hz, 1 1H, 5-CHH), 2.35 (s, 3 1H, 1-NCH3), 2.21 (d, J = 9.9 Hz, 1 1H, 2-CHH), 1.35 (bs, 2 H,
1

Molecules 2010, 15
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13
NH2). C-NMR [75 MHz, δ (ppm), CDCl3]: 177.1 (CO2), 129.8 (2′-C), 122.3 (5′-C), 107.8 (3′-C),
107.3 (4′-C), 65.3 (2-C), 62.5 (5-C), 58.4 (3-C), 52.5 (OCH3), 46.7 (CH2NH2), 42.2 (1-NCH3), 40.9 (4-
C), 34.2 (1′-NCH3). FTIR [ν (cm–1), neat]: 3390, 3099, 2946, 2839, 2780, 1729, 1242, 712. HRMS
[ESI (m/z)] calcd for (C13H21N3O2 + H)+ = 252.17120, found 252.17083 (|Δ| = 1.49 ppm). RF: 0.24
(CH2Cl2/MeOH, 8:1). Purity: 97.7% (GC).
(±)-Methyl
(3R,4S)-3-(aminomethyl)-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrolidine-3-carboxylate
(6{6}): According to the general procedure, α-cyano ester 7{6} (7.628 g, 25.65 mmol) afforded 6{6}
1
(7.337 g, 95%) as a yellow oil, after column chromatography (CH2Cl2/MeOH, 9:1). H-NMR [400
MHz, δ (ppm), CDCl3]: 7.72 (dt; J = 8.0, 1.0 Hz; 1 1H, 4′-CH), 7.28 (dt; J = 8.0, 1.0 Hz; 1 1H, 7′-CH),
1
1
7.21 (ddd; J = 8.0, 6.8, 1.0 Hz; 1 H, 6′-CH), 7.11 (ddd; J = 8.0, 6.8, 1.0 Hz; 1 H, 5′-CH), 6.98 (s, 1
1H, 2′-CH), 4.32 (dd; J = 9.3, 7.3 Hz; 1 1H, 4-CH), 3.83 (s, 3 1H, OCH3), 3.76 (s, 3 1H, 1′-NCH3), 3.43
1
1
1
(d, J = 10.0 Hz, 1 H, 2-CHH), 3.17 (dd; J = 9.3, 7.3 Hz; 1 H, 5-CHH), 2.75 (d, J = 13.2 Hz, 1 H,
CHHNH2), 2.68 (t, J = 9.3 Hz, 1 1H, 5-CHH), 2.60 (d, J = 13.2 Hz, 1 1H, CHHNH2), 2.45 (d, J = 10.0
Hz, 1 1H, 2-CHH), 2.42 (s, 3 1H, 1-NCH3), 1.04 (bs, 2 1H, NH2). 13C-NMR [75 MHz, δ (ppm), CDCl3]:
177.1 (CO2), 136.9 (7′a-C), 128.3 (3′a-C), 127.3 (2′-C), 122.0 (6′-C), 119.9 (5′-C), 119.3 (4′-C), 112.0
(3′-C), 109.3 (7′-C), 64.8 (2-C), 62.5 (5-C), 58.4 (3-C), 52.4 (OCH3), 47.1 (CH2NH2), 42.5 (4-C), 41.6
_
(1-NCH3), 32.9 (1′-NCH3). FTIR [ν (cm–1), neat]: 3386, 3047, 2946, 2834, 2779, 1720, 1472, 1172,
741. HRMS [EI (m/z)] calcd for C17H23N3O2 = 301.1790, found for [M+•] = 301.1776 (|Δ| = 4.7 ppm),
peaks at (relative intensity): 301 (7), 284 (93), 228 (18), 157 (100), 144 (22), 57 (27). RF: 0.22
(CH2Cl2/MeOH, 8:1). Purity: 98.0% (GC).
1
(±)-(3R,4R)-3-Cyano-1-methyl-4-phenylpyrrolidine-3-carboxamide (12{1}): H-NMR [300 MHz, δ
(ppm), CDCl3]: 7.41–7.26 (m, 5 1H, Ph), 6.58 (s, 1 1H, NHH), 6.40 (s, 1 1H, NHH), 3.99 (app t, J = 8.1
1
1
1
Hz, 1 H, 4-CH), 3.34 (d, J = 9.8 Hz, 1 H, 2-CHH), 3.16 (app t, J = 8.7 Hz, 1 H, 5-CHH), 3.12 (d,
J = 9.8 Hz, 1 1H, 2-CHH), 3.03 (app t, J = 8.9 Hz, 1 1H, 5-CHH), 2.47 (s, 3 1H, NCH3). 13C-NMR [75
MHz, δ (ppm), CDCl3]: 169.4 (CON), 137.1 (1′-C), 128.6 (2′-C + 6′-C), 128.4 (3′-C + 5′-C), 128.2 (4′-
C), 119.0 (CN), 65.2 (2-C), 60.9 (5-C), 55.9 (3-C), 53.1 (4-C), 41.6 (NCH3). FTIR [ν (cm–1), neat]:
3334, 3192, 2950, 2846, 2794, 2241, 1684, 772, 698. Elem. anal. calcd for C13H15N3O: C 68.11%, H
6.59%, N 18.33%; found C 68.10%, H 6.48%, N 18.13%. RF: 0.40 (AcOEt). Mp: 121.7 °C (from
propan-2-ol, small white needles). Purity: >99.5% (GC).
3.5. Parallel synthesis
3.5.1. General procedure 1 for spiro dihydrouracil/α-ureidomethyl acid formation using parallel
synthesis
A solution of isocyanate 13 (0.12 mmol for 1, 0.10 mmol for 3–5) from a 0.3 M stock solution in
CH2Cl2 was added to a solution of α-aminomethyl ester (0.10 mmol) in CH2Cl2 (1.5 mL). The
resulting reaction mixture was stirred at room temperature for 15 h. After that time, the solvent was
evaporated and THF (1.5 mL) and 1 M KOBut in THF (0.10 mmol) were added. The reaction mixture
was then stirred at room temperature for 15 h. A saturated solution of NH4Cl (1.0 mL) was added and
the layers were separated (centrifugation was needed for the separation when aryl isocyanate was

Molecules 2010, 15
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used). The aqueous layer was extracted with CH2Cl2 (2 × 1.5 mL) and the combined organic layers
were evaporated to dryness under vacuum.
3.5.2. General procedure 2 for spiro dihydrouracil/α-ureidomethyl acid formation using parallel
synthesis
A solution of isocyanate 13{2,6–8} (0.10 mmol) from a 0.3 M stock solution in DMF was added to
a solution of α-aminomethyl ester (0.10 mmol) in DMF (1.5 mL). The resulting reaction mixture was
stirred at 80 °C for 15 h. After that time, the solvent was evaporated and THF (1.5 mL) and 1 M
KOBut in THF (0.10 mmol) were added. The reaction mixture was then stirred at room temperature for
15 h. A saturated solution of NH4Cl (1.0 mL) was added and the layers were separated (centrifugation
was needed for the separation when aryl isocyanate was used). The aqueous layer was extracted with
CH2Cl2 (2 × 1.5 mL) and the combined organic layers were evaporated to dryness under vacuum.
(±)-(4R,5S)-7-Ethyl-2-methyl-4-phenyl-2,7,9-triazaspiro[4.5]decane-6,8-dione (5{1,1}): (From 6{1})
1H-NMR [400 MHz, δ (ppm), CDCl3]: 7.30–7.19 (m, 5 1H, Ph), 5.60 (bd, J = 2.1 Hz, 1 1H, NH), 4.20
(dd; J = 8.1, 5.4 Hz; 1 1H, 4-CH), 3.85 (dq; J = 12.9, 7.2 Hz; 1 1H, CHHCH3), 3.80 (dq; J = 12.9, 7.2
Hz; 1 1H, CHHCH3), 3.06 (dd; J = 9.6, 5.4 Hz; 1 1H, 3-CHH), 2.99 (dd; J = 9.6, 8.1 Hz; 1 1H, 3-CHH),
1
1
2.95 (d, J = 9.3 Hz, 1 H, 1-CHH), 2.94 (dd; J = 12.6, 4.2 Hz; 1 H, 10-CHH), 2.68 (d, J = 9.3 Hz, 1
1H, 1-CHH), 2.66 (d, J = 12.6 Hz, 1 H, 10-CHH), 2.41 (s, 3 H, NCH3), 1.16 (t, J = 7.2 Hz, 3 H,
CH2CH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 173.1 (6-C), 154.1 (8-C), 139.4 (1′-C), 128.7 (2′-C +
6′-C), 128.6 (3′-C + 5′-C), 127.3 (4′-C), 64.0 (1-C), 62.0 (3-C), 52.0 (5-C), 48.3 (4-C), 43.4 (10-C),
42.0 (NCH3), 36.4 (CH2CH3), 13.8 (CH2CH3). FTIR [ν (cm–1), neat]: 3240, 2937, 2841, 2784, 1716,
1673, 763, 703. MS [APCI (m/z)] calcd for (C16H21N3O2 + H)+ = 288, found 288. Crude yield: 51%.
Purity: 89% (LC).
1
1
1
(±)-(4R,5S)-2-Methyl-7-phenethyl-4-phenyl-2,7,9-triazaspiro[4.5]decane-6,8-dione (5{1,2}): (From
6{1}) 1H-NMR [400 MHz, δ (ppm), CDCl3]: 7.33–7.15 (m, 10 1H, 2 × Ph), 5.66 (bd, J = 3.4 Hz, 1 1H,
NH), 4.16 (dd; J = 8.0, 5.4 Hz; 1 1H, 4-CH), 4.04 (dt; J = 13.0, 7.6 Hz; 1 1H, NCHHCH2), 3.98 (dt; J =
13.0, 7.6 Hz; 1 1H, NCHHCH2), 3.05 (dd; J = 9.3, 5.4 Hz; 1 1H, 3-CHH), 2.98–2.83 (m, 5 1H, 1-CHH
+ 3-CHH + 10-CHH + NCH2CH2), 2.56 (d, J = 9.5 Hz, 1 1H, 1-CHH), 2.55 (d, J = 13.2 Hz, 1 1H, 10-
1
13
CHH), 2.39 (s, 3 H, NCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 173.2 (6-C), 154.0 (8-C), 139.3
(1′′-C), 138.6 (1′-C), 129.2 (2′-C + 6′-C), 128.8 (2′′-C + 6′′-C), 128.6 (3′′-C + 5′′-C), 128.5 (3′-C + 5′-
C), 127.3 (4′′-C), 126.5 (4′-C), 64.0 (1-C), 61.9 (3-C), 52.1 (5-C), 48.2 (4-C), 43.4 (10-C), 42.2
(NCH2CH2), 41.9 (NCH3), 34.5 (NCH2CH2). FTIR [ν (cm–1), neat]: 3254, 2938, 2841, 2784, 1717,
1673, 758, 701. MS [APCI (m/z)] calcd for (C22H25N3O2 + H)+ = 364, found 364. Crude yield: 63%.
Purity: 70% (LC).
(±)-Ethyl
3-{(4R,5S)-2-methyl-6,8-dioxo-4-phenyl-2,7,9-triazaspiro[4.5]decan-7-yl}propanoate
(5{1,3}): (From 6{1}) MS [APCI (m/z)] calcd for (C19H25N3O4 + H)+ = 360, found 360. Crude yield:
80% (combined yield of 5{1,3}, 5{1,9}, 5{1,10}, and 5{1,11}). Purity: 91% (LC; combined purity of
5{1,3}, 5{1,9}, 5{1,10}, and 5{1,11}).

Molecules 2010, 15
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(±)-(4R,5S)-7-Ethyl-4-(4-methoxyphenyl)-2-methyl-2,7,9-triazaspiro[4.5]decane-6,8-dione (5{2,1}):
(From 6{2}) MS [APCI (m/z)] calcd for (C17H23N3O3 + H)+ = 318, found 318. Crude yield: 60%.
Purity: 93% (LC).
(±)-(4R,5S)-4-(4-Methoxyphenyl)-2-methyl-7-phenethyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
(5{2,2}): (From 6{2}) MS [APCI (m/z)] calcd for (C23H27N3O3 + H)+ = 394, found 394. Crude yield:
64%. Purity: 60% (LC).
(±)-Ethyl 3-{(4R,5S)-4-(4-methoxyphenyl)-2-methyl-6,8-dioxo-2,7,9-triazaspiro[4.5]decan-7-yl}prop-
_
anoate (5{2,3}): (From 6{2}) FTIR [ν (cm–1), neat]: 3245, 2935, 2837, 2784, 1719, 1674, 1247, 835.
MS [APCI (m/z)] calcd for (C20H27N3O5 + H)+ = 390, found 390. Crude yield: 49% (combined yield of
5{2,3}, 5{2,9}, 5{2,10}, and 5{2,11}). Purity: 88% (LC; combined purity of 5{2,3}, 5{2,9}, 5{2,10},
and 5{2,11}).
(±)-(4R,5S)-4-(3,5-Dimethoxyphenyl)-7-ethyl-2-methyl-2,7,9-triazaspiro[4.5]decane-6,8-dione 5{3,1}):
(From 6{3}) MS [APCI (m/z)] calcd for (C18H25N3O4 + H)+ = 348, found 348. Crude yield: 66%.
Purity: 90% (LC).
(±)-(4R,5S)-4-(3,5-Dimethoxyphenyl)-2-methyl-7-phenethyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
5{3,2}): (From 6{3}) MS [APCI (m/z)] calcd for (C24H29N3O4 + H)+ = 424, found 424. Crude yield:
60%. Purity: 68% (LC).
(±)-Ethyl 3-{(4R,5S)-4-(3,5-dimethoxyphenyl)-2-methyl-6,8-dioxo-2,7,9-triazaspiro[4.5]decan-7-yl}-
propanoate (5{3,3}): (From 6{3}) MS [APCI (m/z)] calcd for (C21H29N3O6 + H)+ = 420, found 420.
Crude yield: 54% (combined yield of 5{3,3}, 5{3,9}, 5{3,10}, and 5{3,11}). Purity: 95% (LC;
combined purity of 5{3,3}, 5{3,9}, 5{3,10}, and 5{3,11}).
(±)-(4R,5S)-4-(1,3-Benzodioxol-5-yl)-7-ethyl-2-methyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
(5{4,1}): (From 6{4}) MS [APCI (m/z)] calcd for (C17H21N3O4 + H)+ = 332, found 332. Crude yield:
63%. Purity: 95% (LC).
(±)-(4R,5S)-4-(1,3-Benzodioxol-5-yl)-2-methyl-7-phenethyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
5{4,2}): (From 6{4}) MS [APCI (m/z)] calcd for (C23H25N3O4 + H)+ = 408, found 408. Crude yield:
64%. Purity: 68% (LC).
(±)-Ethyl 3-{(4R,5S)-4-(1,3-benzodioxol-5-yl)-2-methyl-6,8-dioxo-2,7,9-triazaspiro[4.5]decan-7-yl}-
propanoate (5{4,3}): (From 6{4}) MS [APCI (m/z)] calcd for (C20H25N3O6 + H)+ = 404, found 404.
Crude yield: 61% (combined yield of 5{4,3}, 5{4,9}, 5{4,10}, and 5{4,11}). Purity: 98% (LC;
combined purity of 5{4,3}, 5{4,9}, 5{4,10}, and 5{4,11}).
(±)-(4R,5S)-7-Ethyl-2-methyl-4-(1-methyl-1H-pyrrol-2-yl)-2,7,9-triazaspiro[4.5]decane-6,8-dione
1
(5{5,1}): (From 6{5}) H-NMR [400 MHz, δ (ppm), CDCl3]: 6.52 (dd; J = 2.8, 1.6 Hz; 1 1H, 5′-CH),
6.05 (dd; J = 3.5, 2.8 Hz; 1 1H, 4′-CH), 6.03 (dd; J = 3.5, 1.6 Hz; 1 1H, 3′-CH), 5.84 (bd, J = 3.5 Hz, 1
1H, NH), 4.35 (app t, J = 8.0 Hz, 1 1H, 4-CH), 3.85 (dq; J = 13.1, 7.0 Hz; 1 1H, CHHCH3), 3.79 (dq; J

Molecules 2010, 15
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= 13.1, 7.0 Hz; 1 1H, CHHCH3), 3.44 (s, 3 1H, 1′-NCH3), 3.15 (app t, J = 8.6 Hz, 1 1H, 3-CHH), 2.96
(dd; J = 13.0, 4.6 Hz; 1 1H, 10-CHH), 2.92 (d, J = 9.8 Hz, 1 1H, 1-CHH), 2.78 (app t, J = 8.8 Hz, 1 1H,
1
1
1
3-CHH), 2.65 (d, J = 9.8 Hz, 1 H, 1-CHH), 2.62 (d, J = 13.0 Hz, 1 H, 10-CHH), 2.37 (s, 3 H, 2-
NCH3), 1.15 (t, J = 7.0 Hz, 3 1H, CH2CH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 173.5 (6-C), 154.2
(8-C), 129.9 (2′-C), 122.4 (5′-C), 107.5 (3′-C), 107.2 (4′-C), 66.0 (1-C), 62.0 (3-C), 51.0 (5-C), 43.9
(10-C), 41.9 (2-NCH3), 39.5 (4-C), 36.4 (CH2CH3), 34.1 (1′-NCH3), 13.7 (CH2CH3). FTIR [ν (cm–1),
neat]: 3329, 2937, 2842, 2784, 1716, 1671, 727. MS [APCI (m/z)] calcd for (C15H22N4O2 + H)+ = 291,
found 291. Crude yield: 61%. Purity: 99% (LC).
(±)-(4R,5S)-2-Methyl-4-(1-methyl-1H-pyrrol-2-yl)-7-phenethyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
1
1
(5{5,2}): (From 6{5}) H-NMR [400 MHz, δ (ppm), CDCl3]: 7.32–7.15 (m, 5 H, Ph), 6.51 (dd; J =
2.8, 1.6 Hz; 1 1H, 5′-CH), 6.05 (dd; J = 3.5, 2.8 Hz; 1 1H, 4′-CH), 6.02 (dd; J = 3.5, 1.6 Hz; 1 H, 3′-
1
1
1
1
CH), 5.96 (bd, J = 4.0 Hz, 1 H, NH), 4.31 (app t, J = 8.1 Hz, 1 H, 4-CH), 4.08–3.95 (m, 2 H,
NCH2CH2), 3.34 (s, 3 1H, 1′-NCH3), 3.13 (app t, J = 8.6 Hz, 1 1H, 3-CHH), 2.92 (dd; J = 12.9, 4.7 Hz;
1
1
1
1 H, 10-CHH), 2.91–2.83 (m, 2 H, NCH2CH2), 2.80 (d, J = 9.8 Hz, 1 H, 1-CHH), 2.76 (app t, J =
8.8 Hz, 1 1H, 3-CHH), 2.62 (d, J = 9.8 Hz, 1 1H, 1-CHH), 2.55 (d, J = 12.9 Hz, 1 H, 10-CHH), 2.35
1
1
13
(s, 3 H, 2-NCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 173.6 (6-C), 154.2 (8-C), 138.6 (1′′-C),
129.8 (2′-C), 129.2 (2′′-C + 6′′-C), 128.5 (3′′-C + 5′′-C), 126.5 (4′′-C), 122.4 (5′-C), 107.5 (3′-C), 107.2
(4′-C), 65.9 (1-C), 62.0 (3-C), 51.0 (5-C), 43.8 (10-C), 42.2 (NCH2CH2), 41.9 (2-NCH3), 39.3 (4-C),
_
34.4 (NCH2CH2), 34.1 (1′-NCH3). FTIR [ν (cm–1), neat]: 3251, 2941, 2843, 2785, 1716, 1671, 761,
728, 699. MS [APCI (m/z)] calcd for (C21H26N4O2 + H)+ = 367, found 367. Crude yield: 54%. Purity:
92% (LC).
(±)-Ethyl 3-{(4R,5S)-2-methyl-4-(1-methyl-1H-pyrrol-2-yl)-6,8-dioxo-2,7,9-triazaspiro[4.5]decan-7-
yl}propanoate (5{5,3}): (From 6{5}) MS [APCI (m/z)] calcd for (C18H26N4O4 + H)+ = 363, found 363.
Crude yield: 66% (combined yield of 5{5,3}, 5{5,9}, 5{5,10}, and 5{5,11}). Purity: 79% (LC;
combined purity of 5{5,3}, 5{5,9}, 5{5,10}, and 5{5,11}).
(±)-(4R,5S)-7-Ethyl-2-methyl-4-(1-methyl-1H-indol-3-yl)-2,7,9-triazaspiro[4.5]decane-6,8-dione
(5{6,1}): (From 6{6}) MS [APCI (m/z)] calcd for (C19H24N4O2 + H)+ = 341, found 341. Crude yield:
69%. Purity: 69% (LC).
(±)-(4R,5S)-2-Methyl-4-(1-methyl-1H-indol-3-yl)-7-phenethyl-2,7,9-triazaspiro[4.5]decane-6,8-dione
(5{6,2}): (From 6{6}) MS [APCI (m/z)] calcd for (C25H28N4O2 + H)+ = 417, found 417. Crude yield:
68%. Purity: 62% (LC).
(±)-Ethyl
3-{(4R,5S)-2-methyl-4-(1-methyl-1H-indol-3-yl)-6,8-dioxo-2,7,9-triazaspiro[4.5]decan-7-
yl}-propanoate (5{6,3}): (From 6{6}) MS [APCI (m/z)] calcd for (C22H28N4O4 + H)+ = 413, found
413. Crude yield: 62% (combined yield of 5{6,3}, 5{6,9}, 5{6,10}, and 5{6,11}). Purity: 86% (LC;
combined purity of 5{6,3}, 5{6,9}, 5{6,10}, and 5{6,11}).

Molecules 2010, 15
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(±)-(3R,4S)-1-Methyl-4-phenyl-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylic acid (14{1,4}):
(From 6{1}) MS [APCI (m/z)] calcd for (C20H23N3O3 + H)+ = 354, found 354. Crude yield: 49%.
Purity: >99% (LC).
(±)-(3R,4S)-1-Methyl-4-phenyl-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)pyrrolidine-3-carboxy-
lic acid (14{1,5}): (From 6{1}) MS [APCI (m/z)] calcd for (C21H22F3N3O3 + H)+ = 422, found 422.
Crude yield: 75%. Purity: 97% (LC).
(±)-(3R,4S)-3-{[3-(4-Ethoxyphenyl)ureido]methyl}-1-methyl-4-phenylpyrrolidine-3-carboxylic
acid
(14{1,6}): (From 6{1}) MS [APCI (m/z)] calcd for (C22H27N3O4 + H)+ = 398, found 398. Crude yield:
48%. Purity: >99% (LC).
(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-1-methyl-4-phenylpyrrolidine-3-carboxylic
acid
(14{1,7}): (From 6{1}) MS [APCI (m/z)] calcd for (C21H22N4O3 + H)+ = 379, found 379. Crude yield:
54%. Purity: >99% (LC).
(±)-(3R,4S)-1-Methyl-4-phenyl-3-{[3-(3-pyridyl)ureido]methyl}pyrrolidine-3-carboxylic
acid
(14{1,8}): (From 6{1}) MS [APCI (m/z)] calcd for (C19H22N4O3 + H)+ = 355, found 355. Crude yield:
49%. Purity: 79% (LC).
(±)-(3R,4S)-4-(4-Methoxyphenyl)-1-methyl-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylic acid
(14{2,4}): (From 6{2}) MS [APCI (m/z)] calcd for (C21H25N3O4 + H)+ = 384, found 384. Crude yield:
60%. Purity: 99% (LC).
(±)-(3R,4S)-4-(4-Methoxyphenyl)-1-methyl-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)-pyrroli-
dine-3-carboxylic acid (14{2,5}): (From 6{2}) MS [APCI (m/z)] calcd for (C22H24F3N3O4 + H)+ =
452, found 452. Crude yield: 65%. Purity: 98% (LC).
(±)-(3R,4S)-3-{[3-(4-Ethoxyphenyl)ureido]methyl}-4-(4-methoxyphenyl)-1-methylpyrrolidine-3-car-
boxylic acid (14{2,6}): (From 6{2}) MS [APCI (m/z)] calcd for (C23H29N3O5 + H)+ = 428, found 428.
Crude yield: 70%. Purity: >99% (LC).
(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-4-(4-methoxyphenyl)-1-methylpyrrolidine-3-car-
boxylic acid (14{2,7}): (From 6{2}) MS [APCI (m/z)] calcd for (C22H24N4O4 + H)+ = 409, found 409.
Crude yield: 60%. Purity: 96% (LC).
(±)-(3R,4S)-4-(4-Methoxyphenyl)-1-methyl-3-{[3-(3-pyridyl)ureido]methyl}pyrrolidine-3-carboxylic
acid (14{2,8}): (From 6{2}) MS [APCI (m/z)] calcd for (C20H24N4O4 + H)+ = 385, found 385. Crude
yield: 45%. Purity: 76% (LC).
(±)-(3R,4S)-4-(3,5-Dimethoxyphenyl)-1-methyl-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylic
acid (14{3,4}): (From 6{3}) MS [APCI (m/z)] calcd for (C22H27N3O5 + H)+ = 414, found 414. Crude
yield: 76%. Purity: 97% (LC).

Molecules 2010, 15
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(±)-(3R,4S)-4-(3,5-Dimethoxyphenyl)-1-methyl-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)pyrro-
lidine-3-carboxylic acid (14{3,5}): (From 6{3}) MS [APCI (m/z)] calcd for (C23H26F3N3O5 + H)+ =
482, found 482. Crude yield: 63%. Purity: 99% (LC).
(±)-(3R,4S)-4-(3,5-Dimethoxyphenyl)-3-{[3-(4-ethoxyphenyl)ureido]methyl}-1-methylpyrrolidine-3-
1
1
carboxylic acid (14{3,6}): (From 6{3}) H-NMR [300 MHz, δ (ppm), CD3SOCD3]: 8.83 (bs, 1 H,
1
1
NHAr), 7.30–7.21 (m, 2 H, 2′′-CH + 6′′-CH), 6.79–6.70 (m, 2 H, 3′′-CH + 5′′-CH), 6.47 (d, J = 2.1
Hz, 2 1H, 2′-CH + 6′-CH), 6.41 (t, J = 2.1 Hz, 1 1H, 4′-CH), 6.12 (bs, 1 H, CH2NH), 3.92 (q, J = 6.9
1
Hz, 2 1H, CH2CH3), 3.72 (s, 6 1H, 2 × OCH3), 3.74–3.68 (m, 1 1H, 4-CH), 3.45 (d, J = 10.2 Hz, 1 1H,
2-CHH), 3.39 (dd; J = 9.6, 7.5 Hz; 1 1H, 5-CHH), 3.24–3.18 (m, 1 1H, 5-CHH), 3.17 (dd; J = 12.9, 8.1
Hz; 1 1H, CHHNH), 2.86 (d, J = 10.2 Hz, 1 1H, 2-CHH), 2.64 (s, 3 1H, NCH3), 2.59 (dd; J = 12.9, 2.1
Hz; 1 1H, CHHNH), 1.28 (t, J = 6.9 Hz, 1 1H, CH2CH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 176.7
(CO2), 160.2 (3′-C + 5′-C), 155.6 (NCON), 152.9 (4′′-C), 139.9 (1′-C), 133.9 (1′′-C), 119.0 (2′′-C + 6′′-
C), 114.4 (3′′-C + 5′′-C), 107.1 (2′-C + 6′-C), 98.3 (4′-C), 63.0 (CH2CH3), 62.2 (2-C), 59.1 (5-C), 55.8
_
(3-C), 55.1 (2 × OCH3), 49.8 (4-C), 42.6 (NCH3), 40.8 (CH2NH), 14.7 (CH2CH3). FTIR [ν (cm–1),
neat]: 3354, 3250, 2947, 2836, 1671, 1594, 1542, 1204, 1153, 824. MS [APCI (m/z)] calcd for
(C24H31N3O6 + H)+ = 458, found 458. Crude yield: 52%. Purity: 99% (LC).
(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-4-(3,5-dimethoxyphenyl)-1-methylpyrrolidine-3-
1
1
carboxylic acid (14{3,7}): (From 6{3}) H-NMR [300 MHz, δ (ppm), CD3SOCD3]: 9.88 (bs, 1 H,
NHAr), 7.99 (s, 1 1H, 2′-CH), 7.63 (d, J = 8.4 Hz, 1 1H, 6′-CH), 7.38 (app t, J = 7.8 Hz, 1 1H, 5′-CH),
7.28 (d, J = 7.5 Hz, 1 1H, 4′-CH), 6.66 (bs, 1 1H, CH2NH), 6.47 (d, J = 2.1 Hz, 2 1H, 2′′-CH + 6′′-CH),
6.40 (t, J = 2.1 Hz, 1 1H, 4′′-CH), 3.77 (app t, J = 8.7 Hz, 1 1H, 4-CH), 3.71 (s, 6 1H, 2 × OCH3), 3.59
(d, J = 10.5 Hz, 1 1H, 2-CHH), 3.54 (dd; J = 9.9, 7.5 Hz; 1 1H, 5-CHH), 3.37 (app t, J = 9.0 Hz, 1 1H,
5-CHH), 3.23 (dd; J = 12.8, 8.4 Hz; 1 1H, CHHNH), 2.97 (d, J = 10.5 Hz, 1 1H, 2-CHH), 2.75 (s, 3 1H,
NCH3), 2.63 (dd; J = 12.8, 1.8 Hz; 1 1H, CHHNH). 13C-NMR [75 MHz, δ (ppm), CD3SOCD3]: 176.7
(CO2), 160.2 (3′′-C + 5′′-C), 155.4 (NCON), 141.8 (1′-C), 139.3 (1′′-C), 129.9 (5′-C), 124.0 (4′-C),
122.0 (6′-C), 119.8 (2′-C), 119.1 (CN), 111.3 (3′-C), 107.0 (2′′-C + 6′′-C), 98.4 (4′′-C), 62.3 (2-C), 58.6
_
(5-C), 55.9 (3-C), 55.1 (2 × OCH3), 49.8 (4-C), 42.4 (NCH3), 40.7 (CH2NH). FTIR [ν (cm–1), neat]:
3377, 3184, 2942, 2838, 2790, 2234, 1679, 1594, 1543, 1203, 1150, 830. MS [APCI (m/z)] calcd for
(C23H26N4O5 + H)+ = 439, found 439. Crude yield: 58%. Purity: >99% (LC).
(±)-(3R,4S)-4-(3,5-Dimethoxyphenyl)-1-methyl-3-{[3-(3-pyridyl)ureido]methyl}pyrrolidine-3-car-
boxylic acid (14{3,8}): (From 6{3}) MS [APCI (m/z)] calcd for (C21H26N4O5 + H)+ = 415, found 415.
Crude yield: 48%. Purity: 43% (LC).
(±)-(3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-methyl-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylic
acid (14{4,4}): (From 6{4}) 1H-NMR [300 MHz, δ (ppm), CD3SOCD3]: 9.01 (bs, 1 1H, NHPh), 7.42–
1
1
1
7.34 (m, 2 H, 2′′-CH + 6′′-CH), 7.22–7.12 (m, 2 H, 3′′-CH + 5′′-CH), 6.96 (d, J = 1.2 Hz, 1 H, 4′-
CH), 6.86 (d, J = 8.1 Hz, 1 1H, 7′-CH), 6.87–6.80 (m, 1 1H, 4′′-CH), 6.76 (dd; J = 8.1, 1.2 Hz; 1 1H, 6′-
CH), 6.26 (bd, J = 6.0 Hz, 1 1H, CH2NH), 6.01–5.97 (m, 2 1H, 2′-CH2), 3.72 (app t, J = 8.2 Hz, 1 1H,
4-CH), 3.46 (d, J = 10.5 Hz, 1 1H, 2-CHH), 3.42 (dd; J = 9.9, 7.5 Hz; 1 1H, 5-CHH), 3.25–3.17 (m, 1
1H, 5-CHH), 3.16 (dd; J = 12.9, 8.4 Hz; 1 1H, CHHNH), 2.88 (d, J = 10.5 Hz, 1 1H, 2-CHH), 2.65 (s, 3

Molecules 2010, 15
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1
13
1H, NCH3), 2.58 (dd; J = 12.9, 2.4 Hz; 1 H, CHHNH). C-NMR [75 MHz, δ (ppm), CD3SOCD3]:
176.7 (CO2), 155.4 (NCON), 147.1 (3′a-C), 146.1 (7′a-C), 140.8 (1′′-C), 131.3 (5′-C), 128.5 (3′′-C +
5′′-C), 121.9 (6′-C), 120.7 (4′′-C), 117.4 (2′′-C + 6′′-C), 108.9 (7′-C), 107.9 (4′-C), 100.9 (2′-C), 62.2
_
(2-C), 59.4 (5-C), 55.9 (3-C), 49.5 (4-C), 42.8 (NCH3), 40.5 (CH2NH). FTIR [ν (cm–1), neat]: 3359,
3254, 2954, 2898, 2780, 1671, 1597, 1549, 1495, 1228, 1035, 931, 756, 694. MS [APCI (m/z)] calcd
for (C21H23N3O5 + H)+ = 398, found 398. Crude yield: 74%. Purity: >99% (LC).
(±)-(3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-methyl-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)pyrrol-
idine-3-carboxylic acid (14{4,5}): (From 6{4}) FTIR [ν (cm–1), neat]: 3358, 3254, 2958, 2904, 1675,
1601, 1546, 1504, 1489, 1321, 1231, 1035, 931. MS [APCI (m/z)] calcd for (C22H22F3N3O5 + H)+ =
466, found 466. Crude yield: 68%. Purity: >99% (LC).
(±)-(3R,4S)-4-(1,3-Benzodioxol-5-yl)-3-{[3-(4-ethoxyphenyl)ureido]methyl}-1-methylpyrrolidine-3-
carboxylic acid (14{4,6}): (From 6{4}) MS [APCI (m/z)] calcd for (C23H27N3O6 + H)+ = 442, found
442. Crude yield: 61%. Purity: 77% (LC).
(±)-(3R,4S)-4-(1,3-Benzodioxol-5-yl)-3-{[3-(3-cyanophenyl)ureido]methyl}-1-methylpyrrolidine-3-
carboxylic acid (14{4,7}): (From 6{4}) MS [APCI (m/z)] calcd for (C22H22N4O5 + H)+ = 423, found
423. Crude yield: 62%. Purity: 99% (LC).
(±)-(3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-methyl-3-{[3-(3-pyridyl)ureido]methyl}pyrrolidine-3-car-
boxylic acid (14{4,8}): (From 6{4}) MS [APCI (m/z)] calcd for (C20H22N4O5 + H)+ = 399, found 399.
Crude yield: 54%. Purity: 71% (LC).
(±)-(3R,4S)-1-Methyl-4-(1-methyl-1H-pyrrol-2-yl)-3-[(3-phenylureido)methyl]pyrrolidine-3-
carboxylic acid (14{5,4}): (From 6{5}) MS [APCI (m/z)] calcd for (C19H24N4O3 + H)+ = 357, found
357. Crude yield: 58%. Purity: 14% (LC).
(±)-(3R,4S)-1-Methyl-4-(1-methyl-1H-pyrrol-2-yl)-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)-
pyrrolidine-3-carboxylic acid (14{5,5}): (From 6{5}) MS [APCI (m/z)] calcd for (C20H23F3N4O3 +
H)+ = 425, found 425. Crude yield: 65%. Purity: 79% (LC).
(±)-(3R,4S)-3-{[3-(4-Ethoxyphenyl)ureido]methyl}-1-methyl-4-(1-methyl-1H-pyrrol-2-yl)pyrrolidine-
3-carboxylic acid (14{5,6}): (From 6{5}) MS [APCI (m/z)] calcd for (C21H28N4O4 + H)+ = 401, found
401. Crude yield: 62%. Purity: 16% (LC).
(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-1-methyl-4-(1-methyl-1H-pyrrol-2-yl)pyrrolidine-3-
carboxylic acid (14{5,7}): (From 6{5}) MS [APCI (m/z)] calcd for (C20H23N5O3 + H)+ = 382, found
382. Crude yield: 61%. Purity: 99% (LC).
(±)-(3R,4S)-1-Methyl-4-(1-methyl-1H-indol-3-yl)-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylic
acid (14{6,4}): (From 6{6}) MS [APCI (m/z)] calcd for (C23H26N4O3 + H)+ = 407, found 407. Crude
yield: 79%. Purity: 97% (LC).

Molecules 2010, 15
2296
(±)-(3R,4S)-1-Methyl-4-(1-methyl-1H-indol-3-yl)-3-({3-[4-(trifluoromethyl)phenyl]ureido}methyl)-
pyrrolidine-3-carboxylic acid (14{6,5}): (From 6{6}) MS [APCI (m/z)] calcd for (C24H25F3N4O3 +
H)+ = 475, found 475. Crude yield: 76%. Purity: >99% (LC).
(±)-(3R,4S)-3-{[3-(4-Ethoxyphenyl)ureido]methyl}-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrolidine-3-
1
1
carboxylic acid (14{6,6}): (From 6{6}) H-NMR [400 MHz, δ (ppm), CD3SOCD3]: 8.92 (bs, 1 H,
1
1
1
NHAr), 7.62 (d, J = 7.8 Hz, 1 H, 4′′-CH), 7.38 (d, J = 8.4 Hz, 1 H, 7′′-CH), 7.34 (s, 1 H, 2′′-CH),
7.29–7.21 (m, 2 1H, 2′-CH + 6′-CH), 7.12 (app t, J = 7.5 Hz, 1 1H, 6′′-CH), 6.96 (app t, J = 7.5 Hz, 1
1H, 5′′-CH), 6.77–6.69 (m, 2 H, 3′-CH + 5′-CH), 6.18 (bd, J = 6.9 Hz, 1 H, CH2NH), 4.11 (dd;
1
1
1
1
1
J = 9.6, 7.5 Hz; 1 H, 4-CH), 3.91 (q, J = 6.9 Hz, 2 H, CH2CH3), 3.77 (s, 3 H, 1′′-NCH3), 3.54 (d,
J = 10.2 Hz, 1 1H, 2-CHH), 3.53–3.49 (m, 1 1H, 5-CHH), 3.21 (dd; J = 13.2, 8.4 Hz; 1 1H, CHHNH),
1
1
1
3.22–3.16 (m, 1 H, 5-CHH), 2.86 (d, J = 10.2 Hz, 1 H, 2-CHH), 2.68 (s, 3 H, 1-NCH3), 2.66 (dd;
_
J = 13.2, 2.1 Hz; 1 H, CHHNH), 1.27 (t, J = 6.9 Hz, 3 H, CH2CH3). FTIR [ν (cm–1), neat]: 3330,
2938, 2880, 1664, 1595, 1540, 827, 733. MS [APCI (m/z)] calcd for (C25H30N4O4 + H)+ = 451, found
451. Crude yield: 70%. Purity: 94% (LC).
1
1
(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrolidine-3-
1
1
carboxylic acid (14{6,7}): (From 6{6}) H-NMR [400 MHz, δ (ppm), CD3SOCD3]: 10.07 (bs, 1 H,
1
1
1
NHAr), 8.02 (s, 1 H, 2′-CH), 7.67 (d, J = 8.1 Hz, 1 H, 6′-CH), 7.61 (d, J = 7.8 Hz, 1 H, 4′′-CH),
7.39–7.36 (m, 1 1H, 7′′-CH), 7.37 (app t, J = 7.8 Hz, 1 1H, 5′-CH), 7.36 (s, 1 1H, 2′′-CH), 7.27 (d, J =
7.5 Hz, 1 1H, 4′-CH), 7.10 (app t, J = 7.5 Hz, 1 1H, 6′′-CH), 6.88 (app t, J = 7.5 Hz, 1 1H, 5′′-CH), 6.74
1
1
1
(bs, 1 H, CH2NH), 4.17 (dd; J = 9.9, 7.8 Hz; 1 H, 4-CH), 3.77 (s, 3 H, 1′′-NCH3), 3.73–3.63 (m, 2
1H, 2-CHH + 5-CHH), 3.36 (app t, J = 9.9 Hz, 1 H, 5-CHH), 3.29 (dd; J = 13.4, 9.0 Hz; 1 H,
CHHNH), 2.99 (d, J = 9.9 Hz, 1 1H, 2-CHH), 2.80 (s, 3 1H, 1-NCH3), 2.68 (dd; J = 13.4, 2.1 Hz; 1 1H,
CHHNH). 13C-NMR [75 MHz, δ (ppm), CD3SOCD3]: 177.3 (CO2), 155.5 (NCON), 142.0 (1′-C),
136.6 (7′′a-C), 129.8 (5′-C), 127.7 (3′′a-C), 127.6 (2′′-C), 123.9 (4′-C), 122.0 (6′-C), 121.3 (6′′-C),
119.8 (2′-C), 119.4 (5′′-C), 119.1 (CN), 118.6 (4′′-C), 111.3 (3′-C), 109.6 (3′′-C), 109.3 (7′′-C), 62.6
(2-C), 59.1 (5-C), 55.4 (3-C), 42.4 (1-NCH3), 41.9 (4-C), 41.0 (CH2NH), 32.5 (1′′-NCH3). FTIR [ν
(cm–1), neat]: 3361, 2940, 2226, 1685, 1583, 1564, 742. MS [APCI (m/z)] calcd for (C24H25N5O3 + H)+
= 432, found 432. Crude yield: 67%. Purity: 99% (LC).
1
1
(±)-(3R,4S)-1-Methyl-4-(1-methyl-1H-indol-3-yl)-3-{[3-(3-pyridyl)ureido]methyl}pyrrolidine-3-car-
boxylic acid (14{6,8}): (From 6{6}) MS [APCI (m/z)] calcd for (C22H25N5O3 + H)+ = 408, found 408.
Crude yield: 71%. Purity: 36% (LC).
(±)-Methyl (3R,4S)-1-methyl-4-phenyl-3-[(3-phenylureido)methyl]pyrrolidine-3-carboxylate (15{1,4}):
Phenyl isocyanate (2.563 g, 21.52 mmol) was added to a solution of α-aminomethyl ester 6{1} (4.858
g, 19.56 mmol) in dry CH2Cl2 (40 mL). The resulting reaction mixture was stirred at room temperature
for 2.5 h and the solvent was then evaporated to afford 15{1,4} (6.895 g, 96%) as a white foam, after
column chromatography (CH2Cl2/MeOH, 14:1). 1H-NMR [300 MHz, δ (ppm), CDCl3]: 7.47 (bs, 1 1H,
1
1
NHPh), 7.28–7.15 (m, 9 H, Ph′ + 2′′-CH + 3′′-CH + 5′′-CH + 6′′-CH), 7.03–6.96 (m, 1 H, 4′′-CH),
5.35 (bdd; J = 7.8, 3.6 Hz; 1 1H, CH2NH), 3.91 (app t, J = 8.2 Hz, 1 1H, 4-CH), 3.70 (s, 3 1H, OCH3),
3.44 (dd; J = 14.1, 8.4 Hz; 1 1H, CHHNH), 3.20 (d, J = 9.6 Hz, 1 1H, 2-CHH), 3.05 (app t, J = 8.6 Hz,

Molecules 2010, 15
1 1H, 5-CHH), 2.96 (app t, J = 9.0 Hz, 1 1H, 5-CHH), 2.80 (dd; J = 14.1, 3.9 Hz; 1 1H, CHHNH), 2.72
2297
1
1
(d, J = 9.6 Hz, 1 H, 2-CHH), 2.39 (s, 3 H, NCH3). 13C-NMR [75 MHz, δ (ppm), CDCl3]: 176.0
(CO2), 156.1 (NCON), 138.8 (1′′-C), 137.3 (1′-C), 129.0 (2′-C + 6′-C)*, 128.5 (3′-C + 5′-C)*, 128.4
(3′′-C + 5′′-C)*, 127.2 (4′-C), 123.2 (4′′-C), 120.5 (2′′-C + 6′′-C), 63.3 (2-C), 60.4 (5-C), 57.0 (3-C),
52.8 (OCH3), 50.8 (4-C), 44.0 (CH2NH), 42.3 (NCH3). FTIR [ν (cm–1), neat]: 3323, 2952, 2836, 2790,
1725, 1656, 1597, 1554, 751, 701. HRMS [ESI (m/z)] calcd for (C21H25N3O3 + H)+ = 368.19687,
found 368.19803 (|Δ| = 1.7 ppm). RF: 0.40 (CH2Cl2/MeOH, 8:1). Mp: 160.6 °C.
(±)-(4R,5S)-2-Methyl-4,7-diphenyl-2,7,9-triazaspiro[4.5]decane-6,8-dione (5{1,4}): A 1 M solution of
KOBut in THF (120 μL, 120 μmol) was added to a solution of α-ureido ester 15{1,4} (44 mg, 120
μmol) in THF (4 mL). The resulting reaction mixture was stirred for 55 min at 31 °C. Brine (1 mL)
was then added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2 × 1.5
mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue
afforded 5{1,4} (23 mg, 57%) as a white solid, after column chromatography (CH2Cl2/MeOH, 19:1).
1H-NMR [300 MHz, δ (ppm), CD3SOCD3]: 7.79 (bd, J = 3.0 Hz, 1 1H, NH), 7.43–7.20 (m, 8 1H, Ph′ +
3′′-CH + 4′′-CH + 5′′-CH), 7.16–7.11 (m, 2 1H, 2′′-CH + 6′′-CH), 4.05 (app t, J = 6.9 Hz, 1 1H, 4-CH),
1
1
2.98 (dd; J = 9.0, 6.6 Hz; 1 H, 3-CHH), 2.95–2.84 (m, 4 H, 1-CH2 + 3-CHH + 10-CHH), 2.67 (dd;
1
1
13
J = 12.6, 1.5 Hz; 1 H, 10-CHH), 2.36 (s, 3 H, NCH3). C-NMR [75 MHz, δ (ppm), CDCl3]: 173.3
(6-C), 153.9 (8-C), 139.0 (1′-C), 135.4 (1′′-C), 129.1 (3′′-C + 5′′-C), 128.63 (3′-C + 5′-C)*, 128.58 (2′′-
C + 6′′-C)*, 128.5 (2′-C + 6′-C)*, 128.4 (4′′-C), 127.2 (4′-C), 64.0 (1-C), 62.0 (3-C), 52.5 (5-C), 48.3
(4-C), 43.7 (10-C), 42.1 (NCH3). FTIR [ν (cm–1), neat]: 3254, 2945, 2835, 2792, 1725, 1684, 767,
753, 707, 693. Elem. anal. calcd for C20H21N3O2: C 71.62%, H 6.31%, N 12.53%; found C 71.70%, H
6.17%, N 12.48%. RF: 0.44 (CH2Cl2/MeOH, 8:1). Mp: 231.5 °C (from MeOH, colorless crystals).
Purity: >99.5% (GC).
5. Conclusions
In summary, we have developed a general high-yielding method for the synthesis of trans-4-aryl-
substituted 3-(aminomethyl)pyrrolidine-3-carboxylates. We have shown that these aryl groups can be
phenyl or electron-rich aryls (4-methoxyphenyl, 3,5-dimethoxyphenyl, and 1,3-benzodioxol-5-yl) and
electron-rich heteroaryls (1-methylpyrrol-2-yl and 1-methylindol-3-yl). As a result, we anticipate that
this methodology can be successfully applied for a wide range of aromatic groups, although with
electron-poor heteroaryls (2-, 3-, and 4-pyridyl) mixtures of cis–trans isomers are formed after the
cycloaddition step.
We have also developed a method for the synthesis of a small library of 7-alkyldihydrouracils spiro-
fused to pyrrolidines to the 3-position. The corresponding 7-aryl derivatives hydrolyzed under the
conditions utilized for the cyclization and yielded α-ureidomethyl acids. The optimization of this
cyclization should be further developed.
Acknowledgements
We would like to thank Richard H. Blaauw and Chiralix B.V. (Nijmegen, The Netherlands) for the
use of their parallel-synthesis facilities. This work was financially supported by the Council of

Molecules 2010, 15
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Chemical Sciences of The Netherlands Organization for Scientific Research (NWO), MSD Research
Laboratories (former N.V. Organon; Oss, The Netherlands), and Solvay Pharmaceuticals (Weesp, The
Netherlands).
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