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

Molecules 2010, 15, 2269-2301; doi:10.3390/molecules15042269

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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

O

Me

NH₂

HO

Ar

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

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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

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

O

CHO

N

Me

MeO

Me

OMe

1

3

2

4

5

6

N

CHO

N

CHO

S

N

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

40

Yield

(%)

99

94

99

95

96

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

30

480^a

30

10

11

12

30

90

25

99

^aTHF 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

7{1–6,9–13}

8{1–12}

Time

(min)

20

75

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

87^b

90^c

S

11{9}

CO₂Me

CN

MeN

7{10}

N

10

8{10}

+

11{10}

CO₂Me

CN

MeN

7{11}

11

8{11}

25

72^d

85^e

+

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;

^b7{9}/11{9} = 70:1; ^c7{10}/11{10} = 6.5:1; ^d7{11}/11{11} = 6.6:1; ^e7{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 NH₃or Et₃N was crucial for the reaction to go to completion [45].

Eventually, Et₃N was used since with NH₃amide 12 (Figure 3) was formed alongside the product.

Molecules 2010, 15

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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

MeOH, 21 °C, 15 h

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

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

1

3

2

4

NCO

EtO

F₃C

N

5

7

6

8

The reactions for the formation of the α-ureidomethyl esters were run in either CH₂Cl₂or 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 KOBu^tin

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

RNCO 13{2}, DMF

80 °C, 15 h

Ar

6{1–6}

Ar

5{1–6,1–3}

2. KOBu^t, THF, 21 °C, 15 h

R = Et, PhCH₂CH_2,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

MeN

H

RNCO 13{6–8}, DMF

80 °C, 15 h

Ar

6{1–6}

Ar

14{1–6,4–8}

2. KOBu^t, 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

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Figure 5. Products formed from the reaction with reagent 13{3}.

CO₂Et

CO₂Me

CO₂H

H

N

O

N

O

N

O

N

O

NH

MeN

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

H

N

O

N

O

N

O

N

O

base

work-up

NH

MeN

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 KOBu^tcould 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

N

O

N

O

NH

MeN

5{1,1}

51% (89%)

5{1,2}

63% (70%)

5{1,3}

80% (91%)^c

Ph

R

O

N

O

N

O

N

O

NH

MeN

OMe

5{2,1}

60% (93%)

5{2,2}

64% (60%)

5{2,3}

49% (88%)^c

Molecules 2010, 15

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Table 4. Cont.

Ph

R

N

O

N

O

N

O

NH

MeN

OMe

5{3,1}

66% (90%)

5{3,2}

60% (68%)

5{3,3}

54% (95%)^c

Ph

R

O

N

O

N

O

N

O

NH

MeN

O

5{4,1}

63% (95%)

5{4,2}

64% (68%)

5{4,3}

61% (98%)^c

Ph

R

O

N

O

N

O

N

O

NH

MeN

N

Me

5{5,1}

61% (99%)

5{5,2}

54% (92%)

5{5,3}

66% (79%)^c

Ph

R

O

N

O

N

O

N

O

NH

MeN

N

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;

^cMixture 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

CO₂H

N

CN

MeN

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

CO₂H

N

H

N

H

N

H

N

H

CN

N

H

MeN

H

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

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Table 5. Cont.

OEt

CF₃

N

O

CO₂H

N

H

N

CN

N

MeN

H

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

OEt

N

O

CO₂H

N

H

N

H

N

H

N

H

CN

N

H

O

MeN

H

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

CO₂H

N

CN

N

MeN

H

N

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

CO₂H

N

CN

N

MeN

H

N

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%);

^hPlus 5{6,4} (2%); ⁱPlus 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

CO₂Me

CO₂H

Ph

N

H

N

NH

N

+

MeN

H

Ph

15{1,4}

5{1,4}

14{1,4}

Products^a

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

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

KOBu^t(1 equiv), THF, 29 °C, 30 min

10

11

12

13

14

15

KOBu^t(1 equiv), THF, 31 °C, 55 min

KOBu^t(1 equiv), THF, Ar, 21 °C, 2 h

KOBu^t(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

^aRatio 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 R_Fvalues 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 KMnO₄or 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

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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%. R_F: 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

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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%. R_F: 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

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%. R_F: 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%. R_F: 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

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

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%. R_F: 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

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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%. R_F: 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

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

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%. R_F: 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

[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%. R_F: 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%. R_F: 0.61

(heptane/AcOEt, 1:1). Mp: 106.9 °C (from MeOH, light brown needles). Purity: >99.5% (GC).

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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

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%. R_F: 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

(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

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. R_F: 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

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%. R_F: 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. R_F: 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

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

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. R_F: 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

[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%. R_F: 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

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

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%. R_F: 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

(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. R_F: 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

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

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). R_F: 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

1.0 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

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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%. R_F: 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

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

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

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. R_F: 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. R_F: 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. R_F: 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

(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

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). R_F: 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. R_F: 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

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).

R_F: 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

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

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

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). R_F: 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

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

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). R_F: 0.30 (CH₂Cl₂/MeOH, 8:1).

Purity: 98.2% (GC).

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). R_F: 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

[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

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

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). R_F: 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

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

(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). R_F: 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

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%. R_F: 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

CH₂Cl₂was 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 KOBu^tin 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

KOBu^tin 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

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

(±)-(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}).

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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

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

(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

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 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

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}).

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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

carboxylic acid (14{3,6}): (From 6{3}) H-NMR [300 MHz, δ (ppm), CD₃SOCD₃]: 8.83 (bs, 1 H,

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

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

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).

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(±)-(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

carboxylic acid (14{6,6}): (From 6{6}) H-NMR [400 MHz, δ (ppm), CD₃SOCD₃]: 8.92 (bs, 1 H,

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

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

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

(±)-(3R,4S)-3-{[3-(3-Cyanophenyl)ureido]methyl}-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrolidine-3-

1

carboxylic acid (14{6,7}): (From 6{6}) H-NMR [400 MHz, δ (ppm), CD₃SOCD₃]: 10.07 (bs, 1 H,

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

(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

(±)-(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

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

(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). R_F: 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

KOBu^tin 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 Na₂SO₄and 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

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

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%. R_F: 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

2298

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

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