Acid-Catalyzed Reaction of (4,4-Diethoxybutyl)ureas with Phenols as a Novel Approach to the Synthesis of α-Arylpyrrolidines

Article abstract of DOI:10.1080/00397911.2015.1011340

1-(4,4-Diethoxybutyl)-3-alkylureas undergo intramolecular cyclization in the presence of trifluoroacetic acid and various phenols, leading to the new N-alkyl-2-arylpyrrolidine-1-carboxamides with moderate to excellent yields. It was found that these compo

Full text of DOI:10.1080/00397911.2015.1011340

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Acid-Catalyzed Reaction of (4,4-
Diethoxybutyl)ureas with Phenols as a
Novel Approach to the Synthesis of α-
Arylpyrrolidines
Almir S. Gazizova, Andrey V. Smolobochkina, Julia K. Voroninaa,
Alexander R. Burilova & Michail A. Pudovika
a A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan
Scientific Center, Russian Academy of Sciences, Kazan, Russian
Federation
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Accepted author version posted online: 11 Feb 2015.Published
online: 11 Feb 2015.
To cite this article: Almir S. Gazizov, Andrey V. Smolobochkin, Julia K. Voronina, Alexander R.
Burilov & Michail A. Pudovik (2015) Acid-Catalyzed Reaction of (4,4-Diethoxybutyl)ureas with
Phenols as a Novel Approach to the Synthesis of α-Arylpyrrolidines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 45:10, 1215-1221,
DOI: 10.1080/00397911.2015.1011340
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Synthetic Communications1, 45: 1215–1221, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1011340
ACID-CATALYZED REACTION OF (4,4-
DIETHOXYBUTYL)UREAS WITH PHENOLS AS
A NOVEL APPROACH TO THE SYNTHESIS OF
a-ARYLPYRROLIDINES
Almir S. Gazizov, Andrey V. Smolobochkin, Julia K. Voronina,
Alexander R. Burilov, and Michail A. Pudovik
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific
Center, Russian Academy of Sciences, Kazan, Russian Federation
GRAPHICAL ABSTRACT
Abstract 1-(4,4-Diethoxybutyl)-3-alkylureas undergo intramolecular cyclization in the
presence of trifluoroacetic acid and various phenols, leading to the new N-alkyl-2-
arylpyrrolidine-1-carboxamides with moderate to excellent yields. It was found that these
compounds undergo spontaneous solid-phase epimerization at room temperature.
Advantages of the proposed approach are mild reaction conditions and no need for
expensive reagents or catalysts.
Keywords 2-Arylpyrrolidine; cyclization; electrophilic aromatic substitution; phenols;
ureas
INTRODUCTION
There are many known alkaloids, antibiotics, and synthetic drugs that contain
pyrrolidine cores substituted at the a-carbon atoms.[1–6] Among them, a-arylpyrroli-
dines are of particular interest. These compounds are used as chiral cataliysts[7] and
organocatalysts.[8–10] Also a-arylpyrrolidines possessing carboxamide substituent at
Received December 3, 2014.
Address correspondence to Almir S. Gazizov, A. E. Arbuzov Institute of Organic and Physical
Chemistry, Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzova str., Kazan 420088,
Russian Federation. E-mail: agazizov@iopc.ru
1215

1216
A. S. GAZIZOV ET AL.
the nitrogen atom have been patented as somatostatin receptor inhibitors,[11]
glutamate receptors modulators,[12] histamine-H3 receptor antagonists,[13] anticancer
drugs,[14] inhibitors of phosphoinositide 3-kinase,[15] and drugs for the treatment of
neurological and neurodegenerative disorders such as Parkinson’s disease[16] and
Alzheimer’s disease.[16,17]
Most of the strategies for the synthesis of substituted pyrrolidines employ intra-
molecular C–N bond-forming reactions for the construction of the heterocyclic
ring.[18,19] However, very few methods allow for simultaneous intramolecular C–N
bond formation and intermolecular formation of a a -C carbon–carbon bond.[20–23]
Existing methods require harsh reaction conditions or toxic or expensive reagents,
such as Pd complexes.[24] There is only one example of synthesis of a-substituted
pyrrolidine via reaction of 1-(4-oxobutyl)urea derivative with thiophenol in acidic
media.[25]
It should be noted that the vast majority of the published papers refer to
2-arylpyrrolidine-1-carboxamides having an aryl substituent at the nitrogen atom.
2-Arylpyrrolidine-1-carboxamides containing alkyl substituents received much less
attention from the researchers. Methods of synthesis of such compounds include
reactions of appropriate 2-arylpyrrolidines with isocyanates[26–28] or triphosgene
followed by treatment of an intermediate product with amine[29] or interaction of
amines with pyrrolidinecarbonylchloride.[12] There are virtually no methods allowing
for the one-pot synthesis of N-alkyl-2-arylpyrrolidine-1-carboxamides, without the
need to isolate intermediate 2-arylpyrrolidines.
DISCUSSION
Earlier, we have reported a method of synthesis of 2-arylpyrrolidines based on
intramolecular cyclization of 1-(4,4-diethoxybutyl)-3-arylureas in the presence of
phenols and trifluoroacetic acid as catalyst.[30–32] The reaction proceeds smoothly
at room temperature and allows wide variation in both aryl substituent of urea
and structure of phenol. Herein, we report the application of this method to the
one-pot synthesis of 2-arylpyrrolidine-1-carboxamides having an alkyl substituent
at the nitrogen atom.
Starting 1-(4,4-diethoxybutyl)-3-alkylureas (c-ureidoacetals) 1a–d were
obtained via the reaction of aliphatic amines with 1,10-carbonyldiimidazole (CDI)
followed by treatment of intermediate N-alkyl-1H-imidazole-1-carboxamides with
4,4-diethoxybutan-1-amine (Scheme 1).
Scheme 1. Synthesis of starting ureas 1.

REACTION OF (4,4-DIETHOXYBUTYL)UREAS WITH PHENOLS
1217
Scheme 2. Reaction of ureas 1 with 2-naphthol.
Interaction of compounds 1a–d with 2-naphthol in a 1:1 molar ratio in chloro-
form in the presence of trifluoroacetic acid leads to the formation of pyrrolidine
derivatives 2a–d (Scheme 2). It should be noted that the compound 2a was isolated
as a mixture of two diastereomers.
Structures of the compounds 2b,c were proved by x-ray analysis (Figs. 1 and 2).
The crystal structures of both compounds represent the infinite chains oriented via
0a axis, which are formed by the classical O-H … O H-bonds. The chains are linked
by the CH … O interactions.
Further investigations showed that the acid-catalyzed intramolecular cycliza-
tion of ureas 1a–d at the presence of diatomic phenols, namely, resorcinol, 2-methyl-
resorcinol, and pyrogallol, gives rise to the bis(pyrrolidine-1-carboxamides) 3a–d,
4a–d, and 5a–d (Scheme 3).
All of the synthesized compounds were isolated as a mixture of diastereomers.
Analysis of NMR data revealed that in the cases of compounds 3–5d containing
Figure 1. Molecular structure of compound 2b in crystal. The minor component of the disordered hexyl
chain and H-atoms are omitted for clarity.

1218
A. S. GAZIZOV ET AL.
Figure 2. Molecular structure of compound 2c in crystal.
dodecyl substituent, and compound 3b, containing n-hexyl substituent, one of the
diastereomers predominates slightly [dr 40:60 (3d, 4d, 3b) and 35:65 (5d)]. Diastereo-
meric ratios for the compound 3c and compounds 4b and 5c are much greater and
equal 15:85 and ꢀ0:100 respectively. In all other cases, except for compounds
3–5a, products were isolated as equimolar mixtures of diastereomers (Table 1).
Spectral data for bis(pyrrolidine-1-carboxamides) 3–5a having four chiral centers
confirm the presence of multiple diastereomers; however, exact diastereomeric
composition of these compounds could not be determined due to heavy signal over-
lapping in NMR spectra.
Scheme 3. Reaction of ureas 1 with diatomic phenols.

REACTION OF (4,4-DIETHOXYBUTYL)UREAS WITH PHENOLS
1219
Table 1. Synthesis of bis(pyrrolidine-1-carboxamides) 3a–d, 4a–d, and 5a–d
Compound
R
R1
Yielda (%)
drb
c
3a
4a
5a
3b
4b
5b
sec-C4H9
sec-C4H9
sec-C4H9
n-C6H13
n-C6H13
n-C6H13
H
71
35
61
29
24
24
—
c
Me
OH
H
Me
OH
—
c
—
40:60
0:100
50:50
H
3c
4c
5c
69
75
52
15:85
50:50
0:100
Me
OH
3d
4d
5d
n-C12H25
n-C12H25
n-C12H25
H
Me
OH
16
63
51
40:60
40:60
35:65
aIsolated yield.
bDetermined by 1H NMR.
cNot determined due to heavy signal overlapping.
Interestingly, compounds 3c and 5c undergo spontaneous solid-phase
epimerization upon standing at room temperature. According to NMR data, after
2 months, the amount of diastereomers was almost equal for both compounds
(see spectra in Supplementary Material). Although solid-phase interconversion of
stereoisomers is discussed in several papers,[33–35] we could not find examples of such
transformations for pyrrolidine derivatives. We suggest that different diastereoselec-
tivity of the abovementioned reactions, as well as failure of our attempts to isolate
individual diastereomers, may be attributed to their easy interconversion.
In summary, we have successfully applied our method to the synthesis of
2-arylpyrrolidine-1-carboxamides containing various alkyl substituents at the
nitrogen atom. The proposed approach allows for one-pot synthesis of target
N-alkyl-2-arylpyrrolidine-1-carboxamides with simultaneous closure of the pyrroli-
dine ring and formation of C-C bond at the a-position, and compares favorably
with the existing methods. Additional advantage of the method is the use of readily
available trifluoroacetic acid as catalyst.
EXPERIMENTAL
To the solution of appropriate urea (1) (0.58 mmol) in dry chloroform (5 ml),
2-naphthol (0.15 g, 0.58 mmol) and trifluoroacetic acid (0.07 g, 0.58 mmol) were
added. The reaction mixture was stirred at 20 °C for 3 days. Solvent was evaporated
on a rotary evaporator, and the crude product washed thoroughly with diethyl ether
and dried in vacuo (2 h, 0.01 torr, 20 °C) to give desired compound 2.
FUNDING
This work was supported by the Russian Foundation for Basic Research
(Grant Nos. 14-03-00191-a and 14-03-31740 mol_a).

1220
A. S. GAZIZOV ET AL.
SUPPORTING INFORMATION
Full experimental procedures, characterization data, and copies of NMR
spectra for all synthesized compounds can be accessed on the publisher’s website.
Crystallographic data (excluding structure factors) for the structures in this article
have been deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC 1031375-1031376. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
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