Toward lead-oriented synthesis: One-pot version of castagnoli condensation with nonactivated alicyclic anhydrides

Article abstract of DOI:10.1021/co4001277

One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues. Utility of the method to multigram preparation of building blocks and synthetic intermediates was also demonstrated. The final products are obtained in high yields and diastereoselectivity. The method fits well in the concept of lead-oriented synthesis; in particular, it can be used for the design of lead-like compound libraries, even if the strictest cut-offs are applied to the physicochemical properties of their members.

Full text of DOI:10.1021/co4001277

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Article
Towards lead-oriented synthesis: one-pot version of Castagnoli
condensation with non-activated alicyclic anhydrides
Sergey V. Ryabukhin, Dmitriy M. Panov, Dmitry S. Granat, Eugeniy
N. Ostapchuk, Dmitriy V. Kryvoruchko, and Oleksandr O. Grygorenko
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co4001277 • Publication Date (Web): 30 Jan 2014
Downloaded from http://pubs.acs.org on February 3, 2014
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Towards leadꢀoriented synthesis: oneꢀpot version of
Castagnoli condensation with nonꢀactivated
alicyclic anhydrides
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Sergey V. Ryabukhin,†,‡* Dmitriy M. Panov,‡,§ Dmitry S. Granat,‡,§ Eugeniy N. Ostapchuk,§
Dmitriy V. Kryvoruchko,§ and Oleksandr O. Grygorenko‡
†The Institute of High Technologies, Taras Shevchenko National University of Kyiv, Glushkov
Street 4, Kyiv 03187, Ukraine
‡Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Street
60, Kyiv 01601, Ukraine
§Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
s.v.ryabukhin@gmail.com
Abstract. Oneꢀpot variation of Castagnoli condensation, i. e. reaction of cyclic anhydrides,
amines, and aldehydes, has been developed as a combinatorial approach to 1,2ꢀdisubstituted 5ꢀ
oxopyrrolidineꢀ and 6ꢀoxopiperidineꢀ3ꢀcarboxylic acids, as well as their benzoꢀanalogues. Utility
of the method to multigram preparation of building blocks and synthetic intermediates was also
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demonstrated. The final products are obtained in high yields and diastereoselectivity. The method
fits well in the concept of leadꢀoriented synthesis; in particular, it can be used for the design of
leadꢀlike compound libraries, even if the strictest cutꢀoffs are applied to the physicoꢀchemical
properties of their members.
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Keywords: multicomponent reaction, condensation, anhydride, aldehyde, amine, leadꢀoriented
synthesis
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Introduction.
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Modern drug discovery relies heavily on the ability of synthetic chemists to provide
compounds with favourable physicoꢀchemical properties in an efficient manner. Since the
cornerstone work of Lipinski and coꢀworkers,1 the “drugꢀlikeness” concept has evolved
significantly: apart from more rigorous restrictions imposed on molecular weight and
lipophilicity of the compounds,2 additional molecular properties are considered such as
conformational flexibility3 and threeꢀdimensionality.4 As a result, a “leadꢀlikeness” concept
emerged in drug discovery.5
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Although the criteria that define the part of chemical space, which is attractive for starting
medicinal chemistry projects, are more or less clear, the synthetic methodology, which would
allow navigating this chemical space, is not easily accessible. A challenge of “leadꢀoriented
synthesis”6 should be addressed by developing approaches to the libraries of highly polar,
conformationally restricted, sp3ꢀenriched compounds with low molecular weight. One of such
approaches pursued by us recently7 relies on design of building blocks with molecular properties
vastly shifted to the appropriate part of chemical space; this leaves much room for applying
classical combinatorial chemistry modifications (i. e. acylation, arylation, alkylation, reductive
amination etc.), which normally increase both MW and LogP. Nevertheless, novel combinatorial
reactions producing leadꢀlike libraries from common building blocks might be more beneficial.
In particular, advantages of oneꢀpot multicomponent reactions8 could be used to ensure huge
diversity of the compound libraries produced.
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Scheme 1. Condensation of alicyclic anhydrides, primary amines and aldehydes: (a) Castagnoli
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reaction; (b) illustrative examples of the products obtained in this work
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O
(a)
O
O
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n
rac
O
R1
N
1(1), n = 1
1(2), n = 2
R1
R2
N
R2
R1 NH2
R2 CHO
+
2
3
n
HOOC
O
5
4
(b)
O
rac
rac
HO
O
HO
N
N
O
HO
O
N
N
N
N
O
OH
N
F
rac
N
4{1(2),2(43),3(41)}
4{1(1),2(17),3(38)}
4{1(2),2(2),3(33)}
In this work, we report a oneꢀpot reaction of alicyclic anhydrides (1), primary amines (2) and
aldehydes (3) as a combinatorial approach to 1,2ꢀdisubstituted 5ꢀoxopyrrolidineꢀ and 6ꢀ
oxopiperidineꢀ3ꢀcarboxylic acids (4) (Scheme 1); the utility of the method for the multigram
preparation of building blocks is also demonstrated. The reaction is a modification of Castagnoli
condensation, i. e. reaction of succinic anhydride (1(1)) with imines (5).9, 10 Compounds 4 and
their derivatives have great potential for a broad spectrum of biological activities: they were
evaluated as protein tyrosine phosphatase 1B inhibitors,11 transcription factor inhibitors,12
antiepileptic,13 antilipidemic,14 and antiviral15 agents, topoisomerase I inhibitors,16 and
progesterone receptor agonists.17 They were also used in the synthesis of amino acids,18
alkaloilds19 and other natural products.20 Notably, compounds 4 are carboxylic acids, which are
hardly accessible via combinatorial methods and are therefore underrepresented in current
screening collections.21
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Results and discussion.
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The classical Castagnoli condensation involving simple alicylic anhydrides gives moderate yields
of the products, but includes a preliminary synthesis of an imine;9 it is therefore unsuitable for
parallel synthesis. Milder reaction conditions, including oneꢀpot multicomponent variations, have
been developed only for more CHꢀacidic and hence more reactive substrates, such as
(arylthio)succinic20, 22 (generated in situ) and homophtalic anhydrides. The latter reaction was
promoted by ionic liquids and InCl3,23 Yb(OTf)3,24 KAl(SO4)2⋅12H2O,25 iodine,26 sulfuric27 and
sulfonic28 acid functionalized silica, ZnCl2 – AlCl3/SiO2,29 and Lꢀproline.30
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First of all, we have focused on developing a method for introducing simple alicylic anhydrides,
i. e. succinic 1(1) and glutaric 1(2) (Figure 1), into a oneꢀpot variation of Castagnoli reaction,
which would be amendable for parallel synthesis. To demonstrate the scope of the reaction, 44
amines 2(1–44) (Figure 2) and 44 aldehydes 3(1–44) (Figure 3) were selected. It was found that
the optimal procedure includes sonication of 2(1–44) and 3(1–44) in MeOH for 6 h, evaporation
of the solvent in the vacuum drying oven, and heating of the residue with 1(1,2) in dry xylenes at
140–180 °C for 6–8 h. 125 products, 4{1(1,2), 2(1–44), 3(1–44)} were randomly selected from
the virtually possible library to demonstrate the scope of the protocol and were synthesized in
67–88% yields (see Table S1 in the Supporting information). It should be noted that in most
cases the reaction proceeded in a diastereoselective manner, resulting in the formation of the final
products with more than 85% of major diastereomer content. In the case of racemic amines
containing chiral centers (2(8,9,40,41,43,44)), the products were obtained as nearly ~1 : 1
mixtures of the diastereomers.
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O
O
O
4
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O
O
O
O
O
O
7
1(1)
1(2)
1(3)
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Figure 1. Anhydrides 1(1–3) used in this work for the synthesis of carboxylic acids 4
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NH2
NH2
NH2
NH2
NH2
NH2
NH2
O
O
2(1)
2(2)
NH2
2(3)
2(4)
2(5)
2(6)
H2N
2(7)
H2N
NH2
NH2
NH2
H2N
H2N
O
O
O
O
2(8)
2(10)
2(11)
NH2
2(12)
2(13)
2(14)
2(15)
2(9)
NH2
NH2
NH2
H2N
NH2
H2N
H2N
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S
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2(19)
2(20)
2(21)
2(22)
2(23)
2(16)
2(17)
2(18)
NH2
H2N
H2N
NH2
NH2
H2N
H2N
H2N
N
N
N
N
N
N
N
N
O
N
S
S
S
N
2(24)
2(25)
2(26)
2(27)
2(28)
H2N
2(29)
2(30)
2(31)
NH2
N
NH2
NH2
NH2
NH2
H2N
NH2
NH
N
N
N
N
N
N
N
N
N
N
O
2(32)
2(33)
2(34)
2(35)
2(36)
2(37)
2(38)
2(39)
OH
O
S
N
H2N
H2N
O
NH2
N
NH2
OH
O
H2N
2(40)
2(41)
2(42)
2(43)
2(44)
Figure 2. Amines 2(1–44) used in this work for the synthesis of carboxylic acids 4
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O
O
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O
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O
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O
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3(2)
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3(5)
3(6)
3(7)
3(8)
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F
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O
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O F
F
O
O
N
O
O
N
3(9)
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3(11)
3(12)
3(13)
3(14)
3(15)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3(19)
3(20)
3(21)
3(22)
3(16)
3(17)
3(18)
O
O
O
O
O
O
O
O
S
O
S
O
3(27)
F
O
3(23)
3(24)
3(25)
3(26)
3(28)
3(29)
O
O
O
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O
N
N
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S
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S
N
N
N
N
N
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O
3(30)
3(31)
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3(33)
3(34)
3(35)
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3(37)
O
N
S
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O
N
N
N
O
N
N
N
N
N
N
N
O
O
O
N
O
O
3(38)
3(39)
3(40)
3(41)
3(42)
3(43)
3(44)
Figure 3. Aldehydes 3(1–44) used in this work for the synthesis of carboxylic acids 4
It was found that the method gave excellent yields with αꢀbranched aliphatic, aromatic and
heteroaromatic aldehydes. The method was equally efficient with aliphatic amines 2(1–10), as
well as amines bearing aromatic (2(11–22)) and heteroaromatic (2(23–36)) substituents, sulphone
(2(42)) or hydroxy (2(43,44)) groups.
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It was also shown that the method works well with homophtalic anhydride 1(3): the
corresponding 7 products 4{1(3), 2(4,6,7), 3(4,5,14,36,37)} were obtained in 75–93% yields.
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Predicted physicoꢀchemical properties of 132 synthesized library members 4{1(1,2), 2(1–
44), 3(1–44)} are summarized in Figure 4 (see also Figure S1 in the Supporting Information).31
The value ranges are: molecular weight (MW) 265…349 (average 335), calculated logP
–1.25…3.32 (average 1.29) , number of Hꢀdonors 1…2 (average 1.03), Hꢀacceptors – 3…7
(average 4.30), rotatable bonds – 4…8 (average 5.20), fraction of sp3 carbons (Fsp3) 0.25…0.82
(average 0.51), total polar surface area (TPSA) 57.6…109.6 Å (average 75.9 Å).2 These data
show that the oneꢀpot version of Castagnoli condensation developed in this work can be used for
the design of leadꢀlike compound libraries, even if the strictest leadꢀlikeness cutꢀoffs6 are applied.
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Figure 4. Physicoꢀchemical properties of 132 library members 4{1(1–3), 2(1–44), 3(1–44)}
shown in cLogP – MW plot
The method was also applicable for the scaled preparation of building blocks and synthetic
intermediates. In particular, reaction of anhydrides 1(1) or 1(2) with aldehydes 3(3), 3(18), 3(28)
or 3(32) and methylamine led to the formation of carboxylic acids 6 – 12 in 71–80% yields
(Scheme 2). It should be noted that the reaction was performed on a multigram scale (up to
100 g) without considerable effect on its outcome. The products 6 – 12 were obtained in a
diastereoselective manner (more than 85% of the major diastereomer). The carboxylic acids 6 –
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12 can be used for the preparation of other building blocks of potential interest to synthetic and
medicinal chemistry, e. g. alcohols 13 – 17 (either via complete or partial selective reduction) or
primary amines 18 – 24 (via reduction of the corresponding amides 25 – 29).
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Scheme 2. Preparation of buildingꢀblocks 6 – 29
rac
rac
1. CH3NH2, MeOH
ultrasound
N
N
R
O
R
O
(NH4)2CO3
R CHO
n
n
CDI, DMF
80 - 85%
2. 1{1,2}, xylenes,
H2N
HO
reflux
71 - 80%
25 - 29
6 - 12
O
O
1. MeI, Et3N,
DMF, 50 oC
2. NaBH4, MeOH
LiAlH4
THF
81 - 83%
72 - 74%
LiAlH4
THF
68 - 81%
rac
rac
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N
N
N
O
R
R
R
n
n
n
HO
H2N
HO
13, 14
18 - 24
15 - 17
6, 8, 10, 13, 15, 17, 18, 20, 22, 26: n = 1
7, 9, 11, 12, 14, 16, 19, 21, 23 - 25, 27 - 29: n = 2
6, 7, 18, 19: R = Ph
8, 9, 13 - 16, 20, 21. 26, 27: R = 4-MeOC6H4
10, 11, 17, 22, 23, 28: R = 2-thienyl
12, 24, 29: R = 1-methylpyrazol-4-yl
The relative configuration for the pyrrolidineꢀderived carboxylic acids 6, 8, and 10 was
established using an analysis of the coupling constants for the signal of 2ꢀCH proton (observed at
4.7–4.9 p.p.m.) as compared to the literature data for 6 and 8.9a, 10b For the major isomers, the
value J ~ 5 Hz was observed, which is consistent with trans configuration, whereas for the
impurities of minor isomers, the corresponding value was J ~ 9 Hz – a feature characteristic for
the cis stereoisomer. In the case of piperidineꢀderived compounds 7, 9, 11 and 12, the
corresponding J values were not informative since they were ~ 4 Hz for both major isomers and
impurities – a feature discussed previously in the literature for the trans isomer.10d Since no
useful correlations were found in NOESY spectrum of the carboxylic acid 7, NOESY experiment
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was carried out with the diamine 21 (Figure 5). The spectral data confirmed trans configuration
for this compound; the trans configuration can be assumed for all other compounds obtained.
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H
H
H
H
Strong
Weak
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H
H
O
H
N
H
NH2
H
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21
Figure 5. Significant correlations in NOESY spectra of compound 21
Conclusions.
The classical Castagnoli reaction with alicyclic anhydrides can be adopted for the conditions of
the parallel synthesis if it is performed in an oneꢀpot twoꢀstep manner, namely, sonication of
amine and aldehyde in MeOH, followed by replacing the solvent with xylenes and heating the
mixture at 140 – 180 °C. The target 1,2ꢀdisubstituted 5ꢀoxopyrrolidineꢀ and 6ꢀoxopiperidineꢀ3ꢀ
carboxylic acids were obtained in 67 – 88% yields in a diastereoselective manner. The method
allowed for vast variation of both aldehyde and amine components: αꢀbranched aliphatic,
aromatic and heteroaromatic aldehydes, as well as primary amines amines bearing aliphatic,
aromatic, heteroaromatic substituents, sulphone or hydroxy groups. Utility of the method to the
preparation of building blocks on a 100 g scale was also demonstrated.
Experimental part.
Solvents were purified according to the standard procedures. All the starting materials were
purchased from Acros, Merck, Fluka, and Ukrorgsyntez. Melting points were measured on
MPA100 OptiMelt automated melting point system. Analytical TLC was performed using
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Polychrom SI F254 plates. Column chromatography was performed using Kieselgel Merck 60
(230–400 mesh) as the stationary phase. 1H and 13C NMR spectra were recorded on a Bruker 170
Avance 500 spectrometer (at 499.9 MHz for protons, 124.9 MHz for carbonꢀ13) and Varian
Unity Plus 400 spectrometer (at 400.4 MHz for protons, 100.7 MHz for carbonꢀ13). Chemical
shifts are reported in ppm downfield from TMS (1H, 13C) as an internal standard. HPLCꢀMS
analyses were done on an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and
Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)).
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General procedure for the synthesis of compound library members 4.
A mixture of aldehyde 2 (1 mmol) and amine 3 (1 mmol) in MeOH (3 mL) was sonicated for
6 h. The solvent was removed in vacuum drying oven, and the residue was dissolved in dry
xylenes (3 mL). Anhydride 1 (1 mmol) was added, and the mixture was heated at 140 °C for 6–
8 h. The precipitate was filtered to give the product 4. If the precipitate was not formed, the
solvent was removed in vacuum drying oven, the residue was triturated with hexanes, and the
precipitate was filtered to give the product 4.
1-(2-Methoxyethyl)-6-oxo-2-(2-(trifluoromethyl)phenyl)piperidine-3-carboxylic
acid
(4{1(2), 2(6), 3(12)}).
Yield 80%. White crystals. Mp 154–155°C. MS (m/z, CI): 346 (MH+). Anal. Calcd. for
1
C16H18F3NO4 C 55.65, H 5.25, N 4.06. Found C 55.94, H 4.97, N 4.09. H NMR (500 MHz,
DMSOꢀd6) δ 12.91 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.6 Hz,
1H), 7.45 (d, J = 7.7 Hz, 1H), 5.54 (s, 1H), 3.78 (dt, J = 12.6, 6.1 Hz, 1H), 3.34 (t, J = 6.2 Hz,
13
2H), 3.13 (s, 3H), 2.73 (s, 1H), 2.57–2.48 (m, 2H), 2.37–2.24 (m, 1H), 2.04 – 1.82 (m, 2H). C
NMR (126 MHz, DMSOꢀd6) δ 173.4, 169.1, 139.4, 133.3, 129.0, 128.6, 127.0 (q, J = 6.1 Hz),
126.9 (q, J = 29.5 Hz), 126.3 (q, J = 116.2 Hz), 69.1, 58.4, 58.3, 45.4, 44.0, 28.8, 18.0.
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2-(Cyclopropylmethyl)-1-oxo-3-(thiazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic
acid (4{1(3), 2(4), 3(36)}).
7
8
9
Yield 78%. White crystals. Mp 218–219°C. MS (m/z, CI): 329 (MH+). Anal. Calcd. for
C17H16N2O3S C 62.18, H 4.91, N 8.53, S 9.76. Found C 61.96, H 4.72, N 8.37, S 9.89. 1H NMR
(500 MHz, DMSOꢀd6) δ 8.99 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.42 (td, J = 7.4, 1.3
Hz, 1H), 7.36 (td, J = 7.5, 1.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 0.7 Hz, 1H), 5.62 (s,
1H), 4.40 (s, 1H), 3.85 (dd, J = 13.9, 6.8 Hz, 1H), 3.03 (dd, J = 13.9, 7.2 Hz, 1H), 1.10–0.92 (m,
J = 5.0 Hz, 1H), 0.56–0.41 (m, J = 17.1 Hz, 1H), 0.39–0.26 (m, 2H), 0.23–0.13 (m, J = 18.0 Hz,
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1H); COOH is not observed due to exchange. C NMR (126 MHz, DMSOꢀd6) δ 172.4, 163.2,
156.1, 155.3, 134.4, 132.1, 129.8, 129.6, 128.1, 127.4, 116.3, 59.2, 50.9, 49.1, 10.3, 4.3, 3.4.
2-(1-Methyl-1H-imidazol-2-yl)-1-[2-(2-methylphenyl)ethyl]-5-oxopyrrolidine-3-carboxylic
acid (4{1(1), 2(15), 3(38)}).
Yield 79%. White crystals. Mp 201–203°C. MS (m/z, CI): 328 (MH+). Anal. Calcd. for
C18H21N3O3 C 66.04, H 6.47, N 12.84. Found C 65.72, H 6.31, N 13.03.1H NMR (500 MHz,
DMSOꢀd6) δ 7.16 (s, 1H), 7.13–7.05 (m, 3H), 7.03 – 6.95 (m, 1H), 6.92 (s, 1H), 5.07 (d, J = 5.2
Hz, 1H), 3.64 (s, 3H), 3.52–3.39 (m, 1H), 3.32–3.23 (m, 1H), 2.83–2.72 (m, 1H), 2.72–2.63 (m,
2H), 2.65–2.53 (m, 1H), 2.46–2.35 (m, 1H), 2.12 (s, 3H); COOH and NH are not observed due to
exchange. 13C NMR (126 MHz, DMSOꢀd6) δ 173.9, 172.3, 137.4, 136.2, 130.6, 129.5, 127.7,
126.9, 126.5, 122.8, 56.1, 43.6, 41.8, 33.1, 32.7, 31.0, 19.0.
2-(4-Methoxyphenyl)-6-oxo-1-(thiophen-2-ylmethyl)piperidine-3-carboxylic
acid
(4{1(2), 2(23), 3(18)}).
Yield 79%. White crystals. Mp 192–193°C. MS (m/z, CI): 346 (MH+). Anal. Calcd. for
1
C18H19NO4S C 62.59, H 5.54, N 4.05, S 9.28. Found C 62.84, H 5.59, N 4.28, S 9.01. H NMR
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(500 MHz, DMSOꢀd6) δ 12.56 (s, 1H), 7.40 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.95 (d,
J = 8.4 Hz, 2H), 6.92–6.88 (m, 1H), 6.77 (d, J = 3.0 Hz, 1H), 5.16 (d, J = 15.1 Hz, 1H), 4.76 (d, J
= 6.4 Hz, 1H), 3.77 (s, 3H), 3.64 (d, J = 15.1 Hz, 1H), 2.79 (dt, J = 11.3, 6.7 Hz, 1H), 2.63–2.53
(m, 1H), 2.48–2.40 (m, 1H), 1.94–1.84 (m, 1H), 1.84–1.72 (m, 1H). 13C NMR (126 MHz,
DMSOꢀd6) δ 173.8, 169.2, 159.3, 139.9, 132.4, 128.8, 127.1, 126.8, 126.3, 114.6, 61.4, 55.6,
47.5, 42.4, 30.6, 21.6.
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1-(3-Methylbutyl)-6-oxo-2-(thiophen-2-yl)piperidine-3-carboxylic
acid
(4{1(2), 2(2), 3(28)}).
Yield 73%. White crystals. Mp 158–159°C. MS (m/z, CI): 296 (MH+). Anal. Calcd. for
1
C15H21NO3S C 60.99, H 7.17, N 4.74, S 10.85. Found C 61.27, H 7.02, N 4.55, S 10.99. H
NMR (500 MHz, DMSOꢀd6) δ 12.84 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.15–6.91 (m, 2H), 5.22
(d, J = 3.7 Hz, 1H), 3.87–3.78 (m, 1H), 2.93 (dd, J = 8.5, 4.3 Hz, 1H), 2.60–2.52 (m, 1H), 2.43–
2.25 (m, 2H), 1.94 (t, J = 9.4 Hz, 2H), 1.51–1.38 (m, 1H), 1.39–1.21 (m, 2H), 0.82 (d, J =
13
7.0 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H). C NMR (126 MHz, DMSOꢀd6) δ 173.4, 168.2, 145.5,
127.6, 126.2, 125.9, 57.7, 46.7, 43.8, 35.9, 29.6, 25.9, 23.0, 22.7, 20.2.
General procedure for the preparation of carboxylic acids 6 – 12.
To a solution of aldehyde 2{3,18,28,32} (0.7 mol) in MeOH (700 mL), MeNH2 (2.2 mol, 25%
in MeOH) was added. The mixture was sonicated for 2 h and then evaporated in vacuo. The
residue was dissolved in dry xylenes (700 mL), anhydride 1(1,2) (0.7 mol) was added, and the
mixture was refluxed for 6 h. After cooling, yellow oil separated from the solution, which
solidified upon standing overnight. The precipitate was filtered and washed with hexanes to give
carboxylic acid 6 – 12.
1-Methyl-2-oxo-5-phenylpyrrolidine-3-carboxylic acid (6).
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Yield 116 g (76%). White crystals. MS (m/z, CI): 220 (MH+). Anal. Calcd. for C12H13NO3
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4
5
6
1
C 65.74, H 5.98, N 6.39. Found C 65.83, H 6.27, N 6.55. H NMR (500 MHz, DMSOꢀd6) δ
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8
9
12.75 (s, 1H, COOH), 7.42 (t, J = 6.8 Hz, 2H, 3′ꢀCH of C6H5), 7.36 (t, J = 7.1 Hz, 1H, 4′ꢀCH of
C6H5), 7.29 (d, J = 7.1 Hz, 2H, 2′ꢀCH of C6H5), 4.72 (d, J = 5.0 Hz, 1H, 5ꢀCH), 3.05–2.96 (m,
1H, 4ꢀCH), 2.75 (dd, J = 16.7, 10.0 Hz, 1H, 3ꢀCHH), 2.56 (dd, J = 16.2, 5.6 Hz, 1H, 3ꢀCHH),
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2.49 (s, 3H, 1ꢀCH3). C NMR (126 MHz, DMSOꢀd6) δ 174.2 (C=O), 172.5 (C=O), 140.6 (1′ꢀC
of C6H5), 129.4 (3′ꢀCH of C6H5), 128.6 (4′ꢀCH of C6H5), 127.3 (2′ꢀCH of C6H5), 66.2 (5ꢀCH),
45.8 (4ꢀCH), 33.6 (3ꢀCH2), 28.1 (1ꢀCH3).
1-Methyl-2-oxo-6-phenylpiperidine-3-carboxylic acid (7).
Yield 129 g (79%). White crystals. MS (m/z, CI): 234 (MH+). Anal. Calcd. for C13H15NO3
1
C 66.94, H 6.48, N 6.00. Found C 67.25, H 6.63, N 6.31. H NMR (500 MHz, DMSOꢀd6) δ
12.72 (s, 1H, COOH), 7.40 (t, J = 7.0 Hz, 2H, 3′ꢀCH of C6H5), 7.31 (t, J = 6.8 Hz, 1H, 4′ꢀCH of
C6H5), 7.23 (d, J = 7.4 Hz, 2H, 2′ꢀCH of C6H5), 4.86 (d, J = 4.6 Hz, 1H, 6ꢀCH), 2.85–2.76 (m,
1H, 5ꢀCH), 2.63 (s, J = 13.9 Hz, 3H, 1ꢀCH3), 2.49–2.41 (m, 1H, 3ꢀCHH), 2.38–2.26 (m, 1H, 3ꢀ
CHH), 1.95–1.86 (m, 1H, 4ꢀCHH), 1.86–1.76 (m, 1H, 4ꢀCHH). 13C NMR (126 MHz, DMSOꢀd6)
δ 174.0 (C=O), 169.1 (C=O), 141.0 (1′ꢀC of C6H5), 129.2 (3′ꢀCH of C6H5), 128.1 (4′ꢀCH of
C6H5), 127.2 (2′ꢀCH of C6H5), 64.1 (6ꢀCH), 46.9 (5ꢀCH), 33.7 (1ꢀCH3), 30.0 (3ꢀCH2), 20.80 (4ꢀ
CH2).
5-(4-Methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylic acid (8).
Yield 123 g (71%). Mixture of isomers, dr 87 : 13. White crystals. MS (m/z, CI): 250 (MH+).
Anal. Calcd. For C13H15NO4 C 62.64, H 6.07, N 5.62. Found C 62.82, H 5.76, N 5.40. 1H NMR
(500 MHz, DMSOꢀd6, major isomer) δ 12.64 (s, 1H), 7.22 (d, J = 7.1 Hz, 2H), 6.97 (d, J = 7.2
Hz, 2H), 4.65 (d, J = 5.2 Hz, 1H), 3.77 (s, 3H), 3.00 (dd, J = 8.5, 5.2 Hz, 1H), 2.73 (dd, J = 16.8,
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9.9 Hz, 1H), 2.53 (dd, J = 16.3, 6.0 Hz, 1H), 2.46 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6, major
isomer) δ 174.3, 172.4, 159.6, 132.3, 128.7, 114.7, 65.7, 55.6, 45.9, 33.7, 28.0.
6-(4-Methoxyphenyl)-1-methyl-2-oxopiperidine-3-carboxylic acid (9).
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Yield 132 g (72%). Mixture of isomers, dr 88 : 12. White crystals. MS (m/z, CI): 264 (MH+).
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Anal. Calcd. for C14H17NO4 C 63.87, H 6.51, N 5.32. Found C 64.06, H 6.32, N 4.99. H NMR
(500 MHz, DMSOꢀd6, major isomer) δ 12.65 (s, 1H), 7.15 (d, J = 7.5 Hz, 2H), 6.95 (d, J = 7.6
Hz, 2H), 4.78 (d, J = 3.9 Hz, 1H), 3.75 (s, 3H), 2.80–2.73 (m, 1H), 2.60 (s, 3H), 2.49–2.39 (m,
1H), 2.36–2.27 (m, 1H), 1.94–1.79 (m, 2H). 13C NMR (126 MHz, DMSOꢀd6, major isomer) δ
174.0, 169.1, 159.1, 132.8, 128.4, 114.5, 63.7, 55.6, 47.2, 33.5, 30.2, 21.1.
General procedure for the preparation of alcohols 13, 14.
To freshly distilled THF (200 mL), LiAlH4 (0.44 mol) was added portionwise upon vigorous
stirring. The resulting suspension was stirred for additional 10 min, and 8 or 9 (0.1 mol) was
added in small portions over 1 h. The resulting mixture was refluxed for 2 d, then cooled, and
excess of hydride was quenched by dropwise addition of 1 : 1 THF – H2O mixture. The
precipitate was filtered off and washed with THF (3×300 mL). The combined extracts were
evaporated in vacuo, and the crude product was purified by flash chromatography.
(5-(4-Methoxyphenyl)-1-methylpyrrolidin-3-yl)methanol (13).
Yield 17.9 g (81%). Mixture of isomers, dr 92 : 8. White crystals. MS (m/z, CI): 222 (MH+).
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Anal. Calcd. for C13H19NO2 C 70.56, H 8.65, N 6.33. Found C 70.31, H 8.94, N 6.02. H NMR
(500 MHz, DMSOꢀd6, major isomer) δ 7.23 (d, J = 7.2 Hz, 2H), 6.88 (d, J = 7.2 Hz, 2H), 4.52 (s,
1H), 3.74 (s, 3H), 3.41–3.31 (m, 1H), 3.30–3.23 (m, 1H), 3.11–3.04 (m, 1H), 2.67 (d, J = 6.1 Hz,
13
1H), 2.25–2.16 (m, 1H), 2.01 (s, J = 18.0 Hz, 3H), 1.97–1.89 (m, 2H), 1.68–1.62 (m, 1H). C
NMR (126 MHz, DMSOꢀd6, major isomer) δ 158.7, 135.3, 129.0, 114.1, 73.1, 62.7, 55.8, 55.43,
51.0, 40.7, 26.9.
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(6-(4-Methoxyphenyl)-1-methylpiperidin-3-yl)methanol (14).
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6
Yield 19.5 g (83%). Mixture of isomers, dr 88 : 12. White crystals. MS (m/z, CI): 236 (MH+).
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Anal. Calcd. for C14H21NO2 C 71.46, H 8.99, N 5.95. Found C 71.27, H 9.08, N 5.83. H NMR
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(500 MHz, DMSOꢀd6, major isomer) δ 7.21–7.13 (d, J = 7.7 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H),
4.19 (s, 1H), 3.74 (s, 3H), 2.97 (d, J = 9.6 Hz, 1H), 2.93–2.82 (m, 2H), 2.51 (s, 2H), 2.05–1.92
(m, 2H), 1.81 (s, 3H), 1.73–1.57 (m, 1H), 1.56–1.46 (m, 1H), 1.16 (qd, J = 12.6, 3.4 Hz, 1H). 13C
NMR (126 MHz, DMSOꢀd6, major isomer) δ 158.6, 135.4, 129.3, 113.9, 71.3, 63.4, 57.1, 55.4,
45.8, 44.8, 28.4, 25.4.
General procedure for the preparation of alcohols 15 – 17.
To a solution of carboxylic acid 6 – 12 (0.1 mol) and Et3N (0.12 mol) in DMF (150 mL), MeI
(0.11 mol) was added dropwise. The resulting mixture was stirred at 50 °C for 1 d, then cooled,
poured into H2O and extracted with CH2Cl2. The combined extracts were washed with H2O,
evaporated, and the residue was dissolved in THF (200 mL). To this solution, NaBH4 (0.1 mol)
was added, followed by dry MeOH (ca. 20 mL). The resulting mixture was refluxed for 1 h, then
cooled and evaporated in vacuo. CH2Cl2 (200 mL) was added, and the mixture was washed with
H2O (3×100 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo. The
residue was recrystallized from Et2O to give 15 – 17.
3-(Hydroxymethyl)-5-(4-methoxyphenyl)-1-methylpyrrolidin-2-one (15).
Yield 17.4 g (74%). White crystals. MS (m/z, CI): 236 (MH+). Anal. Calcd. for C13H17NO3 C
66.36, H 7.28, N 5.95. Found 66.24, H 7.40, N 5.69. 1H NMR (500 MHz, DMSOꢀd6) δ 7.16 (d, J
= 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.86 (s, 1H), 4.27 (d, J = 4.4 Hz, 1H), 3.76 (s, 3H), 3.41
(s, 2H), 2.48 (s, 3H), 2.21–2.09 (m, 2H). 13C NMR (126 MHz, DMSOꢀd6) δ 173.8, 159.3, 133.4,
128.4, 114.7, 65.6, 62.4, 55.6, 44.0, 33.4, 28.0.
3-(Hydroxymethyl)-6-(4-methoxyphenyl)-1-methylpiperidin-2-one (16).
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Yield 17.9 g (72%). White crystals. MS (m/z, CI): 250 (MH+). Anal. Calcd. for C14H19NO3 C
3
4
5
6
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67.45, H 7.68, N 5.62. Found C 67.49, H 7.36, N 5.90. H NMR (500 MHz, DMSOꢀd6) δ 7.13
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8
9
(d, J = 6.9 Hz, 2H), 6.95 (d, J = 6.7 Hz, 2H), 4.75 (s, 1H), 4.28 (d, J = 4.7 Hz, 1H), 3.76 (s, 3H),
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3.45–3.38 (m, 1H), 3.32–3.23 (m, 1H), 2.56–2.52 (m, 3H), 2.43–2.27 (m, 2H), 1.79 (m, 2H),
13
1.61–1.51 (m, 1H). C NMR (126 MHz, DMSOꢀd6) δ 169.8, 158.9, 134.1, 128.5, 114.5, 64.1,
61.8, 55.5, 44.6, 33.4, 30.6, 21.4.
General procedure for the preparation of amides 25 – 29.
Compound 6 – 12 (0.5 mol) was dissolved in DMF (750 mL), and CDI (0.52 mol) was added.
The mixture was kept at 50 °C for 1 h, then (NH4)2CO3 (1.5 mol) was added, and the resulting
mixture was heated at 70 °C for 2 d. DMF was removed in vacuo, the residue was triturated with
H2O, filtered and dried to give 25 – 29.
5-(4-Methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (26).
Yield 101 g (82%). White crystals. MS (m/z, CI): 249 (MH+). Anal. Calcd. for C13H16N2O3
1
C 62.89, H 6.50, N 11.28. Found C 63.07, H 6.43, N 10.81. H NMR (500 MHz, DMSOꢀd6) δ
7.41 (s, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.03 (s, 1H), 6.97 (d, J = 7.5 Hz, 2H), 4.57 (d, J = 5.7 Hz,
1H), 3.77 (s, 3H), 2.86 (dd, J = 14.5, 7.3 Hz, 1H), 2.67 (dd, J = 16.4, 9.6 Hz, 1H), 2.47 (s, 3H),
13
2.40 (dd, J = 16.6, 7.4 Hz, 1H). C NMR (126 MHz, DMSOꢀd6) δ 174.2, 172.7, 159.5, 132.5,
128.6, 114.7, 66.3, 55.6, 46.7, 34.8, 28.1.
6-(4-Methoxyphenyl)-1-methyl-2-oxopiperidine-3-carboxamide (27).
Yield 111 g (85%). White crystals. MS (m/z, CI): 263 (MH+). Anal. Calcd. for C14H18N2O3
1
C 64.11, H 6.92, N 10.68. Found C 63.74, H 6.59, N 10.40. H NMR (500 MHz, DMSOꢀd6) δ
7.34 (s, 1H), 7.12 (d, J = 6.5 Hz, 2H), 6.93 (d, J = 6.5 Hz, 2H), 6.91 (s, 1H), 4.68 (d, J = 5.1 Hz,
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1H), 3.75 (s, 3H), 2.63–2.57 (m, 1H), 2.54 (s, 3H), 2.41–2.31 (m, 2H), 1.83 (m, 2H). C NMR
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(126 MHz, DMSOꢀd6) δ 174.0, 169.4, 159.0, 133.4, 128.5, 114.4, 64.1, 55.5, 48.6, 33.1, 31.0,
23.1.
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General procedure for the preparation of amines 18 – 24.
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To freshly distilled THF (500 mL), LiAlH4 (1.3 mol) was added portionꢀwise upon vigorous
stirring. The resulting suspension was stirred for additional 10 min, and amide 25 – 29 (0.3 mol)
was added in small portions over 1 h. The resulting mixture was refluxed for 2 d, then cooled,
and excess of hydride was quenched by dropꢀwise addition of 1:1 THF–H2O mixture. The
precipitate was filtered off and washed with THF (3×180 mL). The combined extracts were
evaporated in vacuo, and the crude product was purified by flash chromatography. Compound 18
was isolated as dihydrochloride.
3-(Aminomethyl)-5-(4-methoxyphenyl)-1-methylpyrrolidin-2-one (20).
Yield 52.8 g (80%). White crystals. MS (m/z, CI): 221 (MH+). Anal. Calcd. for C13H20N2O
1
C 70.87, H 9.15, N 12.72. Found C 70.53, H 9.11, N 12.52. H NMR (500 MHz, DMSOꢀd6) δ
7.24 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 3.74 (s, 3H), 3.09 (t, J = 7.9 Hz, 1H), 2.60 (d, J
= 8.1 Hz, 1H), 2.54 (dd, J = 12.3, 3.4 Hz, 1H), 2.40 (dd, J = 11.9, 8.3 Hz, 1H), 2.20 (dd, J = 17.3,
8.5 Hz, 1H), 1.99 (s, 3H), 1.97–1.91 (m, 1H), 1.90–1.82 (m, 1H), 1.64–1.53 (m, 1H); NH2 is not
13
observed due to exchange. C NMR (126 MHz, DMSOꢀd6) δ 158.8, 135.3, 129.1, 114.1, 74.6,
55.7, 55.4, 51.8, 44.8, 40.6, 27.4.
3-(Aminomethyl)-6-(4-methoxyphenyl)-1-methylpiperidin-2-one (21).
Yield 51.9 g (74%). White crystals. MS (m/z, CI): 235 (MH+). Anal. Calcd. for C14H22N2O
1
C 71.76, H 9.46, N 11.95. Found C 71.92, H 9.17, N 12.24. H NMR (500 MHz, DMSOꢀd6) δ
7.18 (d, J = 7.8 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H), 3.74 (s, 3H), 2.91 (d, J = 10.9 Hz, 1H), 2.44 (d,
J = 9.9 Hz, 1H), 2.14 (dd, J = 12.4, 3.1 Hz, 1H), 2.06–1.89 (m, 3H), 1.80 (s, 3H), 1.72–1.55 (m,
2H), 1.43 (s, 1H), 1.05 (qd, J = 12.8, 3.9 Hz, 1H); NH2 is not observed due to exchange. 13C
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NMR (126 MHz, DMSOꢀd6) δ 158.6, 135.4, 129.4, 114.0, 72.7, 57.1, 55.4, 45.8, 44.8, 44.7,
5
6
28.5, 25.5.
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Supporting Information Available: compound characterization data, copies of H, 13C and
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2D NMR spectra, and Table S1. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgments. The authors thank Mr. Vitaliy V. Polovinko for NMR measurements and
Prof. Igor V. Komarov for his help with Instant JChem calculations.
References and footnotes.
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