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Synthesis Decarboxylation and Nitrosation of 1-Acyl-2-pyrrolidone-3-carboxylic AcidsA Convenient Novel Entry to 23-Dioxopyrrolidine Derivatives.

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1 -Acyl-2-pyrrolidone-3-carboxylic
Synthesis, Decarboxylation, and Nitrosation of 1-Acyl-2-pyrrolidone3-carboxylic Acids: A Convenient Novel Entry to 2,3=Dioxopyrrolidine
Viktoras Gailius and Helmut Stamm*"
Pharmazeutisch-ChemischesInstituf Fakultit Pharmazie, Universitiit Heidelberg, NeuenheimerFeld 346, D-6900 Heidelberg
Received January 10.1991
Esters 1of l-acyl-2-pyrrolidone-3-carboxylic
acids 2 were hydmlized to 2
with acetic acid/HC1 at 60-70°C. Reaction of l a with formic acid/HCl at
60-75OC led to (not isolated) 2a which began to decarbxylate to 3a during
the convemion of la to 2a even at this low temp. Decarboxylation of k-f
was accomplished at 160OC without solvent. Decarbxylative nitrosation of
2 - f yielded the oximes 4 - f of 1-acyl-2.3-dioxopyrmlidines.Treatmentof 4f
with magic methyl provided the en01 ether 5f of the respective dioxopyrrolidine.
1,3-Diacy1-2-pyrrolidones(1and related structures) are attacked by nucleophiles preferrably in position 2, leading to
cleavage of the pyrrolidone ring'). Basic hydrolysis provided P(amidoethy1)-malonic acids. Only once 1 could be
converted to 2. It appears likely that, also in this case (la),
ring cleavage occurs first to form the anion of the respective
monoethyl malonate.
Subsequent ring closure by amidolysis of the ester group
would yield the isolated 2a and thus pretend a selective
hydrolysis of the ester function. However, the 1-acylpyrrolidone moiety of 1is fairly stabIe towards acids. Under acid
catalysis it is even possible to reconvert a P-amidoethylmalonic acid into the educt 1').
We now report on a convenient way to generate 2 in good
yields. 1was heated for 2-3 h at 60-7OoC (bath temp.) in a
6:l mixture of glacial acetic acid and conc. HC1. Subsequent dilution with water precipitated 2. No attempts were
made to isolate dissolved 2 from the mother liquor. Consequently, the yields may reflect both the solubility of the
pertinent compounds 2 and experimental details of the respective run (e.g. degree of dilution): 85% 2b,54% 2c, 75%
2d, 93% 2e, and 74% 2f. At room temp. conversion of 1to
2 requires several days.
The conversion of 1into 2 can occur by hydrolysis or by
transesterification. Both possible products, ethanol and ethyl
acetate, are difficult to isolate. Direct 'H-NMR control of
the reaction was considered an easier way to differentiate
between the two possibilities. The multiplets of the pyrrolidone ring are practically identical for 1 and 2, but one of
these multiplets in 1 overlaps with the OCH2 quartet. In
+) Dedicated
Synthese, Deeprboxylierungund Nitrosiemngvon 1-Acyl-2-pyrrolidonJ-carbonslluren: Urnwandlung eines Oxims in den Enolether eines 1Acyl-2,3dioxopyrrolidines
Ester 1von l-Acyl-2-pyrrolidon-3-carbon~uren
2 wurden zu 2 umgewandelt durch Umesterung mit Essigsiiure/HCl bei 60-70°C. Reaktion von la
mit AmeisemiiudHCl bei 60-75OC fiihrte zum (nicht isolierten) 2a, das
bereits bei dieser Temp. anfing. zu 3a zu decarbxylieren, withrend die
Umwandlung von la in 2a bei weitem noch nicht beendet war. Decarbxylierung von 2c-f zu 3c-f wurde bei 160°C ohne Ldsungsmittel durchgefiihrt.
Decarbxylierende Nitrosiemng von k-f gab die Oxime 4c-f von 1-Acyl2.3-dioxopyrrolidinen. Behandlung von 4f mit "Magic Methyl" lieferte den
Fholether 5f des entspr. Dioxopyrmlidines.
9 1%
from laM
CF3 S03Me
M e H
C 1 H
to Professor Herbert Oelschldget on the occasion of his 70th birthday.
Arch. P h ~ r m(Weinheim)
325,89-92 (1992)
OVCH VerlagsgesellschaftmbH, D-6940 Weinheim, 1992
+ .25/0
order to simplify the spectral analysis, the methyl ester laM
was selected for this experiment. Expensive deuterated
acetic acid was substituted by formic acid. Heating laM in
formic acid to 60°C for 36 h had no effect, but after addition
of HC1 the reaction proceeded. After 12 h at 6OoC (bath
temp.) the methoxy singlet of laM had practically disappeared. At that time (or at a shorter time) no other methoxy
singlet could be detected. This can be expected only in the
case of transesterification, since methyl acetate is highly
volatile (b.p. 32"C), while methanol (b.p. 65°C) should have
been detected. To our surprise, however, a substantial part
of 2a had undergone decarboxylation which was easily recognisable from the methyl doublet of 3a upfield from the
methyl singlet of 2a. Further heating to 70-75°C (bath
temp.) for 4 days provided a high yield of 3a, contaminated
with 2a, which could be removed with NaOH solution.
Since decarboxylation of 2 normally requires much higher
temp. (videinfra), we performed a control experiment: 2b is
stable for 1 day at 100°C in acetic acid/HCl. Thus formic
acid specifically accelerates the decarboxylation, probably
due to its high dielectric constant: HCO2H 58, MeCOzH
The acids 2b-d were decarboxylated by heating at 160165°C for about 1 h. The yields of the products 3b-d were
97-98%. Decarboxylation of 2 under much milder conditions was possible with carbonyl diimidazole (98% 3d, 3
days at room temp. in THF).
The carboxylic acids 2c-f offer a novel opportunity to obtain derivatives of 1-acyl-2,3-dioxopyrrolidines.This type
of compounds, in the enolic form and properly substituted,
may be used for syntheses in the cytochalasin series2). Indeed, simple nitrosation of 2c-f afforded the oximes 4c-f of
pertinent dioxopyrrolidines in (nearly) quantitative yields:
100% 4c, 96% 4d, 89% 4e, and 96% 4f.
In order to examine the usefulness of this entry into the
dioxopyrrolidine class, we tried to convert one of these
oximes into the parent ketone (or its enol). Hydrolytic
cleavage of oximes usually requires rather harsh experimental conditions which may affect the two carbonyl
functions already present in 4. Since acid catalyzed hydre
lytic cleavage of a nitrone appears to proceed under milder
conditions, we tried to prepare a nitrone by heating 4f with
magic methyl (CF3SO2Me) in methyl acetate under exclusion of moisture. It was expected that the nitrone would
precipitate. Some days were required to form a precipitate.
After six days reflux the precipitate was collected. To our
surprise, the spectral data as well as the elementary analysis
(Experim. Part) proved the product to be the enol ether 5f.
Thus, we could show that starting with the respective Na~ylaziridine~),
there is a convenient four step way to the
1-acyl-2,3-dioxopyrrolidinesystem with high yields in each
The formation of 5f is not clear. A reasonable explanation may be the
generation of the expected nitrone (or its enamine tautomer) followed by
methanolysis. This would require the presence of water in the mixture of
magic acid and methyl acetate. We cannot exclude that moisture penetrated
during six days reflux, e.g. by washing out the grease from the ground
Gailius and Stamm
Experimental Part
'H-NMR Spectra (CDC13 unless otherwise stated): 60 MHz (Varian T
60-A) or 90 MHz (Bruker HX-90 E).- IR Spectra: Perkin-Elmer 257 or
283.- M~SS
S ~ ~ C ~Varian
MAT 311.
Compounds la-f are
Conversionoflb-f into 2b-f
5 ml (10 ml for l c and le) of conc. HCI were added to a solution of 1
(amount given below) in 30 ml (50 ml for lb, 60 ml for l c and le) of
glacial acetic acid. The mixture was heated to 60-7OoC for 2-3 h. After
cooling to mom temp. addition of water precipitated 2. After washing with
water and dichloromethane 2 was dried in a desiccator.
acid (2b)
11.25 g (85%) of Zb from 14.71 g (50.7 mmol) of 1b.- Mp. 127-144OC
(dec.).- IR (KBr): 3145 (NH), 3400-2800 (CO2H), 1725 (C02H), 1715
(pyrrolidone), 1695 (NCON, amide I), 1548cm-' (amide II).- 'H-NMR (60
MHz): 6 = 1.58 (s, Me), 1.73-2.26 (m, COCCH cis to methyl), 2.41-2.87
(m, C 4 H trans to methyl), 4.01 (mc, NH$, 7.07-7.76 (m, 5 aromatic H),
(262.3) Calcd. C 59.5 H
10.12 (s br, C02H). 10.45 (s, NH).- C13H14N204
5.38 N 10.7 Found C 59.6 H 5.36 N 10.6.
I -(Phenylcarbamoyl)-2-oxopy1rolidine-3-carbo~lic
acid (2c)
0.90 g (54%) of 2c from 1.85 g (6.7 mmol) of 1c.- Mp. 146-150°C.- IR
(KBr): 3450-3250 (NH, C02H), 1746 (CO2H), I701 (pyrrolidone), 1659
(NCON, amide I), 1552 cm-I (amide II).- 'H-NMR (60MHz, DMSO-d6): 6
= 2.02-2.5 (m, COCCH$. 3.58-4.08 (m, NCH2, COCH), 6.85-7.70 (m, 5
aromatic H), 10.30 (s, NH), 12.80 (s vbr, C02H).- Cl2Hl2N2O4(248.2)
Calcd. C 58.1 H 4.87 N 11.3 Found C 57.8 H 4.82 N 11.2.
I -(4-Chlorophenylcarbamoyl)-2-oxopyrrolidine-3-car~~lic
acid (2d)
0.68 g (75%) of 2d from 1.00 g (3.22 mmol) of Id.- Mp. 155-160OC.- IR
(KBr): 3240 (NH), 3120 (NH), 3100-2450 (COzH), 1721 (C02H). 1718 sh
(pynolidone), 1691 (NCON, amide I), 1552 (amide II).- 'H-NMR (60
MHz, acetone-d&DCls 1:2): 6 = 2.27-2.70 (m. COCCH2), 3.474.17 (m,
NCH2, COCH), 7.50 (mc, 4 aromatic H), 10.46 (s, NH), COzH not detectable.- C12HllC1N204(282.7) Calcd. C 51.0 H 3.92 N 9.9 Found C 51.0 H
3.84 N 9.9.
I -(3-Chlorophenylcarbamoyl)-2-oxopyrrolidine-3-car~~lic
acid (2e).
mono hydrate
1.81 g (93%) of 2e as its mono hydrate from 2.00 g (6.44 mmol) of 1e.Mp. 148-152OC.- IR (KBr): 3245 (NH),3205 (NH), 3400-2400 (CQH),
1725 sh (COzH), 1715 (pyrrolidone), 1695 (NCON, amide I), 1548 (amide
II).- 'H-NMR (60 MHz, DMSO-4): 6 = 2.02-2.5 (m, COCCHz), 3.60-4.00
(m, NCH2, COCH), 6.90-7.43 (m, 4-H, 5-H, and 6-H of Ar), 7.79 (mc. 2-H
of Ar), 10.46 (s, NH), C02H not detectable.- C12H13ClN20s(300.7, mono
hydrate)Calcd.C47.9 H4.36N9.3FoundC48.0H4.30N9.3.
I -(3P-Dichlorophenylcarbamoyl)-2-oxopy1rolidi~-3-carboxylicacid (20
0.64 g (74%) of 2f from 0.94 g (2.72 mmol) of If.- Mp. 150-154OC.- IR
(KBr): 3220 (NH), 3175 (NH), 3110 (NH), 340-2000 (COzH), 1741
(C02H). 1728 (pyrrolidone), 1677 (NCON, amide I), 1558 (amide II).1
H-NMR (60 MHz, acetone-&): 6 = 2.20-2.65 (m, COCCH2),3.704.20
(m, NCH2, COCH), 6.93 (s br, COzH), 7.42 (mc, 5-H and 6-H of Ar), 7.90
(m, 2-H of Ar), 10.55 (s, NH).- Cl2H1&12N2O4 (317.1) Calcd. C 45.4 H
3.18 N 8.8 Found C 45.4H 3.13 N 8.9.
The t-butyl ester analogue of If provided a yield of 84% 2f.
Arch. Pharm. (Weinheirn)325.89-92 (1992)
Conversion of laM into 3a via non-isolated2a
Nitrosation of Zc-f providing 4c-f
A solution of 5.00 g (14.5 mmol) of l a M in 30 ml of formic acid (98%)
provided an 'H-NMR spectrum very similar to the spectrum in CM313''.
The chemical shifts were not detennined due to the absence of TMS, but the
appearance of each multiplet agreed exactly in both solvents.- Heating the
solution to 60°C (bath temp.) for 36 h did not influence the spectrum. 1 ml
of conc. HCI was added and heating was continued. Within two days the
methoxy singlet of laM disappeared (laM + 2a) while the other signals
(especially the C-CH3 singlet) did not reveal any change except for the appearance of a small doublet (J = 6.4 Hz, C-CH3 of 39)0.27 ppm downfield
from the C-CH3 singlet of Za. Further heating to 70-75OC (bath temp.) for 4
days increased the doublet to the expected intensity while the CH3-singlet
of 2a practically disappeared and the multiplets of the pyrrolidone ring markedly changed their appearance. The solution was diluted with a large volume of CH2C12 at room temp. and exhaustively washed with dil. aqueous
NaOH. Evaporation of the org. layer provided 4.02 g (97%) of 1-(3,4-dichlorophenylcarbamoyl)-3-methylpyrrolidin-2-one(3a).- Mp. 132-136°C.IR (KBr): 3220 (NH), 1709 (pyrrolidone), 1685, 1665 (both: amide I of
NCON), 1541cm" (amide II).- 'H-NMR (60 MHz): 6 = 1.28 (d, J = 6.4 Hz,
CH3), 1.43-3.00 (m, COCHCHd, 3.44-4.21 (m, NCH2), 7.36 (mc, 5-H and
6-H of aryl), 7.80 (mc, 2-H of aryl), 10.67 (s br, NH).- C12H12ClzNOz
(287.1)Calcd.C 50.2H4.21 N9.8FoundC50.4N4.35N9.7.
An excess (2-5 g) of NaN02 was added to a solution of 2 in glacial acetic
acid (10 ml for each 0.5 g of 2) and a few drops of conc. HCI. A transient
green-blue colour indicated the fonnation of the nitroso compound of 2.
Spontaneous precipitation of 4 began after about 5 min. Addition of
water (about 200 ml) completed precipitation. The precipitate was collected, washed with water and dried in a desiccator (P205).
Thermaldecarbonylationof 2b-d
2 was heated to 160-165OC until completion of gas evolution (about 1 h).
The cold residue was dissolved in CHzClz and washed with dil. aqueous
NaOH. Evaporation of the org. layer provided 3. Analytical samples were
recrystallized from Et20/CHC13 (101).
I -Phenylcarbamoyl-3-methylpyrrolidin-2-one
2.13 g (97%) from 3.00 g (11.4 mmol) of 2b.- Mp. 77-78°C.- IR (KBr):
3220 (NH), 1712 (pymlidone), 1685 sh, 1695 (both amide I of NCON),
1541 cm-' (amide 10.- 'H-NMR (60 MHz): 6 = 1.25 (d, J = 6.4 Hz, CH3),
1.40-3.00 (m. COCHCH2), 3.42-4.30 (m, NCH3, 6.94-7.72 (m, aryl),
10.65 (s br, NH).- C12Hl4N2OZ(218.2) Calcd. C 66.0 H 6.47 N 12.8 Found
C 65.9 H 6.42 N 12.6.
97 mg (98%) from 120 mg (0.48 mmol) of 2c,- Mp. 87-88°C.- IR (KBr):
3220 (NH), 3190 (NH), 1722, 1714 (both: pymlidone), 1688 (amide I of
NCON), 1562, 1552 cm-' (both:amide It).- 'H-NMR (60 MHz): 6 = 1.802.33 (m, COCCH2), 2.43-2.83 (m, COCH2), 3.76-4.10 (m, NCH2), 7.007.66 (m, w l ) , 10.53 (S br, NH).- CllH12N202(204.2) Calcd. C 64.7 H 5.92
N 13.7 Found C 64.8 H 5.89 N 13.5.
I -(4-Chlorophenylcarbamoyl)pyrrolidin-2-one
165 mg (98%) from 200 mg (0.71 mmol) of 2d.- Mp. 132-135OC.- IR
(KBr): 3220 (NH), 1717 (pyrmlidone), 1698 sh, 1688 sh (both amide I of
NCON), 1550,1541 cm-' (both:amide II).- 'H-NMR (60 MHz): 6 = 1.832.33 (m, COCCHd, 2.50-2.86 (m, COCHd, 3.70-4.10 (m, NCH2), 7.38
(mc, aryl), 10.59 (s br, NH).- CllHllClN202 (238.7) Calcd. C 55.4 H 4.65
N 11.7FoundC55.4H4.76N 11.8.
Decarboxylation of Zd with N,"-carbonyl-diimidazole
Two solutions of 1.00 g (3.54 mmol) 2d in 50-100 ml of THF and of 0.86
g (5.3 mmol) of N,"-carbonyl-diimidazole in 50 ml of THF were cooled to
5'C and mixed. After 3 days at room temp. a large volume of CH2Cl2 was
added and the resulting mixture was thoroughly washed with water. Evaporation of the org. layer provided 827 mg (98%) of 3d.
Arch. Pharm. (Weinheim)325,89-92(1992)
Mp. 185°C then recrystallization, final mp. 212°C.- IR (KBr): 35002800 (OH), 3240 (NH), 1730 (pynolidone), 1705 (amide I of NCON),
1678 (C=N), 1564, 1558 (both:amide 11), 947 cm" (NOH).- 'H-NMR (60
MHz), DMSO-4): 6 = 2.67-2.83 (m, N=CCHL), 3.75-3.90 (m, NCH2).
7.10-7.60 (m, Ph). 10.63 (s br, NH), OH not detectable.- CllHLlN303
(233.2) Calcd. C 56.6 H 4.75 N 18.0 Found C 56,7 H 4.89 N 17.8.
517 mg (96%) from 575 mg (2.03 mmol) of 2d.- Mp. 216-219°C.- IR
(KBr): 3500-2800 (OH), 3330 (NH), 1738 (pyrrolidone), 1688 sh (amide I
of NCON), 1682 (C=N), 1566 (amide II), 932 cm-' (NOH).- 'H-NMR (60
MHz,DMSO-&): 6= 2.68-2.83(m,N=CCH2),3.74-3.89(m,
(mc, aryl), 10.66 (s br, NH), OH not detectable.- CllH10CINf13 (267.7)
Calcd.C49.4H3.77N 15.7 FoundC49.5 H 3.88 N 15.5.
442 mg (89%) from 521 mg (11.84 mmol) of 2e.- Mp. 217-218°C.- IR
(KBr): 3500-2800 (OH), 3215 (NH), 1744 (pyrrolidone), 1728 (amide 1 of
NCON), 1690 (C=N), 1562 (amide II), 955 cm" (NOH).- 'H-NMR (60
MHz, DMSO-d6): 6 = 2.75-2.93 (m, N=CCH2), 3.86-4.00 (m,NCHz),
7.00-7.53 (m. aryl), 10.73 (s br. MI), 12.59 (s br, OH).- CllHIOC1N303
(267.7)Calcd.C49.4H3.77 N 15.7FoundC49.6H 3.82N 15.7.
955 mg (96%) from 1040 mg (3.28 mmol) of 2f.- Mp. 241-242°C.- IR
(KBr): 3500-2800 (OH), 3240 (NH). 3175 (NH), 1725 (pyrrolidone), 1703
(amide I of NCON), 1670 (C=N), 1542, 1537 (both: amide 11). 949 cm-'
(NOH).- 'H-NMR (60 MHg DMSO-4): 6 = 2.68-2.83 (m, N=CCH2),
3.74-3.89 (m, NCHd, 7.50 (mc, 5-H and 6-H of aryl), 7.98 (mc, 2-H of
aryl), 10.71 (s br, NH), 12.60 (s br, OH).- C1lH9C12N3O3(302.1) Calcd. C
43.7H 3.00N 13.9FoundC43.8 H3.06N 13.6.
A solution of 621 mg (2.05 mmol) of 4f and 2.0 g (12 mmol) of methyl
nifluoromethanesulfonate in 70 ml of dry.methyl acetate was refluxed
under exclusion of moisture. After 3 days the solution became turbid. After
another 2 days the precipitate was filtered off and washed with CC14. Evap
oration of the mother liquor left a residue that was washed with refluxing
EtzO to give a residue (130 mg) which was combined with the precipitate
(580 mg). This product was dissolved in warm glacial acetic acid and reprecipitated by water. This precipitate consisted (after drying) of 476 mg
(77%) of 5f.- Mp. 232°C.- IR (KBr): 3220 (MI), 3190 (NH), 2850 (OMe),
1724 (pymlinone), 1705 sh, 1700 sh, 1690 sh (all: amide I of NCON),
1648 (C=C), 1538 cm-' (amide II).- 'H-NMR (90 MHz, CF3C02D): 6 =
3.80 (s, Me), 4.33 (d, J = 2.5 Hz, NCH2). 6.00 (t, J = 2.5 Hz. C=CH), 7.37
(mc, 5-H and 6-H of aryl), 7.82 (mc, 2-H of aryl).- MS (130°C. ions
with3'C1 are not given, the isotopic molecular ions appear in the correct
ratio of 9:61): m/z (%) = 300 (30, M"), 265 (22, M - C1). 187 (83,
C6H3C12NCO). 113 (100, M - 187). 98 (21, 113 - Me).- C12HI~CI~N203
(301.1) Calcd. C 47.9 H 3.35 N 9.3 Found C47.8 H 3.34 N 9.0.
Gailius and Stamm
V. Gailius and H. Stamm,Arch. Pharm. (Weinheim) 321,337 (1987).
G. Stork, Yo. Nakahara, Yu. Nakahara, and W.J. Greenlee, J. Am.
Chem. SOC.100,7775 (1978).
3 J. Hamer and A. Macaluso, Chem. Rev. 64,461 (1964).
4 H. Stamm and L. Schneider, Chem. Ber. 108, 500 (1975). - Yield
enhancement: H. Stamm and J. Budny, Chemiker-Ztg. 109, 103
( 1979).
Arch. Pharm. (Weinheim)325.89-92 (1992)
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entry, synthesis, nitrosative, pyrrolidone, dioxopyrrolidine, carboxylic, acidsa, convenient, novem, decarboxylation, acyl, derivatives
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