The synthetic utility of amide and amidine derivatives containing polycarbonyl moieties in the synthesis of β-aminoenones

Article abstract of DOI:10.1007/s007060200002

The application of derivatives of the easily decomposing weak bases formamide, semicarbazide, urea, or formamidine in the synthesis of β-aminoenones is described. These compounds readily undergo transamination with strong bases, thus opening the way to various heterocyclic compounds.

Full text of DOI:10.1007/s007060200002

Monatshefte fuÈr Chemie 133, 249±254 ꢀ2002)
The Synthetic Utility of Amide and Amidine
Derivatives Containing Polycarbonyl Moieties
in the Synthesis of b-Aminoenonesa
Ã
Katarzyna Ostrowska
ꢀ
Department of Organic Chemistry, Jagiellonian University, PL-30060 Krakow, Poland
Summary. The application of derivatives of the easilydecomposing weak bases formamide, semi-
carbazide, urea, or formamidine in the synthesis of ꢀ-aminoenones is described. These compounds
readilyundergo transamination with strong bases, thus opening the wayto various heterocyclic
compounds.
Keywords. Polycarbonyls; Amides; Amidines; ꢀ-Aminoenones; Transamination.
Introduction
The decomposition of formamide into ammonia and carbon oxide in the
condensation±reduction reaction with carbonyl compounds has been widely used
to prepare amine derivatives [1±4]. In addition to the synthesis of enaminones
[5±8] and pyrimidines [9±11], many heterocyclic derivatives have been prepared
bythis method. As part of our ongoing efforts to obtain the pryrolo[3,4-
d]pyrimidine system, a general and ef®cient synthesis of 1-phenyl-4-ꢀphenyl-
aminomethylidene)-pyrrolidine-2,3,5-trione via condensation or transamination is
reported. As starting materials, 4-ꢀphenylhydroxymethylidene)-pyrrolidine-2,3,5-
trione or enaminone derivatives and easilydecomposing formamide, amidine, urea,
or semicarbazide derivatives were used. It has been reported that the basicityof
nitrogen bases limits the condensation reaction of the latter with a polycarbonyl
compound. Thus, veryweak bases like urea and thiourea did not form anyproduct
in ethanolic solution, but stronglybasic compounds like guanidine, triphenylgua-
nidine, and 1,5- or 1,6- aliphatic diamines gave thermallystable salts up to 260 ꢀC,
regardless of the reaction conditions [12±15].
Results and Discussion
Upon reaction with formamide which was also used as solvent, polycarbonyl
derivatives 1 gave exclusivelythe enaminones 2 ꢀScheme 1). The same result was
a
th
Dedicated to Prof. Dr. W. Zankowska-Jasinska on the occasion of her 80 birthday
_
ꢀ
Ã
E-mail: ostrowsk@chemia.uj.edu.pl

250
K. Ostrowska
Scheme 1
Scheme 2
obtained when the reaction of 1a was performed with a varietyof weak bases such
as urea, formamidine, or semicarbazide derivatives in boiling dowtherm with addi-
tion of acetic acid to facilitate the removal of the hydroxyl group ꢀScheme 2).
Replacement of the high-boiling solvent byethanol caused the formation of an
additional open-chain derivative. Thus, reaction of 1a with formamide in boiling
ethanol resulted in the formation of 2a and 3a, the latter being the product of the
succinimide N1±C2 bond cleavage. Furthermore, at room temperature, 1a with

Synthesis of ꢀ-Aminoenones
251
formamidine yielded the salt 4a which converted quantitativelyto the intermediate
5a under these conditions. The latter underwent further reaction in boiling dow-
therm to 2a ꢀScheme 2).
These results show that the condensation is followed bythe decomposition of an
amine and that high temperature favours both decomposition and formation of the
cyclic product. Heating 40-phenylmethylene-pyrrolidinetrione-1-semicarbazone ꢀ6)
[15] in dowtherm led to pyrrolo[3,4-c]pyrazole derivative 7 [16], thus con®rming
the proposed mechanism ꢀScheme 3). The enaminone 2a was also readilyobtained,
regardless of reaction temperature, bytransamination of 8 and 9 with formamide
and benzamidine, respectivelyꢀScheme 4).
The ꢀ-aminoenone moietycould be ef®cientlyreacted with a range of nucleo-
philes to afford the corresponding heterocyclic derivatives. Thus, 2a and 7 under-
went facile transamination to the pyrrolo[3,4-e]diazepine 10 [17]; it is a useful
precursor to a variety of fused heterocyclic systems.
It is important to point out that it is possible to synthesize the enaminones of
strong nitrogen bases bytransamination which are hard to obtain bythe formation
of salts with polycarbonyls. No method of aminoenone synthesis based on the de-
composition of urea, amidine, or semicarbazide derivatives could be found in the
Scheme 3
Scheme 4

252
K. Ostrowska
literature. In the case of formamide, the reaction seems to be slightlymore
ef®cient. However, heating 2a with formamidine in dowtherm effectivelyshortens
the reaction time. Under these conditions, polycarbonyl compounds sensitive to pH
can be safelyconverted to aminoenones because weak bases decompose to ammo-
nia during heating. Moreover, products formed in dowtherm solution are easily
precipitated bypetroleum.
In conclusion, these procedures represent a convenient method for the ef®cient
synthesis of ꢀ-aminoenones; what is more, the transamination extends their appli-
cation to the formation of various heterocyclic systems.
Experimental
Melting points were determined on a Boetius PHMK 05 melting point apparatus and are uncorrected.
The 1H and 13C NMR spectra were recorded in DMSO-d6 and CDCl3 with a Bruker AMX 500 NMR
spectrometer using TMS as internal standard. The IR spectra were measured in Nujol and hexa-
chlorobutadiene ꢀHCBN) with a Bruker IFS 48 spectrometer. The EI mass spectra were obtained on
an LKB 9000 S spectrometer and a Finnigan TSQ 700 triple quadruple mass spectrometer. Elemental
analyses were carried out with an Eurovector analyser; their results were in good agreement with the
calculated values.
1-Phenyl-4-ꢀaminophenylmethylene)-pyrrolidine-2,3,5-trione ꢀ2a; C17H12N2O3)
i) A solution of 0.01 mol of 1a in 10 cm3 formamide was heated to 130ꢀC for 4 h and cooled. The
precipitate was ®ltered off and crystallized from DMF. Yield: 89%.
ii) To a solution of 0.01 mol of 1a in 10 cm3 dowtherm and 1 cm3 acetic acid, 0.012 mol of form-
amidine acetate were added. The mixture was re¯uxed for 10 min. The aminoenone was pre-
cipitated with petroleum, ®ltered off, and crystallized from DMF. Yield: 73%.
iii) To a solution of 0.01 mol of 1a in 10 cm3 dowtherm and 1 cm3 acetic acid, 0.012 mol of semi-
carbazide, thiosemicarbazide, urea, or thiourea were added. The mixture was re¯uxed for 2 min.
The aminoenone was precipitated with petroleum, ®ltered off, and crystallized from DMF.
Yields: 20, 15, 61, and 42%.
iv) To a solution of 0.01 mol of 1a in 50 cm3 EtOH, 0.012 mol of formamide were added. The solu-
tion was re¯uxed for 8 h and cooled. The precipitate was ®ltered and washed with boiling EtOH.
The ®ltrate was left for crystallization ꢀ3a). The precipitate ꢀ2a) was crystallized from DMF or
acetic acid. Yield: 2a: 61%, 3a: 11%.
v) A solution of 0.01 mol of 5a in 10 cm3 dowtherm was heated to 260ꢀC for 2 min and cooled. The
aminoenone was precipitated with petroleum, ®ltered off, and crystallized from DMF. Yield:
39%.
vi) To a solution of 0.01 mol of 8 in 50 cm3 EtOH, or 10 cm3 dowtherm, respectively, 0.012 mol of
formamide were added. The solution was re¯uxed for 4 h and cooled. The precipitate was
®ltered and crystallized from DMF. Yields: 5, 20%.
vii) To a solution of 0.01 mol of 9 in 50 cm3 EtOH, 0.012 mol of benzamidine hydrochloride were
added. The solution was re¯uxed for 8 h and cooled. The precipitate was ®ltered and crystallized
from DMF. Yield: 18%.
M.p.: 289ꢀC; IR ꢀHCBN): ꢁ ˆ 3374, 3166 ꢀNH), 3060 ꢀC±H arom.), 1769, 1706 ꢀCˆO), 1612 ꢀCˆC
arom.) cmÀ1; 1H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 9.72 ꢀ2H, s, NH2), 7.56±7.60 ꢀ3H, m, H arom.),
7.45±7.51 ꢀ4H, m, H arom.), 7.36±7.39 ꢀ3H, m, H arom.) ppm; 13C NMR ꢀDMSO-d6, ꢂ,
125.75 MHz): 167.45, 161.93, 132.047, 131.78, 131.49, 128.81, 128.58, 127.84, 127.69, 126.96,
‡
‡
‡
‡
79.13 ppm; MS: m=z ꢀ%) ˆ 292 ꢀ26.2) [M ], 264 ꢀ65.4) [M ±CO] , 145 ꢀ100) [C9H7NO] .

Synthesis of ꢀ-Aminoenones
253
1-Phenyl-4-ꢀamino-4-chloro-phenylmethylene)-pyrrolidine-2,3,5-trione ꢀ2b; C17H11N2O2Cl)
A solution of 0.01 mol of 1b in 10 cm3 formamide was heated to 130ꢀC for 4 h and cooled. The
precipitate was ®ltered off and crystallized from DMF.
Yield: 87%; m.p.: 305ꢀC; IR ꢀHCBN): ꢁ ˆ 3395, 3206 ꢀNH), 3053 ꢀC±H arom.), 1764, 1703
ꢀCˆO), 1602 ꢀCˆC arom.) cmÀ1; 1H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 9.78 ꢀ2H, s, NH2), 7.60 ꢀ2H,
d, J ˆ 9 Hz), 7.57 ꢀ2H, d, J ˆ 9 Hz), 7.47 ꢀ2H, t, J ˆ 7 Hz), 7.36 ꢀ3H, m) ppm; 13C NMR ꢀDMSO-d6,
ꢂ, 125.75 MHz): 166.07, 161.93, 136.32, 131.76, 130.83, 128.64, 127.98, 127.77, 126.96 ppm;
‡
‡
‡
MS: m=z ꢀ%) ˆ 328 ꢀ13.08) [M ‡ 2] , 326 ꢀ39.38) [M ], 298 ꢀ33.08) [M ±CO], 179 ꢀ100)
[35ClC6H4NCO] , 181 ꢀ33.08) [37ClC6H4NCO]
‡
‡
.
1-ꢀ4-Methylphenyl)-4-ꢀaminophenylmethylene)-pyrrolidine-2,3,5-trione ꢀ2c; C18H14N2O3)
A solution of 0.01 mol of 1c in 10 cm3 formamide was heated to 130ꢀC for 4 h and cooled. The
precipitate was ®ltered off and crystallized from DMF.
Yield: 82%; m.p.: 272±274ꢀC; IR ꢀHCBN): ꢁ ˆ 3372, 3172 ꢀNH), 3035 ꢀC±H arom.), 1764, 1701
ꢀCˆO), 1615 ꢀCˆC arom.) cmÀ1; 1H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 9.71 ꢀ2H, s, NH2), 7.59 ꢀ3H,
t, J ˆ 7 Hz), 7.5 ꢀ2H, t, J ˆ 8 Hz), 7.27 ꢀ2H, d, J ˆ 8 Hz), 7.23 ꢀ2H, d, J ˆ 8 Hz), 2.34 ꢀ3H, s, CH3)
ppm; 13C NMR ꢀDMSO-d6, ꢂ, 125.75 MHz): 167.52, 162.16, 137.30, 132.14, 131.61, 129.24, 129.19,
‡
‡
128.92, 127.95, 126.84, 95.2, 20.78 ppm; MS: m=z ꢀ%) ˆ 306 ꢀ29.56) [M ], 278 ꢀ63.24) [M ±CO],
‡
133 ꢀ100) [CH3C6H4NCO]
.
2-ꢀHydroxyphenylmethylene)-3-oxo-N1-phenylsuccinamide ꢀ3a; C17H13N2O4)
Yield: 11%; m.p.: 175ꢀC; IR ꢀHCBN): ꢁ ˆ 3171 ꢀNH), 3100±2600 ꢀN±H bonded, C±H arom.), 1763,
1716 ꢀCˆO), 1633 ꢀCˆN), 1612 ꢀN±H bending), 1601 ꢀCˆC arom.) cmÀ1; 1H NMR ꢀDMSO-d6, ꢂ,
500.13 MHz): 7.55±7.29 ꢀ10H, H arom.), 7.25 ꢀ1H, s, NH), 7.15 ꢀ1H, s, NH), 7.05 ꢀ1H, s, NH) ppm;
13C NMR ꢀDMSO-d6, ꢂ, 125.75 MHz): 186.95, 174.245, 170.21, 164.53, 141.21, 132.92, 129.89,
‡
128.50, 128.38, 127.08, 126.81, 126.60, 97.88 ppm; MS: m=z ꢀ%) ˆ 293 ꢀ10) [M ±NH2], 265 ꢀ78.4)
‡
‡
.
[M ±NH2±CO], 105 ꢀ100) [C6H5CO]
Salt of 4-ꢀphenylhydroxymethylidene)-pyrrolidine-2,3,5-trione
with formamidine ꢀ4a; C18H16N3O4)
To a solution of 0.01 mol of 1a in 50 cm3 EtOH, 0.012 mol of formamidine acetate were added. The
solution was left overnight at room temperature. The precipitate was ®ltered off.
‡
Yield: 65%; m.p.: 205ꢀC; IR ꢀHCBN): ꢁ ˆ 3500±3000 ꢀNH2, NH2 ), 1780, 1710, 1700 ꢀCˆO),
1
1660 ꢀCˆC arom.) cmÀ1; H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 9.04 ꢀ2H, s, ˆNH2 ), 8.71 ꢀ2H, s,
‡
NH2), 7.87 ꢀ1H, s, CH), 7.54 ꢀ2H, d, J ˆ 7 Hz), 7.37±7.45 ꢀ3H, m, H arom.), 7.29±7.35 ꢀ5H, m, H
arom.) ppm; 13C NMR ꢀDMSO-d6, ꢂ, 125.75 MHz): 186.91, 174.27, 170.165, 164.58, 157.18,
141.38, 132.99, 129.74, 128.39, 127.01, 126.75, 126.48, 97.76 ppm; MS: m=z ꢀ%) ˆ 293 ꢀ25)
‡
‡
‡
.
[C17H11NO4] , 265 ꢀ26) [M ±NH2CHˆNH±CO], 105 ꢀ100) [C6H5CO]
2-ꢀHydroxyphenylmethylene)-N4-iminomethyl-3-oxo-N1-phenylsuccinamide ꢀ5a; C18H16N3O4)
A solution of 0.01 mol of 4a in 50 cm3 EtOH was re¯uxed for 30 min and cooled. The precipitate was
®ltered off and crystallized from EtOH.
Yield: 43%; m.p.: 154ꢀC; IR ꢀHCBN): ꢁ ˆ 3280, 3200 ꢀNH), 3070 ꢀC±H arom.), 1750, 1720,
1708 ꢀCˆO), 1600 ꢀCˆC arom.) cmÀ1; 1H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 8.07 ꢀ3H, br s, 2NH,
OH), 7.88 ꢀ1H, s, CH), 7.55 ꢀ2H, d, J ˆ 8 Hz), 738±7.46 ꢀ4H, m, 3H arom., NH), 7.29±7.35 ꢀ5H, m,

254
K. Ostrowska: Synthesis of ꢀ-Aminoenones
H arom.) ppm; 13C NMR ꢀDMSO-d6, ꢂ, 125.75 MHz): 187.03, 174.38, 170.24, 164.57, 157.21,
141.32, 132.96, 129.80, 128.40, 128.29, 127.03, 126.77, 126.53, 97.82 ppm; MS: m=z ꢀ%) ˆ 293 ꢀ10)
‡
‡
‡
.
[M ±NH2CHˆNH], 265 ꢀ26) [M ±NH2CHˆNH±CO], 105 ꢀ100) [C6H5CO]
3,5-Diphenylpyrrolo[3,4-c]pyrazole-4,6ꢀ1H)-dione ꢀ7; C17H11N2O2; [16])
A solution of 0.01 mol of 6 in 10 cm3 dowtherm was heated to 260ꢀC for 1 h and cooled. The
pyrrolo[3,4-c]pyrazole was precipitated with petroleum, ®ltered off, and crystallized from EtOH.
Yield: 43%; m.p.: 259±261ꢀC; 1H NMR ꢀDMSO-d6, ꢂ, 500.13 MHz): 14.79 ꢀ1H, br s, NH), 8.19
ꢀ2H, d, J ˆ 8.6 Hz), 7.59 ꢀ2H, t, J ˆ 7.2 Hz), 7.55±7.51 ꢀ3H, m, 3H arom.), 7.45±7.42 ꢀ3H, m, H
arom.) ppm; 13C NMR ꢀDMSO-d6, ꢂ, 125.75 MHz): 161.44, 161.15, 152.20, 141.05, 132.22, 130.59,
129.27, 128.68, 127.90, 127.62, 126.62, 126.25, 114.56.
5,7-Diphenylpyrrolo[3,4-e][1,4]diazepine-6,8ꢀ4H,8H)-dione ꢀ10; C19H15N3O2; [17])
To a solution of 0.01 mol of 2a or 9 in 50 cm3 EtOH, 0.012 mol of ethylenediamine were added. The
solution was re¯uxed for 2 h and cooled. The precipitate was ®ltered and crystallized from DMF=
H2O. Yields: 72, 39%.
Acknowledgements
I thank Dr. A. Kolasa for useful discussions and help with the preparation of the manuscript.
References
[1] Ingersoll AW, Brown JH, Kim CK, Beauchamp WD, Jennings G ꢀ1936) J Amer Chem Soc 58:
1808
[2] Burger A, Ullyot GE ꢀ1947) J Org Chem 12: 342
[3] Christiansen RG, Brown RR, HayAS, Nickon A, Sandin RB ꢀ1955) J Amer Chem Soc 77: 948
[4] Meglio P, Ravenna F, Carenini G, Gentili P, Mazardo S ꢀ1982) Farmaco Ed Sci 12: 836
[5] BallyI, Ciornei E, Vasilescu A, Balaban AT ꢀ1973) Tetrahedron 29: 3185
[6] Bredeck H, Gompper R, Morlock G ꢀ1957) Chem Ber 90: 942
[7] Ridi M, Checchi S, ꢀ1953) Gazz Chim Ital 83: 36
[8] Logemann W, Almirante L, Caprio L ꢀ1955) Chem Ber 88: 1353
[9] Sugimoto N ꢀ1944) Yakugaku Zasshi 64: 192
[10] Bredeck H, Gompper R, Morlock G ꢀ1956) Angew Chem 68: 151
[11] Phillips IG, Steel PJ ꢀ1988) Aust J Chem 51: 371
_
ꢀ
[12] Zankowska-Jasinska W, Zaleska B, Walocha K ꢀ1973) Zesz Nauk Uniw Jagiellonskiego 18: 137
_
[13] Zankowska-Jasinska W, Zaleska B, Walocha K ꢀ1976) Zesz Nauk Uniw Jagiellonskiego 21: 133
ꢀ
[14] Ostrowska K, Ciechanowicz-Rutkowska M, Pilati T, Zuchowski G ꢀ1999) Monatsh Chem 130:
555
_
_
ꢀ
[15] Zankowska-Jasinska W, Ostrowska K ꢀ1991) J Prakt Chemie 333: 619
[16] Arakawa K, Miyasaka T, Hammamichi N ꢀ1977) Yakugaku Zasshi 97: 410
_
[17] Zankowska-Jasinska W, Borowiec H, Kolasa A, Zaleska B ꢀ1985) Pol J Chem 59: 169
ꢀ
Received July 16,2001. Accepted ꢀrevised) September 17,2001