Studies on the reactivity of α-cyano-α-isocyanoalkanoates - Versatile synthons for the assembly of imidazoles

Article abstract of DOI:10.1002/(SICI)1522-2675(19990609)82:6<909::AID-HLCA909>3.0.CO;2-T

The reactivity and the synthetic potential of α-cyano-α- isocyanoalkanoates 2 were investigated. Interestingly, reaction of 2 with alkoxides gave (alkoxy)(alkyl)imidazoles 5, whereas the analogous thiolates led to different products, namely substituted 4H-imidazoles 7, together with compounds 6, which formed by addition of thiolate to the isocyano group. Primary amines reacted, on one hand, in the same manner as thiolates to form of 4H-imidazoles 10, and, on the other hand, cleavage of the molecule to the proposed unstable aminoimidazole 8 and the carbamate 9 was observed. Secondary amines add selectively to the isocyano group to form compounds 11. Like simple isocyanides, α-cyano-α-isocyanoalkanoates 2 can be subjected to [4+1] cycloadditions and multicomponent reactions of the Passerini type. Mechanisms for the described reactions are discussed.

Full text of DOI:10.1002/(SICI)1522-2675(19990609)82:6<909::AID-HLCA909>3.0.CO;2-T

Helvetica Chimica Acta ± Vol. 82 (1999)
909
Studies on the Reactivity of a-Cyano-a-isocyanoalkanoates ±
Versatile Synthons for the Assembly of Imidazoles
by Marco Bergemann and Richard Neidlein*
Pharmazeutisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 364, D-69120 Heidelberg
Dedicated to Professor Dr. Werner Schroth, Halle/Saale, on the occasion of his 70th birthday
The reactivity and the synthetic potential of a-cyano-a-isocyanoalkanoates
2 were investigated.
Interestingly, reaction of 2 with alkoxides gave (alkoxy)(alkyl)imidazoles 5, whereas the analogous thiolates
led to different products, namely substituted 4H-imidazoles 7, together with compounds 6, which formed by
addition of thiolate to the isocyano group. Primary amines reacted, on one hand, in the same manner as thiolates
to form of 4H-imidazoles 10, and, on the other hand, cleavage of the molecule to the proposed unstable
aminoimidazole 8 and the carbamate 9 was observed. Secondary amines add selectively to the isocyano group to
form compounds 11. Like simple isocyanides, a-cyano-a-isocyanoalkanoates 2 can be subjected to [4 ‡ 1]
cycloadditions and multicomponent reactions of the Passerini type. Mechanisms for the described reactions are
discussed.
Introduction. ± In previous publications, we reported on the synthesis of a-cyano-a-
isocyanoalkanoates 2 [1] (Scheme 1) and their application to the preparation of 5,5-
disubstituted 2,4-dithiohydantoins [2].
Scheme 1
To further explore the reactivity of compounds of type 2 and their application to the
synthesis of heterocycles, we chose to investigate the reaction of 2 with various
nucleophiles. Since a-cyano-a-isocyanoalkanoates 2 contain numerous functional
groups, they should be suitable precursors for the assembly of more complex systems,
especially for substituted five-membered azacycles like imidazoles.
Results and Discussion. ± Schöllkopf and Handke reported on the reaction of
(cyano)(isocyano)alkanes with alkoxides yielding (alkoxy)(alkyl)imidazoles of type 5

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[3] (Scheme 2). a-Cyano-a-isocyanoalkanoates 2, containing no a-H-atom, should give
alkoxy-substituted 4H-imidazoles under analogous conditions. However, on reaction of
2 with alkoxides, compounds 5 were obtained (Scheme 2).
Scheme 2
The formation of 5 can be explained by nucleophilic attack of the alkoxide ion at
the CˆO group followed by cleavage of the C C bond between the C(a)-atom and the
ester-carbonyl C-atom under formation of alkyl carbonate 4 and (cyano)(isocyano)al-
kanes 3 as intermediates. The latter reacted to give the isolated product 5, similar to the
work published by Schöllkopf and Handke [3]. The by-product 4 could be isolated and
characterized spectroscopically. The spectroscopic data of 5a are identical to those
published in [3]; products 5b ± d could be unambiguously identified by their spectral
data.
To determine whether other nucleophiles also cleave the C C bond, 2 was reacted
with thiolates, as well as with primary and secondary amines. In contrast to alkoxides,
ethylthiolate ± generated from EtSH and Et3N ± reacted with 2 in CH2Cl2 to form 6 and
7 (Scheme 3).
Scheme 3
4H-Imidazole 7 is the product of a nucleophilic attack of thiolate ion on the CN
group and subsequent ring closure with the isocyano C-atom. This mechanism seems
plausible and is supported by the molecular structure of 7, which was determined by
standard spectroscopic methods and by a selective INEPT-NMR experiment.

Helvetica Chimica Acta ± Vol. 82 (1999)
911
As already observed by Schöllkopf and Handke [3] and Saegusa et al. [4][5],
thiolates add to the isocyano C-atom, leading to thioimino esters 6, which, in the
present case, could also be isolated and characterized as by-products. As opposed to
alkoxides, thiolates attack parallel to the isocyanido and the CN C-atom. They do not
cleave the C C bond as observed with alkoxides.
When 2 was reacted with amines, a wide range of products was obtained, depending
on the nature of the amine. Secondary amines furnished the addition products 11 which
were formed by selective attack on the isocyano group (Scheme 4) [6][7]. Primary
amines, however, showed a completely different behavior. On the one hand, the CN
group was attacked by the same mechanism observed with the thiolates, leading to
substituted 4H-imidazoles 10, the molecular structures of which could be determined
spectroscopically and by selective INEPT-NMR experiments. On the other hand, the
amines cleaved the C C bond as observed with alkoxides. The resulting carbamate 9
could be isolated and clearly identified, whereas the corresponding aminoimidazole 8,
proposed as the second product, decomposed spontaneously. When 2c was subjected to
the same conditions, exclusively the corresponding cleavage product 9 was formed,
supposedly because of steric constraints. The spectroscopic data of 4H-imidazoles 10
are generally similar to those of 4H-imidazoles 7.
Scheme 4
There are two possible pathways for the formation of products 8 and 9. One is
cleavage of the C C bond by the amine in the a-cyano-a-isocyanoalkanoate 2 or in the
4H-imidazole 10. Both mechanisms lead to the same reaction products.
To verify the proposed mechanism, we tried to react 4H-imidazole 10b in the
presence of the amine. After stirring for 48 h at room temperature, no reaction was
observed, providing evidence that compound 10 is not an intermediate in the formation
of 8 and 9 (Scheme 4).
It is known that isocyanides undergo [4 ‡ 1] cycloadditions with aromatic acyl
isocyanates [13 ± 17]. Therefore, we treated 2 with various aromatic acyl isocyanates in
Et2O at low temperature. The expected cycloaddition products 12 are unstable, and
only their hydrolysis products 13 could be isolated (Scheme 5).

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 5
The characterization of 13 may serve as a proof for the intermediate formation of
12. 1H{13C}-NOE, 1H{1H}-NOE, and selective decoupling experiments served to
establish the structure of 13 and allowed complete assignment of the signals in the
NMR spectra.
The high tendency of isocyanides to undergo cycloaddition and multicomponent
reactions ± like the Passerini [8 ± 10] and the Ugi-4CC reactions [11][12] ± is
documented in the literature1). We decided to investigate whether a-cyano-a-
isocyanoalkanoates 2 would react in this way like simple isocyanides.
Application of these reactions to a-cyano-a-isocyanoalkanoates 2 should be of
particular interest because of the large variety of substituents on 2, leading to novel
compounds with potential applications in drug research. To evaluate the potential of 2
for such reactions, Cl3CCOOH and isobutanal were chosen as other components
because of their high reactivity. These two components were allowed to react with
various derivatives of 2. Because an additional chiral center was formed during the
Passerini reaction with the asymmetric a-cyano-a-isocyanoalkanoates 2, the formation
of a mixture of both diastereoisomers 14/15 was observed (Scheme 6).
Scheme 6
The NMR spectra of the crude products proved the presence of two stereoisomers.
Fortunately, the diastereoisomeric compounds could be separated by fractional
crystallization from Et2O. No efforts have been made to determine the absolute
configurations of the separated isomers.
1
)
The Passerini reaction and the Ugi-4CC reaction can be used to synthesize depsipeptides and tripeptides in
a one-pot reaction.

Helvetica Chimica Acta ± Vol. 82 (1999)
913
Conclusion. ± The synthetic potential of a-cyano-a-isocyanoalkanoates 2 was
explored by reacting them with various nucleophiles, by cycloaddition, and by using
them in multicomponent reactions. Different nucleophiles showed different reactiv-
ities, and plausible mechanisms are proposed. The a-cyano-a-isocyanoalkanoates 2
proved to be a versatile class of compounds, and further work in this direction is in
progress.
We thank BASF AG, Bayer AG, and Hoechst AG, the Fonds der Chemischen Industrie, as well as the
Deutsche Forschungsgemeinschaft for support of this work. Thanks go to Hewlett-Packard for providing UV/VIS
spectrometers. We would also like to thank Dr. W. Kramer and Ms. U. Hertle for NMR spectra, Mr. H. Rudy and
Mr. P. Weyrich for elemental analysis and mass spectra. Dr. R. Faust is warmly thanked for many helpful
discussions and Dr. M. Winter for help with the manuscript.
Experimental Part
General. All reactions were carried out under Ar in flame-dried glassware. CH2Cl2 was freshly distilled
from CaH2; Et2O, THF, and benzene were distilled from Na/benzophenone before use. Column chromatog-
raphy (CC): silica gel (60 ± 200 mesh) from ICN-Biomedicals. M.p.: Reichert melting-point microscope;
uncorrected. UV/VIS Spectra: MeCN solns.; Hewlett Packard HP 8453 UV/VIS ChemStation and Hewlett
Packard HP8452A diode array spectrophotometer: l in nm (log e). IR Spectra: KBr pellets or films; Perkin-
1
Elmer PE 1600 FT-IR spectrophotometer, nÄ in cm
.
1H-NMR Spectra: at 250.13 MHz on Bruker WM-250
spectrometer; at 360.12 Hz on Bruker AM-360 spectrometer, and at 299.95 MHz on Varian XL 300
spectrometer; d in ppm rel. to TMS, J in Hz. 13C-NMR Spectra: at 62.89, 90.56, and 75.43 MHz on the same
spectrometers (the degree of substitution was determined by J-modulated spin-echo experiments). MS: Varian
MAT-311 A spectrometer at 70 eV; m/z (rel. %). Elemental analyses: Foss-Heraeus Vario EL; all compounds
gave satisfactory analyses (C, H, S Æ 0.3%).
Ethyl 2-Cyano-2-formamido-3-phenylpropanoate (1d). Compound 1d was obtained from a soln. of Na
(0.25 g, 10.86 mmol) in EtOH (10 ml), tert-butyl 2-cyano-2-formamidoacetate (1.7 g, 10.86 mmol) in EtOH
(3 ml), and PhCH2I (2.84 g, 13 mmol) in EtOH (8 ml) as described in [1]. Recrystallization from EtOH: 4.8 g
(73%) of 1d. Colorless crystals. M.p. 83 ± 858 (EtOH). (KBr): 3311s (NH), 2988m, 2936m, 2244w (CN), 1747s
1
(CO), 1690s (CHO), 1670s (CHO), 1506s, 1385m, 1267s, 1082m, 1047m, 773m, 708s. H-NMR (CDCl3): 1.23
(t, 3J ˆ 7.2, MeCH2); 3.40 (d, 2J ˆ 13.4, 1 H, PhCH2); 3.55 (d, 2J ˆ 13.4, 1 H, PhCH2); 4.22 (q, 3J ˆ 7.2, MeCH2);
7.04 (s, NH); 7.22 ± 7.36 (m, 5 arom. H); 8.19 (s, CHO). 13C-NMR (CDCl3): 13.7 (MeCH2); 41.5 (PhCH2); 56.7
(CCO); 63.9 (MeCH2); 115.6 (CN); 128.4, 128.7, 129.9, 131.2 (arom. C); 160.5 (CHO); 165.0 (CO). FAB-MS
‡
‡
(NBA matrix): 247 (90, [M ‡ H] ); 91 (100, [C7H7] ).
Ethyl 2-Cyano-2-isocyano-3-phenylpropanoate (2d). To a soln. of 1d (0.615 g, 2.5 mmol) in CH2Cl2 (7.5 ml)
were added, under stirring at 788, Et3N (1.75 ml) at once and trichloromethyl chloroformate (diphosgene;
0.3 g, 0.183 ml) dropwise during 10 min. The soln. turned slightly brown, and a white precipitate was formed.
After stirring for 15 min. at 788, the mixture was allowed to warm to r.t., and H2O (25 ml) was added. The org.
layer was separated, washed with H2O, and dried with Na2SO4. The resulting soln. was filtered over silica (15 Â
1 cm), and the pure product 2d was obtained as a soln. in CH2Cl2. Compound 2d can be stored at 258 for a few
months. Yield: 342 mg (60%). Rf (hexane/AcOEt 3 : 1) 0.49. IR (film): 3066m, 3035m, 2986m, 2940w, 2256w
(CN), 2140s (NC), 1766s (CO), 1456m, 1370m, 1265s, 1094m, 852m, 738s, 701m. 1H-NMR (CH2Cl2): 1.30
(t, 3J ˆ 7.5, MeCH2); 3.49 (s, PhCH2); 4.32 (q, 3J ˆ 7.5, MeCH2); 7.30 ± 7.45 (m, 5 arom. H). 13C-NMR (CH2Cl2):
13.5 (MeCH2); 44.8 (PhCH2); 53.8 (CH2Cl2); 65.6 (MeCH2); 112.4 (CN); 128.9; 129.1; 130.3; 130.4 (arom. C);
‡
‡
161.0 (NC); 166.5 (CO). FAB-MS (NBA matrix) 229 (4, [M ‡ H] ), 91 (100, [C7H7] ). FAB-MS (LiCl
‡
matrix): 235 (25, [M ‡ Li] ). HR-MS (C13H12N2O2): 228.0899 (calc. 228.0899).
4-Alkoxy-5-alkylimidazoles 5. General Procedure. a-Cyano-a-isocyanoalkanoates 2a ± d (1 mmol) were
dissolved in 6 ml of the corresponding alcohol, and anh. K2CO3 (21 mg, 1.5 mmol) was added at r.t. under
stirring. After additional stirring for 6 h, the mixture turned pale-yellow. The residue was filtered off, washed
with alcohol, and the resulting alcoholic soln. was evaporated. Recrystallization of the remaining solid from
cyclohexane yielded the pure products as fine colorless needles.
4-Ethoxy-5-methylimidazole (5a). tert-Butyl 2-cyano-2-isocyanopropanoate (2a; 180 mg, 1 mmol) in EtOH
yielded 102 mg (80%) of 5a. M.p. 92 ± 938 (C6H12) ([3]: 938).

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4-Ethoxy-5-ethylimidazole (5b): From tert-butyl 2-cyano-2-isocyanobutanoate (2b; 194 mg, 1 mmol) in
EtOH: 111 mg (79%) of 5b. M.p. 97 ± 998 (C6H12). IR (KBr): 3123m, 3038m, 2972s, 2934s, 2835m, 2676m, 1616s,
1472m, 1384m, 1306m, 1138m, 1050s, 972m. 1H-NMR (CDCl3): 1.18 (t, 3J ˆ 7.7, MeCH2); 1.31 (t, 3J ˆ 7.1,
MeCH2O); 2.57 (q, 3J ˆ 7.7, MeCH2); 4.16 (q, 3J ˆ 7.1, MeCH2O); 7.17 (s, H C(2)); 9.05 (s, NH). 13C-NMR
(CDCl3): 13.8 (MeCH2); 15.1 (MeCH2O); 16.5 (MeCH2); 66.9 (MeCH2O); 113.1 (C(5)); 127.8 (C(2)); 149.7
‡
‡
‡
(C(4)). EI-MS (618): 140 (43, M ), 112 (20, [M C2H4] ), 97 (100 [M C2H4Me] ). HR-MS (C7H12N2O):
140.0949 (calc. 140.0950).
5-Benzyl-4-ethoxyimidazole (5c). Procedure A: Compound 2d (228 mg, 1 mmol) in EtOH yielded 150 mg
(74%) of 5c. M.p. 121 ± 1238 (AcOEt; subl. at 1058). Procedure B: From tert-butyl 2-cyano-2-isocyano-3-
phenylpropanoate (2c, 256 mg, 1 mmol) in EtOH gave 154 mg (76%) of 5c. M.p. 121 ± 1238 (AcOEt; subl. at
1058). IR (KBr): 3110m, 3030s, 2977s, 2883s, 2832s, 2733m, 2640m, 1615s, 1473s, 1375m, 1243m, 1101s, 1039s,
960m, 722s. 1H-NMR (CDCl3): 1.29 (t, 3J ˆ 7.1, MeCH2O); 3.87 (s, PhCH2); 4.15 (q, 3J ˆ 7.1, MeCH2O); 6.99
(s, H C(2)); 7.13 ± 7.25 (m, 5 arom. H); 9.95 (s, NH). 13C-NMR (CDCl3): 15.2 (MeCH2O); 29.2 (PhCH2); 66.3
(MeCH2O); 109.1 (C(5)); 126.4, 128.4, 139.3 (arom. C); 128.6 (arom. C, C(2)); 151.1 (C(4)). EI-MS (1048): 202
‡
‡
‡
(100, M ), 174 (34, M C2H4] ), 91 (46, [C7H7] ). HR-MS (C12H14N2O): 202.1106 (calc. 202.1106).
5-Ethyl-4-methoxyimidazole (5d): tert-Butyl 2-cyano-2-isocyanobutanoate (2b; 194 mg, 1 mmol) in MeOH
yielded 101 mg (80%) of 5d. M.p. 98 ± 1008 (C6H12). IR (KBr): 3123m, 3026m, 2970s, 2934s, 2833s, 2677m, 1617s,
1499m, 1473s, 1382m, 1369m, 1300m, 1132m, 1044m, 1014m. H-NMR (CDCl3): 1.19 (t, 3J ˆ 7.6, MeCH2); 2.58
1
(q, 3J ˆ 7.6, MeCH2); 3.87 (s, MeO); 7.18 (s, H C(2)); 8.45 (s, NH). 13C-NMR (CDCl3): 13.9 (MeCH2); 16.6
‡
(MeCH2); 58.2 (MeO); 112.2 (C(5)); 127.7 (C(2)); 150.8 (C(4)). EI-MS (498): 126 (55, M ), 111 (100, [M
‡
Me] ). HR-MS (C6H10N2O): 126.0793 (calc. 126.0793).
Alkyl 4-Alkyl-5-(alkylthio)-4H-imidazole-4-carboxylates 7 and a-Cyano-a-{[(alkylthio)methylidene]imino}-
alkanoates 6. General Procedure. a-Cyano-a-isocyanoalkanoate 2 (1 mmol) was dissolved in CH2Cl2 (15 ml),
and the soln. was cooled to 08. Then, EtSH (69 mg, 0.082 ml, 1.1 mmol) and Et3N (203 mg, 0.28 ml, 2 mmol)
were added under stirring during 10 min. The mixture was allowed to warm to r.t., stirred for additional 72 h,
and adsorbed on silica (3 g). CC (silica gel; 20 Â 3 cm) of the crude products first with CH2Cl2 gave 6 as pure
yellow oil after evaporation of the solvent. Further elution with Et2O yielded the crude product 7 as colorless oil.
Purification of 7 was accomplished by CC (silica gel; 20 Â 3 cm, Et2O).
tert-Butyl 5-(Ethylthio)-4-methyl-4H-imidazole-4-carboxylate (7a) and tert-Butyl 2-cyano-2-{[(ethylthio)-
methyliden]amino}propanoate (6a). Compound 2a (180 mg, 1 mmol) yielded 6a (pale yellow oil; 60 mg (24%);
Rf (CH2Cl2) 0.60) and 7a (colorless oil; 121 mg; (50%); Rf (Et2O) 0.55).
Data of 7a: IR (film): 3061w, 2979m, 2934m, 2875w, 1738s (CO), 1567m, 1466s, 1370s, 1257s, 1253m, 1129s,
1065m, 1036s, 914w, 843m. 1H-NMR (CDCl3): 1.41 (t, 3J ˆ 8.8, MeCH2S); 1.42 (s, t-Bu); 1.53 (s, Me); 1.67
(m, 3J ˆ 8.8, MeCH2S); 8.00 (s, H C(2)). 13C-NMR (CDCl3): 13.9 (MeCH2S); 21.6 (Me); 26.9 (MeCH2S); 27.7
‡
(Me3C); 82.9 (Me3C); 88.6 (C(4)); 165.1 (C(2)); 165.6 (CO); 199.9 (C(5)). EI-MS (558): 242 (0.2, M ), 227 (2,
‡
‡
‡
[M CH3] ), 141 (10, [M CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C11H18N2O2S): 242.1089 (calc. 242.1089).
Data of 6a: IR (film): 2980s, 2933m, 2872m, 2250m (CN), 1741s (CO), 1592s, 1458m, 1370m, 1258s, 1157s,
1128s, 1123s, 840s. H-NMR (CDCl3): 1.32 (t, 3J ˆ 7.1, MeCH2S); 1.49 (s, t-Bu); 1.75 (s, Me); 2.99 (m, 3J ˆ 7.1,
1
MeCH2S); 8.12 (s, H C(2)). 13C-NMR (CDCl3): 15.3 (MeCH2S); 23.5 (MeCH2S); 25.3 (Me); 27.7 (Me3C);
‡
66.8 (C(2)); 83.9 (Me3C); 117.2 (CN); 162.1 (CH); 164.8 (CO). EI-MS (578): 242 (0.1, M ), 227 (3, [M
Me] ), 142 (23, [M CO2C4H8] ), 141 (21, [M CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C11H18N2O2S):
242.1089 (calc. 242.1089).
‡
‡
‡
‡
tert-Butyl 4-Ethyl-5-ethylthio-4H-imidazole-4-carboxylate (7b) and tert-Butyl 2-cyano-2-{[(ethylthio)-
methylidene]amino}butanoate (6b). Compound 2b (194 mg, 1 mmol) yielded 6b (pale-yellow oil; 54 mg
(21%); Rf (CH2Cl2) 0.61) and 7b (colorless oil; 159 mg (62%); Rf (Et2O) 0.56).
Data of 7b: IR (film): 3063w, 2977s, 2934m, 2879w, 1738s (CO), 1567m, 1468s, 1458s, 1370m, 1255s, 1153s,
1
1066m, 1039m, 970w, 842m. H-NMR (CDCl3): 0.68 (t, 3J ˆ 7.3, MeCH2); 1.40 (t, 3J ˆ 7.4, MeCH2S); 1.49 (s, t-
Bu); 1.82 (m, 3J ˆ 7.4, 1 H, MeCH2); 2.35 (m, 3J ˆ 7.4, 1 H, MeCH2); 3.21 (q, 3J ˆ 7.4, MeCH2S); 8.04
(s, H C(2)). 13C-NMR (CDCl3): 7.5 (MeCH2); 13.8 (MeCH2S); 26.9 (MeCH2S); 27.8 (Me3C); 29.4 (MeCH2);
‡
82.6 (Me3C); 92.2 (C(4)); 165.0 (C(2)); 165.5 (CO); 197.9 (C(5)). EI-MS (678): 256 (0.3, M ), 241 (3, [M
‡
‡
‡
‡
Me] ), 156 (16, [M CO2C4H8] ), 155 (13, [M CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C12H20N2O2S):
256.1245 (calc. 256.1246).
Data of 6b: IR (film): 2979m, 2935m, 2882w, 2247w (CN), 1742s (CO), 1589m, 1459w, 1371m, 1255m,
1156m, 840m. 1H-NMR (CDCl3): 1.00 (t, 3J ˆ 7.4, MeCH2); 1.33 (t, 3J ˆ 7.1, MeCH2S); 1.50 (s, t-Bu); 2.13
(m, 3J ˆ 7.4, MeCH2); 3.01 (m, 3J ˆ 7.1, MeCH2S); 8.60 (s, CH). 13C-NMR (CDCl3): 8.5 (MeCH2); 11.12
(MeCH2S); 23.6 (MeCH2S); 27.8 (Me3C); 31.6 (MeCH2); 63.3 (C(2)); 84.3 (Me3C); 116.1 (CN); 162.0 (CH);

Helvetica Chimica Acta ± Vol. 82 (1999)
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‡
‡
‡
165.1 (CO). EI-MS (578): 256 (0.1, M ), 241 (2, [M Me] ), 156 (23, [M CO2C4H8] ), 155 (21, [M
‡
‡
CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C12H20N2O2S): 256.1245 (calc. 256.1246).
tert-Butyl 4-Benzyl-5-(ethylthio)-4H-imidazole-4-carboxylate (7c) and tert-Butyl 2-cyano-a-{[(ethylthio)-
methylidene]amino}-3-phenylpropanoate (6c). Compound 2c (256 mg, 1 mmol) yielded 6c (pale-yellow oil;
80 mg (25%); Rf (CH2Cl2) 0.72) and 7c (colorless oil; 162 mg (51%); Rf (Et2O) 0.50).
Data of 7c: IR (film): 3087w, 3062w, 3032w, 2979m, 2932m, 2879w, 1738s (CO), 1567m, 1467s, 1370m, 1256s,
1257s, 1066m, 989w, 840m, 701m. 1H-NMR (CDCl3): 1.35 (t, 3J ˆ 7.3, MeCH2S); 1.42 (s, t-Bu); 3.10 ± 3.20 (d, 2J ˆ
13.5, 1 H, PhCH2; m, 3J ˆ 7.3, MeCH2S); 3.63 (d, 2J ˆ 13.5, 1 H, PhCH2); 7.16 ± 7.2 (m, 5 arom. H); 7.83
(s, H C(2)). 13C-NMR (CDCl3): 13.8 (MeCH2S); 27.0 (MeCH2S); 27.7 (Me3C); 42.1 (PhCH2); 83.4 (Me3C);
92.3 (C(4)); 127.2; 127.7, 130.4, 134.0 (arom. C); 165.1 (C(2)); 165.2 (CO); 197.6 (C(5)). EI-MS (1018): 318
‡
‡
‡
‡
‡
(0.4, M ), 227 (5, [M C7H7] ), 217 (10, [M CO2C4H9] ), 91 (100, [C7H7] ), 57 (76, [C4H9] ). HR-MS
(C17H22N2O2S): 318.1404 (calc. 318.1402).
Data of 6c: IR (film): 3062w, 3031w, 2976m, 2930m, 2238w (CN), 1743s (CO), 1580m, 1455m, 1371m,
1155m, 1032m, 841m. 1H-NMR (CDCl3): 1.32 (t, 3J ˆ 7.1, MeCH2S); 1.50 (s, Me3C); 2.90 ± 3.20 (m, MeCH2);
3.39 (d, 2J ˆ 13.5, 1 H, PhCH2); 3.69 (d, 2J ˆ 13.5, 1 H, PhCH2); 7.20 ± 7.40 (m, 5 arom. H); 8.25 (s, CH).
13C-NMR (CDCl3): 13.8 (MeCH2S); 27.0 (MeCH2S); 27.9 (Me3C); 35.8 (PhCH2); 67.4 (C(2)); 84.3 (Me3C);
‡
116.6 (CN); 127.7, 128.9, 130.2, 135.5 (arom. C); 159.8 (CH); 165.2 (CO). EI-MS (1058): 318 (0.1, M ), 91 (87,
‡
‡
[C7H7] ), 57 (100, [C4H9] ). HR-MS (C17H22N2O2S): 318.1404 (calc. 318.1403).
Alkyl 4-alkyl-5-(alkylamino)-4H-imidazole-4-carboxylate 10a ± c. General Procedure. A soln. of a-cyano-a-
isocyanoalkanoate (2, 1 mmol) in CH2Cl2 (10 ml) was cooled to 08, followed by dropwise addition of dry PrNH2
(590 mg, 0.82 ml, 10 mmol) under stirring. The mixture was allowed to warm to r.t. and stirred for 120 h. After
evaporation of the solvent, the remaining yellow oil was diluted with Et2O (3 ml). Crystals of 10 formed, which
were separated and recrystallized from cyclohexane. Evaporation of the mother liquor and CC (silica gel, 10 Â
1 cm, Et2O) of the residue led to the pure by-product 9.
tert-Butyl 4-Methyl-5-(propylamino)-4H-imidazole-4-carboxylate (10a). Compound 2a (180 mg, 1 mmol)
yielded 10a (colorless crystals; 103 mg (43%); m.p. 156 ± 1588 (C6H12)) and tert-butyl N-propylcarbamate (9;
colorless oil; 59 mg (37%)).
Data of 10a: IR (KBr): 3432m (NH), 3256s (NH), 2982m, 2935m, 2878w, 1730s (CO), 1623s, 1499s, 1368s,
1278m, 1251m, 1157s, 1124s, 934w, 841m, 606w. 1H-NMR (CDCl3): 0.98 (t, 3J ˆ 7.4, MeCH2CH2); 1.47 (s, t-Bu);
1.54 (s, Me); 1.67 (q, 3J ˆ 7.4, MeCH2CH2); 3.43 (q, 3J ˆ 4.1, MeCH2CH2); 6.29 (s, NH); 7.72 (s, H C(2)).
13C-NMR (CDCl3): 11.0 (MeCH2CH2); 22.3 (MeCH2CH2); 24.3 (Me); 27.7 (Me3C); 45.5 (MeCH2CH2); 79.2
‡
(C(4)); 83.1 (Me3C); 166.9 (C(2)); 169.3 (CO); 184.1 (C(5)). EI-MS (208): 239 (6, M ), 180 (6, [M
‡
‡
‡
‡
NHC3H7] ), 139 (22, [M CO2C4H9] ), 110 (33, [M CO2C4H9 C2H4] ), 57 (100, [C4H9] ). HR-MS (C12
H21N3O2): 239.1634 (calc. 239.1634).
tert-Butyl 4-Ethyl-5-(propylamino)-4H-imidazole-4-carboxylate (10b). Compound 2b (194 mg, 1 mmol)
yielded 10b (colorless crystals; 57 mg (22%); m.p. 155 ± 1568 (C6H12)) and 9 (colorless oil; 56 mg (35%)).
Data of 10b: IR (KBr): 3433m (NH), 3246s (NH), 2971s, 2935m, 2877m, 1729s (CO), 1617s, 1502m, 1437w,
1
1371w, 1322w, 1258m, 1155s, 1101m, 992w, 840w. H-NMR (CDCl3): 0.81 (t, 3J ˆ 7.3, MeCH2); 0.97 (t, 3J ˆ 7.5,
MeCH2CH2NH); 1.48 (s, t-Bu); 1.61 ± 1.82 (m, 1 H of MeCH2 and MeCH2CH2NH); 2.09 ± 2.29 (m, 1 H,
MeCH2); 3.42 (q, 3J ˆ 6.3, MeCH2CH2NH); 6.15 (s, NH); 7.77 (s, H C(2)). 13C-NMR (CDCl3): 7.7 (MeCH2);
11.0 (MeCH2CH2NH); 22.3 (MeCH2CH2NH); 27.8 (Me3C); 32.0 (MeCH2); 45.4 (MeCH2CH2NH); 78.4
‡
(C(4)); 83.2 (Me3C); 167.0 (C(2)); 169.5 (CO); 182.5 (C(5)). EI-MS (208): 253 (4, M ), 194 (3, [M
‡
‡
‡
‡
NHC3H7] ), 153 (14, [M CO2C4H9] ), 124 (13, [M CO2C4H9 C2H4] ), 57 (100, [C4H9] ). HR-MS (C13
H23N3O2): 253.1791 (calc. 253.1790).
tert-Butyl 4-Benzyl-5-(propylamino)-4H-imidazole-4-carboxylate (10c). Compound 2c (256 mg, 1 mmol)
yielded 9 (94 mg, 59%) as only product. Colorless oil. a-Cyano-a-{[(dialkylamino)methylidene]amino}alkanoic
acid esters 11a ± d ± General Procedure: a-Cyano-a-isocyanoalkanoic acid ester (2, 2 mmol) was dissolved in
15 ml of the cooled (08) corresponding secondary amine. After stirring for 1 h at 08 and for 20 h at r.t., the amine
was removed in vacuo. The crude products remained as pale yellow oils. CC (silica 10 Â 3 cm, diethyl ether) gave
the pure compounds 11 as colorless oils after evaporation of the solvent.
tert-Butyl 2-Cyano-2-{[(diethylamino)methylidene]amino}propanoate (11a): Compound 2a (360 mg,
2 mmol) and Et2NH yielded 455 mg (90%) of 11a. Colorless oil. Rf (Et2O) 0.75. IR (film): 2978s, 2937m,
2875m, 2228w (CN), 1744s (CO), 1636s, 1457m, 1370m, 1270s, 1221m, 1161s, 1121s, 845s. 1H-NMR (CDCl3): 1.14
(t, 3J ˆ 7.1, 2 MeCH2); 1.48 (s, t-Bu); 1.70 (s, 3 H C(3)); 3.28 (m, 3J ˆ 7.1, 2 MeCH2); 7.62 (s, CH). 13C-NMR
(CDCl3): 26.5 (Me); 27.8 (Me3C); 62.6 (C(2)); 83.1 (Me3C); 119.2 (CN); 154.5 (CH); 167.9 (CO). EI-MS

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Helvetica Chimica Acta ± Vol. 82 (1999)
‡
‡
‡
(978): 253 (1.1, M ), 152 (100, [M CO2C4H9] ), 57 (22, [C4H9] ). HR-MS (C13H23N3O2): 253.1791 (calc.
253.1790).
tert-Butyl 2-Cyano-2-{[(diethylamino)methylidene]amino}butanoate (11b). Compound 2b (388 mg,
2 mmol) and Et2NH yielded 422 mg (79%) of 11b. Colorless-to-pale-yellow oil. Rf (Et2O) 0.78. IR (film):
2977m, 2936m, 2880w, 2228w (CN), 1745s (CO), 1636s, 1460m, 1390m, 1370m, 1250m, 1156m, 999w, 968w, 840m.
1H-NMR (CDCl3): 1.00 (t, 3J ˆ 7.4, 3 H C(4)); 1.14 (t, 3J ˆ 7.1, 2 MeCH2); 1.48 (s, t-Bu); 2.06 (m, 3J ˆ 7.4,
2 H C(3)); 3.29 (m, 3J ˆ 7.1, 2 MeCH2); 7.59 (s, CH). 13C-NMR (CDCl3): 8.5 (C(4)); 27.8 (Me3C); 32.3
‡
(C(3)); 68.3 (C(2)); 83.0 (Me3C); 118.2 (CN); 154.4 (CH); 167.1 (CO). EI-MS (748): 267 (1, M ), 166 (100,
‡
‡
[M CO2C4H9] )57 (17, [C4H9] ). HR-MS (C14H25N3O2): 267.1947 (calc. 267.1947).
tert-Butyl 2-Cyano-2-{[(diethylamino)methylidene]amino}-3-phenylpropanoate (11c). Compound 2c
(512 mg, 2 mmol) and Et2NH yielded 546 mg (83%) of 11c. Pale-yellow oil. Rf (Et2O) 0.70. IR (film): 3064w,
3032w, 2976m, 2934m, 2872w, 2238w (CN), 1743s (CO), 1636s, 1455m, 1370m, 1268m, 1155m, 1082m, 1032m,
841m, 701s. 1H-NMR (CDCl3): 1.08 (t, 3J ˆ 7.1, 2 MeCH2); 1.47 (s, t-Bu); 3.1 ± 3.4 (m, PhCH2, 2 MeCH2); 7.19 ±
7.42 (m, 6 arom. H, CH). 13C-NMR (CDCl3): 27.7 (Me3C); 44.5 (PhCH2); 68.5 (C(2)); 83.3 (Me3C); 117.6
‡
(CN); 127.2, 127.9, 131.0, 134.5 (arom. C); 154.4 (CH); 166.7 (CO). EI-MS (1218): 329 (1, M ), 238 (25, [M
‡
‡
‡
‡
C7H7] ), 228 (100, [M CO2C4H9] ), 91 (7, [C7H7] ), 57 (25, [C4H9] ). HR-MS (C19H27N3O2): 329.2102 (calc.
329.2103).
tert-Butyl 2-cyano-2-{[(diisopropylamino)methylidene]amino}butanoate (11d). From 2b (388 mg, 2 mmol)
(i-Pr)2NH, and Cu2O (200 mg) as catalyst. In contrast to the General Procedure, the mixture was stirred for 72 h
and the catalyst was filtered off: 490 mg (83%) of 11d. Colorless-to-pale-yellow oil. Rf (Et2O) 0.75. IR (film):
2976s, 2936m, 2880m, 2202w (CN), 1745s (CO), 1632s, 1461m, 1440m, 1369s, 1294m, 1250m, 1161s, 1132s, 997m,
971m, 843m. 1H-NMR (CDCl3): 1.00 (t, 3J ˆ 7.4, 3 H C(4)); 1.22 (d, 3J ˆ 6.9, 2 Me2CH); 1.47 (s, t-Bu); 2.06
(m, 3J ˆ 7.4, 2 H C(3)); 3.5 ± 4.4 (m, 2 Me2CH); 7.74 (s, CH). 13C-NMR (CDCl3): 8.5 (C(4)); 27.8 (Me3C);
‡
32.0 (C(3)); 68.7 (C(2)); 82.8 (Me3C); 118.3 (CN); 152.5 (CH); 167.2 (CO). EI-MS (208): 295 (6, M ), 194
‡
‡
(100, [M CO2C4H9] ), 57 (24, [C4H9] ). HR-MS (C16H29N3O2): 295.2259 (calc. 295.2260).
Alkyl 2-(2-Arenamido-2-oxoacetamido)-2-cyano-3-phenylpropanoates 13a ± d. General Procedure. A soln.
of a-cyano-a-isocyanoalkanoate 2 in CH2Cl2 (10 ml) was dried for several days over activated molecular sieve
(4 Š) at 258 and evaporated at max. 158. Compound 2 (1 mmol) was dissolved in dry Et2O (4 ml), and a soln.
of the corresponding acyl isocyanate (1 mmol) in dry Et2O (3 ml) was added dropwise during 10 min under
stirring at 08. After stirring for 3 h, H2O-saturated Et2O (5 ml) was added. Stirring for additional 15 min,
evaporation of the solvent in vacuo, and recrystallization of the resulting solids from EtOH gave the pure
compounds 13 as colorless crystals.
Ethyl 2-(2-Benzamido-2-oxoacetamido)-2-cyano-3-phenylpropanoate (13a). Compound 2d (228 mg,
1 mmol) and benzoyl isocyanate (147 mg, 1 mmol) yielded 162 mg (41%) of 13a. M.p. 151 ± 1538 (EtOH). IR
(KBr): 3351s (NH), 3315s (NH), 3170m, 3064m, 2980w, 2254w (CN), 1758s (CO), 1748s (CO), 1696s (CO),
1683s (CO), 1465s, 1172m, 700s, 608m. 1H-NMR (CDCl3): 1.28 (t, 3J ˆ 7.1, MeCH2); 3.53 (d, 2J ˆ 13.6, 1 H,
PhCH2); 3.63 (d, 2J ˆ 13.6, 1 H, PhCH2); 4.30 (m, 3J ˆ 7.1, MeCH2); 7.2 ± 7.9 (m, 10 arom. H); 8.24
(s, PhCONH); 10.34 (s, NH C(2)). 13C-NMR (CDCl3): 13.3 (MeCH2); 41.3 (PhCH2); 57.0 (C(2)); 63.8
(MeCH2); 114.1 (CN); 127.2, 127.3, 128.3, 128.7, 129.3, 130.1, 131.2, 133.2 (arom. C); 155.5 (CONH C(2));
‡
157.6 (PhCONHCO); 163.2 (C(1)); 163.7 (PhCO). EI-MS (1698): 393 (8, M ), 201 (13, [M CO2C4H8
‡
‡
‡
C7H7] ), 105 (100, [Ph CO] ), 91 (100, [C7H7] ). HR-MS (C21H19N3O5): 393.1325 (calc. 393.1325).
Ethyl 2-[2-(4-Chlorobenzamido)-2-oxoacetamido]-2-cyano-3-phenylpropanoate (13b). Compound 2d
(228 mg, 1 mmol) and 4-chlorobenzoyl isocyanate (181 mg, 1 mmol) yielded 231 mg (54%) of 13b. M.p.
158 ± 1608 (EtOH). IR (KBr): 3354s (NH), 3319s (NH), 3090w, 3034w, 2992w, 2254w (CN), 1767s (CO), 1746s
(CO), 1695s (CO), 1681s (CO), 1592m, 1465s, 1257m, 1221m, 1171m, 1094m, 1011m, 703m. 1H-NMR (CDCl3):
1.28 (t, 3J ˆ 7.2, MeCH2); 3.52 (d, 2J ˆ 13.6, 1 H, PhCH2); 3.62 (d, 2J ˆ 13.6, 1 H, PhCH2); 4.30 (m, 3J ˆ 7.2,
MeCH2); 7.2 ± 7.4 (m, 5 arom. H); 7.49 (d, 3J ˆ 8.7, 2 arom. H); 7.85 (d, 3J ˆ 8.7,
2 arom. H); 8.18
(s, NH C(2)); 10.31 (s, 4-ClC6H4CONH). 13C-NMR (CDCl3): 13.8 (MeCH2); 41.7 (PhCH2); 57.4 (C(2));
64.4 (MeCH2); 114.5 (CN); 128.8, 129.1, 129.2, 129.3, 129.7, 130.0, 130.5, 140.3 (arom. C); 155.9
(CONH C(2)); 157.9 (CO CO NH C(2)); 162.8 (C(1)); 164.1 (4-ClC6H4CO). EI-MS (1898): 429 (4,
‡
‡
‡
‡
‡
[M(37Cl)] ), 427 (11, [M(35Cl)] ), 141 (29, [37ClC6H4CO] ), 139 (94, [35ClC6H4CO] ), 91 (100, [C7H7] ). HR-
MS (C21H1835ClN3O5): 427.0935 (calc. 427.0935).
tert-Butyl 2-(2-Benzamido-2-oxoacetamido)-2-cyano-3-phenylpropanoate (13c). Compound 2c (256 mg,
1 mmol) and benzoyl isocyanate (147 mg, 1 mmol), yielded 200 mg (47%) of 13c. M.p. 147 ± 1498 (EtOH). IR
(KBr): 3366s (NH), 3316s (NH), 2984m, 2254w (CN), 1764s (CO), 1748s (CO), 1695s (CO), 1599m, 1464s,
1155s, 702s. 1H-NMR (CDCl3): 1.49 (s, t-Bu); 3.47 (d, 2J ˆ 13.8, 1 H, PhCH2); 3.63 (d, 2J ˆ 13.8, 1 H, PhCH2);

Helvetica Chimica Acta ± Vol. 82 (1999)
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7.21-7.92 (m, 10 arom. H); 8.12 (s, NH C(2)); 10.39 (s, PhCONH). 13C-NMR (CDCl3): 27.6 (Me3C); 41.4
(PhCH2); 57.6 (C(2)); 86.6 (Me3C); 114.9 (CN); 127.7, 128.6, 128.9, 129.9, 130.8, 131.7, 133.6 (arom. C); 156.0
‡
(CO NH C(2)); 157.9 (CO CO NH C(2)); 162.6 (C(1)); 163.6 (PhCO). EI-MS (1558): 421 (1, M ), 365
‡
‡
‡
‡
(9, [M C4H8] ), 321 (8, [M C4H8 CO2] ), 105 (100, [PhCO] ), 91 (100, [C7H7] ). HR-MS (C23H23N3O5):
421.1639 (calc. 421.1638).
tert-Butyl 2-[2-(4-Chlorobenzamido)-2-oxoacetamido]-2-cyano-3-phenylpropanoate (13d). Compound 2c
(256 mg, 1 mmol) and 4-chlorobenzoyl isocyanate (181 mg, 1 mmol) yielded 302 mg (66%) of 13d. M.p. 148 ±
1508 (EtOH). IR (KBr): 3347s (NH), 3324s (NH), 3065w, 2997w, 2988w, 2934w, 2243w (CN), 1770s (CO),
1751s (CO), 1696s (CO), 1592m, 1457s, 1260m, 1158m, 1091m, 1011m, 788m, 703m. 1H-NMR (CDCl3): 1.48 (s, t-
Bu); 3.47 (d, 2J ˆ 13.8, 1 H, PhCH2); 3.62 (d, 2J ˆ 13.8, 1 H, PhCH2); 7.22 ± 7.41 (m, 5 arom. H); 7.50 (d, 3J ˆ 8.7,
2 arom. H); 7.86 (d, 3J ˆ 8.7, 2 arom. H); 8.11 (s, NH C(2)); 10.32 (s, 4-ClC6H4CO NH). 13C-NMR (CDCl3):
27.6 (Me3C); 41.4 (PhCH2); 57.5 (C(2)); 86.8 (Me3C); 114.9 (CN); 128.7, 129.0, 129.2, 129.9, 130.1, 130.8, 140.3
(arom. C); 156.0 (CO NH C(2)); 157.8 (CO CO NH C(2)); 162.6 (C(1)); 162.8 (4-ClC6H4CO). EI-MS
‡
‡
‡
‡
(1528): 457 (1, [M(37Cl)] ), 455 (3, [M(35Cl)] ), 141 (12, [37ClC6H4CO] ), 139 (35, [35ClC6H4CO] ), 91 (26,
‡
[C7H7] ). HR-MS (C23H22ClN3O5): 455.1250 (calc. 455.1248).
tert-Butyl 2-[2-(2-Chloroacetoxy)-3-methylbutanamido]-2-cyanoalkanoates 14/15. General Procedure. To a
soln. of 2 (2 mmol) in AcOEt (3 ml) were added, under stirring at 08, 2-methylpropanal (216 mg, 0.27 ml,
3 mmol) and a soln. of ClCH2COOH (284 mg, 3 mmol) in AcOEt (3 ml). After stirring for 15 min, the mixture
was allowed to warm to r.t. and stirred for another 72 h. AcOEt was removed in vacuo, and CH2Cl2 (15 ml) and
H2O (25 ml) were added. The org. layer was separated, washed twice with H2O (25 ml), and dried (MgSO4).
Evaporation of the solvent gave colorless oils which were dissolved in Et2O (10 ml). After 30 min. in an ice bath,
diastereoisomer 14 crystallized from the Et2O soln. The crystals were separated and washed with a small amount
of Et2O. The mother liquor was evaporated, dissolved in CH2Cl2, and filtered over silica gel (5 Â 1 cm). Removal
of the solvent in vacuo gave the other diastereoisomer 15 as a pale-yellow oil, which crystallized very slowly. The
crystals were washed with pentane, separated, and dried on air.
tert-Butyl 2-[2-(2-chloroacetoxy)-3-methylbutanamido]-2-cyanopropanoate (14a/15a): From 2a (360 mg,
2 mmol): 14a (356 mg (50%); m.p. 113 ± 1158 (Et2O)), and colorless crystals of 15a (121 mg (17%); m.p. 78 ± 808
(Et2O)).
Data of 14a: IR (KBr): 3286s (NH), 2977m, 2936m, 2255w (CN), 1769s (CO), 1750s (CO), 1740s (CO),
1669s (CO), 1534s, 1457m, 1372m, 1291m, 1180m, 1134s, 1022m, 844w. 1H-NMR (CDCl3): 0.99 (d, 3J ˆ 7.0,
Me2CH); 1.53 (s, t-Bu); 1.87 (s, 3 H C(3)); 2.30 ± 2.45 (m, Me2CH); 4.14 (d, 2J ˆ 13.9, 1 H, CH2Cl); 4.21
(d, 2J ˆ 13.9, 1 H, CH2Cl); 5.19 (d, 3J ˆ 3.9, 1 H, Me2CHCH); 6.86 (s, NH). 13C-NMR (CDCl3): 16.9 (1 C,
Me2CH); 18.4 (1 C, Me2CH); 23.5 (C(3)); 27.6 (Me3C); 31.0 (Me2CH); 40.6 (CH2Cl); 52.8 (C(2)); 78.9
‡
(Me2CHCH); 86.0 (Me3C); 116.4 (CN); 165.1 (CO); 165.9 (CO); 168.1 (CO). EI-MS (898): 346 (0.2, M ), 246
(3 [M CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C15H2335ClN2O5): 346.1295 (calc. 346.1296).
Data of 15a: 1H-NMR (CDCl3): 1.01 (d, 3J ˆ 6.8, Me2CH); 1.52 (s, t-Bu); 1.85 (s, 3 H C(3)); 2.30 ± 2.45
(m, Me2CH); 4.20 (d, 2J ˆ 15.0, 1 H, CH2Cl); 4.29 (d, 2J ˆ 15.0, 1 H, CH2Cl); 5.14 (d, 3J ˆ 4.1, Me2CHCH); 7.35
(s, NH). 13C-NMR (CDCl3): 16.7 (1 C, Me2CH); 18.2 (1 C, Me2CH); 23.0 (C(3)); 27.6 (Me3C); 30.7 (Me2CH);
40.5 (CH2Cl); 53.0 (C(2)); 78.5 (Me2CHCH); 85.3 (Me3C); 116.7 (CN); 164.9 (CO); 166.2 (CO); 168.4 (CO).
tert-Butyl 2-[2-(2-chloroacetoxy)-3-methylbutanamido]-2-cyanobutanoate (14b/15b). From 2b (388 mg,
2 mmol): 14b (322 mg (34%); m.p. 136 ± 1378 (Et2O)), and colorless crystals of 15b (118 mg (23%); m.p. 83 ± 858
(Et2O)).
‡
‡
Data for 14b: IR (KBr): 3282s (NH), 2973m, 2939m, 2881w, 2244w (CN), 1775s (CO), 1764s (CO), 1732s
(CO), 1689s (CO), 1517s, 1457m, 1373m, 1261m, 1167s, 1017w, 979w, 856w, 795w). 1H-NMR (CDCl3): 1.00
(d, 3J ˆ 7.0, Me2CH); 1.07 (t, 3J ˆ 7.4, 3 H C(4)); 1.53 (s, t-Bu); 2.05 ± 2.18 (m, 3J ˆ 7.4, 1 H C(3)); 2.28 ± 2.45
(m, Me2CH, 1 H C(3)); 4.15 (d, 2J ˆ 13.7, 1 H, CH2Cl); 4.22 (d, 2J ˆ 13.7, 1 H, CH2Cl); 5.15 (d, 3J ˆ 3.9,
Me2CHCH); 6.35 (s, NH). 13C-NMR (CDCl3): 7.9 (C(4)); 16.8 (1 C, Me2CH); 18.3 (1 C, Me2CH); 27.6
(Me3C); 29.7 (C(3)); 30.9 (Me2CH); 40.5 (CH2Cl); 57.6 (C(2)); 78.8 (Me2CHCH); 85.6 (Me3C); 115.9 (CN);
‡
‡
164.3 (CO); 165.9 (CO); 168.1 (CO). EI-MS (1008): 360 (0.2, M ), 304 (4.3, [M C4H8] ), 260 (3, [M
CO2C4H9] ), 57 (100, [C4H9] ). HR-MS (C16H2535ClN2O5): 360.1452 (calc. 360.1452).
‡
‡
Data of 15b: 1H-NMR (CDCl3): 1.01 (d, 3J ˆ 7.0, Me2CH); 1.05 (t, 3J ˆ 7.4, 3 H C(4)); 1.54 (s, Me3C);
2.05 ± 2.20 (m, 3J ˆ 7.4, 1 H C(3)); 2.25 ± 2.40 (m, Me2CH, 1 H C(3)); 4.16 (d, 2J ˆ 14.4, 1 H, CH2Cl); 4.23
(d, 2J ˆ 14.4, 1 H, CH2Cl); 5.18 (d, 3J ˆ 4.4, Me2CHCH); 6.83 (s, NH). 13C-NMR (CDCl3): 8.0 (C(4)); 16.8 (1 C,
Me2CH); 18.5 (1 C, Me2CH); 27.7 (Me3C); 29.6 (C(3)); 31.0 (Me2CH); 40.6 (CH2Cl); 57.6 (C(2)); 79.0
(Me2CHCH); 85.8 (Me3C); 116.0 (CN); 164.6 (CO); 166.1 (CO); 168.2 (CO).

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tert-Butyl 2-[2-(2-chloroacetoxy)-3-methylbutanamido]-2-cyano-3-phenylpropanoate (14c/15c). From 2c
(512 mg, 2 mmol): 14c (350 mg (33%); m.p.: 128 ± 1298 (Et2O)) and a pale-yellow oil of 15c (318 mg (30%)).
Data of 14c: IR (KBr): 3311s (NH), 3061m, 3034m, 2971m, 2938m, 2882w, 2245w (CN), 1772s (CO), 1720s
(CO), 1690s (CO), 1517s, 1457m, 1372m, 1322m, 1234m, 1178m, 1156m, 1140s, 1018m, 849w, 699s. 1H-NMR
(CDCl3): 0.98 (d, 3J ˆ 7.0, 3 H, Me2CH); 1.00 (d, 3J ˆ 7.0, 3 H, Me2CH); 1.50 (s, t-Bu); 2.25 ± 2.45 (m, Me2CH);
3.33 (d, 2J ˆ 13.7, 1 H, PhCH2); 3.65 (d, 2J ˆ 13.7, 1 H, PhCH2); 3.93 (s, CH2Cl); 5.21 (d, 3J ˆ 4.4, Me2CHCH);
6.77 (s, NH); 7.19 ± 7.34 (m, 5 arom. H). 13C-NMR (CDCl3): 16.8 (1 C, Me2CH); 18.4 (1 C, Me2CH); 27.7
(Me3C); 31.0 (Me2CH); 40.4 (CH2Cl); 41.1 (PhCH2); 57.1 (C(2)); 79.0 (Me2CHCH); 86.4 (Me3C); 115.9
‡
(CN); 128.5; 128.9; 130.2; 131.8 (arom. C); 164.0 (CO); 165.8 (CO); 168.1 (CO). EI-MS (968): 422 (0.5, M ),
322 (1.5, [M CO2C4H9] ), 91 (100, [C7H7] ), 57 (96, [C4H9] ). HR-MS (C21H2735ClN2O5): 422.1608 (calc.
‡
‡
‡
422.1607).
1
Data of 15c: H-NMR (CDCl3): 0.93 (d, 3J ˆ 7.0, 3 H, Me2CH); 0.94 (d, 3J ˆ 7.0, 3 H, Me2CH); 1.46 (s, t-
Bu); 2.20 ± 2.40 (m, Me2CH); 3.37 (d, 2J ˆ 13.7, 1 H, PhCH2); 3.52 (d, 2J ˆ 13.7, 1 H, PhCH2); 4.12 (s, CH2Cl);
5.12 (d, 3J ˆ 4.4, Me2CHCH); 6.76 (s, NH); 7.20 ± 7.37 (m, 5 arom. H). 13C-NMR (CDCl3): 16.8 (1 C, Me2CH);
18.4 (1 C, Me2CH); 27.7 (Me3C); 30.8 (Me2CH); 40.5 (CH2Cl); 41.5 (PhCH2); 57.4 (C(2)); 78.8 (Me2CHCH);
86.0 (Me3C); 116.1 (CN); 128.6, 129.0, 130.4, 131.7 (arom. C); 163.9 (CO); 166.0 (CO); 168.2 (CO).
REFERENCES
[1] M. Bergemann, R. Neidlein, Synthesis 1996, 8, 975.
[2] M. Bergemann, R. Neidlein, Synthesis 1998, 10, 1437.
[3] U. Schöllkopf, K. Handke, Liebigs Ann. Chem. 1979, 1602.
[4] T. Saegusa, S. Kobayashi, Y. Ito, J. Org. Chem. 1970, 35, 2118.
[5] T. Saegusa, S. Kobayashi, K. Hirota, Y. Okumura, Y. Ito, Bull. Chem. Soc. Jpn. 1968, 41, 1638.
[6] T. Saegusa, S. Kobayashi, K. Hirota, H. Yoshioka, Y. Ito, Tetrahedron Lett. 1966, 49, 6121.
[7] T. Saegusa, S. Kobayashi, K. Hirota, Y. Ito, Tetrahedron Lett. 1967, 6, 521.
[8] M. Passerini, Gazz. Chim. Ital. 1921, 51, II, 126.
[9] M. Passerini, Gazz. Chim. Ital. 1921, 51, II, 181.
[10] M. Passerini, Atti Reale Accad. Naz. Lincei, Mem. Cl. Sci. Fis. Mat. Natur. 1927, 2, 377.
[11] I. Ugi, ꢀIsonitrile Chemistryꢁ, Academic Press, New York and London 1971, p. 145.
[12] D. Marquarding, Angew. Chem. 1973, 85, 92; Angew. Chem. Int. Ed. Engl. 1973, 12, 79.
[13] R. Neidlein, Angew. Chem. 1964, 76, 500; Angew. Chem. Int. Ed. Engl. 1964, 3, 446.
[14] R. Neidlein, Chem. Ber. 1964, 97, 3476.
[15] R. Neidlein, Arch. Pharm. 1965, 298, 124.
[16] J. Goerdeler, H. Schenk, Chem. Ber. 1965, 98, 3831.
[17] H. Schenk, Chem. Ber. 1966, 99, 1258.
Received March 5, 1999