S. V. Ryabukhin et al. / Tetrahedron Letters 49 (2008) 3997–4002
4001
Table 1 (continued)
Entry
Acid Amine
Product
Yield
(%)
Mp
(°C)
Typical NMR data
M+1
3
d = 2.21 (s, 3H, CH3Ph), 3.25 (dd, JHH = 6.2 Hz,
N
N
3
2JHH = 15.2 Hz, 1H, CH2CH), 3.35 (dd, JHH = 9.3 Hz,
NH2
2JHH = 15.2 Hz, 1H, CH2CH), 5.89 (m, 1H, CH2CH), 6.88
O
56
195
336
3
19
1f
(s, 1H, CHim.), 7.06 (d, JHH = 7.9 Hz, 2H, 2CHPh), 7.29
N
H
(m, 2H, CHim., CHPh), 7.37 (m, 6H, (2+4)HPh), 7.81 (s, 1H,
CHim.), 9.95 (s, 1H, NH)
Ph
2l
4s
a
Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
b
c
Yields refer to pure isolated product. According to HPLC MS data all the synthesized compounds have purity >95%.
Melting points were measured with a Buchi melting points apparatus and are uncorrected.
1H NMR (500 MHz) were recorded on a Varian Mercury-400 and Bruker Avance DRX 500 spectrometers with TMS as an internal standard in
d
DMSO-d6.
e
LC/MS spectra were recorded using chromatography/mass spectrometric system that consists of high-performance liquid chromatograph ‘Agilent
1100 Series’ equipped with diode-matrix and mass-selective detector ‘Agilent LC/MSD SL’.
dazolylpropionic acid 7a6 did not react with benzylamine
2a in the presence of CDI (under the acylation conditions
of 1a). This can be explained by low activity of the zwitter-
ionic structure of acid 7a (Scheme 3).
On the basis of the results described above we have
found the conditions for the one-pot synthesis of structur-
ally and functionally diverse compounds 4. Equimolar
amount of CDI was added to the DMF solution of acids
1a–e and the reaction mixture was being heated at 70 °C
for 2 h to ensure the formation of intermediate 6. The latter
was reacted with equimolar amount of amines 2a–e at
100 °C (6 h) to give target compounds 4a–r in 84–99%
yields. Compounds 4a–r could be easily isolated in pure
form by precipitation or extraction.7
References and notes
1. (a) Ustunes, L.; Pabuccuoglu, V.; Berkan, T.; Ozer, A. J. Fac. Pharm.
Ankara 1989, 19, 39–45; (b) Aktuerk, Z.; Kilic, F. S.; Erol, K.;
Pabuccuoglu, V. Farmaco 2002, 57, 201–206; (c) Soyer, Z.; Kilic, F. S.;
Erol, K.; Pabuccuoglu, V. Farmaco 2004, 59, 595–600.
2. Young, R.; Chang, C. K. J. Am. Chem. Soc. 1985, 107, 898–909.
3. Cruz, A.; Elguero, J.; Goya, P.; Martinez, A. J. Heterocycl. Chem.
1988, 25, 225–229.
4. Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82, 4596–
4600.
5. Benzylacrylamide 5a was obtained by the reaction of acrylic acid 1a
with benzylamine 2a with N-methyl-2-chloropyridin iodide (Mukaiy-
ama’s reagent): Mukaiyama, T. Angew. Chem. 1979, 91, 798–812.
6. b-Imidazolylpropionic acid 7a was obtained by the addition of
imidazole to acrylic acid: Mroczkiewicz, A. Acta Pol. Pharm. 1984,
41, 435–440.
In the case of cinnamic acid 1f, the yields of compounds
4 were considerably lower (55–60%)8 most probably due to
the lower activity of the allylic double bond conjugated
with the phenyl ring (Scheme 4, Table 1).
7. General procedure. Acid 1a–f (2.2 mmol) and CDI (2.4 mmol) were
placed in 15 mL tube and dissolved in 3–4 mL of DMF. The tube was
heated at 70 °C for 2 h (caution: the tube must be opened for free
evaporation of CO2). After that, amine 2a–l (2 mmol) was added, the
tube was thoroughly sealed, and heated at 100 °C for 6 h. Then, the
reaction mixture was diluted by 8–10 mL of water and sonicated at rt
for 1–2 h (BRANSON 2510E-MT). The precipitate was filtered and
washed with i-PrOH (2 mL). Targeted b-imidazolylpropionamides 4e,
4f, 4h, 4n were obtained as white powders. In the case of water-soluble
compounds the extraction by DCM was used. DCM’s solution washed
with 2% aq solution of NaHCO3 (8 mL). Targeted products 4a–d, 4g,
4i–m, 4o–r were formed after the evaporation of DCM.
The composition and structure of all the compounds
1
were established through LC/MS, elemental analysis, H
1
and 13C NMR spectroscopy. The H NMR of compounds
contained one set of signals for the imidazole protons and
two characteristic signals for a- and b-protons of the pro-
pionyl fragment.
8. b-Imidazolylpropionamide 4s was synthesized by general procedure
and isolated by preparative chromatography.
3. Conclusion
9. 13C NMR analysis for targeted compounds: 4a: d = 37.3, 42.6, 42.9,
119.8, 127.2, 127.7, 128.7, 128.7, 137.7, 139.7, 169.9; 4b: d = 34.2, 41.9,
42.6, 45.6, 66.4, 119.9, 128.6, 137.9, 168.9; 4c: 37.7, 42.7, 119.8, 126.8,
126.9, 127.2, 127.9, 128.8, 129.9, 135.1, 137.8, 169.5; 4d: d = 23.7, 27.5,
37.6, 42.9, 119.7, 126.0, 126.1, 126.8, 127.4, 128.8, 134.9, 137.8, 143.9,
169.5; 4e: d = 14.5, 38.3, 42.3, 42.4, 117.3, 119.7, 121.7, 123.1, 128.9,
130.4, 137.8, 140.1, 140.7, 169.6; 4f: d = 37.4, 42.1, 119.8, 121.04, 122.2,
124.06, 126.6, 128.9, 131.9, 137.8, 148.9, 158.1, 170.3; 4g: d = 22.1,
42.5, 43.7, 50.5, 117.7, 127.2, 127.5, 128.6, 128.7, 136.4, 139.7, 169.5;
4h: d = 21.9, 43.5, 49.8, 117.7, 121.0, 122.1, 124.1, 126.6, 128.8, 131.9,
136.5, 148.9, 158.0, 169.7; 4i: d = 22.0, 44.3, 50.2, 114.0, 117.7, 119.9,
128.7, 136.5, 138.6, 148.4, 152.2, 169.5; 4j: d = 22.3, 41.4, 45,1, 48.7,
49.1, 50.3, 55.3, 116.3, 117.9, 119.8, 128.6, 129.4, 136.6, 151.2, 168.4;
4k: d = 21.9, 44.5, 50.4, 55.6, 144.3, 117.8, 121.3, 128.6, 132.5, 136.5,
155.8, 168.0; 4l: d = 21.9, 44.6, 50.2, 117.7, 121.2, 127.4, 128.8, 129.1,
136.5, 138.3, 168.7; 4m: d = 28.7, 42.6, 48.4, 56.5, 117.6, 127.2, 127.7,
128.5, 128.7, 135.2, 139.7, 169.0; 4n: d = 28.8, 41.2, 43.9, 45.6, 48.7,
Acrylic acids react with CDI to give active intermediate
that can be readily transformed into various b-imidazolyl-
propionamides through the amidation with primary and
secondary amines. The elaborated one-pot methodology
is applicable to a variety of substituted acrylic acids and
amines and affords structurally and functionally diverse
target compounds in high preparative yields.
Acknowledgment
The authors acknowledge V. V. Polovinko (Enamine
Ltd) for spectral measurements.
Ryabukhin, Sergey V.
