JOURNAL OF CHEMICAL RESEARCH 2009 509
CH3). HRMS (m/z): 141.1162 (Calcd for C8H15NO, 141.1153). Anal.
Calcd for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 67.74; H,
11.01; N, 9.24%.
with a better yield of amide compared to the use of DMF. The
experimental results presented coincide with those obtained
by Cvetovich and DiMichele.13
N-Methyl-2,2,3,3-tetramethylcyclopropanecarboxamide
(2b):
The generality of amide derivatives of TMCA formation in
DMAC with this simple and efficient procedure using various
reactant amines was tested and the results are summarised
in the experimental section. In each case, the amines were
successfully converted to amide derivatives of TMCA and
reactions were completed rapidly and gave good isolated
yields of the corresponding amides as crystalline solids.
Although excellent yields (> 90%) of amide derivatives
of TMCA were obtained using aromatic amines as
reactants in DMAC in the absence of bases alkylamines
gave poorer yields. When TMCA was treated with thionyl
chloride and butylamine, the product N-butyl-2,2,3,3-
tetramethylcyclopropanecarboxamide (2d) was obtained in an
74% yield, even in the presence of excess butylamine. The
influence of reactant amine types on the yields is mainly due to
the poor solubility of the alkylamine HCl salt in DMAC and is
independent of the basicity of reactant amine. This conclusion
was confirmed by using aromatic amines which contain
various substituent groups as reactants and the similar isolated
yields of amide derivatives of TMCA could be observed.
Amine derivatives of TMCA can be obtained by reducing
the corresponding amide with a Lewis acid/NaBH4 reduction
system, the reducing properties of which are milder than that
of LiAlH4.14-16 We found that the combined reagent TiCl4/
NaBH4 can be used to advantage for the reduction of amide
derivatives of TMCA. Thus, a series of amide derivatives
of TMCA were subjected to reduction in the presence
of NaBH4 and TiCl4 to furnish the corresponding amine
compounds. The results are summarised in the corresponding
experimental section.
White crystalline solid (88% yield) m.p. 97–99°C (lit.10 98°C).
1H NMR (400 MHz, CDCl3, d TMS): 5.672 (s, 1H, NH), 2.761–2.782
(d, J = 8.4, 3H, NHCH3), 1.146–1.254 (12H, CH3), 0.836 (s, 1H,
CH). HRMS (m/z): 155.1332 (Calcd for C9H17NO,155.1310). Anal.
Calcd for C9H17NO: C, 69.62; H, 11.04; N, 9.03. Found: C, 68.91; H,
10.86; N, 9.74%.
N-Ethyl-2,2,3,3-tetramethylcyclopropanecarboxamide
(2c):
White needle-like solid (80% yield) m.p. 80–82°C (lit.9 81–82°C).
1H NMR (400 MHz, CDCl3, d TMS): 5.782–5.816 (t, J = 6.8, 1H, NH),
3.131–3.223 (m, 2H, NHC2H5), 1.082–1.123 (t, J = 8.2, 3H, CH3),
1.148–1.253 (12H, CH3), 0.821 (s, 1H, CH). HRMS (m/z): 169.1432
(Calcd for C10H19NO, 169.1466). Anal. Calcd for C10H19NO: C, 70.96;
H, 11.31; N, 8.28. Found: C,70.91; H, 11.39; N, 8.31%.
N-(n-Butyl)-2,2,3,3-tetramethylcyclopropanecarboxamide (2d):
1
White crystalline solid (74% yield) m.p. 124–126°C. H NMR (400
MHz, CDCl3, d TMS): 5.450 (s, 1H, NH), 3.217–3.249 (t, J = 6.4, 2H,
NHC4H9), 1.454–1.506 (m, 2H, NHC4H9), 1.319–1.372 (m, 2H,
NHC4H9), 1.149–1.258 (12H, CH3), 0.905–0.940 (t, J = 7.0, 3H,
NHC4H9), 0.825 (s, 1H, CH). HRMS (m/z): 197.1790 (Calcd for
C14H19NO, 197.1778). Anal. Calcd. for C12H23NO: C, 73.04; H,
11.75; N, 7.10. Found: C, 72.92; H, 11.96; N, 7.09%.
N-Phenyl-2,2,3,3-tetramethylcyclopropanecarboxamide
(2e):
White crystalline solid (95% yield) m.p. 152–154°C (lit.10 149°C).
1H NMR (400 MHz, CDCl3, d TMS): 7.472 (s, 1H, NH), 7.330–7.047
(m, 5H, ArH), 1.195–1.319 (d, J = 27.8, 12H, CH3), 0.999 (s, 1H,
CH). HRMS (m/z): 217.1474 (Calcd for C14H19NO, 217.1466). Anal.
Calcd for C14H19NO: C, 77.37; H, 8.82; N, 6.45. Found: C, 77.62; H,
8.55; N, 6.53%.
N-(3-Methylphenyl)-2,2,3,3-tetramethylcyclopropanecarboxamide
1
(2f): White crystalline solid (92% yield) m.p. 146–147°C. H NMR
(400 MHz, CDCl3, d TMS): 7.417 (s, 1H, NH), 6.883–7.259 (m, 4H,
ArH), 2.321 (s, 3H, ArCH3), 1.206–1.321 (12H, CH3), 0.980 (s, 1H,
CH). HRMS m/z: 231.1598 (Calcd for C15H21NO, 231.1623). Anal.
Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.90; H,
9.09; N, 6.02%.
Inconclusion, wehavedevelopedamildandefficientmethod
to convert TMCA to amide derivatives directly in a one-pot
reaction by the action of TMCA, thionyl chloride and reactant
amines in N,N-dimethylacetamide. The amide derivatives of
TMCA can be smoothly reduced to corresponding amines by
using the combined reagent TiCl4/NaBH4.
N-(3-Trifluoromethylphenyl)-2,2,3,3-tetramethylcyclopropane-
carboxamide (2g): White crystalline solid (94% yield) m.p. 136–
1
138°C. H NMR (CDCl3): 7.793 (s, 1H, NH), 7.262–7.677 (m, 4H,
ArH), 1.223–1.329 (12H, CH3), 0.995 (1H, s). HRMS m/z: 285.1362
(Calcd for C15H18F3NO, 285.1340). Anal. Calcd for C15H18F3NO: C,
63.15; H, 6.36; N, 4.91. Found: C, 63.12; H, 6.42; N, 4.95%.
N-(3-Nitrophenyl)-2,2,3,3-tetramethylcyclopropanecarboxamide
(2h): White crystalline solid (90% yield) m.p. 146–147°C.
1H NMR (400 MHz, CDCl3, d TMS): 8.360 (s, 1H, NH), 7.264–7.911
(m, 4H, ArH), 1.239–1.336 (12H, CH3), 1.022 (s, 1H, CH). HRMS
(m/z): 262.1326 (Calcd for C14H18N2O3, 262.1317). Anal. Calcd for
C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.30; H, 6.63;
N, 10.74%.
Experimental
Chemicals, materials, and methods
All the reagents used in the experiment were AR grade and purchased
from Sigma-Aldrich. All melting points (°C) were determined on an
X-4 microscopic digital melting-point apparatus. 1H NMR spectra
were recorded on a Varian INOVA 400 spectrometer at ambient
temperature in CDCl3 using TMS as internal standard, and NMR
chemical shifts (d) were quoted in ppm. Coupling constants (J values)
were given in Hz. High-resolution mass spectra were measured using
a JEOL JMS-DX300 mass spectrometer. IR spectra of the compounds
were measured on a Nicolet Avatar 360 FT-IR instrument using
KBr discs in the 4000–400 cm-1 regions. Elemental analyses were
obtained in an EA 1112 elemental analyser. C, H, N analyses of all
newly synthesised compounds had satisfactory results (within ±0.4 of
theoretical values).
N-(4-Nitrophenyl)-2,2,3,3-tetramethylcyclopropanecarboxamide
1
(2i): White crystalline solid (92% yield) m.p. 169–171°C. H NMR
(400 MHz, CDCl3, d TMS): 8.187 (s, 1H, NH), 7.629–8.164
(m, 4H, ArH), 1.233–1.329 (12H, CH3), 1.045(s, 1H, CH). HRMS
(m/z): 262.1326 (Calcd for C14H18N2O3, 262.1317). Anal. Calcd for
C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.32; H, 6.65;
N, 10.76%.
N,N-Dimethyl-2,2,3,3-tetramethylcyclopropanecarboxamide
1
(2j): Oil (93% yield). H NMR (400 MHz, CDCl3, d TMS): 3.061
(s, 1H, NCH3), 1.153–1.262 (12H, CH3), 1.042 (s, 1H, CH). HRMS
(m/z): 169.1482 (Calcd for C10H19NO, 169.1466). Anal. Calcd for
C10H19NO: C, 70.96; H, 11.31; N, 8.28. Found: C, 70.86; H, 11.46;
N, 8.26%.
General procedure for the synthesis of 2a-j
In a standard reaction procedure, a solution mixture of dimethyl-
acetamide (20 mL) and 2,2,3,3-tetramethylpropanecarboxylic acid
(0.06 mol) was cooled to –5°C in a mechanically stirred three-necked
flask equipped with a an exit gas absorber. Then, thionyl chloride
(0.072 mol) and stoichiometric amounts of the reactant amine
(0.06 mol) were added slowly from a dropping funnel with sufficient
stirring. When the addition was complete, the reaction mixture was
warmed to room temperature (20°C) and stirred for 60 min. With the
reaction mixture at 20°C, water (300 mL) was added dropwise over
30 min and stirred for a further 60 min. The product was then filtered
and washed with water. Recrystallisation from EtOH/H2O gave the
pure target compounds (2a–j).
General procedure for the synthesis of compounds 3a–e
In a standard reaction procedure, a solution mixture of 2,2,3,3-
tetramethylcyclopropanecarboxamide (10 mmol) in anhydrous 1,2-
dimethoxyethane (DME) was added dropwise to an ice-cooled, stirred
mixture of TiCl4 (20 mmol) and sodium borohydride (20 mmol) of
anhydrous DME (30 mL) in 0.5 h. After the addition was complete,
the reaction mixture was warmed to 60°C, and stirred for 14 h.
It was then quenched by the addition of water (50 mL) with ice
cooling. The mixture was basified with concentrated aqueous
ammonia (28%) and then extracted with ethyl acetate (2¥70 mL).
The extract was washed with saturated sodium chloride solution
(100 mL) and dried over Na2SO4. The target product (3a–e) was then
further purified by distillation under reduced pressure.
2,2,3,3-tetramethylcyclopropanecarboxamide
(2a):
White
crystalline solid, 89% yield, m.p. 89–91°C. 1H NMR (400 MHz,
CDCl3, d TMS): 7.16 (s, 1H, NH), 1.48 (s, 1H, CH), 1.25–1.15 (12H,