Journal of Medicinal Chemistry
Article
3,3-dimethyl-1-butanol (26), 2,4,4-trimethyl-1-pentanol (27), 3-
methyl-1-pentanol (28), 2-ethyl-1-hexanol (29), and 2-phenyl-ethanol
(30) and all common reagents were obtained from Sigma-Aldrich
(United States) and used without further purification. DCM,
tetrahydrofuran (THF), petroleum ether, and ethyl acetate were
A.R. grade and obtained from Frutarom Israel. DCM was dried by
refluxing over CaH2 for 2 h and distillation prior to use. THF was
dried by refluxing over CaH2 for 2 h, distillation, and refluxing over
LAH for 2 h and distillation prior to use. N,N-Dimethylpropyleneurea
(DMPU) was dried by its refluxing over CaH2 for 2 h and distillation
under reduced pressure. It was stored over 4 Å molecular sieves under
a nitrogen atmosphere.
Materials and Methods. Product formation follow-up was
performed by means of gas chromatography−mass spectroscopy
(GC-MS) and thin-layer chromatography (TLC). TLC analyses were
performed on precoated silica gel on aluminum sheets (Kieselgal 60
F254, Merck). A GC-MS assay was performed on a HP5890 Series II
GC equipped with a Hewlett-Packard MS Engine (HP5989A) single
quadrupole MS, HP7673 autosampler, HP MS-DOS Chemstation, and
HP-5MS capillary column (0.25 μm × 15 m × 0.25 mm). The
temperature program was as follows: injector temperature, 180 °C;
initial temperature, 40 °C for 6 min; gradient of 20 °C/min until
140 °C; gradient of 10 °C/min until 200 °C; and hold time, 3 min.
The MS parameters were set as follows: source temperature,
180 °C; transfer line, 280 °C; positive ion monitoring; and EI-MS
(70 eV). The molecular ion and the five most-pronounced ions
are provided.
in 100 mL of dry DCM. The reaction mixture was stirred for 5 h at
room temperature. Water (15 mL) was added, and the organic layer
was separated. The aqueous phase washed three times with 20 mL of
DCM. The organic extracts were combined and washed three times
with brine, dried over MgSO4, filtered, and evaporated under reduced
pressure. The obtained products were purified by crystallization using
ethyl acetate/hexane mixture (1:3) to give (42−98% yield) of white
crystals.
2,3-Dimethyl-butyl Carbamate (32). Silver plates; 60% yield, mp
55−57 °C. MS-EI, m/z (%): 146 (M+ + 1, 0.12), 102 (36), 84 (73), 69
1
(100), 55 (20). H NMR (300 MHz, CDCl3 δ TMS): 0.80−0.98 (m,
9H), 1.61−1.79 (m, 2H), 3.88 (dd, J = 6, 11.4, 1H), 4.02 (dd, J = 6,
11.4, 1H), 4.50−4.80 (br s, 2H: NH). Anal. (C7H15NO2) C, H, N.
2-Ethyl-3-methyl-butyl Carbamate (34). White crystals; 54% yield,
mp 61−63 °C. MS-EI, m/z (%): 158 (M+ − 1, 0.14), 116 (22), 98
(34), 83 (54), 62 (100). 1H NMR (300 MHz, CDCl3 δ TMS): 0.87−
0.95 (m, 9H), 1.22−1.47 (m, 3H), 1.77 (m, 1H), 4.33 (m, 2H), 4.42−
4.68 (br s, 2H: NH). Anal. (C8H17NO2) C, H, N.
2-Isopropyl-3-methyl-butyl Carbamate (35). White crystals; 77%
yield, mp 49−52 °C. MS-EI, m/z (%): 130 (M+ − 43, 7), 112 (12), 97
(30), 69 (100), 57 (86). 1H NMR (300 MHz, CDCl3 δ TMS): 0.86−
0.98 (dd, J = 9, 18 12H), 1.22 (m, 1H), 1.93 (m, 2H), 4.15 (d, J = 5.1,
2H), 4.42−4.68 (br s, 2H: NH). Anal. (C9H19NO2) C, H, N.
2-Ethyl-3-methyl-pentyl Carbamate (38). Oil; 67% yield. MS-EI,
m/z (%): 144 (M+ − 29, 0.4), 112 (14), 83 (100), 62 (96), 55 (96).
1H NMR (300 MHz, CDCl3 δ TMS): 0.81−0.94 (br m, 9H), 1.18 (m,
1H), 1.36 (m, 4H), 1.51 (m, 1H), 3.92−4.12 (br m, 2H), 4.46−4.72
(br s, 2H: NH). Anal. (C9H19NO2) C, H, N.
1H NMR spectra, in CDCl3 using TMS as the internal standard,
were recorded on a Varian Mercury series NMR 300 spectrometer.
Chemical shifts (δ scale) are reported in parts per million (ppm) rel-
ative to residual TMS. Multiplicity is indicated as follows: s (singlet), d
(doublet), t (triplet), m (multiplet), dd (doublet of doublet), and br m
(broad multiplet). Coupling constants (J) are given in (Hz).
Chemical structures of the newly synthesized compounds were
2-Ethyl-4-methyl-pentyl Carbamate (39). White crystals; 68%
yield, mp 39−42 °C. MS-EI, m/z (%): 144 (M+ − 29, 0.27), 130 (6),
83 (39), 75 (33), 57 (100). 1H NMR (300 MHz, CDCl3 δ TMS): 0.89
(m, 9H), 1.14 (m, 1H), 1.34 (m, 4H), 1.63 (m, 1H), 3.90−4.09 (br m,
2H), 4.42−4.72 (br s, 2H: NH). Anal. (C9H19NO2) C, H, N.
2-Propyl-pentyl Carbamate (40). White crystals; 98% yield, mp
68−70 °C. MS-EI, m/z (%): 130 (M+ − 43, 0.68), 112 (18), 84 (47),
1
assessed by H NMR and elemental analyses. The melting point was
1
determined on a Buchi 530 capillary melting point apparatus.
Elemental analyses were performed on a 2400-2 Perkin-Elmer C, H, N
analyzer. Elemental analysis (C, H, N) were used to confirm the purity
of all newly synthesized compounds (>95%), results within 0.4 of
theoretical values (see the Supporting Information).
70 (100), 57 (96). H NMR (300 MHz, CDCl3 δ TMS): 0.88 (m,
6H), 1.24−1.36 (br m, 8H), 1.63 (m, 1H), 3.96 (d, J = 5.7, 2H), 4.48−
4.70 (br s, 2H: NH). Anal. (C9H19NO2) C, H, N.
2-Propyl-3-methyl-pentyl Carbamate (41). Oil; 89% yield. MS-EI,
m/z (%): 158 (M+ − 29, 0.36), 130 (9), 97 (74), 70 (77), 55 (100).
1H NMR (300 MHz, CDCl3 δ TMS): 0.80−0.94 (br m, 9H), 1.08−
1.56 (br m, 7H), 1.61 (m, 1H), 3.82−4.12 (br m, 2H), 4.44−4.70 (br s,
2H: NH). Anal. (C10H21NO2) C, H, N.
General Procedure for the Synthesis of Compounds 32, 34,
35, 38−43, and 46. To a solution of 160 mmol of diisopropylamine
in 70 mL of anhydrous THF kept at −15 °C under nitrogen (N2)
atmosphere was added dropwise 160 mmol of n-butyllithium. The
reaction mixture was stirred for 30 min, and then, 10 mL of dry THF
and 72 mmol of valeric acid (for the synthesis of compounds 9 and
11), isovaleric acid (for the synthesis of compound 4−6), 3-methyl-
valeric acid (for the synthesis of compounds 7, 10, and 12), or 4-
methylvaleric acid (for the synthesis of compound 8), were added and
allowed to stir for an additional 15 min at −5 °C. A 72 mmol amount
of DMPU was added dropwise, and the reaction mixture was stirred
for 30 min at 5 °C followed by the dropwise addition of 160 mmol of
the corresponding alkyliodide (either methyliodide, ethyliodide,
propyliodide, or isopropyliodide) in 10 mL of anhydrous THF. The
reaction mixture was allowed to stir at room temperature for 2 h, and
THF was evaporated. The oily product was dispersed in petroleum
ether (50 mL), and 10% HCl solution was added until pH = 1 was
reached. The organic phase was separated from the aqueous phase and
washed three times with brine. The aqueous solutions were combined
and extracted with petroleum ether (3 × 50 mL). The petroleum ether
extracts were combined, dried over MgSO4, filtered, and evaporated
under reduced pressure. The oily products were further distilled under
reduced pressure to yield the pure corresponding acids. The
synthesized carboxylic acids (4−13) were converted by LAH
(LiAlH4) in DCM to primary alcohols by using 2 equiv of LiAlH4
for each equiv of an acid according to a previously published
procedure.26 The oily crude product was distilled under reduced
pressure to afford the desire primary alcohols. TFA (105 mmol)
dissolved in 50 mL of dry DCM was added dropwise to a stirred mix-
ture of primary alcohol (50 mmol) and sodium isocyanate (100 mmol)
2-Isopropyl-pentyl Carbamate (42). White crystals; 42% yield, mp
66−68 °C. MS-EI, m/z (%): 130 (M+ − 43, 9), 112 (14), 83 (31), 69
(95), 57 (100). 1H NMR (300 MHz, CDCl3 δ TMS): 0.89 (t, J = 8.7,
9H), 1.16−1.42 (br m, 7H), 1.48 (m, 1H), 1.76 (m, 1H), 4.02 (dd, J =
1.5, 5.7, 2H), 4.44−4.68 (br s, 2H: NH). Anal. (C9H19NO2) C, H, N.
2-Isopropyl-3-methyl-pentyl Carbamate (43). Oil; 76% yield. MS-
EI, m/z (%): 158 (M+ − 29, 0.13), 126 (4), 83 (43), 70 (100), 55
1
(84). H NMR (300 MHz, CDCl3 δ TMS): 0.82−0.98 (br m, 12H),
1.20−1.52 (br m, 4H), 1.81 (m, 1H), 4.09 (m, 2H), 4.46−4.68 (br s,
2H: NH). Anal. (C10H21NO2) C, H, N.
2,2,3,3-Tetramethylcyclopropylmethylen Carbamate (46). White
crystals; 68% yield, mp 77−80 °C. MS-EI, m/z (%): 171 (M+, 0.2),
1
110 (29), 95 (100), 67 (38), 55 (62). H NMR (300 MHz, CDCl3 δ
TMS): 0.58 (t, J = 9, 1H), 1.05 (S, 6H), 1.18 (S, 6H), 4.10 (d, J = 9,
2H), 4.46−4.68 (br s, 2H: NH). Anal. (C9H17NO2) C, H, N.
General Procedure for the Synthesis of Compounds 31, 33,
36, 37, 44, 45, and 47. TFA (105 mmol) dissolved in 50 mL of dry
DCM was added dropwise to a stirred mixture of the commercially
available primary alcohol (24−30) (50 mmol) and sodium isocyanate
(100 mmol) in 100 mL of dry DCM. The reaction mixture was stirred
for 5 h at room temperature. Water (15 mL) was added, and the
organic layer was separated. The aqueous phase washed three times
with 20 mL of DCM. The organic extracts were combined and washed
three times with brine, dried over MgSO4, filtered, and evaporated
under reduced pressure. The obtained products were purified by
crystallization using ethyl acetate/hexane mixture (1:3) to give (79−
98% yield) of white crystals.
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dx.doi.org/10.1021/jm201751x | J. Med. Chem. 2012, 55, 2835−2845