Journal of Medicinal Chemistry
ARTICLE
Jeol JNM EX 400 spectrometer at 400 MHz with tetramethylsilane
(TMS) as internal standard. 13C spectra were recorded on the same
spectrometer in DMSO-d6 solution at 100 MHz. Chemical shifts (δ) are
expressed in ppm downfield from tetramethylsilane. The microwave-
assisted syntheses were carried out in an Initiator 16 single-mode
microwave instrument producing controlled irradiation at 2.450 GHz
(BiotageAB, Uppsala, Sweden). Reaction times refer to hold times at the
temperatures indicated, not to total irradiation times. The temperature
was measured with an IR sensor on the outside of the reaction vessel.
Elemental analyses (C, H, N) were performed on a Thermo Finnigan-
FlashEA 1112 apparatus. Analytical LC/MS analyses were performed on
an Agilent 1100 series HPLC coupled with an MSD Trap SL system
using UV detection at 254 and 361 nm. Mass spectra were recorded
using electron spray ionization (ESI) operating in positive mode, unless
stated otherwise. The following method was applied: injection of 10 μL
in dry tetrahydrofuran (THF, 1 mL/mmol of starting nitrile) at 0 °C.
Sodium azide (2.80 mol equiv) was added, the ice/water bath was
removed, and the off-white suspension was stirred at the reflux tem-
perature for 2 h. Upon brief cooling of the mixture, a nitrile (1 mol equiv)
was added. The reaction mixture was stirred at reflux temperature for the
reaction time indicated. The resulting suspension was cooled, poured
into 1 M aqueous citric acid, and extracted several times with ethyl
acetate. The combined organic layers were washed with brine and dried
over MgSO4. Purification by flash chromatography followed by crystal-
lization as described above furnished the title product.
(E)-3-(2-Pyridin-3-ylvinyl)-1H-indole (3).31. 3 was prepared
with general synthetic method A, with reaction time of 18 h. Yellow
ochre powder, 190 mg (86%). Mp 191ꢀ192 °C. LC/MS tR = 5.2 min,
m/z [MH+] 221. 1H NMR δ 11.38 (1H, bs, indole-H1), 8.72 (1H, d, J =
1.8 Hz, ArH), 8.34 (1H, dd, J = 4.6, 1.4 Hz, ArH), 8.01 (1H, d, J = 7.6 Hz,
ArH), 7.98 (1H, d, J = 8.0 Hz, ArH), 7.65 (1H, bs, ArH), 7.53 (1H, d, J =
16.7 Hz, HCdCH), 7.40 (1H, d, J = 8.0 Hz, ArH), 7.32 (1H, dd, J = 7.9,
4.7 Hz, ArH), 7.05ꢀ7.15 (3H, m, 2 ArH, HCd=CH). 13C NMR δ
148.0, 147.5, 137.6, 134.8, 132.0, 127.3, 125.6, 125.2, 124.2, 122.4, 120.5,
120.4, 120.0, 114.1, 112.5.
of a 20 μg mLꢀ1 acetonitrile solution onto a C18 3.5 μm Zorbax SB
3
column (100 mm ꢁ 3 mm); separation using a gradient (flow rate of
0.5 mL minꢀ1) of acetonitrile in acetic acid (0.1% v/v in water) from 5%
3
to 95% acetonitrile over 5 min, holding for 3 min, then reversing to 5%
acetonitrile within 0.1 min and holding for an additional 5.4 min. Automated
flash chromatography was performed on a Biotage AB SP1 system equipped
with prepacked flash KP-Sil silica cartridges. The following gradient of ethyl
acetate in cyclohexane (unless stated otherwise) was used for elution:
the elution started with an ethyl acetate/cyclohexane ratio of 12/88 for
one column volume (CV); the ratio increased to 62/38 over 5 CV, kept
for 1 CV, then increased to 100/0 over 7 CV, and finally kept at this value
over 5 CV. The product detection was by UV absorption at 254 and
320 nm. The products were precipitated by concentration of the pooled
column fractions combined with the addition of cyclohexane. The
precipitate formed was filtered off, washed twice with cyclohexane,
and dried at 40 °C in vacuo to yield an analytically pure sample. All new
compounds were determined to be >95% pure by LC/MS. The yields
reported refer to combined yields of chromatographically and spectro-
scopically pure product fractions, and crops were recovered from mother
liquors.
(E)-6-Fluoro-3-(2-pyridin-3-ylvinyl)-1H-indole (30)31,33,34
.
30 was prepared with general synthetic method A, with reaction time
of 18 h. Yellow powder, 229 mg (96%). Mp 180ꢀ181 °C. LC/MS tR =
5.5 min, m/z [MH+] 239. 1H NMR δ 11.43 (1H, bs, indole-H1), 8.72
(1H, d, J = 1.4 Hz, ArH), 8.34 (1H, d, J = 4.8 Hz, ArH) 8.00 (2H, m, 2
ArH), 7.65 (1H, s, ArH), 7.50 (1H, d, J = 16.7 Hz, HCdCH), 7.33 (1H,
dd, J = 7.9, 4.7 Hz, ArH), 7.18 (1H, dd, J = 9.8, 2.3 Hz, ArH), 7.07 (1H, d,
J = 16.7 Hz, HCdCH), 6.96 (1H, dt, 3J = 9.2 Hz, 4J = 2.4 Hz, ArH). 13
C
NMR δ 159.6 (d, JCF = 234.6 Hz), 148.1, 147.7, 137.6 (d, JCF = 12.4 Hz),
134.7, 132.1, 127.7 (d, JCF = 2.9 Hz), 124.7, 124.2, 122.5, 121.5 (d, JCF
=
10.5 Hz), 120.4, 114.2, 108.7 (d, JCF = 23.8 Hz), 98.5 (d, JCF = 24.8 Hz).
(E)-3-[2-(3-Chlorophenyl)vinyl]-6-fluoro-1H-indole (50).
50 was synthesized from 3-chlorophenylacetic acid and without triethy-
lamine using the general synthetic method B, with reaction time of 6 h.
Yellowish solid, 223 mg (82%). Mp 153ꢀ155 °C. LC/MS tR = 7.6 min,
m/z [MH+] 272, 274. 1H NMR δ 11.41 (1H, bs, indole-H1), 8.01 (1H,
dd, J = 8.7, 5.5 Hz, ArH), 7.64 (1H, d, overlapped, ArH), 7.63 (1H, d,
overlapped, ArH), 7.50 (1H, d, overlapped, ArH), 7.47 (1H, d, over-
lapped, HCdCH), 7.32 (1H, t, J = 7.9 Hz, ArH), 7.16ꢀ7.20 (2H,
overlapped, 2 ArH), 7.05 (1H, d, J = 16.7 Hz, HCdCH), 6.95 (1H, dt,
3J = 9.2 Hz, 4J = 2.3 Hz, ArH). 13C NMR δ 159.5 (d, JCF = 234.6 Hz),
141.4, 137.5 (d, JCF = 12.4 Hz), 134.0, 130.9, 127.8, 126.4, 125.5, 124.6,
124.4, 122.5 (2C), 121.6 (d, JCF = 10.5 Hz), 114.1, 108.6 (d, JCF = 23.8
Hz), 98.5 (d, JCF = 25.8 Hz).
General Synthetic Procedures. Method A (Knoevenagel Con-
densation by Conventional Heating). A round-bottom flask was
charged with dioxane (3 mL), pyrid-3-ylacetic acid hydrochloride or
another active methylene compound as indicated (1.5 mmol), and
triethylamine (535 μL, 3.8 mol, unless stated otherwise), and the resulting
mixture was stirred for approximately 10 min at room temperature.
Suitably substituted 1H-indole-3-carbaldehyde (1.0 mmol, either from a
commercial source or prepared by VilsmeierꢀHaack formylation of the
commercial 3-nonsubstituted indole according to the literature procedure,52
where this product was used crude in the next step) and piperidine
(220 μL, 2.2 mmol) were added, and the mixture (typically a yellow
suspension that darkens to orange as the reaction progresses) was stirred
at reflux temperature for the reaction time indicated. In some cases
where the reaction progress was slow (as monitored by TLC in ethyl
acetate/cyclohexane 2:1), a piperidine aliquot was added, typically at a
reaction time of approximately 24 h. Upon completion of the reaction,
the mixture was diluted with ethyl acetate and evaporated on silica. This
sample was loaded onto a silica column, and the title product was purified by
flash chromatography and crystallized from the pooled column fractions
as described above.
(Z)-3-(6-Fluoro-1H-indol-3-yl)acrylonitrile (56-cis) and (E)-
3-(6-fluoro-1H-indol-3-yl)acrylonitrile (56-trans). 56-trans was
synthesized from cyanoacetic acid using 2.5 mmol of triethylamine.
General synthetic method B was used, with reaction time of 10 h. 56-cis:
white powder, 26 mg (14%). Mp 144ꢀ145 °C. LC/MS tR = 5.9 min,
1
m/z [MH+] 187. H NMR δ 11.90 (1H, bs, indole-H1), 8.17 (1H, s,
indole-H2), 7.82 (1H, dd, J = 8.7, 5.3 Hz, ArH), 7.64 (1H, d, J = 11.8 Hz,
HCdCH), 7.26 (1H, dd, J = 9.8, 2.3 Hz, ArH), 6.99 (1H, dt, 3J = 9.2 Hz,
4J = 2.3 Hz, ArH), 5.45 (1H, d, J = 11.8 Hz, HCdCH). 13C NMR δ
159.9 (d, JCF = 235.5 Hz), 141.4, 136.1 (d, JCF = 12.4 Hz), 128.1, 123.8,
120.3, 120.2 (d, JCF = 10.5 Hz), 111.7, 109.6 (d, JCF = 24.8 Hz), 98.9
(d, JCF = 24.8 Hz), 88.5. 56-trans: yellow powder, 69 mg (37%).
Mp 170ꢀ172 °C. LC/MS tR = 5.8 min, m/z [MH+] 187. 1H NMR δ
11.85 (1H, bs, indole-H1), 7.90 (1H, dd, J = 8.8, 5.4 Hz, ArH), 7.85
(1H, s, indole-H2), 7.68 (1H, d, J = 16.7 Hz, HC=CH), 7.23 (1H, dd,
Method B (Knoevenagel Condensation by Microwave Heating).
Method B is analogous to method A except that methanol (3 mL) was
used as the solvent instead of dioxane (in this case the reaction mixture
was typically a clear solution from the beginning) and microwave heating
at 150 °C in a sealed tube was applied for the reaction time indicated.
6-Fluoro-1H-indole-3-carbaldehyde (163 mg, 1 mmol) was used as the
starting material in all cases.
3
4
J = 9.9, 2.5 Hz, ArH), 6.98 (1H, dt, J = 9.3 Hz, J = 2.3 Hz, ArH),
6.05 (1H, d, J = 16.7 Hz, HCdCH). 13C NMR δ 159.8 (d, JCF = 235.5
Hz), 144.5, 137.9 (d, JCF = 12.4 Hz), 132.5, 121.8, 121.6 (d, JCF = 10.5
Hz), 121.0, 112.6, 109.8 (d, JCF = 24.8 Hz), 99.2 (d, JCF = 25.7
Hz), 89.6.
Method C (Tetrazole Synthesis). A literature procedure41,42 was
followed: anhydrous aluminum chloride (1.05 mol equiv) was suspended
5331
dx.doi.org/10.1021/jm2006782 |J. Med. Chem. 2011, 54, 5320–5334