6
C. Carpenter et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
J = 5.4 Hz, 2H), 3.83 (t, J = 5.3 Hz, 2H). MS TOFES+: m/z 305.0, 307.0
acetate). MS TOFES+: m/z 411.1 (M+H)+. Upon standing at room
temperature (ꢀ1 month) the syrup crystallized. The solids were
triturated in a few mL of ethanol with sonication, collected, washed
with ethanol, and dried to leave an isomeric mixture of products
(150 mg, 23%) as a cream-colored powder, mp 135–142 °C, shown
by HPLC to be a 91:9 mixture of 3a/4a. 1H NMR (400 MHz, DMSO-
d6): d 7.47 (m), 7.43–7.36 (m), 7.33–7.21 (m), 6.88–6.82 (m), 6.81–
6.75 (m), 4.01 (t, J = 5.7 Hz), 3.53 (t, J = 4.7 Hz), 2.62 (t, J = 5.7 Hz),
2.41 (t, J = 4.7 Hz), remaining protons hidden under DMSO signal.
The mother liquor was concentrated to leave ꢀ400 mg of an iso-
meric mixture for further processing. Run 2: The above reaction
was repeated on starting ketone 2a (550 mg, 1.8 mmol) to give
crude product (700 mg, 97%) that was processed as above to leave
164 mg (23%) of a powder, mp 136–142°, shown by HPLC to be a
82:18 mixture of 3a/4a. The mother liquor was concentrated to
leave ꢀ530 mg of an isomeric mixture for further processing. To
a stirred solution of 100 mg (0.24 mmol) of the 82:18 mixture of
3a/4a from Run 2 in 5:1 ethanol/dichloromethane (6 mL) was
added HCl in ether (0.26 mL of 1 M solution). After 3 h the mixture
was concentrated to a glassy residue that eventually crystallized
after treatment with a few drops of methanol. The solids were col-
lected, washed with 2-propanol, and dried to give 3a hydrochloride
(54 mg, 50%) as a white powder; mp 200–202 °C; Rf 0.85 (97:3
methanol/conc. ammonium hydroxide); Rf 0.66 (85:15:2 ethyl
acetate/methanol/triethylamine). HPLC rt 6.1 min (98%), 6.3 min
(2%). 1H NMR (400 MHz, DMSO-d6): d 7.48 (m, 3H), 7.43–7.36 (m,
2H), 7.33–7.22 (m, 5H), 6.91 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz,
2H), 4.33 (t, J = 4.7 Hz, 2H), 3.93 (d, J = 13.0 Hz, 2H), 3.73 (t,
J = 12.2 Hz, 2H), 3.55–3.39 (m, 4H), 3.15 (d, J = 5.2 Hz, 2H); 1H
NMR (600 MHz, DMSO-d6): d 3.02–3.18 (m, 2H, (CHH)2N–), 3.29–
3.48a (m, 2H, (CHH)2N–)), 3.38–3.52a (m, 2H, NCH2CH2O), 3.69–
3.98 (m, 4H, (CH2)2O), 4.25–4.44 (m, 2H, NCH2CH2O), 6.68–6.84
(M+H)+.
6.1.2. Bis(4-(2-bromoethoxy)phenyl)methanone (1d)50
A
stirred suspension of 4,40-dihydroxybenzophenone (1c;
1.93 g. 9 mmol), 1,2-dibromoethane (15.5 mL, 180 mmol), cesium
carbonate (11.77 g, 36.1 mmol) and acetonitrile (66 mL) was
heated at reflux for 22 h. The suspension was filtered and the salts
washed well with dichloromethane. The combined filtrate was fil-
tered through a small pad of flash silica gel, washing the pad well
with dichloromethane. The filtrate was concentrated to a semisolid
that was diluted with 2-propanol. The suspension was heated for
ꢀ5 min and allowed to cool. The resulting solids were collected,
washed with 2-propanol, and dried to leave 2.3 g of 1d, mp 125–
127 °C. Upon standing for several days, additional product crystal-
lized from the mother liquor and was collected to give 130 mg of
1d, mp 120–125 °C. Total yield = 2.43 g (63%). 1H NMR (400 MHz,
DMSO-d6): d 7.73–7.64 (m, 4H), 7.13–7.04 (m, 4H), 4.45–4.37 (m,
4H), 3.87–3.79 (m, 4H). MS TOFES+: m/z 427.9 (M+), 428.9 (M+H)+.
6.1.3. (4-(2-Morpholinoethoxy)phenyl)(phenyl)methanone
(2a)51
A stirred suspension of 4-hydroxybenzophenone (1a; 750 mg,
3.8 mmol), 4-(2-chloroethyl)morpholine hydrochloride, (739 mg,
4 mmol), cesium carbonate (3.7 g, 11.4 mmol) and acetonitrile
(30 mL) was heated at reflux for 21 h. The mixture was poured into
250 mL of water and stirred overnight. The formed suspension was
collected, washed with water, and dried to give 2a (1.0 g, 85%) as
an off-white powder, mp 64–66 °C. Rf 0.61 (85:15:2 ethyl acet-
ate/methanol/triethylamine. 1H NMR (400 MHz, DMSO-d6):
d
7.75–7.60 (m, 5H), 7.53 (t, J = 7.5 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H),
4.17 (t, J = 5.7 Hz, 2H), 3.55 (t, J = 4.6 Hz, 4H), 2.70 (t, J = 5.7 Hz,
2H); remaining protons overlap DMSO peak. MS TOFES+: m/z
312.1 (M+H)+, 334.1 (M+Na)+.
0
0
(m, 2H, Ar H), 6.84–6.93 (m, 2H, Ar H), 7.15–7.32 (m, 5H, ArbH),
a
a
7.33–7.51 (m, 5H, Ar H); 1H NMR (600 MHz, DMSO-d6:CD3OD,
a
1:1 v:v): d 3.08–3.17 (m, 2H, (CHH)2N–), 3.36–3.46 (m, 2H, (CHH)2-
N–)), 3.46–3.52 (m, 2 H, NCH2CH2O), 3.65–3.78 (m, 2H, (CHH)2O),
3.85–3.98 (m, 2H, (CHH)2O), 4.22–4.28a (m, 2H, NCH2CH2O), 6.80
6.1.4. (4-(2-(Dimethylamino)ethoxy)phenyl)(phenyl)methanone
(2b)51
0
0
A
stirred mixture of (4-(2-bromoethoxy)phenyl)(phenyl)
(d, J = 8.1 Hz, 2H, Ar H), 6.88 (d, J = 8.1 Hz, 2H, Ar H), 7.21 (m,
a a
methanone (1b; 750 mg, 2.5 mmol), dimethylamine hydrochloride
(301 mg, 3.7 mmol), potassium carbonate (1.36 g, 9.8 mmol), and
acetone (10 mL) was heated at reflux for 16 h. The mixture was
concentrated to a solid residue that was partitioned between ethyl
acetate and water. The aqueous layer was further extracted with
ethyl acetate and the combined organic phases were washed
sequentially with water and sat. brine, dried and concentrated to
an oil that was purified by flash silica gel chromatography eluting
with 4:1 dichloromethane/methanol. Concentration of product
fractions left 2b (0.50 g, 76%) as a colorless syrup; Rf 0.25
(85:15:2 ethyl acetate/methanol/trimethylamine). 1H NMR
(400 MHz, DMSO-d6): d 7.71 (d, J = 8.3 Hz, 2H), 7.69–7.59 (m,
3H), 7.53 (t, J = 7.4 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 4.13 (t,
J = 5.7 Hz, 2H), 2.63 (t, J = 5.8 Hz, 2H), 2.20 (s, 6H). MS TOF-ES+:
m/z 270.2 (M+H)+.
5H, ArbH), 7.31–7.49 (m, 5H, Ar H); 13C NMR (150 MHz, DMSO-
a
d6): d 51.7, 54.9, 62.3, 63.2, 110.0, 114.4, 119.9, 128.5, 128.6,
128.8, 129.4, 129.6, 129.9, 131.2, 132.1, 134.7, 140.3, 157.1,
157.9; (apeaks overlapped with solvent, determined from HSQC).
The sticky semisolid from the above combined mother liquors
(ꢀ930 mg) was triturated in ethanol to leave solids that were col-
lected, washed well with ethanol, and dried to leave 250 mg of a
different mixture of isomers from above, as shown by TLC (95:5
dichloromethane/methanol), as an off-white powder; mp 123–
135 °C. The mixture was dissolved in 5 mL of 4:1 methanol/
dichloromethane, and anhydrous HCl in ether (0.7 mL of 1 M solu-
tion) was added. The mixture was stirred at room temperature for
18 h and concentrated to a solid residue, which was triturated in
several mL of 2-propanol, sonicated briefly, and stored overnight.
The solids were collected, washed with 2-propanol, and dried to
leave enriched 4a (165 mg), mp 144–169 °C; Rf 0.72 (97:3
methanol/conc. ammonium hydroxide); Rf 0.55 (95:5 dichloro-
methane/methanol). The product was recrystallized from 2–3 mL
of ethanol to leave highly pure 4a, hydrochloride (45 mg) as a beige
powder; mp 144–146 °C. HPLC: rt 6.1 min (6%), 6.3 min (94%). 1H
NMR (400 MHz, DMSO-d6): d 7.35 (d, J = 8.6 Hz, 2H), 7.27–7.17
(m, 8H), 7.04 (d, J = 8.4 Hz, 2H), 6.97 (dt, J = 6.8, 1.5 Hz, 2H),
4.25–4.15 (m, 2H), 3.65–3.58 (m, 4H), remaining protons hidden
under DMSO signal. 1H NMR (600 MHz, DMSO-d6): d 2.38–2.62a
(m, 4H, (CH2)2N–), 2.64–2.88 (m, 2H,NCH2CH2O), 3.50–3.84
(m, 4H, (CH2)2O), 4.03–4.47 (m, 2H, NCH2CH2O), 6.95–7.04 (m,
0
6.1.5. (E and Z)-3-(4-(2-Morpholinoethoxy)phenyl)-2,3-dipheny-
lacrylonitrile, hydrochloride (3a and 4a)
Run 1: The anion of phenylacetonitrile (32.1 mmol) in THF
(30 mL) was generated as described below for the synthesis of
6c. A solution of (4-(2-morpholinoethoxy)phenyl)(phenyl)metha-
none (2a; 500 mg, 1.6 mmol) in THF (5 mL) was added over a per-
iod of 5 min. After 30 min the cooling bath was removed and the
mixture warmed gradually to room temperature. After stirring
for 48 h, the mixture was poured into 150 mL of 2 N aq HCl and
further worked up as described below for 6c below to leave a crude
mixture by NMR of 3a and 3b (570 mg, 86%) as a syrup; Rf 0.44
(85:15:2 ethyl acetate/methanol/trimethylamine); Rf 0.18 (ethyl
2H, Ar H), 7.05–7.12 (m, 2H, Ar H), 7.18–7.34 (m, 8H, Ar H, ArbH),
7.35–7.44 (m, 2H, Ar H); H NMR (600 MHz, DMSO-d6:CD3OD, 1:1
a
a
a
1
0
a