The Journal of Organic Chemistry
Article
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a 250 mL round-bottom flask. The solution was cooled to 0 °C, and
NBS (10.147 g, 57.01 mmol) was added portionwise. The mixture was
stirred for 30 min at 0 °C, then warmed to room temperature, and
stirred for an additional 48 h. The reaction was quenched with
aqueous Na2S2O3 and extracted with ether. The extracts were
combined and washed, dried with MgSO4, filtered, and concentrated
to obtain approximately 10 g of crude material. This was purified by
column chromatography (hexanes), yielding a clear oil (7.373 g, 92%).
Data matched literature precedent.35 1H NMR (400 MHz, CDCl3): δ
7.91−7.79 (m, 2H), 7.56−7.35 (m, 3H). 13C NMR (101 MHz,
CDCl3): δ 138.4, 137.3, 125.1, 124.9, 123.4, 122.9, 122.6, 107.6.
HRMS (ESI-TOF) m/z [M]+ calcd for C8H5BrS = 211.9295, found =
211.9294. FTIR: ν = 3104, 3058, 1492, 1453, 1429, 1316, 1253, 1145,
1060, 1017, 929, 820 cm−1.
Synthesis of 3-Bromo-2-nitrobenzo[b]thiophene (3). To a 500 mL
round-bottom flask was added 3-bromobenzo[b]thiophene (12.795 g,
60.045 mmol) and 200 mL of acetic anhydride. The solution was
cooled to 0 °C, and a mixture of 25 mL of nitric acid and 20 mL of
acetic acid was added dropwise with vigorous stirring. A yellow
precipitate began to form after several minutes. Once the addition was
complete, the ice bath was removed and the reaction mixture stirred
for 2 h at room temperature. The mixture was then poured into ice
water and the resulting precipitate collected by filtration. The solid was
washed with water and crystallized from ethanol, yielding a fluffy
golden solid (4.926 g, 32%). Only the first crop of material contains
the desired product. Data matched literature precedent.36 Mp: 160−
162 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (ddd, J = 8.2, 7.2, 1.1
Hz, 1H), 7.73 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.99 (ddd, J = 8.2, 1.2,
0.7 Hz, 1H), 8.16 (ddd, J = 8.2, 1.4, 0.9 Hz, 1H). 13C NMR (101
MHz, DMSO-d6): δ 111.9, 123.8, 126.3, 127.3, 130.7, 136.5, 136.6,
145.9. HRMS (ESI-TOF) [M + H]+ calcd for C8H5BrNO2S =
257.9224, found = 257.9220. FTIR: ν = 3074, 1591, 1552, 1520, 1484,
1334, 1303, 1243, 917, 867, 803, 761, 740, 727, 710 cm−1.
184−185 °C (dec; sample darkened at 175 °C without melting). H
NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 7.70−7.48 (m, 6H),
7.39−7.30 (m, 1H), 6.89 (ddd, J = 8.4, 7.4, 1.2 Hz, 1H), 6.38 (dd, J =
8.2, 0.5 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 150.9, 142.2,
139.1, 134.4, 132.3, 131.8, 130.1, 128.8, 128.7, 126.6, 125.3, 123.8,
119.4, 106.6. HRMS [M + H]+ calcd for C16H11N2OS = 279.0592,
found = 279.0590. FTIR: ν = 3325, 3061, 2201, 1583, 1546, 1487,
1445, 1363, 1308, 1286, 1261, 1211, 1166, 988, 892, 766 cm−1.
Synthesis of (Z)-2-((Z)-2-(Dipentylcarbamoyloxyimino)benzo[b]-
thiophen-3(2H)-ylidene)-2-phenylacetonitrile (6a). To a 5 mL
round-bottom flask were added (Z)-2-((Z)-2-(hydroxyimino)benzo-
[b]thiophen-3(2H)-ylidene)-2-phenylacetonitrile (0.109 g, 0.392
mmol), dry THF (3 mL), and dipentylcarbamyl chloride (0.315 g,
1.43 mmol). This solution was cooled to −78 °C, and NaH (0.037 g,
60% mineral oil dispersion0.925 mmol) was added in one portion.
The reaction was then shielded from light and warmed to room
temperature. Stirring was continued for 3 h, at which point all starting
material was consumed, as determined by TLC. The reaction was then
quenched with water and diluted with ethyl acetate (50 mL). This was
washed three times with water and once with brine, dried over MgSO4,
filtered, and concentrated to obtain 0.286 g of crude material.
Crystallization from hexanes yielded carbamate as a yellow solid (0.077
g, 43%). Mp: 106−108 °C (dec; pronounced outgassing from the melt
was observed, suggesting carbamate thermolysis). 1H NMR (400
MHz, CD3CN): δ 7.66−7.46 (m, 5H), 7.42 (d, J = 7.9 Hz, 1H), 7.34
(t, J = 7.6 Hz, 1H), 6.88 (dd, J = 8.2, 7.3 Hz, 1H), 6.50 (d, J = 8.3 Hz,
1H), 3.33 (t, J = 7.1 Hz, 4H), 1.65 (d, J = 27.1 Hz, 4H), 1.38 (s, 8H),
0.94 (s, 6H). 13C NMR (101 MHz, CD3CN): δ 159.5, 153.2, 142.8,
139.2, 135.5, 133.4, 132.7, 131.3, 131.1, 129.4, 128.1, 126.8, 124.3,
119.5, 111.9, 49.1, 48.6, 29.8, 29.6, 29.3, 28.3, 23.2, 14.4. HRMS (ESI-
TOF) [M + Na]+ calcd for C27H31N3O2SNa = 484.2029, found =
484.2039. FTIR: ν = 2956, 2927, 2858, 2199, 1739, 1584, 1538, 1489,
1460, 1440, 1414, 1312, 1272, 1232, 1204, 1139, 1010, 972, 859, 757
cm−1.
Synthesis of 2-Nitrobenzo[b]thiophene (4). 3-Bromo-2-
nitrobenzo[b]thiophene (4.313 g, 16.71 mmol) and benzoic acid
(7.555 g, 61.87 mmol) were added to a 3-neck 100 mL round-bottom
flask. The solids were mixed thoroughly with a magnetic stir bar, and
the reaction was purged 3 times before heating to 150 °C. Under a
cone of nitrogen, copper powder (5.159 g, 81.19 mmol) was then
added to the melt. The reaction was stirred for an additional 30 min at
150 °C and then slowly cooled to room temperature. The resulting
solid was suspended in dichloromethane, and the residual copper was
removed by gravity filtration. The DCM solution was washed three
times with saturated NaHCO3, once with water, and once with brine.
This was then dried over MgSO4, filtered, and concentrated to obtain a
golden power (2.326 g, 78%). Data matched literature precedent.37−39
Mp: 109−112 °C. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 3.3 Hz,
1H), 7.93 (dd, J = 8.0, 2.5 Hz, 1H), 7.83 (dd, J = 8.2, 2.9 Hz, 1H),
7.61−7.53 (m, 1H), 7.49 (td, J = 7.6, 2.9 Hz, 1H). 13C NMR (101
MHz, CDCl3): δ 151.3, 140.3, 136.1, 129.1, 127.0, 126.1, 125.6, 122.9.
HRMS (ESI-TOF) [M]+ calcd for C8H5NO2S = 179.0041, found =
179.0044. FTIR: ν = 3098, 1594, 1558, 1516, 1496, 1451, 1424, 1346,
1315, 1250, 1190, 1160, 1126, 1081, 1052, 872, 849, 802, 757 cm−1.
Synthesis of (Z)-2-((Z)-2-(Hydroxyimino)benzo[b]thiophen-3(2H)-
ylidene)-2-phenylacetonitrile (5a). Potassium hydroxide (0.530 g,
9.44 mmol) was dissolved in 10 mL of methanol and added to a 50 mL
round-bottom flask. The solution was then cooled to 0 °C and benzyl
cyanide (0.276 g, 2.36 mmol) was added dropwise. 2-Nitrobenzo[b]-
thiophene (0.422 g, 2.36 mmol) was dissolved in 25 mL of methanol
and added dropwise to the reaction vessel. The solution immediately
became brilliant yellow and gradually darkened to a vibrant orange
color. The reaction was then protected from light by covering the flask
with aluminum foil and stirred overnight at room temperature. Upon
completion as determined by TLC, the reaction was poured into 200
mL of water and then acidified with 50% acetic acid/water. The
resulting suspension was extracted 3 times with ethyl acetate. The
extracts were combined, washed with water and brine, dried with
MgSO4, filtered, and concentrated to obtain 0.62 g of crude material.
Purification by column chromatography (20% ethyl acetate in
hexanes) yielded oxime as a yellow powder (0.389 g, 59%). Mp:
Formation of Photoproduct Benzo[4,5]thieno[2,3-b]quinoline-
11-carbonitrile (9a). To a quartz cuvette was added (Z)-2-((Z)-2-
(dipentylcarbamoyloxyimino)benzo[b]thiophen-3(2H)-ylidene)-2-
phenylacetonitrile (22.6 mg, 0.056 mmol) in acetonitrile (8 mL, 7
mM), and the mixture was exposed for 30 min through a 405 nm
bandpass filter. Upon completion, a solid had precipitated in solution,
which was filtered and washed with hexanes to give a pale yellow solid,
identified as benzo[4,5]thieno[2,3-b]quinoline-11-carbonitrile (11.7
1
mg, 92%). Mp: 208−213 °C. H NMR (500 MHz, CDCl3): δ 9.01
(ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 8.44 (ddd, J = 8.4, 1.4, 0.6 Hz, 1H),
8.25 (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.96−7.90 (m, 2H), 7.81 (ddd, J =
8.2, 6.9, 1.2 Hz, 1H), 7.69 (td, J = 7.6, 1.3 Hz, 1H), 7.64 (ddd, J = 7.9,
7.3, 1.3 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 162.8, 146.6, 139.8,
130.8, 130.4, 130.3, 129.2, 128.9, 128.1, 125.8, 125.14, 125.08, 124.1,
123.3, 115.3, 109.8. HRMS (ESI-TOF) (M+) calcd for C16H8N2S =
260.0408, found = 260.0408. FT-IR (neat): 2923, 2360 (strong), 1736,
1599, 1454, 1367, 1216, 1115, 844, 754 cm−1.
Synthesis of (Z)-2-((Z)-2-(((Dibenzylcarbamoyl)oxy)imino)benzo-
[b]thiophen-3(2H)-ylidene)-2-phenylacetonitrile (7a). To a 25 mL
round-bottom flask were added (Z)-2-((Z)-2-(hydroxyimino)benzo-
[b]thiophen-3(2H)-ylidene)-2-phenylacetonitrile (0.370 g, 1.329
mmol), dry THF (13 mL), and dibenzylcarbamyl chloride (1.208 g,
4.652 mmol). This solution was cooled to −78 °C, and NaH (0.080 g,
60% mineral oil dispersion3.3 mmol) was added in one portion.
The reaction was then shielded from light and warmed to room
temperature. Stirring was continued for 3 h, at which point all starting
material was consumed, as determined by TLC. The reaction was then
quenched with water and diluted with ethyl acetate (50 mL). This was
washed three times with water and once with brine, dried over MgSO4,
filtered, and concentrated to obtain 0.880 g of crude material.
Crystallization from hexanes yielded carbamate as a yellow solid (0.373
g, 56%). Mp: 172−175 °C. 1H NMR (400 MHz, CDCl3): δ 7.58−7.17
(m, 17H), 6.83 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 6.59 (d, J = 8.1 Hz,
1H), 4.49−4.62 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 158.6,
153.2, 141.6, 138.3, 136.5, 133.9, 132.1, 131.7, 130.3, 129.9, 128.8,
128.7, 127.8, 127.7, 127.3, 125.7, 123.0, 118.4, 112.0, 50.2, 49.3.
D
J. Org. Chem. XXXX, XXX, XXX−XXX