The Journal of Organic Chemistry
Page 10 of 13
in petroleum ether) to give the titled product as a white solid (20
seen in the 13C{1H} NMR spectrum. HRMS (ESI) calcd for
+
1
2
3
4
5
6
7
8
mg, 59%). 1H NMR (600 MHz, CDCl3) δ 7.56 (dd, J = 6.0, 3.2 Hz,
2H, HAr), 7.21 (dd, J = 6.0, 3.1 Hz, 2H, HAr), 3.80 (p, J = 8.7 Hz,
1H, CCH), 2.58 – 2.47 (m, 2H, CHa + CHb), 2.47 – 2.38 (m, 2H,
CHa’ + CHb’), 2.14 – 2.01 (m, 1H, CHc), 1.99 – 1.91 (m, 1H, CHc’);
13C{1H} NMR (151 MHz, CDCl3) δ 158.1 (CAr), 138.6 (br, CAr),
122.3 (CArH), 114.8 (br, CArH), 34.3 (CCH), 28.2 (Ca + Cb), 18.8
C13H17N2 [M+H]+ 201.1386, found 201.1379. IR ν max (film):
3074, 2968, 2932, 2736, 1818, 1640, 1538, 1454, 1426, 1330, 1272,
989, 906, 745, 729 cm-1. M.p.: 182 – 185 °C.
2-(4,4-Dimethylhept-6-yn-2-yl)-1H-benzimidazole (5o)
General Procedure C was followed using 2-(2,2-dimethylpent-
4-yn-1-yl)-5-methoxy-2,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole
(45 mg, 0.2 mmol, 1.0 eq.), formaldehyde (0.16 mL, 37 wt% in
H2O, 2.0 mmol, 10 eq.) and o-phenylenediamine (32 mg, 0.3 mmol,
1.5 eq.). The crude mixture was purified via flash column chroma-
tography (10 – 40% EtOAc in petroleum ether) to give the titled
product as a white solid (19 mg, 39%). 1H NMR (600 MHz, CDCl3)
δ 9.68 (br s, 1H, NH), 7.71 (br s, 1H, HAr), 7.38 (br s, 1H, HAr),
7.21 (dd, J = 6.2, 2.9 Hz, 2H, HAr), 3.29 – 3.21 (m, 1H, CCHCH3),
2.12 (dd, J = 14.4, 8.9 Hz, 1H, CHCCHb), 2.07 (dd, J = 16.2, 3.2
Hz, 1H, CHCCHa), 2.02 – 1.93 (m, 2H, CHCCH2 + CHCCHa’),
1.72 (dd, J = 14.4, 4.0 Hz, 1H, CHCCHb’), 1.44 (d, J = 7.1 Hz, 3H,
CHCH3), 0.92 (d, J = 17.9 Hz, 6H, C(CH3)2); 13C{1H} NMR (151
MHz, CDCl3) δ 159.7 (CAr), 122.3 (br, CArH), 110.7 (br, CArH),
82.6 (CHCCH2), 70.5 (CHCCH2), 47.1 (Cb), 34.0 (C(CH3)2), 31.9
(Ca), 31.2 (CCHCH3), 27.3 (C(CH3)2), 27.1 (C(CH3)2), 23.3
(CCHCH3). One aromatic carbon is not seen in the 13C{1H} NMR
+
(Cc). HRMS (ESI) calcd for C11H13N2 [M+H]+ 173.1073, found
173.1069. IR ν max (film): 2942, 1537, 1455, 1419, 1328, 1272,
982, 740 cm-1. M.p.: 186 – 188 °C. The data presented are con-
sistent with literature precedent.46
9
2-[1-(Pyridin-4-yl)propan-2-yl]-1H-benzimidazole (5l)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure C was followed using 2-methoxy-2,5-dime-
thyl-5-(pyridin-4-ylmethyl)-2,5-dihydro-1,3,4-oxadiazole (44 mg,
0.2 mmol, 1.0 eq.), formaldehyde (0.16 mL, 37 wt% in H2O, 2.0
mmol, 10 eq.) and o-phenylenediamine (32 mg, 0.3 mmol, 1.5 eq.).
The crude mixture was purified via flash column chromatography
(10 – 100% EtOAc in petroleum ether) to give the titled product as
a yellow solid (23 mg, 48%). 1H NMR (600 MHz, CDCl3) δ 10.14
(br s, 1H, NH), 8.40 – 8.36 (m, 2H, HPyridine), 7.73 (br s, 1H, HAr),
7.34 (br s, 1H, HAr), 7.23 (s, 2H, HAr), 7.00 – 6.98 (m, 2H, HPyridine),
3.35 (p, J = 7.0 Hz, 1H, CCH), 3.28 (dd, J = 13.4, 7.5 Hz, 1H,
CHCHa), 3.00 (dd, J = 13.4, 6.8 Hz, 1H, CHCHa’), 1.47 (d, J = 6.9
Hz, 3H, CH3); 13C{1H} NMR (151 MHz, CDCl3) δ 157.3 (CAr),
149.5 (CPyridineH), 148.8 (CPyridine), 143.1 (br, CAr), 124.5 (CPyridineH),
122.3 (br, CArH), 110.5 (br, CArH), 41.8 (Ca), 35.9 (CCH), 19.4
(CH3). HRMS (ESI) calcd for C15H16N3+ [M+H]+ 238.1344, found
238.1344. IR ν max (film): 3051, 2969, 1603, 1559, 1535, 1484,
1454, 1419, 1328, 1272, 1219, 1110, 1070, 1043, 993, 907, 843,
795, 768, 747 cm-1. M.p.: 188 – 190 °C.
+
spectrum. HRMS (ESI) calcd for C16H21N2 [M+H]+ 241.1699,
found 241.1690. IR ν max (film): 3311, 2965, 2752, 2367, 1538,
1453, 1424, 1335, 1269, 994, 746 cm-1. M.p.: 191 – 192 °C.
2-(1-Cyclopropylethyl)-1H-benzimidazole (5p)
General Procedure C was followed using 2-cyclopropyl-5-
methoxy-2,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole (34 mg, 0.2
mmol, 1.0 eq.), formaldehyde (0.16 mL, 37 wt% in H2O, 2.0 mmol,
10 eq.) and o-phenylenediamine (32 mg, 0.3 mmol, 1.5 eq.). The
crude mixture was purified via flash column chromatography (10 –
40% EtOAc in petroleum ether) to give the titled product as a white
solid (26 mg, 69%). 1H NMR (600 MHz, CDCl3) δ 9.49 (br s, 1H,
NH), 7.73 (br s, 1H, HAr), 7.41 (br s, 1H, HAr), 7.22 (dd, J = 6.1,
3.1 Hz, 2H, HAr), 2.36 (dq, J = 9.6, 7.0 Hz, 1H, CCH), 1.56 (d, J =
7.0 Hz, 3H, CH3), 1.10 (dddd, J = 13.0, 9.6, 8.0, 4.9 Hz, 1H,
CHCHCH2), 0.71 – 0.63 (m, 2H, CHa + CHa’), 0.44 – 0.38 (m, 1H,
CHb), 0.36 – 0.30 (m, 1H, CHb’); 13C{1H} NMR (151 MHz, CDCl3)
δ 158.7 (CAr), 143.4 (br, CAr), 133.5 (br, CAr), 122.3 (CArH), 119.4
(br, CArH), 110.4 (br, CArH), 39.5 (CCH), 19.0 (CH3), 16.6
2-[1-(Furan-2-yl)propan-2-yl]-1H-benzimidazole (5m)
General Procedure
C was followed using 2-(furan-2-
ylmethyl)-5-methoxy-2,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole
(42 mg, 0.2 mmol, 1.0 eq.), formaldehyde (0.15 mL, 37 wt% in
H2O, 2 mmol, 10 eq.) and o-phenylenediamine (32 mg, 0.3 mmol,
1.5 eq.). The crude mixture was purified via flash column chroma-
tography (10 – 40% EtOAc in petroleum ether) to give the titled
product as a white solid (34 mg, 75%). 1H NMR (600 MHz, CDCl3)
δ 7.53 (dd, J = 6.1, 3.2 Hz, 2H, HAr), 7.30 – 7.27 (m, 1H, HFuran),
7.23 – 7.18 (m, 2H, HAr), 6.24 (dd, J = 3.2, 1.9 Hz, 1H, HFuran), 5.96
(d, J = 3.2 Hz, 1H, HFuran), 3.51 (h, J = 7.1 Hz, 1H, CCH), 3.24 (dd,
J = 15.0, 7.2 Hz, 1H, CHCHa), 3.06 (dd, J = 15.0, 7.2 Hz, 1H,
CHCHa’), 1.48 (d, J = 7.0 Hz, 3H, CHCH3); 13C{1H} NMR (151
MHz, CDCl3) δ 158.1 (CFuran), 153.3 (CAr), 141.5 (CFuranH), 122.4
(CArH), 115.1 (br, CArH), 110.5 (CFuranH), 107.1(CFuranH), 34.6 (Ca),
34.1 (CCH), 19.3 (CH3). One aromatic carbon is not seen in the
13C{1H} NMR spectrum. HRMS (ESI+): m/z calcd for
C14H15N2O+ [M+H]+: 227.1177, found 227.1184. IR ν max (film):
2921, 1423, 1275, 1009, 993, 932, 743 cm-1. M.p.: 180 – 182 °C.
+
(CCHCH), 4.8 (Ca), 4.4 (Cb); HRMS (ESI) calcd for C12H15N2
[M+H]+ 187.1230, found 187.1221. IR ν max (film): 2969, 2317,
2135, 1456, 1414, 1274, 1076, 744 cm-1. M.p.: 187 – 189 °C.
Synthesis of aldehydes from aryl hydrazones
General Procedure D for the synthesis of aldehydes from aryl
hydrazones
Conditioning phase: A solution of triethylamine in MeOH (5
mL, 20% v/v) was passed through the column reactor (Omnifit®
column, 6.6 mm i.d. × 50 mm length), packed with activated MnO2
(1.0 g), at a flow rate of 1.0 mL/min for 5 min (phase 1) and the
reactor output was monitored using a Flow-IR® device. The flow
was switched to EtOAc for 10 min (phase 2). The column was then
ready for the generation of the diazo compound.
2-(Hex-5-en-2-yl)-1H-benzimidazole (5n)
General Procedure C was followed using 2-(but-3-en-1-yl)-5-
methoxy-2,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole (37 mg, 0.2
mmol, 1.0 eq.), formaldehyde (0.16 mL, 37 wt% in H2O, 2.0 mmol,
10 eq.) and o-phenylenediamine (32 mg, 0.3 mmol, 1.5 eq.). The
crude mixture was purified via flash column chromatography (10 –
40% EtOAc in petroleum ether) to give the titled product as a white
solid (29 mg, 73%). 1H NMR (600 MHz, CDCl3) δ 10.18 (br s, 1H,
NH), 7.55 (br s, 2H, HAr), 7.21 (dd, J = 6.0, 3.1 Hz, 2H, HAr), 5.75
(ddt, J = 17.0, 10.2, 6.6 Hz, 1H, CH2=CH), 4.97 (dd, J = 17.0, 1.8
Hz, 1H, Ha), 4.93 (dd, J = 10.2, 1.8 Hz, 1H, Hb), 3.14 (h, J = 7.0
Hz, 1H, CCH), 2.14 – 2.05 (m, 2H, CH2=CHCH2), 2.04 – 1.97 (m,
1H, CCHCHc), 1.85 – 1.77 (m, 1H, CCHCHc’), 1.45 (d, J = 7.1 Hz,
3H, CH3); 13C{1H} NMR (151 MHz, CDCl3) δ 159.3 (CAr), 137.9
(CH2=CH), 122.3 (CArH), 115.3 (CH2=CH), 35.6 (Cc), 34.2 (CCH),
31.6 (CH2=CHCH2), 19.8 (CH3). Two aromatic carbons are not
Generation phase: A solution of hydrazone (2 mmol, 0.1 M) in
EtOAc (20 mL) was passed through a conditioned column reactor
(Omnifit® column, 6.6 mm i.d. × 50 mm length) (phase 3) at a flow
rate of 1.0 mL/min. When the Mettler Toledo FlowIR® instrument
(SiComp head) showed that the intensity of the diazo peak (region
2060 – 2080 cm-1) was stable, 4 mL of the stream of diazo was
combined with 4 mL of aqueous formaldehyde (37 wt%, 1.0
mL/min) in a UQ5102 Uniqsis Glass Static Mixer at room temper-
ature. The output stream was extracted with extra EtOAc (20 mL ×
2) and washed with water (20 mL). The combined organic phase
was dried over MgSO4, concentrated under vacuum and purified
ACS Paragon Plus Environment