P. Wang et al. / Tetrahedron 66 (2010) 5402e5406
5405
by cold water and dried to give formamide 15 (4.6 g, 90%), which
was used for next step without further purification; mp:
(m, 6H, ArH), 6.97e7.00 (m, 3H, ArH), 7.07 (d, J¼8 Hz, 2H, ArH),
7.18e7.31 (m, 11H, ArH), 7.34e7.38 (m, 1H, ArH), 7.43e7.47 (m, 2H,
103e104 ꢁC; 1H NMR (400 MHz, CDCl3)
d
: 3.94(s, 3H, OCH3),
7.37e7.39 (m, 2H, ArH), 7.50e7.55 (m, 1H, ArH), 8.03 (br s, 1H, NH),
8.54e8.56 (m, 1H, NCOH); 13C NMR (100 MHz, CDCl3)
: 52.7, 112.1,
ArH), 7.91 (dd, J¼1.2, 7.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3)
d:
14.6, 45.1, 52.5, 63.0, 82.9, 116.9, 124.3, 126.4, 126.5, 127.5, 127.6,
128.0, 128.2, 128.5, 129.4, 129.9, 130.2, 130.3, 130.6, 134.9, 137.5,
d
124.8, 126.5, 128.1, 133.2, 135.9, 159.1, 166.6; HRMS (ESI): calcd for
140.2, 141.2, 141.8, 148.2, 152.4, 164.0, 167.7; IR (film, cmꢃ1
)
C9H8BrNNaO3 [MþNa]þ: 279.9580, found 279.9589.
nmax¼3424, 3029, 2924, 1732, 1654, 1458, 1333, 1291, 1241, 1192,
1143,1064,1028, 816, 754, 702; HRMS (ESI): calcd for C44H38BrN6O3
[MþH]þ: 777.2183, found 777.2207.
4.1.4. Methyl 2-bromo-3-(dichloromethyleneamino)benzoate (16).
Under a blanket of argon, sulfuryl chloride (4 g, 30 mmol) was added
to a solution of formamide 15 (2.58 g, 10 mmol) in thionyl chloride
(10 ml) at 0 ꢁC. The mixture was allowed to warm to room temper-
ature and stirred for 24 h. After removal of the solvent under reduced
pressure, the residue was slowly poured into ice-cold water and
extracted with ethyl acetate (100 mlꢂ2). The combined organic layer
was washed with water, satd NaHCO3 solution and brine, dried over
MgSO4, filtered, and evaporated in vacuo. The residue was applied to
flash column chromatography (silica gel) to afford 16 (2.48 g, 80%) as
4.1.8. (E)-2-Bromo-3-(ethoxy((20-(1-trityl-1H-tetrazol-5-yl)bi-
phenyl-4-yl)methylamino)methyleneamino)benzoic acid (19). To
a solution of 18 (1 g, 1.29 mmol) in DMF (5 ml) was added powdered
sodium hydroxide (0.3 g, 7.5 mmol) at room temperature and stirred
for 5 h. The mixture was acidified with acetic acid. After stirring for
further 15 min, the reaction mixture was extracted with ethyl acetate
(50 mlꢂ3). The combined organic layer was washed with water and
brine, dried over MgSO4, filtered, and evaporated in vacuo. The
residue was applied to flash column chromatography (silica gel) to
a colorless oil; 1H NMR (400 MHz, CDCl3)
(dd, J¼1.6, 8.0 Hz,1H, ArH), 7.39 (t, J¼8.0 Hz,1H, ArH), 7.58 (dd, J¼1.6,
5.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3)
: 52.7, 113.2, 123.1,
d: 3.95 (s, 3H, OCH3), 7.00
give 19 (0.9 g, 92%) as a colorless oil; 1H NMR (400 MHz, CDCl3)
d:
d
1.33 (t, J¼6.8 Hz, 3H, CH3), 4.15 (s, 2H, NCH2), 4.44 (q, J¼6.8 Hz, 2H,
OCH2), 6.87e6.88 (m, 6H, ArH), 6.92e7.10 (m, 6H, ArH), 7.18e7.35 (m,
11H, ArH), 7.44e7.45 (m, 2H, ArH), 7.87 (d, J¼7.2 Hz, 1H, ArH).
127.8, 127.9, 131.5, 134.2, 146.0, 166.5; HRMS (ESI): calcd for
C9H6BrCl2NNaO2 [MþNa]þ: 331.8851, found 331.8857.
4.1.5. Methyl 2-bromo-3-(diethoxymethyleneamino)benzoate (17a).
The mixture of 14 (1.38 g, 6 mmol), tetraethoxymethane (1.73 g,
9 mol), and a drop of acetic acid was stirred and heated to 120 ꢁC for
1.5 h, meanwhile the by-product (ethanol) was removed. After
cooling, the mixture was diluted with water and extracted with ethyl
acetate (50 mlꢂ2). The combined organic layer was washed with
water and brine, dried over MgSO4, filtered, and evaporated in vacuo.
The residue was applied to flash column chromatography (silica gel)
to afford 17a (1.5 g, 75%) as a colorless oil; 1H NMR (400 MHz, CDCl3)
4.1.9. (ꢀ)-1-(Cyclohexyloxycarbonyloxy)ethyl
2-bromo-3-(ethoxy
((20-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyl-
eneamino)benzoate (20). Method A: To a solution of 19 (1 g,
1.31 mmol) in DMF (5 ml) was added powdered sodium hydroxide
(0.052 g, 1.31 mmol) at room temperature and stirred for 30 min, 1-
chloroethyl cyclohexyl carbonate (0.54 g, 2.62 mmol) was added
and the mixture was heated to 70 ꢁC for 8 h. The mixture was di-
luted with water and extracted with ethyl acetate (50 mlꢂ3). The
combined organic layer was washed with water and brine, dried
over MgSO4, filtered, and evaporated in vacuo. The residue was
applied to flash column chromatography (silica gel) to afford col-
orless oil 20 (0.92 g, 75%).
d: 1.32e1.35 (m, 6H, 2CH3), 3.91 (s, 3H, OCH3), 4.24e4.28 (m, 4H,
2OCH2), 7.06 (dd, J¼8.0, 1.6 Hz, 1H, ArH), 7.21 (t, J¼7.6 Hz, 1H, ArH),
7.30 (dd, J¼7.6, 1.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3)
d: 14.6
(2C), 52.4 (2C), 64.7,116.6,124.3,126.4,127.1,133.9,147.2,151.0,167.7;
IR (film, cmꢃ1): 2988, 2920, 2364, 2328, 1736, 1682, 1575, 1444,1405,
1372, 1309, 1196, 1145, 1076, 1034, 810, 761, 718; HRMS (ESI): calcd
for C13H16BrNNaO4 [MþNa]þ: 352.0155, found 352.0159.
Method B: To a solution of 18 (1 g, 1.29 mmol) in DMF (5 ml) was
added powdered sodium hydroxide (0.1 g, 2.5 mmol) at room
temperature and stirred for 5 h, 1-chloroethyl cyclohexyl carbonate
(0.53 g, 2.58 mmol) was added and the mixture was heated to 70 ꢁC
for 8 h. The mixture was diluted with water and extracted with
ethyl acetate (50 mlꢂ3). The combined organic layer was washed
with water and brine, dried over MgSO4, filtered, and evaporated in
vacuo. The residue was applied to flash column chromatography
(silica gel) to afford colorless oil 20 (0.84 g, 70%); 1H NMR
4.1.6. Ethyl 2-bromo-3-(diethoxymethyleneamino)benzoate (17b).
Under a blanket of argon, sodium ethoxide (2.04 g, 30 mmol) was
added to a solution of 16 (3.1 g, 10 mmol) in anhydrous ethanol
(10 ml) at room temperature and stirred for 24 h. the mixture was
diluted with water and extracted with ethyl acetate (100 mlꢂ2).
The combined organic layer was washed with water and brine,
dried over MgSO4, filtered, and evaporated in vacuo. The residue
was applied to flash column chromatography (silica gel) to afford
(400 MHz, CDCl3) d: 1.25e1.38 (m, 5H, CH2 and CH3), 1.44e1.53 (m,
4H, 2CH2), 1.68 (d, J¼5.6 Hz, 3H, CH3), 1.72e1.73 (m, 2H, CH2),
1.90e1.93 (m, 2H, CH2), 3.93e3.95 (m, 1H, OCH), 4.21 (d, J¼5.6 Hz,
2H, NCH2), 4.38 (q, J¼6.8 Hz, 2H, OCH2), 4.64e4.67 (m, 1H, OCH),
6.88e6.90 (m, 6H, ArH), 6.96e7.01(m, 4H), 7.06e7.08 (m, 2H, ArH),
7.15e7.49 (m, 14H, ArH), 7.92 (d, J¼7.2 Hz, 1H, ArH); 13C NMR
17b (2.9 g, 83%) as a colorless oil; 1H NMR (400 MHz, CDCl3)
d:
1.30e1.34 (m, 6H, 2CH3), 1.39 (t, J¼7.2 Hz, 3H, CH3), 4.25e4.30 (m,
4H, 2OCH2), 4.39 (t, J¼7.2 Hz, 3H, CH3), 7.04(d, J¼6.8 Hz, 1H, ArH),
7.20 (t, J¼7.6 Hz, 1H, ArH), 7.27 (d, J¼6.8 Hz, 1H, ArH).
(100 MHz, CDCl3) d: 14.6, 19.6, 23.6, 25.2, 29.7, 31.4, 31.5, 45.1, 63.0,
77.6, 82.9, 92.1, 117.3, 124.8, 126.4, 126.6, 127.1, 127.5, 127.6, 128.0,
128.2, 129.4, 130.2, 130.3, 130.6, 133.6, 137.5, 140.2, 141.2, 141.8,
4.1.7. (E)-Methyl
2-bromo-3-(ethoxy((20-(1-trityl-1H-tetrazol-5-yl)
152.4, 152.5, 164.0, 164.8; IR (film, cmꢃ1
)
nmax¼3421, 3028, 2927,
biphenyl-4-yl)methylamino)methyleneamino)benzoate (18). The mix-
ture of 17a (1.98 g, 6 mmol) and (20-(1-trityl-1H-tetrazol-5-yl)
biphenyl-4-yl)methanamine (2.47 g, 5 mmol) in toluene (5 ml) was
stirred and heated to 100 ꢁC for 3 h. The mixture was diluted with
water and extracted with ethyl acetate (100 mlꢂ2). The combined
organic layer was washed with water and brine, dried over MgSO4,
filtered, and evaporated in vacuo. The residue was applied to flash
column chromatography (silica gel) to give compound 18 (2.52 g,
2365, 2329,1756, 1656, 1456, 1288, 1239, 1070, 912, 754, 703; HRMS
(ESI): calcd for C52H50BrN6O6 [MþH]þ: 933.2970, found 933.2941.
4.1.10. (ꢀ)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-((20-(1-
trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-benzo[d]imidazole-
4-carboxylate (21). Under a blanket of argon, the mixture of 20
(3.5 g, 3.75 mmol), copper iodide (0.35 g, 1.88 mmol), potassium
carbonate (0.1 g, 7.25 mmol), and L-proline (0.45 g, 3.75 mmol) in
65%) as a colorless oil; 1H NMR (400 MHz, CDCl3)
d
: 1.36 (t,
DMSO (20 ml) was stirred and heated to 70 ꢁC for 3 h. The mixture
was diluted with water and extracted with ethyl acetate
(150 mlꢂ2). The combined organic layer was washed with water
J¼6.8 Hz, 3H, CH3), 3.91 (s, 3H, OCH3), 3.95 (d, J¼5.6 Hz, 1H, NH),
4.21 (d, J¼5.6 Hz, 2H, NCH2), 4.38(q, J¼6.8 Hz, 2H, OCH2), 6.87e6.89