The Journal of Organic Chemistry
Article
1,5-Diethyl-1H-tetrazole 2m.14,40 Following the general proce-
dure A, a solution of 3-pentanone 1m (34.5 mg, 0.400 mmol, 1.0
equiv) and TMSN3 (115 mg, 1.00 mmol, 2.5 equiv) in HFIP (1.0 mL)
was treated with triflic acid (31.9 μL, 0.360 mmol, 0.90 equiv). The
reaction mixture was stirred at room temperature for 6 h.
Concentration, followed by quenching with triethylamine (≈0.05
mL), and purification using a 12 g flash column on an automated
MPLC system (0−10% MeOH/DCM over 55 min) afforded tetrazole
2m (eluted between 1.1 and 1.9% MeOH/DCM) as a pale yellow oily
solid (33.6 mg, 0.266 mmol, 66% yield). Tetrazole 2m: Rf = 0.50 (2%
MeOH/DCM); IR (neat) 2985, 1521, 1456, 1426, 1094, 1066 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.39 (t, J = 7.6 Hz, 3H), 1.51 (t, J =
3.67 (ddd, J = 15.4, 6.2, 3.5 Hz, 1H), 5.46 (dd, J = 6.1, 3.5 Hz, 1H),
6.87 (br s, 1H), 7.09 (dd, J = 8.1, 0.9 Hz, 1H), 7.22 (td, J = 7.5, 1.0 Hz,
1H), 7.34−7.42 (m, 5H), 7.48 (m, 1H), 7.87 (dd, J = 7.8, 1.7 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 46.6, 86.0, 122.7, 124.0, 126.1, 126.5,
128.8, 128.9, 131.2, 133.6, 139.2, 154.8, 171.0; HRMS (ESI) m/z calcd
for C15H14NO2 [M + H]+ 240.1025, found 240.1012. Lactam 3nb: Rf
= 0.21 (30% EtOAc/hexanes); IR (neat) 3214, 1673, 1597, 1497
cm−1; 1H NMR (500 MHz, CDCl3) δ 2.99 (ddd, J = 14.8, 4.1, 0.8 Hz,
1H), 3.09 (dd, J = 14.8, 8.8 Hz, 1H), 5.66 (dd, J = 8.8, 4.1 Hz, 1H),
6.95−6.98 (m, 1H), 7.05−7.13 (complex, 3H), 7.34−7.44 (complex,
6H); 13C NMR (125 MHz, CDCl3) δ 42.1, 83.3, 122.1, 123.8, 124.6,
126.2, 126.3, 128.8, 128.9, 130.2, 140.2, 148.4, 171.1; HRMS (ESI) m/
z calcd for C15H14NO2 [M + H]+ 240.1025, found 240.1039.
Iminoether 5: Rf = 0.78 (20% EtOAc/hexanes); IR (neat) 1685,
7.3 Hz, 3H), 2.84 (q, J = 7.6 Hz, 2H), 4.28 (q, J = 7.3 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 11.6, 15.1, 16.9, 42.2, 155.5; HRMS (ESI)
m/z calcd for C5H11N4 [M + H]+ 127.0984, found 127.0961. A small
amount of impure amide was also obtained during this purification.
6-Phenyl-5,6-dihydrobenzo[f ]tetrazolo[1,5-d][1,4]oxazepine
2n,18a 2-Phenyl-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
3na,18a 2-Phenyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one
3nb,18a 5-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-2-phenyl-
2,3-dihydrobenzo[f ][1,4]oxazepine 5, (E)-2-Azido-5-phenyl-
4,5-dihydro-1H-benzo[b][1,4,6]oxadiazocine 6, and 2-(Benzo-
[d]oxazol-2-ylamino)-1-phenylethan-1-ol 7. Following the gen-
eral procedure A, a solution of flavanone 1n (89.7 mg, 0.400 mmol, 1.0
equiv) and TMSN3 (115 mg, 1.00 mmol, 2.5 equiv) in HFIP (1.0 mL)
was treated with triflic acid (35.4 μL, 0.400 mmol, 1.0 equiv). The
reaction mixture was stirred at room temperature for 5 h. Reaction
mixture was concentrated under nitrogen, the residue obtained was
diluted with a hexanes−DCM mixture, and loaded on silica gel in a 5 g
sample cartridge. Purification using a 12 g flash column on an
automated MPLC system (0−90% EtOAc/hexanes over 55 min)
afforded iminoether 5 (eluted between 100% hexanes) as a colorless
oil (28.1 mg, 0.0722 mmol, 18% yield), tetrazole 2n (eluted between
3.0 and 5.0% EtOAc/hexanes) as a colorless amorphous solid (52.0
mg, 0.197 mmol, 49% yield), an impure mixture of guanyl azide 6 and
lactam 3nb (eluted between 15 and 35% EtOAc/hexanes), and an
impure mixture of aminobenzoxazole 7 and lactam 3na (eluted
between 40 and 60% EtOAc/hexanes). Recrystallization of 2n from
EtOAc afforded colorless, thick plate-like crystals. The impure mixture
of guanyl azide 6 and lactam 3nb was purified by preparative TLC
developing two times with 30% EtOAc/hexanes. Bands corresponding
to 6 and 3nb were scraped from the plate and separately eluted with
1% MeOH/DCM through a phase separator tabless. Concentration
afforded 6 as a pale orange amorphous solid (8.5 mg, 0.030 mmol, 8%
yield) and 3nb as a colorless waxy solid film (1.1 mg, 0.0046 mmol,
∼1% yield). Recrystallization of 6 from DCM−hexanes afforded
colorless, thread-like, fine crystals. Similarly, the impure mixture of
aminobenzoxazole 7 and lactam 3na was purified by preparative TLC
developing two times with 40% EtOAc/hexanes. Bands corresponding
to 7 and 3na were scraped from the plate and separately eluted with
2% MeOH/DCM through a phase separator tabless. Concentration
afforded a slightly impure sample of 7 as a colorless waxy solid film
(2.8 mg, 0.011 mmol, ∼3% yield) and 3na as colorless viscous oil (7.0
mg, 0.029 mmol, 7% yield). Recrystallization of 7 from EtOAc−
hexanes mixture afforded partial recrystallization into almost colorless,
thin plate-like crystals and a pale brownish residue. Crystals were
utilized for acquiring a single-crystal X-ray diffraction data and for
determining the melting point. Recrystallization of 3na from DCM
afforded partially crystalline, off-white waxy solid. Tetrazole 2n: Rf =
0.33 (20% EtOAc/hexanes); mp 124.5−126.5 °C (lit.16 mp 136−137
°C and lit.18a mp 137−138 °C); IR (neat) 1609, 1484, 1045 cm−1; 1H
NMR (400 MHz, CDCl3) δ 4.83 (dd, J = 14.6, 9.8 Hz, 1H), 5.12 (dd, J
= 14.6, 1.5 Hz, 1H), 5.26 (dd, J = 9.8, 1.3 Hz, 1H), 7.18 (dd, J = 8.3,
1.0 Hz, 1H), 7.26 (m, 1H), 7.44−7.56 (m, 6H), 8.57 (dd, J = 8.0, 1.7
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 56.4, 79.1, 113.1, 121.7,
124.2, 126.2, 129.3, 129.4, 130.5, 133.4, 136.5, 152.1, 157.0; HRMS
(ESI) m/z calcd for C15H13N4O [M + H]+ 265.1089, found 265.1071.
Lactam 3na: Rf = 0.34 (50% EtOAc/hexanes); mp 122.5−125.5 °C
(lit.18a mp 125−126 °C); IR (neat) 3222, 1654, 1603, 1459, 1209
cm−1; 1H NMR (500 MHz, CDCl3) δ 3.54 (dt, J = 15.4, 5.8 Hz, 1H),
1
1605, 1223, 1190, 1105 cm−1; H NMR (400 MHz, CDCl3) δ 3.96
(dd, J = 15.5, 7.8 Hz, 1H), 4.05 (dd, J = 15.5, 2.2 Hz, 1H), 5.35 (dd, J
= 7.8, 2.2 Hz, 1H), 6.51 (hept, J = 6.5 Hz, 1H), 7.16−7.21 (m, 2H),
7.38−7.43 (m, 1H), 7.45 (m, 4H), 7.50 (m, 1H), 7.91 (dd, J = 7.9, 1.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 54.9, 66.2−67.6 (p, J =
135.1 Hz, 1C), 85.7, 118.2, 120.1, 121.9, 122.7, 122.9, 126.3, 128.5,
128.9, 129.8, 133.7, 139.5, 155.4, 158.2; HRMS (ESI) m/z calcd for
C18H14F6NO2 [M + H]+ 390.0929, found 390.0900. Guanyl azide 6: Rf
= 0.43 (30% EtOAc/hexanes); mp 99.5−101 °C; IR (neat) 3209,
1
2101, 1643, 1583, 1459, 1242 cm−1; H NMR (500 MHz, CDCl3) δ
3.62 (dd, J = 14.0, 8.8 Hz, 1H), 3.81 (dd, J = 14.0, 5.1 Hz, 1H), 4.92
(dd, J = 8.8, 5.1 Hz, 1H), 5.46 (br s, 1H), 7.07 (td, J = 7.8, 1.1 Hz,
1H), 7.19 (td, J = 7.7, 1.0 Hz, 1H), 7.27 (m, 1H), 7.36−7.44 (complex,
6H); 13C NMR (125 MHz, CDCl3) δ 48.4, 65.2, 109.2, 116.8, 121.5,
124.3, 127.3, 129.2, 129.3, 136.7, 142.7, 148.7, 161.5; HRMS (ESI) m/
z calcd for C15H14N5O [M + H]+ 280.1198, found 280.1183.
Aminobenzoxazole 7: Rf = 0.39 (50% EtOAc/hexanes); mp 118−
121 °C; IR (neat) 3255, 1647, 1585, 1461, 1244 cm−1; 1H NMR (500
MHz, CDCl3) δ 3.64 (dd, J = 14.1, 8.0 Hz, 1H), 3.84 (dd, J = 14.0, 3.4
Hz, 1H), 5.05 (dd, J = 7.9, 3.4 Hz, 1H), 5.45 (br s, 1H), 7.05 (td, J =
7.8, 1.1 Hz, 1H), 7.18 (td, J = 7.7, 1.0 Hz, 1H), 7.24−7.26 (m, 2H),
7.31 (m, 1H), 7.36−7.39 (complex, 3H), 7.42−7.44 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 50.8, 73.7, 109.1, 116.7, 121.4, 124.3,
126.1, 128.3, 128.9, 141.6, 142.5, 148.8, 162.6; HRMS (ESI) m/z calcd
for C15H15N2O2 [M + H]+ 255.1134, found 255.1136.
(E)-5-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-4,5-dihydro-
1H-benzo[b][1,4,6]oxadiazocine 8. Following a slight modification
of the reported procedure,41 in a one-dram vial, to a clear colorless
solution of guanyl azide 6 (4.0 mg, 0.014 mmol, 1.0 equiv) and phenyl
acetylene (1.8 mg, 0.017 mmol, 1.2 equiv) in tert-butanol and
deionized water mixture (0.6 mL, 1:1) were added copper(II) sulfate
pentahydrate (3.6 mg, 0.014 mmol, 1.0 equiv) and (+)-sodium L-
ascorbate (5.7 mg, 0.029 mmol, 2.0 equiv). The vial was capped, and
the resulting pale yellowish-blue turbid suspension was stirred at room
temperature for 18 h. The reaction mixture was partially concentrated
under N2, diluted with DCM (1 mL), and quenched with NH4OH
solution (five drops). After being stirred at room temperature for 5
min, the biphasic mixture was passed through a hydrophobic phase
separator tabless, which allowed the DCM layer to pass through the
tabless. The blue aqueous layer was further washed with DCM (2 × 1
mL), and the DCM layer was allowed to pass through the tabless. The
combined DCM layer was concentrated, and the residue was purified
by preparative TLC developing one time with 2% MeOH/DCM. The
band corresponding to guanidino triazole 8 was scraped from the plate
and eluted with 5% MeOH/DCM through a phase separator tabless.
Concentration afforded 8 as a colorless amorphous solid (5.2 mg,
0.014 mmol, 95% yield). Guanidino triazole 8: Rf = 0.18 (2% MeOH/
DCM); mp 216.5−218.5 °C; IR (neat) 3087, 1668, 1641, 1586, 1459,
1
1246 cm−1; H NMR (500 MHz, CDCl3 + CD3OD) δ 4.31 (dd, J =
14.6, 4.3 Hz, 1H), 4.51 (dd, J = 14.6, 9.9 Hz, 1H), 6.03 (dd, J = 9.8, 4.4
Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.23 (d, J =
7.8 Hz, 1H), 7.30 (m, 1H), 7.34−7.40 (complex, 8H), 7.74−7.76 (m,
3H); 13C NMR (125 MHz, CDCl3 + CD3OD) δ 47.1, 64.3, 109.3,
116.5, 121.1, 121.6, 124.3, 125.9, 127.0, 128.6, 129.0, 129.3, 129.4,
130.2, 136.8, 142.2, 148.2, 148.6, 161.6; HRMS (ESI) m/z calcd for
C23H20N5O [M + H]+ 382.1668, found 382.1647.
M
J. Org. Chem. XXXX, XXX, XXX−XXX