JOURNAL OF CHEMICAL RESEARCH 2013 307
7
6 mmol) and THF (8 mL) were added and the mixture was allowed
3-Ethoxy-5,8-epoxy-5,8-dihydroisoquinoline (16): An oven-dried
to warm to room temperature overnight. The mixture of the reaction
was taken up in CH Cl (300 mL) and washed with 10% NaHCO
25 mL round-bottomed flask under N
septum was charged with a solution of 2-ethoxy-5-chloropyridine 13
(1.1 g, 6.98 mmol) in dry THF (8 mL) under N and cooled to –78 °C.
2
fitted with a stirring bar and a
2
2
3
(50 mL), water (40 mL), brine (50 mL). The organic phase was dried
2
(
Na SO ) and the solvent removed in vacuo. The crude product was
After 30 min at –78 °C, tBuLi (5.41 mL of a 1.7 M solution in hexane,
9.2 mmol), was added slowly with stirring to give a cloudy bright
yellow solution. After 60 min at –78 °C, freshly distilled furan
(6.6 mL, 69.8 mmol) and THF (5 mL) were added and the mixture
allowed to warm to room temperature overnight. The mixture was
2
4
purified by flash chromatography (EtOAc: hexane 1:9, R 0.35) to give
1
yellow oil. The H NMR spectrum was in agreement with the litera-
ture. H NMR (300 MHz, CDCl ): δ 7.88 (d, 1H, J = 5.0 Hz),
f
-ethoxy-5,8-epoxy-5,8-dihydroisoquinoline 10 (0.52 g, 36%) as a
1
23 1
3
7
(
.10 (dd, A part of AB-system, 1H, J = 5.5, 2.1 Hz, –CH=CH), 6.98
dd, B part of AB-system, 1H, J = 5.5, 2.1 Hz, –CH=CH), 6.91 (d, 1H,
J = 5.0 Hz), 5.89 (m, 1H, –CH–O), 5.69 (m, 1H, –CH–O), 4.38 (q, 2H,
taken up in CH
water (30 mL), brine (30 mL). The organic phase (Na
and the solvent was removed in vacuo. The crude product was purified
by flash chromatography (Et O: hexane 1:1, R 0.56) to give 3-ethoxy-
5,8-epoxy-5,8-dihydroisoquinoline 16 as a yellow oil (0.58 g, 44%).
2
Cl
2
(300 mL) and washed with 10% NaHCO
3
(40 mL),
SO ) was dried
2
4
13
J = 7.1 Hz, –CH ), 1.37 (t, 3H, J = 7.1 Hz, –CH ); C NMR (75 MHz,
CDCl ): δ 163.4, 157.1, 145.5, 144.0, 142.3, 130.1, 111.0, 82.5, 79.8,
2
f
2
3
3
−
1
6
1.8, 15.0.
-(2-Bromophenoxy)-1-ethoxy-7,8-dihydroisoquinolin-8-ol (11a)
and 6-(2-bromophenoxy)-1-ethoxy-5,6-dihydroisoquinolin-5-ol (11b):
Rh(COD)Cl]2 (0.0032 g, 0.00065 mmol) and DPPF (0.0072 g,
.0129 mmol) in 1.5 mL dioxane was added to a flame-dried round-
IR (NaCl, cm ) 3395, 3013, 2978, 2929, 2900, 1633, 1591, 1445,
1
7
1403, 1379, 1337, 1282, 1264, 1225, 1092, 1038, 846. H NMR
(300 MHz, CDCl
J = 5.6, 1.8 Hz, –CH=CH), 6.88 (dd, B part of AB-system, 1H, J = 5.6,
): δ 7.85 (s, 1H), 6.99 (dd, A part of AB-system, 1H,
3
[
0
1
–
–
1
1
7
.9 Hz, –CH=CH), 6.66 (s, 1H), 5.74 (m, 1H, –CH–O), 5.64 (m, 1H,
CH–O), 4.32 (q, 2H, J = 7.1 Hz, –CH ), 1.36 (t, 3H, J = 7.1 Hz,
bottomed flask and stirred at room temperature for 10 min to produce
a red solution. AgOTf (0.0066 g, 0.0258 mmol) was added followed
by sonication for 10 min to produce an orange heterogeneous solu-
tion. Bu NI (0.0143 g, 0.0387 mmol) was added followed by stirring
for another 10 min to give a dark-red solution of the [Rh(COD)I]
catalyst. This catalyst solution was treated with 1-ethoxy-5,8-epoxy-
2
13
CH ); C NMR (75 MHz, CDCl ): δ 161.8, 161.1, 143.5, 140.7,
3
3
35.8, 135.5, 105.6, 81.7, 80.4, 62.3, 14.8. EIMS m/z (%): 190 (100),
62 (40), 136 (10). Anal. Calcd for C H NO : C, 69.83; H, 5.86; N,
11 11
2
4
11 11
.40. Found: C, 69.71; H, 5.79; N, 3.35%. HRMS calcd for C H NO2
(
M+): 189,0790; found: 189.0793.
-(2-Bromophenoxy)-3-ethoxy-7,8-dihydroisoquinolin-8-ol (17a)
7
5
(
,8-dihydroisoquinoline (0.100 g, 0.529 mmol) and 2-bromophenol
0.240g, 1.38 mmol), and heated to 110 °C for 1 h. The mixture was
poured into NaOH solution (1 M, 50 mL) and extracted with Et O
and 6-(2-bromophenoxy)-3-ethoxy-5,6-dihydroisoquinolin-5-ol (17b):
Rh(COD)Cl] (0.0027 g, 0.00055 mmol) and DPPF (0.0072 g, 0.0129
2
2
mmol) in 1.5 mL dioxane was added to a flame-dried round-bottomed
flask and stirred at room temperature for 10 min to produce a red solu-
tion. AgOTf (0.0057 g, 0.0222 mmol) was added followed by sonica-
(
(
3×100 mL). The combined organic phase was washed with NaOH
1 M, 25 mL), brine (25mL) and dried over Na SO . The solvent
2
4
was removed in vacuo and the brown residue was purified by flash
chromatography (EtOAc: hexane 1:9) to give (11a; 77 mg, 40%, 11b;
2
tion for 10 min to produce an orange heterogeneous solution. Bu NI
4
(
1
0.0122 g, 0.0333 mmol) was added followed by stirring for another
0 min to give a dark-red solution of the [Rh(COD)I] catalyst. 3-
2 mg, 12%).
1a: M.p. 148 °C (recrystallised from hexane/EtOAc), IR (NaCl,
1
Ethoxy-5,8-epoxy-5,8-dihydroisoquinoline 16 (0.09 g, 0.476 mmol)
and 2-bromophenol (0.206 g, 1.18 mmol), were added to this catalyst
solution and heated to 110 °C for 32 h. The mixture was poured into
−
1
cm ) 3671, 3582, 3435, 2978, 1558, 1474, 1427, 1376, 1243, 1045,
7
d, 1H, J = 7.5 Hz), 7.26 (m, 1H), 7,21 (d, 1H, J = 5.1 Hz), 6.90 (m,
2
6
1
18. H NMR (300 MHz, CDCl ): δ 8.08 (d, 1H, J = 5.1 Hz), 7.58 (br
3
NaOH solution (1 M, 40 mL) and extracted with Et O (3×100 mL).
2
H), 6.77 (dd, A part of AB-system, 1H, J = 10.1, 1.9 Hz, –CH=CH),
.07 (dd, B part of AB-system, 1H, J = 10.1, 1.8 Hz, –CH=CH), 5.25
The combined organic phase was washed with NaOH (1 M, 20 mL),
brine (20 mL) and dried over Na SO . The solvent was removed in
2
4
(
br d, A part of AB-system, 1H, J = 11.7 Hz, –CH–O), 5.16 (td, B part
vacuo and the brown residue was purified by flash chromatography
of AB-system, 1H, J = 11.7, 2.1 Hz, –CH–OPhBr), 4.40 (q, 2H, J =
7
NMR (75 MHz, CDCl ): δ 159.1, 154.4, 146.9, 146.5, 133.9, 128.9,
1
EIMS m/z (%): 363 (100), 190 (18), 174 (53), 162 (10), 146 (19);
HRMS calcd for C H BrNO (M+): 361,0314; found: 361.0315.
(
EtOAc: hexane 3:7) to give (17a; 21 mg, 13%, 17b; 66 mg, 38%).
13
.1 Hz, –CH ), 3.04 (s,1H, –OH), 1.40 (t, 3H, J = 7.1 Hz, –CH );
C
−1
2
3
1
7a: Brown liquid, (Rf; 0.57), IR (NaCl, cm ) 3394, 2975, 2924,
3
1
1
607, 1557, 1474, 1417, 1326, 1241, 1044, 667. H NMR (300 MHz,
26.4, 123.3, 122.9, 115.7, 114.7, 113.6, 113.3, 82.0, 72.5, 62.2, 14.9.
CDCl ): δ 8.31 (s, 1H), 7.58 (dd, 1H, J = 7.9, 1.9 Hz), 7.26 (m, 2H),
3
6
.93 (m, 2H), 6.48 (dd, A part of AB-system, 1H, J = 9.9, 2.1 Hz,
17
16
3
–CH=CH), 6.25 (dd, B part of AB-system, 1H, J = 9.9, 2.1 Hz,
1
1b: M.p. 165 °C (recrystallised from hexane/EtOAc), IR (NaCl,
1
–
CH=CH), 5.26 (dd, A part of AB-system, 1H, J = 9.3, 0.9 Hz,
CH–O), 5.05 (dt, B part of AB-system, 1H, J = 9.3, 2.1 Hz, –CH–O),
−
cm ) 3851, 3646, 2926, 2851, 1683, 1652, 1558, 1506, 1539, 1472,
1
–
1
456, 1435, 1030, 668. H NMR (300 MHz, CDCl ): δ 8.11 (d, 1H,
13
3
4.37 (q, 2H, J = 7.0 Hz, –CH ), 1.39 (t, 3H, J = 7.0 Hz, –CH ); C
2
3
J = 5.1 Hz), 7.56 (br d, 1H, J = 7.8), 7.26 (m, 2H), 6.90 (m, 1H), 6.74
d, 1H, J = 5.1 Hz), 6.59 (br d, A part of AB-system, 1H, J = 9.7 Hz,
NMR (75 MHz, CDCl ): δ 164.7, 154.5, 144.1, 141.8, 134.0, 131.4,
3
(
1
28.9, 127.8, 123.5, 123.0, 116.2, 113.9, 107.8, 81.7, 70.7, 72.0, 14.9;
–
–
5
CH=CH), 6.32 (dd, B part of AB-system, 1H, J = 9.7, 4.1 Hz,
CH=CH), 5.34 (d, A part of AB-system, 1H, J = 4.1 Hz, –CH–O),
.14 (dt, B part of AB-system, 1H, J = 4.1, 0.9 Hz, –CH–OPhBr), 4.46
HRMS calcd for C H BrNO (M+): 361,0314; found: 361.0317.
17
16
3
1
7b: M.p. 106 °C (recrystallised from hexane/EtOAc), (Rf; 0.74),
IR (NaCl, cm−1) 3334, 3063, 2979, 2930, 2900, 1607, 1557, 1488,
1
(
q, 2H, J = 7.1 Hz, –CH ), 3.14 (s,1H, –OH), 1.42 (t, 3H, J = 7.1 Hz,
1417, 1377, 1336, 1243, 1031, 749. H NMR (300 MHz, CDCl ):
2
3
13
–
1
6
3
CH ); C NMR (75 MHz, CDCl ): δ 161.9, 154.5, 147.5, 140.3,
δ 7.87 (s, 1H), 7.57 (dd, 1H, J = 7.9, 1.6 Hz), 7.25 (m, 1H), 7.04 (m,
1H), 6.90 (m, 2H), 6.48 (dd, A part of AB-system, 1H, J = 9.9, 2.1 Hz,
–CH=CH), 5.94 (dd, B part of AB-system, 1H, J = 9.9, 1.8 Hz,
–CH=CH), 5.21 (dd, A part of AB-system, 1H, J = 10.8, 1.3 Hz, –CH–O),
5.07 (dt, B part of AB-system, 1H, J = 10.8, 2.1 Hz, –CH–OPhBr),
3
3
33.9, 129.0, 128.7, 128.3, 123.3, 117.0, 115.9 (x2), 114.2, 78.1, 66.6,
2.5, 14.9; HRMS calcd for C H BrNO (M+): 361,0314; found:
17
16
3
61.0316.
-Ethoxy-5-chloropyridine (13): Sodium metal (ca 2.14 g) was
2
13
added to dry ethanol (100 mL) in a 250 mL round-bottomed flask
fitted with a stirring bar at 0 °C. The resulting suspension was stirred
until the sodium had disappeared and hydrogen evolution ceased
ca 1h). 2,5-Dichloropyridine 12 (5 g, 33 mmol) was added and the
resulting mixture refluxed for 36 h. The reaction vessel was allowed to
4.36 (q, 2H, J = 7.0 Hz, –CH ), 1.39 (t, 3H, J = 7.0 Hz, –CH ); C
2
3
NMR (75 MHz, CDCl ): δ 164.3, 154.4, 147.9, 143.8, 133.9, 128.9,
3
125.7, 125.0, 123.3, 122.0, 115.9, 113.6, 107.8, 82.0, 72.3, 62.2, 14.8.
Anal. Calcd for C H BrNO : C, 56.37; H, 4.45; N, 3.87. Found: C,
17
16
3
56.41; H, 4.32; N, 3.68%. HRMS calcd for C H BrNO (M+):
17
16
3
cool to room temperature and quenched with saturated aqueous NH Cl
361,0314; found: 361.0316.
4
(
10 mL) and extracted with CH Cl (4x 100 mL). The organic extracts
2 2
were combined and dried (Na SO ). The solvent was removed in
2
4
Received 25 January 2013; accepted 14 March 2013
Paper 1301752 doi: 10.3184/174751913X13663103976700
Published online: 15 May 2013
vacuo to give 2-ethoxy-5-chloropyridine 13 as a yellow liquid (4.09 g,
1
7
7%). H NMR (300 MHz, CDCl ): δ 8.02 (d, 1H, J = 2.6 Hz), 7.43
3
(
dd, 1H, J = 8.8, 2.6 Hz), 6.60 (dd, 1H, J = 8.8, 0.6 Hz), 4.27 (q, 2H,
13
J = 7.1 Hz, –CH ), 1.32 (t, 3H, J = 7.1 Hz, –CH ); C NMR (75 MHz,
2
3
CDCl ): δ 162.5, 145.3, 138.5, 123.9, 112.2, 62.2, 14.7. Anal. Calcd
References
3
for C H ClNO: C, 53.35; H, 5.12; N, 8.89. Found: C, 53.28; H, 5.17;
1
K.W. Bentley, The isoquinoline alkaloids. HarwoodAcademic,Amsterdam,
7
8
N, 8.76%.
1998, Vol. 1.