The Journal of Organic Chemistry
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mmol). The solution was stirred for 2 h at room temperature,
quenched with brine, and concentrated in vacuo, and the residue was
dissolved in EtOAc (150 mL). The organic layer was washed with
brine (3 × 50 mL), dried over Na SO , filtered, and evaporated. The
(dd, J = 8.0, 14.4 Hz, 1 H), 2.37 (dd, J = 4.0, 19.2 Hz, 1 H), 2.17−2.10
(m, 1 H), 1.66 (s, 9 H); 13C NMR (100 MHz, CDCl ) δ 166.3, 149.1,
3
137.9, 137.3, 129.6, 126.8, 126.2, 125.5, 125.0, 123.8, 116.9, 114.0,
84.2, 51.9, 51.5, 44.4, 32.8, 32.4, 28.1; IR (KBr) 3307, 2979, 2947,
2
4
−1
residue was purified by FCC (DCM-MeOH, 30:1) to afford
2818, 1733, 1656, 1424, 1372, 1283, 1256, 1155, 1102, 1042 cm ;
2
0
+
compound 31 as a colorless liquid (935 mg, 95% yield): [α]
2
−
HRMS (ESI) m/z calcd for C H ClN O (M + H) 405.1576; found
D
21 26
2
4
1
4.4 (c 0.5, MeOH); H NMR (400 MHz, CDCl ) δ 6.99 (d, J = 4.8
405.1563.
3
Hz, 1 H), 4.07 (d, J = 18.0 Hz, 1 H), 3.71 (s, 3 H), 3.64 (br s, 2 H),
Compound 24. To a stirred mixture of compound 34 (180 mg,
0.45 mmol) and aqueous formaldehyde (0.18 mL, 2.25 mmol, 37%) in
acetonitrile (11 mL) was added sodium cyanoborohydride (56 mg,
0.90 mmol). After being stirred for 20 min, the reaction was quenched
3
.57 (d, J = 18.8 Hz, 1 H), 3.54 (m, 1 H), 2.65 (dd, J = 3.2, 19.6 Hz, 1
13
H), 2.19−2.09 (m, 2 H), 1.72−1.49 (m, 4 H), 1.17 (s, 9 H); C NMR
(
100 MHz, CDCl ) δ 165.5, 136.6, 128.1, 62.3, 58.8, 54.1, 51.6, 37.2,
3
2
1
9.5, 28.9, 28.8, 23.2; IR (KBr) 3411, 2949, 2870, 1712, 1658, 1436,
with saturated aqueous NH Cl solution and extracted with EtOAc.
The aqueous layer was basified by addition of saturated aqueous
4
−1
384, 1362, 1265, 1186, 1061, 926 cm ; HRMS (ESI) m/z calcd for
+
C H N O S Na (2M + Na) 629.2901; found 629.2918.
Na CO . The aqueous solution was extracted with EtOAc. The
28
50
2
8
2
2
3
Compound 26. To a solution of compound 31 (765 mg, 2.5
mmol) in anhydrous DCM (50 mL) was added the Dess−Martin
periodinane (1.14 g, 2.7 mmol). The solution was stirred for 1 h at
organic layer was then dried over Na SO and concentrated under
2 4
reduced pressure. The residue was purified by FCC (PE-EtOAc, 1:1)
2
0
to afford compound 24 (152 mg, 81% yield) as a yellow liquid: [α] +
D
1
room temperature and quenched with saturated aqueous Na CO3
4.3 (c 0.5, MeOH); H NMR (400 MHz, CDCl ) δ 8.09 (br s, 1 H),
2
3
solution. The aqueous phase was extracted with DCM. The organic
7.39 (s, 1 H), 7.20−7.19 (m, 2 H), 7.00−6.98 (m, 1 H), 3.76 (s, 3 H),
3.52−3.35 (m, 3 H), 3.17 (m, 1 H), 2.70 (dd, J = 10.0, 14.0 Hz, 1 H),
2.58 (s, 3 H), 2.24 (br s, 2 H), 1.67 (s, 9 H); 13C NMR (100 MHz,
layer was combined, dried over Na SO , filtered, and evaporated. The
2
4
residue was purified by FCC (DCM-EtOAc, 3:1) to afford compound
2
0
2
6 (628 mg, 82% yield) as a pale yellow liquid: [α] − 11.6 (c 0.5,
CDCl ) δ 166.4, 149.2, 137.2, 137.1, 128.1, 127.1, 126.2, 125.4, 124.8,
D
3
1
MeOH); H NMR (400 MHz, CDCl ) δ 9.78 (s, 1 H), 6.98 (dd, J =
123.7, 117.6, 114.0, 84.2, 56.8, 51.6, 50.8, 41.0, 28.6, 28.2, 25.7; IR
(KBr) 2959, 2931, 2792, 2343, 2178, 1738, 1704, 1424, 1369, 1354,
3
1
.6, 6.0 Hz, 1 H), 4.11 (d, J = 18.4 Hz, 1 H), 3.71 (s, 3 H), 3.52−3.47
−
1
(
m, 2 H), 2.70 (dd, J = 3.2, 19.6 Hz, 1 H), 2.57 (t, J = 7.6 Hz, 2 H),
1279, 1262, 1145, 1095 cm ; HRMS (ESI) m/z calcd for
13
+
2.11 (m, 1 H), 1.92 (m, 1 H), 1.75 (m, 1 H), 1.17 (s, 9 H); C NMR
C H ClN O (M + H) 419.1732; found 419.1719.
22
28
2
4
(
3
1
100 MHz, CDCl ) δ 201.1, 165.4, 136.1, 128.0, 58.8, 54.0, 51.6, 40.9,
Compound 23. To a stirred solution of 2,2,6,6-tetramethylpiper-
3
6.4, 28.9, 24.5, 23.3; IR (KBr) 3401, 2952, 2927, 1714, 1658, 1435,
idine (123 μL, 0.72 mmol) in THF (1 mL) was added n-BuLi (425 μL,
0.68 mmol, 1.6 M in hexanes) at 0 °C. After stirring for 30 min at
room temperature, the mixture was cooled to −78 °C. Compound 24
(56.7 mg, 0.14 mmol) was dissolved in dried THF (1.5 mL), and
added dropwise to the former mixture solution via syringe. After
−1
385, 1361, 1266, 1075, 1023, 918 cm ; HRMS (ESI) m/z calcd for
+
C H N O S (2M + H) 603.2768; found 603.2779.
28
47
2
8 2
Compound 33. To a solution of compound 26 (400 mg, 1.3
mmol) in anhydrous DMF (4.8 mL) were added the 3-chloro-2-
iodoaniline (25) (676 mg, 2.66 mmol) and DABCO·6H O (876 mg,
stirring for 40 min, saturated aqueous NH Cl solution was added. The
2
4
4
.0 mmol) successively under an argon atmosphere. After oxygen was
reaction mixture was then allowed to warm to 0 °C and stirred for 20
min. The organic layer was separated, and the aqueous phase was
further extracted with EtOAc (2 × 15 mL). The combined organic
phases were dried over Na SO . Purification by FCC (PE-EtOAc, 3:1)
discharged with argon for 0.5 h, Pd(OAc) (119.4 mg, 0.52 mmol) was
2
added, and then the solution was heated at 80 °C for 6 h. The mixture
was then filtered through a pad of Celite, extracted with EtOAc,
washed with brine, dried over anhydrous Na SO , filtered, and
2
4
afforded the mixed epimers 23 (42 mg, 74% yield, ratio = 2:1) as a
2
4
1
evaporated. The residue was purified by FCC (DCM-EtOAc, 3:1) to
yellow oil: H NMR (400 MHz, CDCl ) δ 8.09 (br s, 1 H), 7.48 (s, 0.7
3
afford crude compound 32 (267 mg) as a yellow liquid.
H), 7.44 (s, 0.3 H), 7.18−7.17 (m, 2 H), 5.90−5.87 (m, 1 H), 5.78−
5.70 (m, 1 H), 3.74 (s, 0.9 H), 3.70 (s, 2.1 H), 3.58−3.53 (m, 0.7 H),
3.47−3.41 (m, 1 H), 3.26−3.16 (m, 2.3 H), 2.84−2.76 (m, 1.3 H),
The yellow liquid 32 mentioned above was dissolved in anhydrous
CH CN. To the solution were added Boc O (170 mg, 0.78 mmol) and
3
2
1
3
DMAP (16 mg, 0.13 mmol), and the mixture was stirred for 6 h. The
solution was concentrated in vacuo, and the residue was purified by
FCC (PE-EtOAc, 3:1) to afford compound 33 (272 mg, 39% yield two
2.67−2.62 (m, 0.7 H), 2.54−2.52 (m, 3 H), 1.66 (s, 9 H); C NMR
(100 MHz, CDCl ) δ 173.5, 172.9, 149.2, 136.9, 130.6, 130.4, 127.3,
3
127.2, 126.1, 125.8, 125.8, 124.7, 124.6, 123.7, 123.6, 122.9, 122.3,
117.2, 116.7, 113.9, 84.0, 84.0, 61.2, 60.5, 54.0, 52.0, 51.9, 50.7, 43.0,
42.7, 41.6, 38.8, 29.6, 29.5, 28.1; HRMS (ESI) m/z calcd for
steps) as a white foam: [α]2 + 20.0 (c 0.5, MeOH); H NMR (400
0
1
D
MHz, CDCl ) δ 8.09 (d, J = 2.4 Hz, 1 H), 7.36 (s, 1 H), 7.21−7.19
3
+
(
(
m, 2 H), 7.08 (d, J = 4.4 Hz, 1 H), 4.28 (d, J = 18.4 Hz, 1 H), 3.96
dd, J = 7.2, 14.0 Hz, 1 H), 3.77 (s, 3 H), 3.64 (d, J = 18.4 Hz, 1 H),
C H ClN O (M + H) 419.1732; found 419.1721.
22
28
2
4
Compound 22. Compound 23 (30 mg, 0.072 mmol) dissolved in
3
.18 (dd, J = 7.2, 14.4 Hz, 1 H), 3.04 (dd, J = 8.0, 14.0 Hz, 1 H), 2.61
dry dioxane (3.6 mL) was degassed for 30 min. P(t-Bu) ·HBF (21
3
4
(
dd, J = 2.8, 18.8 Hz, 1 H), 2.24 (dd, J = 4.0, 18.8 Hz, 1 H), 1.67 (s, 9
mg, 0.072 mmol), Pd (dba) ·CHCl (37 mg, 0.036 mmol), and
2 3 3
13
H), 1.02 (s, 9 H); C NMR (100 MHz, CDCl ) δ 165.6, 149.0, 137.1,
Cy MeN (42 mg, 0.22 mmol) were added to the reaction, and the
3
2
1
5
1
36.4, 128.0, 126.7, 125.9, 125.7, 125.0, 123.8, 117.0, 114.0, 84.4, 58.4,
resulting reaction mixture was heated at 100 °C under an argon
6.7, 51.6, 35.3, 29.0, 28.1, 27.2, 23.0; IR (KBr) 2980, 2951, 1737,
atmosphere for 1.5 h. After cooling, the reaction was quenched with
−1
660, 1424, 1372, 1355, 1255, 1153, 1101, 1080 cm ; HRMS (ESI)
saturated aqueous NH Cl, followed by addition of EtOAc (5 mL). The
4
+
m/z calcd for C H ClN O S (M + H) 509.1877; found 509.1881.
organic layer was separated, and the aqueous phase was further
extracted with EtOAc (2 × 30 mL). The combined organic phases
were washed with brine and dried over Na SO . Purification by FCC
25
34
2
5
Compound 34. Compound 33 (360 mg, 0.71 mmol) was
dissolved in a 1:1 mixture of anhydrous 1,4-dioxane and anhydrous
MeOH (4.3 mL), and anhydrous HCl in dioxane (4 M solution in
dioxane, 0.7 mL) was added. After the mixture was stirred at room
temperature for 1 h, all volatiles were removed in vacuo, and the
residue was dissolved in water and extracted with EtOAc. The water
2
4
(PE-EtOAc, 3:1) afforded the starting material 23 (8.1 mg, 27% yield)
2
0
and the product 22 (5.0 mg, 25% yield brsm) as a yellow solid: [α]
−
D
1
163 (c 1.23, CHCl ); H NMR (400 MHz, CDCl ) δ 7.80 (s, 1 H),
3
3
7.29−7.33 (m, 2 H), 7.13 (d, J = 7.28 Hz, 1 H), 7.05 (s, 1 H), 4.06 (s,
layer was basified to pH 8 with aqueous saturated NaHCO and
extracted with EtOAc. Combined organic extracts were washed with
1 H), 3.71 (s, 3 H), 3.50 (d, J = 17.4 Hz, 1 H), 3.35−3.39 (m, 2 H),
3
1
3
2.95 (m, 1 H), 2.70 (m, 1 H), 2.60 (s, 3 H), 1.66 (s, 9 H); C NMR
brine, dried over Na SO , and concentrated in vacuo. The residue was
(100 MHz, CDCl ) δ 166.0, 150.1, 140.4, 133.5, 131.6, 129.0, 127.1,
2
4
3
purified by FCC (EtOAc) to afford compound 34 as a yellow liquid
125.6, 120.0, 119.8, 115.4, 113.5, 83.4, 57.3, 51.6, 48.8, 42.3, 39.3, 37.4,
(
255 mg, 89% yield): [α]2 − 45.0 (c 0.5, MeOH); H NMR (400
0
1
28.2; IR (KBr) 3434, 2922, 1730, 1257, 1116, 802 cm ; HRMS (ESI)
−1
D
+
MHz, CDCl ) δ 8.13 (d, J = 6.4 Hz, 1 H), 7.47 (s, 1 H), 7.23−7.18
m/z calcd for C H N O (2M + H) 765.3858; found 765.3856.
3
44 53
4
8
(
m, 2 H), 7.02 (bs, 1 H), 3.72−3.69 (m, 4 H), 3.47 (dd, J = 2.4, 16.8
(+)-Lysergic Acid (1). To a solution of compound 22 (31 mg, 0.08
mmol) in ethanol (1 mL) was added 1 N KOH (1 mL). The reaction
Hz, 1 H), 3.24 (dd, J = 4.4, 14.4 Hz, 1 H), 3.15−3.08 (m, 1 H), 2.82
G
dx.doi.org/10.1021/jo4018777 | J. Org. Chem. XXXX, XXX, XXX−XXX