N-cumyl benzamide, sulfonamide, and aryl O-carbamate directed metalation groups. Mild hydrolytic lability for facile manipulation of directed ortho metalation derived aromatics

Article abstract of DOI:10.1021/ol990846b

(Matrix Presented) N-Cumyl benzamide (2), sulfonamide (8), and O-carbamate (11) compounds undergo directed ortho metalation under standard conditions to give, after quench with a variety of electrophiles, the substituted products 3, 9, and 12, respectively. Regiospecific and convenient approaches to phthalimides (7), 1,2-benzisothiazole 1,1-dioxides (10b), and ortho-substituted phenols (13a) and salicylamides (13b) are thereby established The mild deprotection protocol for these new cumyl directed metalation groups (DMGs) suggests that they will supersede previous corresponding groups for synthetic anionic aromatic chemistry.

Full text of DOI:10.1021/ol990846b

Supporting Information
General Procedure for Metalation of N-cumylbenzamide and N-1,1-
ethyldiphenylbenzamide (2a,b).
To a solution of 2a (120 mg, 0.5 mmol) and TMEDA (0.24 mL, 1.6 mmol, 3.2 equiv)
in THF (5 mL) at Ð78 °C under Ar was slowly added s-BuLi (1.6 mmol, 3.2 equiv) via
syringe. The resulting yellow solution was stirred for 2 h and the electrophile (1.1
mmol, 2.2 equiv) was added. The reaction mixture was stirred for 1 h at Ð78 °C, or
allowed to warm slowly to rt before satd NH Cl was added. The product was extracted
4
with ether or EtOAc, and the combined organic extract was dried (MgSO
4
) and
concentrated in vacuo to give the crude product.
N-cumyl-2-(trimethylsilyl)benzamide (3a).
Flash chromatography (hexane/EtOAc 9:1) afforded 3a (Table 1, entry 7) as a colorless
solid (147 mg, 94%), mp 75-77 °C.
-
1 1
IR vmax (KBr) 3352, 1657 cm ; H NMR (250 MHz, CDCl ) d 7.64 (dd, J = 6.0, 2.0Hz,
1
3
1
3
H, ArH), 7.52-7.22 (m, 8H), 6.16 (s, 1H), 1.85 (s, 6H), 0.30 (s, 9H); C NMR (63
MHz, CDCl
3
) d 170.1, 146.8, 143.2, 140.1, 135.5, 129.4, 128.6, 125.5, 126.9, 126.1,
1
24.9, 56.3, 28.8, 0.3; HRMS calcd for C19H26NOSi: 312.1784; found 312.1780.
N-1,1-diphenylethyl-2-(trimethylsilyl)benzamide (3b).
Flash chromatography (hexane/EtOAc 13:1) afforded 3b (Table 1, entry 7) as a
colorless solid (170 mg, 91%), mp 99-101 °C.
-
1 1
IR vmax (KBr) 3426, 1665 cm ; H NMR (200 MHz, CDCl ) d 7.67-7.56 (m, 2H), 7.42-
3
1
3
7
.25 (m, 12H), 6.57 (brs, 1H), 2.37 (s, 3H), 0.27 (s, 9H); C NMR (125 MHz, CDCl
3
)
d 169.7, 146.2, 142.9, 140.5, 135.6, 129.5, 128.4, 127.1, 126.6, 126.0, 62.7, 27.1, 0.3;
+
HRMS calcd for C24
H
28NOSi (M +1): 374.1943; found 374.1940.
2
-Trimethylsilylbenzamide (4a) from 3a.
To a solution of BF
added 3a (245 mg, 0.788 mmol) in CH
3
áOEt
2
(0.13 mL, 1.0 mmol) in CH
Cl (10 mL). The resulting brown solution was
stirred for 2 h at rt before water was added, and the product was extracted with CH Cl
The combined organic extract was dried (MgSO ) and concentrated in vacuo to give the
2
Cl
2
(5 mL) at 0 °C under Ar was
2
2
2
2
.
4
crude product. Flash chromatography (hexane/ethyl acetate 5:2) afforded 4a as a
colorless solid (130 mg, 86%).
-
1 1
IR vmax (KBr) 3453, 3288, 1654 cm ; H NMR (200 MHz, CDCl
.8, 7.0Hz), 7.51-7.24 (m, 3H), 6.68 (brs, 1H), 6.13 (brs, 1H), 0.33 (s, 9H); C NMR
50 MHz, CDCl ) d 173.4, 140.9, 140.1, 135.4, 129.8, 128.6, 126.2, 0.1.
3
) d 7.65 (dd, 1H, J =
1
3
1
(
3
2
-Trimethylsilylbenzamide (4a) from 3b.
To 3b (345 mg, 0.924 mmol) was added ice-cooled TFA (4 mL) and the resulting green
solution was stirred for at rt for 15 min. The solvent was removed in vacuo to give the
crude product. Flash chromatography (hexane/EtOAc 2:1) afforded 4a as a colorless
solid (148 mg, 83%).
2
-Trimethylsilylbenzonitrile (4b).

To 3a (312 mg, 1.0 mmol) in CH
2
Cl (5mL) at Ð40 °C under Ar was sequentially added
2
pyridine (0.25 mL, 3.0 mmol) and triflic anhydride (0.22 mL, 1.3 mmol) dropwise.
The resulting solution was allowed to warm to 0 °C (2 h) and kept at this temperature
for 5 h. Ethanol was added (2 mL, >30mmol) and the mixture was stirred at rt for 18 h.
To the resulting pale yellow solution was added 1N HCl and the product was extracted
with ether. The combined organic extract was washed once with 1N KHCO
MgSO ) and concentrated in vacuo. Flash chromatography (hexane/EtOAc 19:1) gave
b as a volatile colorless oil (89 mg, 51%).
3
, dried
(
4
4
-
1 1
IR vmax (NaCl, neat) 2222 cm ; H NMR (200 MHz, CDCl
3
) d 7.70-7.44 (m, 4H), 0.45
1
3
(
s ,
9 H ) ;
C
N M R
( 5 0
M H z , C D C l
3
)
d 144.7, 134.4, 133.3, 131.5, 129.0, 119.8, 117.2, -1.5.
3
-Thiomethylphthalimide (7b).
To a solution of N-cumylphthalimidine (5) (1.60 g, 6.0 mmol) and TMEDA (1.99 mL,
3.3 mmol, 2.2 equiv) in THF (60 mL) at Ð78 °C under Ar was slowly added s-BuLi
13.3 mmol, 2.2 equiv) via syringe. The resulting dark green, almost black solution was
stirred for 2 h before methyl disulfide (0.65 mL, 7.2 mmol, 1.2 equiv) was added. The
reaction mixture was allowed to warm slowly to rt and satd NH Cl was added. The
product was extracted with EtOAc, and the combined organic extract dried (MgSO
1
(
4
4
)
and concentrated in vacuo with a bleach trap to give the crude product. Flash
chromatography (hexane/EtOAc 3:2) gave N-cumyl-6-(thiomethyl)phthalimidine a pale
yellow solid (1.68 g, 89%), mp 167-170 °C.
-
1 1
IR vmax (KBr) 3413, 1671 cm ; H NMR (200 MHz, CDCl
d, 1H, J=9.7 Hz), 3.35 (d, 1H, J=9.7 Hz), 2.35, (s, 3H), 1.89 (s, 3H), 1.87 (s, 3H); C
N M R ( 5 0 M H z , C D C l
d 167.4, 146.9, 144.6, 138.4, 132.1, 128.1, 127.1, 126.3, 125.1, 123.8, 118.1, 81.6, 58.9,
8.9, 27.9, 13.6; HRMS calcd for C18 S: 313.1136; found 313.1149.
3
) d 7.42-7.06 (m, 8H), 5.98
1
3
(
3
)
2
H19NO
2
To a solution of N-cumyl-6-(thiomethyl)phthalimidine (940 mg, 3.0 mmol) in DMF (12
mL) under Ar at rt was added pyridinium dichromate (2.26 g, 6.0 mmol, 2.0 equiv) all
at once and the dark mixture was stirred for 2 h. Water was added and the product was
extracted with EtOAc. The combined organic extract was washed with water (3 times),
brine, and dried (MgSO
4
). Evaporation of solvent and flash chromatography
(
hexane/EtOAc 4:1) gave 6b (840 mg, 89%) as a pale yellow solid, mp 168-169 °C.
-
1 1
IR vmax (KBr) 1761, 1699 cm ; H NMR (300 MHz, CDCl
3
) d 7.61-7.20 (m, 8H), 2.53
(75 MHz, CDCl
d 169.1, 169.0, 147.1, 139.9, 134.3, 133.4, 128.8, 127.1, 126.7, 124.9, 121.1, 118.6, 62.
, 29.5, 14.4; HRMS calcd for C18 S: 311.0981; found 311.0988.
1
3
(
s, 3H), 2.04, (s, 6H);
C
NMR
3
)
1
H17NO
2
To 6b (312 mg, 1.0 mmol) was added TFA (4 mL) and the resulting solution was
stirred for 16 h at 50 °C. The solvent was removed on a rotary evaporator to give the
crude product. Gradient flash chromatography (hexane/EtOAc 19:1, then EtOAc)
afforded 7b as a bright yellow solid (168 mg, 87%), subl 195 °C.
-
1 1
IR vmax (KBr) 3188, 1771, 1717 cm ; H NMR (200 MHz, DMSO-d
6
) d 11.27 (brs,
1
3
H), 7.73 (t, 1H, J=8.1 Hz), 7.60 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=7.0 Hz), 2.53 (s,
1
3
H ) ;
C
N M R
( 5 0
M H z ,
D M S O - d
6
)
d 168.9, 168.7, 139.0, 134.5, 133.6, 129.0, ; 1 H2 6R . 5M , S 11c8a. l1c ,d 1 f3 o. 1r
C
9
H
7
NO S: 193.0198; found 193.0207.
2

3
,3-Diphenyl-1,2-benzisothiazole-1,1-dioxide (10b).
To a solution of N-cumylbenzenesulfonamide (8) (551 mg, 2.0 mmol) and TMEDA
0.66 mL, 4.4 mmol, 2.2 equiv) in THF (20 mL) at Ð78 °C under Ar was slowly added
(
s-BuLi (4.4 mmol, 2.2 equiv) via syringe. The resulting mixture was stirred for 2 h
before benzophenone (437 mg, 2.4 mmol, 1.2 equiv) in THF (10mL) was slowly added.
The reaction mixture was left to warm slowly to rt and satd NH
product was extracted with ether, and the combined organic extract dried (MgSO
concentrated in vacuo. Flash chromatography (hexane/EtOAc 6:1) gave N-cumyl-2-
hydroxydiphenylmethyl)benzenesulfonamide (9b) as a colorless solid (868 mg, 95%),
mp 143-145 °C.
IR vmax (KBr) 3451, 3257 cm ; H NMR (200 MHz, CDCl
4
Cl was added. The
4
) and
(
-
1 1
3
, 330K) d 7.83-7.78 (m,
H), 7.22-7.09 (m, 17H), 6.89-6.84 (m, 1H), 6.12 (s, 1H), 5.16 (s, 1H), 1.46 (s, 6H);
1
1
3
C NMR (50 MHz, CDCl
30.5, 127.9, 127.8, 127.5, 127.4, 126.6, 125.2, 82.9, 59.3, 30.0; HRMS calcd for
S: 457.1712; found 457.1685.
3
, 330K) d 146.2, 146.2, 145.4, 144.1, 141.9, 132.5, 130.6,
1
C
28
H27NO
3
To 9b (114 mg, 0.25 mmol) was added ice-cooled TFA (2 mL) and the resulting
solution was stirred for 10 min at rt. The solvent was removed in vacuo to give the
crude product. Flash chromatography (hexane/EtOAc 2:1) afforded 10b as a colorless
solid (79 mg, 99%).
1
H NMR (200 MHz, CDCl ) d 7.79 (dd, 1H, J=1.6, 7.0 Hz), 7.61-7.50 (m, 2H), 7.44-
3
1
3
7
1
.25 (m, 11H), 5.04 (s, 1H); C NMR (50 MHz, CDCl
29.5, 128.7, 128.4, 127.7, 126.6, 121.4, 72.4.
3
) d 143.0, 142.9, 135.1, 133.2,
2
-Trimethylsilylphenol (13a).
To a solution of N-cumyl-N-methyl benzene-O-carbamate (11) (453 mg, 1.68 mmol)
and TMEDA (0.30 mL, 2.0 mmol, 1.2 equiv) in THF (17 mL) at Ð78 °C under Ar was
slowly added s-BuLi (2.0 mmol, 1.2 equiv) via syringe. The resulting mixture was
stirred for 2 h before TMSCl (0.26 mL, 2.0 mmol, 1.2 equiv) was added. The reaction
mixture was stirred for 1.5 h before satd NH
allowed to warm to rt. The product was extracted with ether, and the combined organic
extract dried (MgSO ) in vacuo. Flash chromatography (hexane/EtOAc 9:1) gave N-
4
Cl was added, and the mixture was
4
cumyl-N-methyl-2-(trimethylsilyl)benzene-O-carbamate (12a) as a colorless oil (402
mg, 70%).
-
1 1
IR vmax (NaCl, neat) 1728 cm ; H NMR (200 MHz, CDCl
H), 6.89 (d, 1H, J=8.4 Hz), 3.15 (s, 3H), 1.84 (s, 6H), 0.35 (s, 9H); C NMR (50
MHz, CDCl , 330K) d 156.4, 154.5, 148.2, 134.6, 131.6, 130.1, 128.3, 126.3, 124.8,
3
, 330K) d 7.49-7.12 (m,
1
3
8
3
1
3
24.6, 122.3, 61.6, 32.9, 28.4, -0.7; HRMS calcd for C20
41.1826.
H
27NO Si: 341.1811; found
2
To 12a (338 mg, 0.99 mmol) was added ice-cooled TFA (4 mL) and the resulting
solution was stirred for 6 min at rt. The solvent was removed in vacuo to give the
crude product. Flash chromatography (hexane/EtOAc 3:1) afforded N-methyl-2-
(
trimethylsilyl)benzene-O-carbamate as a colorless oil (177 mg, 80%).
-
1 1
IR vmax (KBr) 3310, 1707 cm ; H NMR (200 MHz, CDCl
3
) d 7.45-7.31 (m, 2H), 7.20-
7
.06 (m, 2H), 5.25 (br, 1H), 2.87 (d, 0.5H, J=4.7 Hz), 2.75 (d, 2.5H, J=4.7Hz), 0.26 (s,

1
3
9
2
H); C NMR (50 MHz, CDCl
7.4, -1.1; HRMS calcd for C11
3
) d 155.7, 155.3, 134.7, 131.4, 130.2, 124.8, 121.9,
Si: 223.1029; found 223.1032.
H
17NO
2
To N-methyl-2-(trimethylsilyl)benzene-O-carbamate (91 mg, 0.40mmol) in EtOH
1mL) was added 10% NaOH (1mL). The mixture was stirred for 4 h at rt and then
neutralized with 1N HCl. . The product was extracted with ether, and the combined
organic extract dried (MgSO ) and concentrated in vacuo. Bulb-to-bulb distillation
gave 13a as a volatile colorless oil (66 mg, 99%), bp 89 °C (14 mmHg).
(
4
-
1 1
IR vmax (NaCl, neat) 3414 cm ; H NMR (200 MHz, CDCl
3
) d 7.36 (d, 7.2 Hz), 7.21
(m, 1H), 6.90 (t, 1H, J=7.2 Hz), 6.67 (d, 1H, J=8.1 Hz), 5.54 (brs, 1H), 0.30 (s, 9H).
N-methyl-2-(hydroxy)benzamide (13b).
To a solution of 11 (269 mg, 1.0 mmol) and TMEDA (0.17 mL, 1.1 mmol, 1.1 equiv)
in THF (10 mL) at Ð78 °C under Ar was slowly added s-BuLi (1.1 mmol, 1.1 equiv) via
syringe. The resulting mixture was stirred for >2 h and then allowed to warm slowly to
rt before satd NH
combined organic extract was washed with 1N NaOH (30 mL). The aqueous extract
was acidified with 1N HCl to pH 2, extracted with CH Cl and dried (MgSO ).
Removal of solvent in vacuo gave a solid (12b) which was recrystallized to give a
colorless solid (220 mg, 82%), mp 183-185 °C (hexane/CH Cl ).
IR vmax (KBr) 3082, 1612 cm ; H NMR (200 MHz, DMSO-d ) d 9.84 (s, 1H), 7.43 (d,
4
Cl was added. The product was extracted with ether, and the
2
2
4
2
2
-
1 1
6
13
2
H, J=8.6 Hz), 7.32-7.06 (m, 5H), 6.89-6.82 (m, 2H), 2.92 (s, 3H), 1.66 (s, 6H); C
NMR (50 MHz, DMSO-d
6
) d 169.0, 153.3, 149.0, 129.8, 127.9, 127.7, 126.3, 125.3,
1
2
24.3, 119.0, 115.7, 60.7, 33.9, 28.1; HRMS calcd for C17
69.1426.
H
19NO
2
: 269.1416; found
To 12b (76 mg, 0.28 mmol) was added 2,2,2-trifluoroethanol (3 mL) and the resulting
solution was heated to reflux for 11 h under a CaCl drying tube attachment. The
solvent was removed in vacuo to give the crude product. Flash chromatography
hexane/EtOAc 7:3) afforded 13b as a colorless solid (37 mg, 87%).
2
(
-
1 1
IR vmax (KBr) 3406, 1645 cm ; H NMR (200 MHz, CDCl
m, 2H), 6.97 (d, 1H, J=8.4 Hz), 6.82 (t, 1H, J=8.4 Hz), 6.63 (brs, 1H), 2.99 (d, 3H,
J=4.6 Hz).
3
) d 12.42 (s, 1H), 7.40-7.34
(