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DOI: 10.1055/s-0029-1219580
Synthesis of N-Arylisoindolin-1-ones via Pd-Catalyzed Intramolecular Decarbonylative Coupling of N-(2-Bromobenzyl)oxanilic Acid Phenyl Esters
Publication History
Publication Date:
10 March 2010 (online)
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Abstract
Ethyl and phenyl oxanilates were readily prepared from N-(2-bromobenzyl)anilines and oxalyl chloride monoethyl and monophenyl esters, respectively. It was found that the ethyl oxanilate survived in the presence of K2CO3 in DMA at 120 ˚C and underwent an intramolecular direct arylation using Pd(OAc)2-dppf, furnishing the 5,6-dihydrophenanthridine derivative. In contrast, the corresponding phenyl oxanilates decomposed upon exposure to K2CO3 in DMA at 120 ˚C and were transformed into N-arylisoindolin-1-ones via Pd(OAc)2-dppf-catalyzed intramolecular decarbonylative coupling. Except for the 4-methoxy-substituted oxanilic acid phenyl ester, other phenyl oxanilates possessing electron-withdrawing (NO2, Cl) and weak electron-donating (Me) substituents provided the N-arylisoindolin-1-ones in 43-80% yields.
Key words
decarbonylative coupling - direct arylation - isoindolin-1-ones - oxanilates - palladium
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
Representative
Procedure for Synthesis of Oxanilates 15
To a solution
of phenol (235.0 mg, 2.0 mmol) and pyridine (0.31 mL, 3.0 mmol)
in dry CH2Cl2 (5 mL) cooled in an ice-water
bath was added oxalyl chloride (0.33 mL, 3.0 mmol) followed by stirring
at r.t. for 30 min. The reaction mixture was evaporated, and hexane
was added to the residue. The pyridinium salt was removed by quick
filtration with washing by hexane. The combined filtrate was condensed under
reduced pressure in a nitrogen atmosphere, and the crude oxalyl
chloride monophenyl ester was used for next step without purification.¹³
To
a separate dry flask was added NaH (60.0 mg, 1.5 mmol) and dry THF
(5 mL). To the resultant suspension cooled in an ice-water
bath was added a solution of 14e (276.0
mg, 1.0 mmol) in dry THF (5 mL). After stirring at the same temperature
for 1 h, a solution of oxalyl chloride monophenyl ester prepared
above in dry THF (5 mL) was added. After stirring at r.t. for 1
h, the reaction was quenched by H2O. The reaction mixture
was extracted with EtOAc (3 × 15 mL),
and the combined organic layer was washed with brine, dried over
anhyd Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatography
over silica gel with elution by 10% EtOAc in PE (60-90 ˚C)
to give the phenyl oxanilate 15e (367.0
mg, 87%). The results are listed in Table
[¹]
.
Characterization
Data for Compound 15e
White crystalline solid; mp
92-93 ˚C (CH2Cl2-hexane); R
f
= 0.59
(20% EtOAc in PE). IR (KBr): 1763, 1668, 1511, 1403, 1163
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 7.52
(d, J = 8.0
Hz, 1 H), 7.45 (d, J = 7.6
Hz, 1 H), 7.31-7.25 (m, 3 H), 7.21-7.12 (m, 6
H), 6.67 (d, J = 7.6
Hz, 2 H), 5.16 (s, 2 H), 2.35 (s, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 161.4, 160.8,
149.4, 139.1, 136.5, 134.8, 132.9, 130.1 (3¥), 129.4 (2¥),
129.3, 127.8, 127.6 (2¥), 126.4, 123.8, 120.9 (2¥), 51.7,
21.1. MS (ESI+): m/z (%) = 448
(75) [M + 2 + Na+], 446
(100) [M + Na+].
Anal. Calcd for C22H18BrNO3: C, 62.28;
H, 4.28; N, 3.30. Found: C, 62.31; H, 4.31; N, 3.37.
We used N,N-dimethylacetamide (DMA) as received from commercial supplies. The anhydrous grade has 99.8% purity with <0.005% water content. In all of our experiments described in this work, water was not added. Upon heating phenyl oxanilate 15a in DMA at 120 ˚C in the presence of K2CO3, all materials in the reaction mixture remained on the base line of the TLC plate while ethyl oxanilate 15j could be developed up on the TLC plate.
16
Representative
Procedure for Formation of 16 and 17
A 10 mL flask
was charged with Pd(OAc)2 (13.5 mg, 6.0¥10-² mmol),
dppf (33.0 mg, 6.0¥10-² mmol),
and K2CO3 (166.0 mg, 1.2 mmol). The loaded
flask was evacuated and backfilled with N2 (repeated
for three times). To the degassed flask was added a solution of
phenyl oxanilate 15e (255.0 mg, 0.6 mmol)
in degassed DMA (3 mL). The resultant mixture was heated at 120 ˚C
for 2 h under a nitrogen atmosphere. After cooling to r.t., the
reaction was quenched by adding CH2Cl2 (20
mL), and the resultant mixture was washing with H2O (3 × 10
mL) to remove DMA. The organic layer was washed with brine, dried
over anhyd Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column chromatography
over silica gel with elution by 20% EtOAc in PE (60-90 ˚C)
to give N-(p-tolyl)isoindolin-1-one
(17e, 61.0 mg, 46%). The results
are given in Scheme
[³]
and Table
[³]
.
Compound 16 was prepared in 71% yield from 15j (Scheme
[³]
)
under the same conditions as described above for 17e.
The sample of 16 contains two atropisomers
along with a minor inseparable debromination byproduct in the ratio
of 75:15:10. The result was confirmed by independent synthesis as
found in Supporting Information.
Characterization
Data for Compound 16
Pale yellow oil; R
f
= 0.27
(20% EtOAc in PE). IR (film): 2928, 1742, 1667, 1185 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 7.83
(d, J = 7.2
Hz, 1 H), 7.81 (d, J = 8.0
Hz, 1 H), 7.43-7.19 (m, 6 H), 4.95 (s, 2 H), 4.16 (q, J = 6.8 Hz,
2 H), 1.12 (t, J = 7.2
Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 162.5, 160.4,
135.6, 133.2, 131.1, 129.0, 128.4, 128.4, 128.1, 127.3, 126.4, 124.7,
123.5, 121.8, 62.1, 44.5, 13.6. MS (ESI+): m/z (%) = 304
(100) [M + Na+].
HRMS (ESI+): m/z calcd
for C17H15NO3Na [M + Na+]:
304.0944; found: 304.0953.
Characterization
Data for Compound 17e
White crystalline solid; mp
126-128 ˚C (CH2Cl2-hexane). R
f
= 0.38
(20% EtOAc in PE). IR (KBr): 2921, 1683, 1513, 1447, 1390,
1305, 1159 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 7.92
(d, J = 7.2
Hz, 1 H), 7.74 (d, J = 8.4
Hz, 2 H), 7.60-7.48 (m, 3 H), 7.23 (d, J = 8.0
Hz, 2 H), 4.83 (s, 2 H), 2.35 (s, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 167.3,
140.1, 136.9, 134.2, 133.3, 131.9, 129.7 (2¥), 128.3, 124.1,
122.5, 119.6 (2¥), 50.8, 20.8. MS (ESI+): m/z (%) = 246
(35) [M + Na+], 224
(100) [M + H+]. Anal.
Calcd for C15H13NO: C, 80.69; H, 5.87; N,
6.27. Found: C, 80.56; H, 5.79; N, 6.28.
Representative
Procedure for Suzuki-Miyaura Coupling of Aryl Chlorides
17b,c
A 10 mL flask was charged with the aryl chloride 17b (24.4 mg, 0.1 mmol), phenyl boronic
acid (19.0 mg, 0.15 mmol), and K3PO4˙3H2O
(80.0 mg, 0.3 mmol). The loaded flask was evacuated and backfilled
with N2 (repeated for three times). To the degassed flask
was added degassed H2O (0.1 mL) and a stock THF (1 mL)
solution containing Pd(OAc)2 (0.23 mg, 1.0¥10-³ mmol)
and Aphos (0.80 mg, 2.0¥10-³ mmol).
The resultant mixture was heated at 60 ˚C for 24 h under
a nitrogen atmosphere. After cooling to r.t., the reaction was quenched
by H2O, and the resultant mixture was extracted with
EtOAc (3 × 5 mL). The combined organic
layer was washed with brine, dried over anhyd Na2SO4,
filtrated, and concentrated under reduced pressure. The residue
was purified by column chromatography over silica gel with elution
by 15% EtOAc in PE (60-90 ˚C) to give
the coupling product 18a (27.0 mg, 95%).
The results are found in Scheme
[4]
.
Characterization Data for Compound 18a
White
crystalline solid; mp 126-128 ˚C (CH2Cl2-hexane). R
f
= 0.38
(20% EtOAc in PE). IR (KBr): 1691, 1600, 1483, 1429, 1376
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 8.13
(dd, J = 2.0,
2.0 Hz, 1 H), 7.93 (d, J = 7.2
Hz, 1 H), 7.85 (dd, J = 8.4,
2.0 Hz, 1 H), 7.65 (d, J = 7.2
Hz, 2 H), 7.60 (ddd, J = 6.4,
6.4, 1.2 Hz, 1 H), 7.52 (d, J = 7.6
Hz, 2 H), 7.50 (d, J = 8.0
Hz, 1 H), 7.48-7.35 (m, 4 H), 4.90 (s, 2 H). ¹³C
NMR (100 MHz, CDCl3): δ = 167.6,
142.2, 140.8, 140.0, 139.9, 133.1, 132.1, 129.5, 128.7 (2¥),
128.4, 127.5, 127.2 (2¥), 124.1, 123.2, 122.6, 118.2, 118.2,
50.8. MS (ESI+): m/z (%) = 308
(95) [M + Na+], 286
(100) [M + H+]. Anal.
Calcd for C20H15NO: C, 84.19; H, 5.30; N,
4.91. Found: C, 84.22; H, 5.32; N, 4.96.