Direct access to anthranilic acid derivatives via CO2 incorporation reaction using arynes

Article abstract of DOI:10.1021/ol801588s

(Chemical Equation Presented) CO₂ was found to be directly convertible into anthranilic acid derivatives of great synthetic value through a three-component coupling using arynes and amines. Zwitterions arising from nucleophilic attack of amines to arynes serve as key intermediates in the coupling.

Full text of DOI:10.1021/ol801588s

Supporting Information for
Direct Access to Anthranilic Acid Derivatives via CO Incorporation Reaction Using
2
Arynes
Hiroto Yoshida,* Takami Morishita and Joji Ohshita
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima 739-8527, Japan
Contents
General Remarks
S2
S2
Aryne Precursors
Experimental Procedures and Characterization Data of Products
References
S3
S11
S12
1
13
H and C NMR Spectra of Products
S1

General remarks.
All manipulations of oxygen- and moisture-sensitive materials were conducted with a
standard Schlenk technique under a purified argon atmosphere. Nuclear magnetic
1
13
resonance spectra were taken on a JEOL EX-270 ( H, 270 MHz; C, 67.8 MHz)
1
13
spectrometer or a JEOL Lambda-400 ( H, 400 MHz; C, 99.5 MHz) spectrometer using
1
13
1
residual chloroform ( H, δ = 7.26) or CDCl ( C, δ = 77.0) as an internal standard. H
3
NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, quint = quintet, sept = septet, br = broad, m = multiplet), coupling
constants (Hz), integration. High-resolution mass spectra were obtained with a JEOL
JMS-SX102A spectrometer. Melting points were measured with Yanaco Micro Melting
Point apparatus and uncorrected. Column chromatography was carried out using Merck
Kieselgel 60. Unless otherwise noted, commercially available reagents were used without
purification. 18-Crown-6 was recrystallized from distilled MeCN. KF (spray-dried) was
vacuum dried at 100 °C for 12 h. THF was distilled from sodium/benzophenone ketyl.
MeCN was distilled from phosphorus pentoxide.
Aryne precursors.
1
2
-(Trimethylsilyl)phenyl triflate (1a), 3-(trimethylsilyl)-5,6,7,8-tetrahydro-2-naphthyl
2
3
triflate
(1b),
6-(trimethylsilyl)-5-indanyl
triflate
(1c),
4,5-dimethyl-2-
3
2
(
trimethylsilyl)phenyl triflate (1d), 3-(trimethylsilyl)-2-naphthyl triflate (1e), 3,6-
2
dimethyl-2-(trimethylsilyl)phenyl triflate (1f), 4-fluoro-2-(trimethylsilyl)phenyl triflate
2
4
(
(
1g),
4-methoxy-2-(trimethylsilyl)phenyl
triflate
(1h)
and
4-methyl-2-
5
trimethylsilyl)phenyl triflate (1i) were prepared according to literature procedures.
S2

Three-component coupling of arynes, amines and CO : a general procedure.
2
A THF solution (1 mL) of an amine (0.165 mmol), 18-Crown-6 (0.079 g, 0.30 mmol) and
KF (0.017 g, 0.30 mmol) was degassed through two freeze-thaw cycles, and the reaction
flask was filled with CO by connecting to a balloon (1 L). To this solution was added an
2
aryne precursor (0.15 mmol), and the resulting mixture was stirred at 0 °C for the period
as specified in Table 1 and Scheme 1. The mixture was diluted with ethyl acetate, filtered
through a Celite plug, and concentrated. Silica-gel column chromatography (ethyl acetate
as an eluent) gave the corresponding product.
In cases that an anthranilic acid was difficult to be isolated (Table 1, entries 3–5, 7, 9, 10,
1
2 or 13), a crude product was treated with 2 M solution of (trimethylsilyl)diazomethane
in hexane (0.083 mL, 0.165 mmol), methanol (0.15 mL) and dichloromethane (3 mL) at
6
room temperature for 12 h before the resulting mixture was quenched with acetic acid.
Evaporation of the solvent followed by silica-gel column chromatography (ethyl acetate as
an eluent) gave the respective methyl ester.
N,N-Di-n-propylanthranilic acid (3aa)
1
Isolated in 84% yield as a white solid: mp 107–115 °C; H NMR (CDCl ) δ 0.85 (d, J =
3
7
.4 Hz, 6 H), 1.15–1.66 (m, 4 H), 3.00 (brs, 4 H), 7.34–7.43 (m, 2 H), 7.59 (td, J =7.7, 1.7
1
3
Hz, 1 H), 7.36 (dd, J = 7.6, 1.6 Hz, 1 H); C NMR (CDCl ) δ 11.4, 19.8, 58.9, 122.2,
3
+
1
27.4, 127.6, 131.7, 133.7 ,148.3, 167.8; HRMS Calcd for C H NO : M , 221.1416.
1
3
19
2
Found: m/z 221.1412.
N,N-Di-n-butylanthranilic acid (3ab)
1
Isolated in 74% yield as a pale yellow solid: mp 54–58 °C; H NMR (CDCl ) δ 0.82 (d, J
3
=
7.1 Hz, 6 H), 1.23 (brs, 6 H), 1.55 (brs, 2 H), 2.82-3.30 (m, 4 H), 7.30-7.48 (m, 2 H),
S3

1
3
7
2
.60 (td, J = 7.7, 1.7 Hz, 1 H), 8.31 (dd, J = 7.8, 1.6 Hz, 1 H); C NMR (CDCl ) δ 13.7,
3
0.3, 28.4, 57.1, 122.1, 127.4, 127.7, 131.7, 133.7, 148.0, 167.9; HRMS Calcd for
+
C H NO : M , 249.1728. Found: m/z 249.1719.
1
5
23
2
N,N-Diethylanthranilic acid methyl ester (3ac)
1
Isolated in 54% yield as a pale yellow oil: H NMR (CDCl ) δ 1.05 (t, J = 7.1 Hz, 3 H),
3
3
1
.14 (q, J = 7.1 Hz, 4 H), 3.87 (s, 3 H), 6.92 (td, J = 7.5, 1.0 Hz, 1 H), 7.05 (d, J = 8.2 Hz,
1
3
H), 7.34 (ddd, J = 8.4, 7.2, 1.7 Hz, 1 H), 7.56 (dd, J = 7.5, 1.7 Hz, 1 H); C NMR
(
CDCl ) δ 12.3, 46.9, 51.97, 51.99, 120.5, 120.9, 126.1, 130.5, 131.5, 150.3, 169.3;
3
+
HRMS Calcd for C H NO : M , 207.1253. Found: m/z 207.1252.
1
2
17
2
N,N-Bis(2-methoxyethyl)anthranilic acid methyl ester (3ad)
1
Isolated in 64% yield as a pale yellow oil: H NMR (CDCl ) δ 3.28 (s, 3 H), 3.63 (t, J =
3
6
.0 Hz, 4 H), 3.46 (t, J = 6.0 Hz, 4 H), 3.87 (s, 3 H), 6.97 (td, J = 7.4, 0.7 Hz, 1 H), 7.18 (d,
1
3
J = 7.6 Hz, 1 H), 7.36 (td, J = 7.8, 1.8 Hz, 1 H), 7.58 (dd, J = 7.6, 1.8 Hz, 1 H),; C NMR
(
CDCl ) δ 52.02, 52.03, 53.5, 58.7, 70.7, 121.4, 122.4, 126.2, 130.63. 130.68, 131.8, 150.3,
3
+
1
68.8; HRMS Calcd for C H NO : M , 267.1471. Found: m/z 267.1462.
1
4
21
4
N,N-Diisopropylanthranilic acid methyl ester (3ae)
1
Isolated in 79% yield as a pale yellow oil: H NMR (CDCl ) δ 0.98 (d, J = 6.5 Hz, 12 H),
3
3
1
.48 (sept, J = 6.5 Hz, 2 H), 3.84 (s, 3 H), 7.17 (td, J = 7.3, 1.2 Hz, 1 H), 7.27 (dd, J = 8.2,
1
3
.0 Hz, 1 H), 7.36 (ddd, J = 8.0, 7.2, 1.7 Hz, 1 H), 7.45 (dd, J = 7.5, 1.7 Hz, 1 H);
C
S4

NMR (CDCl ) δ 21.4, 29.7, 49.7, 51.7, 124.8, 128.2, 129.9, 130.0, 146.6, 170.0; HRMS
3
+
Calcd for C H NO : M , 235.1572. Found: m/z 235.1580.
1
4
21
2
N,N-Dicyclohexylanthranilic acid (3af)
1
Isolated in 68% yield as a white solid: mp 155–157 °C; H NMR (CDCl ) δ 0.92–1.38 (m,
3
1
3
1
5
3
0 H), 1.60 (d, J = 12.8 Hz, 2 H), 1.67–1.85 (m, 6 H), 2.13 (d, J = 12.2 Hz, 2 H), 3.28–
.42 (m, 2 H), 7.25–7.32 (m, 1 H), 2.13 (td, J = 7.2, 1.3 Hz, 1 H), 7.52 (td, J = 7.9, 1.6 Hz,
1
3
H), 8.35 (dd, J = 7.9, 1.6 Hz, 1 H); C NMR (CDCl ) δ 25.30, 25.38, 25.39, 28.1, 30.2,
3
+
8.4, 125.1, 127.8, 129.8, 131.6, 132.2, 143.0, 168.5; HRMS Calcd for C H NO : M ,
1
9
27
2
01.2042. Found: m/z 301.2040.
N-Cyclohexyl-N-methylanthranilic acid methyl ester (3ag)
1
Isolated in 72% yield as a pale yellow oil: H NMR (CDCl ) δ 1.10 (tt, J = 12.7, 3.1 Hz, 1
3
H), 1.15–1.32 (m, 2 H), 1.38–1.54 (m, 2 H), 1.55–1.71 (m, 1 H), 1.72–1.87 (m, 4 H), 2.72
(s, 3 H), 3.07 (tt, J = 11.6, 3.1 Hz, 1 H), 3.88 (s, 3 H), 6.84 (td, J = 7.5, 1.0 Hz, 1 H), 6.97
(
1
d, J = 8.2 Hz, 1 H), 7.32 (ddd, J = 8.7, 7.2, 1.7 Hz, 1 H), 7.58 (dd, J = 7.7, 1.9 Hz, 1 H),;
3
C NMR (CDCl ) δ 25.9, 26.1, 29.5, 33.5, 51.96, 51.99, 64.1, 118.83, 118.86, 122.7,
3
+
1
2
31.1, 131.7, 151.8, 169.6; HRMS Calcd for C H NO : M , 247.1572. Found: m/z
1
5
21
2
47.1567.
N-(Cyclopropylmethyl)-N-propylanthranilic acid (3ah)
S5

1
Isolated in 77% yield as a white solid: mp 107–111 °C; H NMR (CDCl ; 50 °C) δ -0.06–
3
0
4
.18 (m, 2 H), 0.39–0.55 (m, 2 H), 0.75–0.95 (m, 4 H), 1.31–1.75 (m, 2 H), 2.78–3.20 (m,
H), 7.34–7.44 (m, 2 H), 7.60 (td, J = 8.0, 1.7 Hz, 1 H), 8.31 (dd, J = 7.6, 1.4 Hz, 1 H);
1
3
C NMR (CDCl ) δ 4.2, 8.0, 11.5, 19.8, 58.0, 62.4, 122.5, 127.5, 131.7, 133.5, 148.6,
3
+
1
67.9; HRMS Calcd for C H NO : M , 233.1416. Found: m/z 233.1413.
1
4
19
2
2
-(Azepan-1-yl)benzoic acid methyl ester (3ai)
1
Isolated in 62% yield as a pale yellow oil: H NMR (CDCl ) δ 1.53–1.65 (m, 4 H), 1.71–
3
1
.83 (m, 4 H), 3.32 (t, J = 5.6 Hz, 4 H), 3.87 (s, 3 H), 6.74 (td, J = 1.0, 7.4 Hz, 1 H), 6.95
(
1
dd, J = 8.4, 0.7 Hz, 1 H), 7.29 (td, J = 7.7, 1.7 Hz, 1 H), 7.52 (dd, J = 7.7, 1.7 Hz, 1 H),;
3
C NMR (CDCl ) δ 28.1, 28.4, 30.0, 52.0, 52.7, 116.8, 116.9, 119.6, 131.1, 131.6, 151.2,
3
+
1
70.0; HRMS Calcd for C H NO : M , 233.1416. Found: m/z 233.1414.
1
4
19
2
2
-(Piperidin-1-yl)benzoic acid methyl ester (3aj)
1
Isolated in 54% yield as a yellow oil: H NMR (CDCl ) δ 1.52–1.62 (m, 2 H), 1.67–1.78
3
(
m, 4 H), 2.99 (d, J = 5.3 Hz, 4 H), 6.93 (td, J = 7.5, 1.0 Hz, 1 H), 7.01 (dd, J = 8.2, 1.0 Hz,
1
3
1
H), 7.37 (ddd, J = 8.2, 7.2, 1.7 Hz, 1 H), 7.68 (dd, J = 7.7, 1.7 Hz, 1 H),; C NMR
(
CDCl ) δ 24.2, 26.2, 52.0, 53.8, 118.6, 120.6, 123.9, 131.4, 132.4, 153.2, 168.9; HRMS
3
+
Calcd for C H NO : M , 205.1103. Found: m/z 205.1108.
1
2
15
2
2
-(3,4-Dihydro-(1H)-isoquinolin-2-yl)benzoic acid (3ak)
S6

1
Isolated in 38% yield as a white solid: mp 176–179 °C; H NMR (CDCl ) δ 2.90–3.60 (m,
3
4
H), 4.24 (brs, 2 H), 7.03–7.13 (m, 1 H), 7.18–7.35 (m, 3 H), 7.43–7.58 (m, 2 H), 7.64
1
3
(
ddd, J = 8.2, 7.5, 1.7 Hz, 1 H), 8.34 (dd, J = 7.7, 1.7 Hz, 1 H); C NMR (CDCl ) δ 29.0,
3
5
1
1.5, 55.8, 122.5, 125.2, 126.4, 126.5, 127.3, 127.7, 129.0, 132.0, 132.3, 132.4, 134.0,
+
50.7, 167.0; HRMS Calcd for C H NO : M , 253.1103. Found: m/z 253.1103.
1
6
15
2
2
-(Pyrrolidin-1-yl)benzoic acid methyl ester (3al)
1
Isolated in 7% yield as a pale brown oil: H NMR (CDCl ) δ 1.89–1.99 (m, 4 H), 3.18–
3
3
.30 (m, 4 H), 3.88 (s, 3 H), 6.71 (td, J = 7.4, 1.0 Hz, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 7.29
1
3
(
ddd, J = 8.7, 7.0, 1.7 Hz, 1 H), 7.57 (dd, J = 7.7, 1.7 Hz, 1 H); C NMR (CDCl ) δ 25.9,
3
5
0.8, 52.0, 113.9, 115.6, 117.1, 131.1, 131.8, 148.0, 169.6; HRMS Calcd for C H NO :
13 17 2
+
M , 219.1259. Found: m/z 219.1261.
N-[(1,3-Dioxolan-2-yl)methyl]-N-methylanthranilic acid methyl ester (3am)
1
Isolated in 29% yield as a colorless oil: H NMR (CDCl ) δ 2.96 (s, 3 H), 3.30 (d, J = 4.1
3
Hz, 2 H), 3.82-3.88 (m, 2 H), 3.89 (s, 3 H), 3.93-3.98 (m, 2 H), 5.09 (t, J = 4.1 Hz, 1 H),
6
.88 (t, J = 7.5 Hz, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.35 (td, J = 7.8, 1.7 Hz, 1 H), 7.62 (dd,
1
3
J = 7.7, 1.7 Hz, 1 H); C NMR (CDCl ) δ 29.7, 41.2, 52.1, 59.2, 64.8, 103.7, 118.7,
3
+
1
19.6, 122.1, 131.3, 132.1, 151.8, 168.9; HRMS Calcd for C H NO : M , 251.1158.
1
3
17
4
Found: m/z 251.1155.
N-(Cyclopropylmethyl)-N-propyl-4,5-tetramethyleneanthranilic acid (3bh)
S7

1
Isolated in 90% yield as a white solid: mp 142–147 °C; H NMR (CDCl ) δ -0.02–0.09
3
(
m, 1 H), 0.16–0.27 (m, 1 H), 0.36–0.60 (m, 2 H), 0.73–0.92 (m, 4 H), 1.18–1.41 (m, 1 H),
1
1
5
.48–1.68 (m, 1 H), 1.72–1.85 (m, 4 H), 2.72–2.97 (m, 7 H), 3.08–3.21 (m, 1 H), 7.01 (s,
1
3
H), 7.97 (s, 1 H); C NMR (CDCl ) δ 3.9, 4.6, 8.1, 11.5, 19.8, 22.5, 22.7, 28.8, 29.6,
3
8.1, 62.5, 122.5, 124.3, 132.1, 136.8, 143.5, 145.4, 168.5; HRMS Calcd for C H NO :
1
8
25
2
+
M , 287.1885. Found: m/z 287.1881.
N-(Cyclopropylmethyl)-N-propyl-4,5-trimethyleneanthranilic acid (3ch)
1
Isolated in 55% yield as a white solid: mp 119–123 °C; H NMR (CDCl ) δ -0.02–0.11
3
(
m, 1 H), 0.15–0.27 (m, 1 H), 0.37–0.62 (m, 2 H), 0.72–1.01 (m, 4 H), 1.19–1.42 (m, 1 H),
1
1
2
.50–1.70 (m, 1 H), 2.11 (quint, J = 7.5 Hz, 2 H), 2.75–2.14 (m, 7 H), 3.15 (td, J = 5.1,
1
3
1.6 Hz, 1 H), 7.19 (s, 1 H), 8.31 (s, 1 H); C NMR (CDCl ) δ 3.9, 4.6, 8.0, 11.5, 19.7,
3
5.4, 32.2, 33.1, 58.1, 62.5, 117.9, 125.3, 127.0, 143.9, 146.8, 150.6, 168.5; HRMS
+
Calcd for C H NO : M , 273.1729. Found: m/z 273.1735.
1
7
23
2
N-(Cyclopropylmethyl)-N-propyl-4,5-dimethylanthranilic acid (3dh)
1
Isolated in 75% yield as a pale yellow solid: mp 117–121 °C; H NMR (CDCl ) δ -0.06–
3
0
1
.07 (m, 1 H), 0.14–0.25 (m, 1 H), 0.33–0.60 (m, 2 H), 0.73–0.92 (m, 4 H), 1.18–1.39 (m,
H), 1.48–1.68 (m, 1 H), 2.28 (s, 3 H), 2.30 (s, 3 H), 2.79–2.98 (m, 3 H), 3.08–3.21 (m, 1
1
3
H), 7.09 (s, 1 H), 8.04 (s, 1 H); C NMR (CDCl ) δ 3.9, 4.5, 8.1, 11.5, 19.3, 19.8, 20.2,
3
S8

5
8.1, 62.4, 123.1, 124.7, 132.3, 136.3, 143.1, 145.9, 168.5; HRMS Calcd for C H NO :
16 23 2
+
M , 261.1729. Found: m/z 261.1728.
3
-[N-(Cyclopropylmethyl)-N-propylamino]-2-naphthoic acid (3eh)
1
Isolated in 42% yield as a yellow solid: mp 142–146 °C; H NMR (CDCl ) δ -0.04–0.10
3
(
m, 1 H), 0.15–0.30 (m, 1 H), 0.34–0.62 (m, 2 H), 0.76–0.99 (m, 4 H), 1.25–1.43 (m, 1 H),
.55–1.78 (m, 1 H), 2.92–3.20 (m, 3 H), 3.20–3.39 (m, 1 H), 7.56 (ddd, J = 8.2, 7.0, 1.4
Hz, 1 H), 7.61 (ddd, J = 8.0, 6.8, 1.2 Hz, 1 H), 7.80 (s, 1 H), 7.83 (d, J = 7.7 Hz, 1 H),
1
1
3
7
6
.99 (d, J = 8.0 Hz, 1 H), 8.91 (s, 1 H); C NMR (CDCl ) δ 4.1, 4.6, 8.1, 11.5, 19.8, 58.7,
3
3.0, 121.57, 121.59, 124.8, 127.1, 128.7, 129.5, 131.6, 133.4, 135.3, 145.0, 168.2;
+
HRMS Calcd for C H NO : M , 283.1572. Found: m/z 283.1572.
1
8
21
2
N-(Cyclopropylmethyl)-N-propyl-3,6-dimethylanthranilic acid (3fh)
1
Isolated in 71% yield as a yellow oil: H NMR (CDCl ) δ 0.02–0.07 (m, 1 H), 0.21–0.27
3
(
m, 1 H), 0.40–0.47 (m, 1 H), 0.53–0.61 (m, 1 H), 0.83–0.96 (m, 4 H), 1.32–1.46 (m, 1 H),
1
.59–1.75 (m, 1 H), 2.38 (s, 3 H), 2.71 (s, 3 H), 3.06 (dd, J = 7.0, 2.8 Hz, 2 H), 3.11 (td, J
1
3
=
12.1, 5.1 Hz, 1 H), 3.27 (td, J = 12.1, 5.1 Hz, 1 H), 7.13 (s, 2 H); C NMR (CDCl ) δ
3
3
1
.8, 4.7, 8.5, 11.5, 19.7, 20.6, 24.4, 55.9, 59.6, 127.6, 132.08, 132.14, 134.8, 141.9, 145.0,
+
68.6; HRMS Calcd for C H NO : M , 261.1729. Found: m/z 261.1727.
1
6
23
2
A mixture of N-(cyclopropylmethyl)-N-propyl-5-fluoroanthranilic acid (3gh) and N-
(
cyclopropylmethyl)-N-propyl-4-fluoroanthranilic acid (3’gh)
3gh:3’gh = 94:6)
(
S9

1
Isolated in 32% yield as a pale yellow solid: mp 106–109 °C; H NMR (CDCl ) δ -0.06–
3
0
.03 (m), 0.13–0.25 (m), 0.37–0.61 (m), 0.76–0.94 (m), 1.20–1.40 (m), 1.50–1.68 (m),
.76–3.05 (m), 3.10–3.24 (m), 7.06–7.18 (m, minor), 7.23-7.32 (m), 7.37 (dd, J = 8.6, 4.6
2
1
3
Hz), 7.99 (dd, J = 8.9, 3.1 Hz, major), 8.33 (dd, J = 8.7, 6.5 Hz, minor);
C NMR
(
CDCl ) δ 4.2, 4.4, 7.9 (major),8.1 (minor), 11.44, 11.47, 19.8 (major), 20.0 (minor),
3
5
8.21 (minor), 58.29 (major), 62.6, 110.3 (JC-F = 22.1 Hz, minor), 115.1 (JC-F = 21.3 Hz,
minor), 119.1 (JC-F = 23.8 Hz, major), 120.6 (JC-F = 23.8 Hz, major), 124.4 (JC-F = 8.2 Hz,
major), 129.8 (JC-F = 7.4 Hz), 134.0 (JC-F = 9.8 Hz), 144.1 (JC-F = 3.3 Hz), 151.3, 161.0 (JC-
+
=
249.4 Hz), 166.61, 166.62; HRMS Calcd for C H FNO : M , 251.1322. Found:
F
14 18
2
m/z 251.1323.
A mixture of N-(cyclopropylmethyl)-N-propyl-5-methoxyanthranilic acid (3hh) and
N-(cyclopropylmethyl)-N-propyl-4-methoxyanthranilic acid (3’hh)
(
3hh:3’hh = 45:55)
1
Isolated in 64% yield as a brown oil: H NMR (CDCl ) δ -0.05–0.08 (m), 0.13–0.23 (m),
3
0
.34–0.59 (m), 0.76–0.93 (m), 1.17–1.40 (m), 1.50–1.65 (m), 2.77–3.00 (m), 3.03–3.21
(
(
(
m), 3.85 (s), 3.86 (s), 6.84 (d, J = 2.4 Hz, major), 6.90 (dd, J = 8.7, 2.4 Hz, major), 7.10
dd, J = 8.9, 3.0 Hz, minor), 7.25 (d, J = 8.7 Hz, minor), 7.79 (d, J = 8.7 Hz, minor), 8.24
1
3
d, J = 8.7 Hz, major); C NMR (CDCl ) δ 4.0, 4.4, 7.9, 8.1, 11.4, 11.5, 19.7, 19.9, 55.6,
3
5
5.7, 58.1, 58.2, 62.47, 62.49, 109.0, 112.1, 113.9, 120.1, 121.0, 123.3, 128.7, 133.4,
+
1
40.6, 150.6, 158.3, 163.6, 167.7, 167.9; HRMS Calcd for C H NO : M , 263.1521.
1
5
23
3
Found: m/z 263.1521.
A mixture of N-(cyclopropylmethyl)-N-propyl-5-methylanthranilic acid (3ih) and N-
(
cyclopropylmethyl)-N-propyl-4-methylanthranilic acid (3’ih)
3ih:3’ih = 42:58)
(
S10

1
Isolated in 55% yield as a pale yellow solid: mp 57–61 °C; H NMR (CDCl ) δ -0.06–
3
0
2
.08 (m,), 0.11–0.25 (m), 0.34–0.62 (m), 0.76–0.95 (m), 1.20–1.40 (m), 1.50–1.68 (m),
.38 (s, minor), 2.41 (s, major), 2.79-3.02 (m), 3.07-3.23 (m), 7.14 (s, major), 7.19 (dd, J
=
8.0, 1.0 Hz, major), 7.24 (d, J = 8.2 Hz, minor), 7.37 (ddd, J = 7.5, 2.2, 0.7 Hz, minor),
1
3
8
8
1
.11 (d, J = 1.7 Hz, minor), 8.17 (d, J = 8.0 Hz, major); C NMR (CDCl ) δ 4.0, 4.4, 8.0,
3
.1, 11.47, 11.49, 19.78, 19.88, 20.9, 21.6, 58.0, 58.1, 62.40, 62.43, 122.2, 122.9, 124.7,
27.0, 128.4, 131.6, 131.9, 134.2, 137.6, 144.4, 145.8, 148.7, 168.0, 168.2; HRMS Calcd
+
for C H NO : M , 247.1572. Found: m/z 247.1577.
1
5
21
2
References
1
2
3
4
6
5
7
6
. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214.
. Yoshida, H.; Terayama, T.; Ohshita, J.; Kunai, A. Chem. Commun. 2004, 1980–1981.
. Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767–2769.
. Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2003, 125,
638–6639.
. Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
280–7286.
. Yamagishi, T.; Okumura, Y.; Nukui, S.; Nakao, K. (PFIZER INC., PFIZER JAPAN
INC.) WO 2005021508, 2005.
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