PAPER
First Direct Chlorination of Iodoarenes
2413
tion, brine, dried over anhyd MgSO4 and concentrated in vacuum.
The crude product was treated with bromoacetic acid methyl ester
(8.0 mL, 95 mmol) and K2CO3 (26.5 g, 190 mmol) as described for
compound 3. After standard work-up and purification by column
chromatography, 4.3 g (8.5 mmol, 27%) of 4 were obtained as co-
lourless crystals; mp 119–120 °C.
1H NMR (300 MHz, CDCl3): = 3.75 (s, 3 H, OCH3), 3.77 (s, 3 H,
OCH3), 4.60 (s, 2 H, ArOCH2), 4.68 (s, 2 H, ArOCH2), 7.04 (d, 1 H,
4J3,5 = 2.0 Hz, 5-H), 7.70 (d, 1 H, 4J3,5 = 2.0 Hz, 3-H).
13C NMR (75 MHz, CDCl3): = 51.96 (OCH3), 52.28 (OCH3),
66.04 (ArOCH2), 69.03 (ArOCH2), 87.61 (C-2), 93.19 (C-4),
123.76 (C-5), 139.93 (C-3), 147.78 (C-6), 150.21 (C-1), 168.04
(CO), 168.76 (CO).
MS (EI, 70 eV): m/z (%) = 334 (19) [M+], 289 (14) [M+
–
OCH2CH3], 220 (33) [M+ – (CH2)3CO2CH2CH3], 115 (100)
+
[(CH2)3CO2CH2CH3 ].
HRMS: m/z calcd for C12H15IO3 (M+): 344.0066. Found: 344.0018.
(3-Chloro-2,4-diiodo-6-methoxy-phenoxy)acetic Acid Methyl
Ester (5)
To a solution of 3 (807 mg, 1.8 mmol) was in CH2Cl2 (25 mL ) at
25 °C was added MoCl5. The reaction mixture was diluted with
EtOAc (100 mL) and washed with water (100 mL). Subsequent
treatment with brine, anhyd MgSO4, and concentration of the organ-
ic phase provided the crude product, which was purified by column
chromatogaphy yielding 5 as colourless crystals; mp 95–96 °C.
1H NMR (300 MHz, CDCl3): = 3.74 (s, 3 H, OCH3), 3.75 (s, 3 H,
ArOCH3), 4.54 (s, 2 H, ArOCH2), 7.32 (s, 1 H, ArH).
13C NMR (75MHz, CDCl3): = 52.10 (OCH3), 56.55 (ArOCH3),
68.99 (ArOCH2), 89.71 (C-2), 96.11 (C-4), 123.63 (C-5), 138.47
(C-3), 148.71 (C-6), 150.04 (C-1), 168.61 (CO).
MS (EI, 70 eV): m/z (%) = 506 (100) [M+], 433 (16) [M+
–
CH2CO2CH3], 374 (28) [433 – CO2CH3].
Anal. Calcd for C12H12I2O6 (506.03): C, 28.48; H, 2.39. Found: C,
28.57; H, 2.45.
1-(2-Chloro-ethoxy)-2-iodo-benzene (11)
MS (EI, 70 eV): m/z (%) = 482, 484 (100, 33) [M+], 448 (38) [M+ –
Cl], 409, 411 (53, 18) [M+ – CH2CO2CH3], 375 (20) [M+ – Cl –
CH2CO2CH3].
NaH (355 mg, 8.9 mmol; 60% in paraffin) was suspended in anhyd
DMF (30 mL) and 2-iodophenol (1.5 g, 6.8 mmol) was added. After
stirring at 25 °C for 1 h, (2-chloro-ethyl)tosylate (1.6 mL, 8.9
mmol) was injected. The reaction mixture was stirred at 90 °C for 7
h. After cooling to 25 °C, EtOAc (30 mL) were added and the mix-
ture was washed with water (100 mL) and brine, dried over anhyd
MgSO4 and concentrated in vacuum. Purification by column chro-
matography yielded 1.9 g (6.7 mmol, 98%) of 11 as a colourless oil.
Anal. Calcd for C10H9ClI2O4 (482.42): C, 24.90; H, 1.88. Found: C,
25.27; H, 1.83.
X-Ray Structure Analysis
C10H9ClI2O4:
colorless
crystals,
crystal
dimension
0.45 × 0.20 × 0.20 mm3; M = 482.42; monoclinic, space group P21/
1H NMR (300 MHz, CDCl3): = 3.82 (t, 2 H, J7,8 = 6.0 Hz,
c
(No. 14), a = 9.354(1), b = 9.693(1), c = 14.806(1) Å,
= 96.60(1)°, V = 1333.5(2) Å3, Z = 4, = 0.71073 Å, T = 198 K,
calc = 2.403 g cm–3, = 49.16 cm–1, empirical absorption correc-
3
3
CH2Cl), 4.22 (t, 2 H, J7,8 = 6.0; ArOCH2), 6.71 (ddd, 1 H,
3
4
3J3,4 = 7.8 Hz, J4,5 = 7.4 Hz, J4,6 = 1.4 Hz, 4-H), 6.78 (d, 1 H,
3J5,6 = 8.2 Hz, 6-H), 7.26 (ddd, 1 H, J4,5 = 7.4 Hz, J5,6 = 8.2 Hz,
tion via SORTAV (0.216 T 0.440), and scans, 10438 reflec-
3
3
4J3,5 = 1.6 Hz, 5-H), 7.75 (dd, 1 H, 3J3,4 = 7.8 Hz, 4J3,5 = 1.6 Hz, 3-
tions collected ( h, k, l), [(sin )/ ] = 0.68 Å–1, 3251 independent
(Rint = 0.021) and 3090 observed reflections [I 2 (I)], 156 refined
parameters, R = 0.020, wR2 = 0.046, max. residual electron density
0.48 (–0.60) e Å–3, hydrogens calculated and refined as riding at-
oms.
H).
13C NMR (75 MHz, CDCl3): = 41.47 (CH2Cl), 69.28 (ArOCH2),
86.79 (C-2), 112.80 (C-6), 123.23 (C-4), 129.40 (C-5), 139.55 (C-
3), 156.78 (C-1)
Data set was collected with an Nonius KappaCCD diffractometer in
combination with a Nonius FR591 (rotating anode) as X-ray source.
Programs used: data collection COLLECT (Nonius B.V., 1998),
data reduction Denzo-SMN,14 absorption correction SORTAV,15
structure solution SHELXS-97,16a structure refinement SHELXL-
97,16b graphics POV-Ray 3.2.17
MS (EI, 70 eV): m/z (%) = 282, 284 (100, 27) [M+], 233 (5) [M+ –
CH2Cl], 220 (100) [M+ – CH2CH2Cl].
HRMS: m/z calcd for C8H8ClIO (M+): 281.9308. Found: 281.9307.
4-(2-Iodo-phenoxy)butyric Acid Ethyl Ester (12)
2-Iodophenol (5.0 g, 22.7 mmol), K2CO3 (6.3 g, 45.4 mmol) and 4-
bromobutyric acid ethyl ester (3.3 ml, 22.7 mmol) were combined
in cyclohexanone (40 mL) and refluxed for 6 h. After cooling to
25 °C, water (250 mL) and Et2O (100 mL) were added and the aque-
ous layer was extracted with Et2O (3 × 100 mL). The combined or-
ganic layers were subsequently treated with brine and anhyd
MgSO4 and concentrated in vacuum. After removal of the cyclo-
hexanone, the crude product was purified by distillation in high vac-
uum to give 6.9 g (20.6 mmol, 91%) of 12 as a colourless oil; bp
104 °C (2.7 × 10–2 mbar).
Chlorination by MoCl5 (Table 2); General Procedure
Substrate (1.5 mmol) was dissolved in anhyd CH2Cl2 (25 mL) and
treated for 3 h at 25 °C with 3 equivalents MoCl5. Then the reaction
mixture was diluted with EtOAc (100 mL) and washed with water
(100 mL). Subsequent treatment with brine, anhyd MgSO4, and
concentration of the organic phase provided the crude product,
which was purified by column chromatography yielding the desired
products. All chlorinated compounds formed colourless crystalline
compounds immediately upon evaporation of the solvents. The
products were dried in high vacuum.
1H NMR (400 MHz, CDCl3): = 1.25 (t, 3 H, 3J11,12 = 7.2 Hz, CH3),
2.14 (tt, 2 H, 3J7,8 = 6.0 Hz, 3J8,9 = 7.3 Hz, CH2CH2CH2), 2.61 (t, 2
H, 3J8,9 = 7.3, CH2COO), 4.05 (t, 2 H, 3J7,8 = 6.0 Hz, ArOCH2), 4.14
(q, 2 H, 3J11,12 = 7.2 Hz, COOCH2), 6.69 (ddd, 1 H, 3J3,4 = 7.7 Hz,
(4-Chloro-2-iodo-phenoxy)acetic Acid Methyl Ester (13)
Mp 36–37 °C.
4
3
3J4,5 = 7.7 Hz, J4,6 = 1.2 Hz, 4-H), 6.78 (dd, 1 H, J5,6 = 8.2 Hz,
4J4,6 = 1.2 Hz, 6-H), 7.24–7.29 (m, 1 H, 5-H), 7.75 (dd, 1 H,
3J3,4 = 7.7 Hz, 4J3,5 = 1.7 Hz, 3-H).
1H NMR (300 MHz, CDCl3): = 3.80 (s, 3 H, OCH3), 4.67 (s, 2 H,
ArOCH2), 6.64 (d, 1 H, 3J5,6 = 8.7 Hz, 6-H), 7.24 (dd, 1 H, 3J5,6 = 8.7
Hz, 4J3,5 = 2.5 Hz, 5-H), 7.76 (d, 1 H, 4J3,5 = 2.5 Hz, 3-H).
13C NMR (75MHz, CDCl3): = 52.33 (OCH3), 66.55 (ArOCH2),
86.76 (C-2), 112.99 (C-6), 127.63 (C-4), 129.17 (C-5), 138.97 (C-
3), 155.67 (C-1), 168.40 (CO).
13C NMR (100 MHz, CDCl3):
= 14.13 (CH3), 24.39
(CH2CH2CH2), 30.63 (CH2COO), 60.30 (COOCH2), 67.72
(ArOCH2), 86.53 (C-2), 111.97 (C-6), 122.42 (C-4), 129.31 (C-5),
139.25 (C-3), 157.10 (C-1), 173.05 (CO).
Synthesis 2003, No. 15, 2410–2414 © Thieme Stuttgart · New York