The Journal of Organic Chemistry
Note
lane) and are referenced to the residual solvent peak of CDCl3 at δ
7.26 and δ 77.00 in 1H and 13C NMR, respectively, or C6D6 at δ 7.15
and δ 128.00 in 1H and 13C NMR, respectively. Coupling constants are
reported in Hz with multiplicities denoted as s (singlet), d (doublet), t
(triplet), q (quartet), p (pentet), m (multiplet), and br (broad). IR
spectra were acquired by ATR on an FT-IR spectrometer and are
reported in wave numbers (cm−1). Methyl 2-hydroxy-4-methoxy-6-
methylbenzoate (19) was prepared according to the literature
procedure.17
2,6-Dichlorophenol (12). To a solution of 2-chlorophenol (11)
(128.6 mg, 1.00 mmol) and 2,2,6,6-tetramethylpiperidine (0.4 M in
toluene, 25 μL, 0.01 mmol) in toluene (10 mL) at 25 °C was added
SO2Cl2 (90 μL, 1.1 mmol) slowly under N2. After 24 h, the reaction
mixture was concentrated. The residue was dissolved in CH2Cl2, which
was washed with saturated NaCl solution and dried over Na2SO4 to
give 149.1 mg (91%) of analytically pure 12 as a white solid: Rf 0.63
(7:1 hexanes/EtOAc); mp 64−66 °C (lit.21 67−70 °C); H NMR
1
(CDCl3) δ 7.26 (d, 2, J = 8.0), 6.83 (t, 1, J = 8.0), 5.84 (s br, 1, OH);
13C NMR (CDCl3) δ 147.8, 128.3 (2 C), 121.15 (2 C), 121.12; IR
(neat) 3451, 1578, 1464, 1338, 770, 573. The 1H and 13C NMR
spectral data are identical to those previously reported.22
Exploratory Experiments. SO2Cl2 (18 μL, 0.22 mmol, 1.1 equiv)
was added via a 50 μL syringe to a solution of phenol 5 or 8 (0.2
mmol) and the amine or ammonium chloride specified in Tables 1 or
2 in 0.4 mL of C6D6 in an NMR tube. The sample was monitored by
1H NMR spectroscopy for the time indicated in Tables 1 and 2.
Reaction of TMP and SO2Cl2 in CDCl3. SO2Cl2 (8 μL, 0.1 mmol,
0.5 equiv) was added to a solution of TMP (28 mg, 0.2 mmol) in 0.4
3-Chloro-2-hydroxybenzaldehyde (14). To a solution of 2-
hydroxybenzaldehyde (13) (122.5 mg, 1.00 mmol) and 2,2,6,6-
tetramethylpiperidine (14.0 mg, 0.10 mmol) in PhCF3 (10 mL) at 100
°C was added SO2Cl2 (160 μL, 2.00 mmol) slowly under N2. The
reaction mixture was heated for 30 min, cooled, and concentrated. The
residue was dissolved in CH2Cl2, which was washed with saturated
NaCl solution and dried over Na2SO4 to give 158.0 mg of crude 14.
Flash chromatography (20:1 hexanes/EtOAc) gave 3.5 mg (2%) of a
mixture of 13 and the para-chlorophenol, followed by 136.0 mg (87%)
of 14 as an off-white solid: Rf 0.32 (7:1 hexanes/EtOAc); mp 53−54
1
mL of CDl3 in an NMR tube. The H NMR spectrum showed an
approximately 1:1 mixture of TMP·HCl (methyl singlet at δ 1.54) and
TMPCl (methyl singlet at δ 1.19). The 13C NMR spectrum showed an
approximately 1:1 mixture of TMP·HCl (δ 57.0, 35.0, 27.5, 16.2) and
TMPCl (δ 62.5, 40.5, 27.2, 17.1). The peaks at δ 62.5 (C2 and C6) and
27.2 (Me) were broadened by a slow exchange process.
A reference sample of TMP·HCl was prepared by treating TMP
with 4.0 M HCl in dioxane. A reference sample of TMPCl was
prepared by the literature procedure.9
°C (lit.15a 56 °C); H NMR (CDCl3) 11.49 (s, 1, OH), 9.91 (s, 1),
1
7.63 (dd, 1, J = 7.9, 1.2), 7.51 (dd, 1, J = 7.9, 1.2), 7.00 (dd, 1, J = 7.9,
7.9); 13C NMR (CDCl3) 196.0, 157.2, 136.9, 132.1, 122.2, 121.4,
Data for TMP. 1H NMR (CDCl3) 1.68−1.61 (m, 2), 1.32 (br t, 4, J
= 6.1 Hz), 1.11 (s, 12); 1H NMR (C6D6) 1.57−1.48 (m, 2), 1.23 (br t,
4, J = 5.4 Hz), 1.06 (s, 12); 13C NMR (CDCl3) 49.6, 38.5, 31.5, 18.3;
13C NMR (C6D6) 49.6, 38.6, 32.0, 18.8.
120.2; IR (neat) 1645, 1446, 1293, 1223, 745, 677. The 1H NMR, 13
C
NMR, and IR spectral data are identical to those previously
reported.15a
3′-Chloro-2′-hydroxyacetophenone (16). To a solution of 2′-
hydroxyacetophenone (15) (136.3 mg, 1.00 mmol) and 2,2,6,6-
tetramethylpiperidine (15.5 mg, 0.11 mmol) in PhCF3 (10 mL) at 100
°C was added SO2Cl2 (160 μL, 2.00 mmol) slowly under N2. The
reaction mixture was heated for 45 min, cooled, and concentrated. The
residue was dissolved in CH2Cl2, which was washed with saturated
NaCl solution and dried over Na2SO4 to give 181.3 mg of a ∼55:15:30
mixture of 16, para-chlorophenol 17, and dichlorophenol 18. Flash
chromatography (20:1 hexanes/EtOAc) gave 76.8 mg (45%) of a
mixture of 17 and 18 followed by 90.0 mg (53%) of 16 as an off-white
solid: Rf 0.43 (7:1 hexanes/EtOAc); mp 44−47 °C (lit.23 49.5−50
1
Data for TMP·HCl. H NMR (CDCl3) 1.76−1.68 (m, 6), 1.59 (s,
12); 13C NMR (CDCl3) 56.9, 35.2, 27.7, 16.3. Lack of solubility
precluded obtaining data in C6D6.
1
Data for TMPCl. H NMR (CDCl3) 1.65−1.58 (m, 4), 1.58−1.52
(m, 2), 1.23 (s, 12); 1H NMR (C6D6) 1.38 (br t, 4, J = 5.5 Hz), 1.26−
1.20 (m, 2), 1.21 (s, 12); 13C NMR (CDCl3) 62.6, 40.7, 27.4, 17.2; 13
NMR (C6D6) 62.5, 40.8, 27.4, 17.4.
C
Reaction of TMP and SO2Cl2 in C6D6. SO2Cl2 (8 μL, 0.1 mmol,
0.5 equiv) was added to a solution of TMP (28 mg, 0.2 mmol) in 0.4
mL of C6D6 in an NMR tube. TMP·HCl crystallized as colorless
needles. The 1H NMR spectrum showed mainly TMPCl (methyl
singlet at δ 1.20). The 13C NMR spectrum showed a little TMP·HCl
(δ 56.9, 34.8, 27.4, 16.3) and mainly TMPCl (δ 62.5, 40.8, 27.3, 17.4).
The peak at δ 27.3 (Me) was broadened by a slow exchange process.
2-tert-Butyl-6-chlorophenol (6). To a solution of 2-tert-
butylphenol (5) (150.3 mg, 1.00 mmol) and 2,2,6,6-tetramethylpiper-
idine (0.4 M in toluene, 25 μL, 0.01 mmol) in toluene (10 mL) at 25
°C was added SO2Cl2 (90 μL, 1.1 mmol) slowly under N2. After 24 h,
the reaction was concentrated to give 179.6 mg of crude 6. Flash
chromatography (20:1 hexanes/EtOAc) gave 160.6 mg (87%) of 6 as
a clear oil: Rf 0.74 (7:1 hexanes/EtOAc); 1H NMR (CDCl3) 7.22 (dd,
1, J = 7.8, 1.5), 7.20 (dd, 1, J = 7.8, 1.5), 6.82 (dd, 1, J = 7.8, 7.8), 5.87
(s, 1, OH), 1.44 (s, 9); 13C NMR (CDCl3) 149.7, 137.6, 126.4, 125.7,
120.9, 120.3, 35.2, 29.3 (3 C); IR (neat) 3524, 1434, 1242, 1186. The
1H NMR and IR spectral data are identical to those previously
reported.19
1
°C); H NMR (CDCl3) 12.84 (s, 1, OH), 7.68 (dd, 1, J = 8.0, 1.7),
7.57 (dd, 1, J = 8.0, 1.7), 6.87 (dd, 1, J = 8.0, 8.0), 2.66 (s, 3); 13C
NMR (CDCl3) 204.4, 158.0, 136.3, 129.1, 122.8, 120.5, 119.0, 26.7; IR
1
(neat) 2363, 1641, 1430, 770, 735. The H NMR spectral data are
identical to those previously reported.24
Methyl 3-Chloro-2-hydroxy-4-methoxy-6-methylbenzoate
(20). To a solution of methyl 2-hydroxy-4-methoxy-6-methylbenzoate
(19) (137.0 mg, 0.70 mmol) and 2,2,6,6-tetramethylpiperidine (11.0
mg, 0.077 mmol) in toluene (10 mL) at 110 °C was added SO2Cl2 (62
μL, 0.77 mmol) slowly under N2. The reaction mixture was heated for
60 min, cooled, and concentrated. The residue was dissolved in
CH2Cl2, which was washed with saturated NaCl solution and dried
over Na2SO4 to give 140.5 mg of a ∼1:1.9:0.6:0.6 mixture of 20, 21,
dichlorophenol, and recovered 19. Flash chromatography (20:1
hexanes/EtOAc) gave 27.3 mg (17%) of a 2:1:1 mixture of recovered
19, 21, and dichlorophenol followed by 76.6 mg (51%) of a 4:1
mixture of 21 and dichlorophenol. Lastly, 25.4 mg (17%) of 20 was
isolated as a white solid: mp 163−166 °C, 167−169 °C after
recrystallization from CH2Cl2/pentane (lit.16b 169−170 °C); Rf 0.20
3-Chloro-2-hydroxy-4-methoxybenzaldehyde (9). To a sol-
ution of 2-hydroxy-4-methoxybenzaldehyde (8) (248 mg, 1.63 mmol)
and 2,2,6,6-tetramethylpiperidine (28 μL, 0.16 mmol) in toluene (15
mL) at 110 °C was added SO2Cl2 (145 μL, 1.82 mmol) slowly under
N2. The reaction mixture was heated for 30 min, cooled, and
concentrated. The residue was dissolved in CH2Cl2, which was washed
with saturated NaCl solution and dried over Na2SO4 to give 415.1 mg
of a 74:16:10 mixture of 9, para-chlorophenol 10, and recovered 8.
Flash chromatography (15:1 to 10:1 hexanes/EtOAc) gave 91.6 mg
(30%) of a 2:1 mixture of 10 and 8 followed by 168.0 mg (56%) of 9
as a white solid: Rf 0.28 (4:1 hexanes/EtOAc); mp 123−125 °C (lit.20a
1
(7:1 hexanes/EtOAc); H NMR (CDCl3) 12.23 (s, 1, OH), 6.35 (s,
1), 3.96 (s, 3), 3.94 (s, 3), 2.55 (s, 3); 13C NMR (CDCl3) 171.9, 159.9,
158.8, 141.3, 107.3, 106.56, 106.52, 56.2, 52.2, 24.6; IR (neat) 2930,
1
2858, 1652, 1559, 1440, 1317, 1103. The H NMR spectral data are
identical to those previously reported.16
The data for 21 were determined from the mixture: 1H NMR
(CDCl3) 11.55 (s, 1, OH), 6.43 (s, 1), 3.95 (s, 3), 3.90 (s, 3), 2.63 (s,
3). The 1H NMR spectral data are identical to those previously
reported.18,25
125 °C, lit.20b 114−117 °C); H NMR (CDCl3) 11.77 (s, 1, OH),
1
9.75 (s, 1), 7.47 (d, 1, J = 8.6), 6.65 (d, 1, J = 8.6), 4.00 (s, 3); 13C
NMR (CDCl3) 191.7, 161.7, 158.9, 133.4, 115.9, 107.3, 103.6, 56.7; IR
(neat) 1633, 1503, 1294, 1073, 792, 754.
The data for the dichlorophenol were determined from the mixture:
1H NMR (CDCl3) 11.57 (s, 1, OH), 4.00 (s, 3), 3.93 (s, 3), 2.61 (s,
D
dx.doi.org/10.1021/jo402424h | J. Org. Chem. XXXX, XXX, XXX−XXX