Synthesis of substituted salicylamines and dihydro-2H-1,3-benzoxazines

Article abstract of DOI:10.1016/j.tet.2007.07.064

Phenols were converted to their magnesium salts with the MgCl₂-Et₃N base system and subsequently reacted with Eschenmoser's salt, affording N,N-dimethyl substituted benzylamines in high to excellent yields. A series of mono N-substituted benzylamines were prepared in one-pot syntheses by ortho-formylation of phenols to corresponding salicylaldehydes, which in turn reacted with amines to imines. The imines were subsequently reduced to mono N-substituted benzylamines. Some of these benzylamines were further converted, without work-up, to mono N-substituted dihydro-2H-1,3-benzoxazines.

Full text of DOI:10.1016/j.tet.2007.07.064

Tetrahedron 63 (2007) 9997–10002
Synthesis of substituted salicylamines
and dihydro-2H-1,3-benzoxazines
Hany F. Anwar,a Lars Skattebølb and Trond Vidar Hansena,
*
aSchool of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, Blindern, N-0316 Oslo, Norway
bDepartment of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
Received 20 April 2007; revised 4 July 2007; accepted 19 July 2007
Available online 26 July 2007
Abstract—Phenols were converted to their magnesium salts with the MgCl2–Et3N base system and subsequently reacted with Eschenmoser’s
salt, affording N,N-dimethyl substituted benzylamines in high to excellent yields. A series of mono N-substituted benzylamines were prepared
in one-pot syntheses by ortho-formylation of phenols to corresponding salicylaldehydes, which in turn reacted with amines to imines. The
imines were subsequently reduced to mono N-substituted benzylamines. Some of these benzylamines were further converted, without
work-up, to mono N-substituted dihydro-2H-1,3-benzoxazines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of phenols, a similar protocol seemed feasible also for a
regioselective Mannich reaction.
Salicylamines and their derivatives are useful intermediates
for the synthesis of heterocyclic and biologically active com-
pounds.1 Aminomethylation of phenols is traditionally
achieved with formaldehyde and amines under acidic condi-
tions using the Mannich reaction,2,3 which occurs readily in
ortho- and para-positions affording polysubstituted phe-
nols.4 The position and nature of the substituents as well
as the reaction conditions play an important role on the
orientation of the Mannich reaction.
2. Results and discussion
To a dichloromethane suspension of anhydrous MgCl2–Et3N
and 2-bromophenol, N,N-dimethylmethylene iminium
iodide (Eschenmoser’s salt) was added. After stirring for
3 h at ambient temperature, complete conversion of the phe-
nol was observed, and only one regioisomer of the N,N-
dimethylamino Mannich base 1 was isolated in 83% yield
(Scheme 1). Subjecting several other 2-substituted phenols
to the same conditions, the corresponding Mannich bases
2–6 were obtained in 66–82% yields. A quantitative yield
of the product 7 was observed when b-napthol was subjected
to these reaction conditions. According to the 1H NMR spec-
tra of the crude reaction mixtures, complete regioselectivity
was observed in all cases. The products were identified by
physical and spectral data. Mannich bases are versatile inter-
mediates for the synthesis of a wide range of biologically
active compounds, and our protocol compares favorable
with others when considering yields, regioselectivity, and
simplicity.
Pochini et al. reported that phenols reacted with Eschen-
moser’s salt in the presence of potassium carbonate affording
exclusively ortho-substituted products in variable yields.5
Recently Ley and co-workers reported one example of a car-
bonate exchange resin catalyzed reaction between 2-allyl
phenol and Eschenmoser’s salt to yield 2-allyl-6-((dimethyl-
amino)-methyl)phenol in excellent yield.6
We have recently reported a regioselective ortho-formyla-
tion of substituted phenols using the MgCl2–Et3N base sys-
tem and paraformaldehyde to afford salicylaldehydes
in excellent yields.7 The salicylaldehydes obtained by this
method can, without isolation, be converted to salen
ligands,8 catechols,9 and ortho-hydroxycinnamate esters10
in one-pot procedures. With the complete regioselectivity
observed in the aforementioned ortho-formylation method
Since few other methods for the synthesis of salicylamines
have been reported,11 efforts to develop facile and efficient
procedures for the synthesis of mono N-substituted salicyl-
amines are still desirable. Hence, we turned our attention
to the facile imine formation of salicylaldehydes for the syn-
thesis of this class of amines.8,12 Moreover, preparative pro-
cedures in which two or more transformations carried out as
* Corresponding author. Tel.: +47 22857450; fax: +47 22855947; e-mail:
t.v.hansen@farmasi.uio.no
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.064

9998
H. F. Anwar et al. / Tetrahedron 63 (2007) 9997–10002
Table 1
OH
OH
N
I
R
R
N
I
Entry Phenol
Amine
Product
Yield (%)
56
MgCl2, Et3N
NH2
Br
OH
OH
OH
Br
Cl
Br
Cl
Br
Cl
8
OH
OH
N
H
OH
OH
Br
Cl
N
N
N
Br
N
NH2
Br
OH
OH
OH
OH
OH
OH
1 (83%)
3 (77%)
4 (79%)
2 (82%)
9
51
57
58
61
55
68
N
H
Br
N
OH
OH
H
N
NH2
t-Bu
t-Bu
OMe
OMe
OMe
OEt
F
OH
OH
N
Boc
N
Br
10
11
12
13
14
N
H
t-Bu
7 (98%)
5 (82%)
6 (66%)
NH2
Scheme 1.
OH
OH
OH
OH
OH
Cl
Et
N
H
t-Bu
a one-pot process offer a number of advantages. In particu-
lar, they result in a reduced number of operations giving
time–cost benefits by allowing direct transformation of
intermediates to desired products by avoiding isolation,
handling, and chromatography.
NH2
Et
N
H
OMe
NH2
To the THF solution of the appropriate salicylaldehyde pre-
pared as previously described,7 the amine was added fol-
lowed by the addition of NaBH4. After heating to reflux
for 30 min and further stirring the reaction mixture for
another 2–10 h at room temperature, the reaction mixture
was worked up in the usual manner. The products were pu-
rified by column chromatography and characterized by
physical and spectral data (Table 1). This one-pot procedure
was carried out with both alkyl and halogen substituted phe-
nols as starting materials, and the overall yields ranged from
51% to 74% and were not optimized (Scheme 2).
i-Pr
t-Bu
i-Pr
t-Bu
Cl
N
H
OMe
NH2
N
H
OMe
NH2
OH
OH
Cl
Cl
15
16
56
61
N
H
OH
OH
OEt
MgCl2, Et3N, (CH2O)n
O
R
R
THF, Δ
OH
OH
OH
R1NH2/
MeOH
Cl
N
H
H2N
OH
OH
R1
R1
OH
OH
OH
N
H
NaBH4 / MeOH
N
R
Br
R
17
18
19
51
64
63
Br
N
H
H2N
H2N
Scheme 2.
This facile experimental protocol was investigated further
when the solution of mono N-substituted benzylamine was
treated with additional 2 equiv of paraformaldehyde. This
gave, after purification by column chromatography,
substituted dihydro-2H-1,3-benzoxazines in 38–53% iso-
lated yields (Scheme 3). Benzoxazines have previously
been reported to exhibit a wide range of interesting biologi-
cal activities.13 The operational simplicity of this method
makes it attractive for preparative applications as well as
for the synthesis of screening libraries for drug discovery.
Me
Me
Me
N
H
OH
Me
N
H
H2N
(continued)

H. F. Anwar et al. / Tetrahedron 63 (2007) 9997–10002
9999
Table 1. (continued)
Analytical TLC was performed using silica gel 60 F254 glass
plates (Merck). Flash column chromatography was per-
formed on silica gel 60 Geduran (35–75 mm, EM Science).
NMR spectra were recorded on a Bruker Avance DPX-
Entry Phenol
Amine
Product
Yield (%)
74
Br
NH2
OH
OH
Me
1
300 MHz spectrometer for H NMR and 75 MHz for 13C
N
H
20
NMR. Coupling constants (J) are reported in Hertz, and
chemical shifts are reported in parts per million (d) relative
to CHCl3 (7.24 ppm for 1H and 77.2 ppm for 13C) and
Me
Br
1
t-Bu
DMSO-d6 (2.50 ppm for H and 39.5 ppm for 13C). Mass
NH2
OH
OH
spectra were recorded at 70 eV with Fission’s VG Pro spec-
trometer.
N
H
21
73
66
Me
t-Bu
4.2. General procedure for the Mannich reaction
Me
OH
OMe
OMe
NH2
OH
N,N-Dimethylmethylene iminium iodide (0.93 g, 5 mmol)
was added to a solution of the phenol (5 mmol), triethyl-
amine (1.21 g, 12 mmol), and anhydrous magnesium chlo-
ride (0.95 g, 10 mmol) in dichloromethane (20 ml) or
toluene (20 ml) for the synthesis of 2. The reaction mixture
was stirred at room temperature for 0.5–12 h and the reac-
tion monitored by TLC (hexane–EtOAc¼1:1). When neces-
sary, the products were purified by column chromatography.
Spectral and physical data of known compounds 2, 3, and 7
were in accord with previously published data.5
N
H
22
Cl
OMe
NH2
Cl
OH
OH
N
H
23
69
Br
OMe
Br
4.2.1. 2-Bromo-6-((dimethylamino)methyl)phenol (1).
Pale yellow solid; mp 53–55 ꢀC; 1H NMR (CDCl3):
d¼2.33 (s, 6H), 3.64 (s, 2H), 6.63 (t, J¼7.7 Hz, 1H), 6.88
(dt, J¼7.7, 0.7 Hz, 1H), 7.40 (dd, J¼7.7, 0.7 Hz, 1H); 13C
NMR (CDCl3): d¼155.42, 132.45, 127.65, 123.37, 120.07,
110.95, 63.06, 44.68; HRMS calcd for (M+): 229.0102,
found: 229.0096.
OH
OH
R
MgCl2, Et3N, (CH2O)n
R
O
THF, Δ
1) R1NH2, MeOH
2) NaBH4, MeOH
4.2.2. 2-((Dimethylamino)methyl)-6-iodophenol (4). Yel-
1
low solid; mp 64–66 ꢀC; H NMR (CDCl3): d¼2.30 (s,
X
6H), 3.60 (s, 2H), 6.51 (t, J¼7.4 Hz, 1H), 6.91 (dt, J¼7.4,
0.7 Hz, 1H), 7.61 (dd, J¼7.4, 0.7 Hz, 1H); 13C NMR
(CDCl3): d¼157.82, 138.35, 128.70, 122.48, 120.89,
85.30, 63.09, 44.61; HRMS calcd for (M+): 276.9964, found:
276.9974.
OH
O
N
R1
R
(CH2O)n, MeOH
N
H
R
24: R = t-Bu and X = OMe (53%)
25: R = Br and X = OMe (49%)
26: R = Cl and X = Br (38%)
27: R = Cl and X = OMe (51%)
4.2.3. 2-((Dimethylamino)methyl)-6-fluorophenol (5).
Pale yellow oil; 1H NMR (CDCl3): d¼2.32 (s, 6H), 3.66 (s,
2H), 6.65–6.72 (m, 2H), 6.92–7.24 (m, 1H), 10.47 (br s,
1H); 13C NMR (CDCl3): d¼151.70 (d, J¼717 Hz), 146.64
(d, J¼48.9 Hz), 124.46 (d, J¼12.9 Hz), 123.60 (d,
J¼12.9 Hz), 118.75 (d, J¼28.2 Hz), 115.82 (d, J¼72.0 Hz),
62.90 (d, J¼9.6 Hz), 44.83; HRMS calcd for (M+):
169.0903, found: 169.0909.
Scheme 3.
3. Conclusion
In conclusion, using the MgCl2–Et3N base system,
substituted salicylamines are available from the correspond-
ing phenols in good to excellent overall yields. This one-pot
methodology can be further extended to the preparation of
benzoxazines in good overall yields, considering the four
reaction steps.
4.2.4. tert-Butyl-3-((dimethylamino)methyl)-2-hydroxy-
phenylcarbamate (6). Yellow liquid; H NMR (CDCl3):
1
d¼1.50 (s, 9H), 2.31 (s, 6H), 3.62 (s, 2H), 6.59–6.76 (m,
2H), 7.06 (br s, 1H), 7.92 (d, J¼7.9 Hz, 1H), 9.85 (br s,
1H); 13C NMR (CDCl3): d¼153.38, 146.53, 127.40, 121.95,
121.06, 119.37, 117.73, 80.40, 62.96, 44.75, 28.78; HRMS
calcd for (M+): 266.1630, found: 266.1626.
4. Experimental
4.1. General
4.3. General procedure for the preparation of salicyl-
amines 8–24
All reagents and solvents were used as purchased without
further purification. Melting points are uncorrected.
To a dry THF solution (30 ml) of the phenol (5 mmol),
anhydrous magnesium chloride (0.95 g, 10 mmol) and

10000
H. F. Anwar et al. / Tetrahedron 63 (2007) 9997–10002
triethylamine (1.01 g, 10 mmol), paraformaldehyde (0.45 g,
15 mmol) was added. The reaction mixture was heated to re-
flux under an argon atmosphere for 2–4 h and the reaction
was monitored by TLC (hexane–EtOAc¼9:1). After com-
plete consumption of the phenol, a solution of the amine
(5 mmol) in MeOH (5 ml) was added dropwise. The reaction
mixturewas heated to reflux for 30 min and further stirred for
an additional 2–10 h. After complete consumption of the sal-
icylaldehyde, a solution of NaBH4 (0.38 g, 10 mmol) in
MeOH (10 ml) was added dropwise over 15–30 min. The re-
action mixture was stirred at ambient temperature for 2–10 h
and the reaction monitored by TLC (hexane–EtOAc¼8:2).
After complete reduction of the imines, pH was adjusted to
8 by addition of HCl (1 N) and the reaction mixture extracted
with Et2O (2ꢁ30 ml). The organic layer was washed with
brine (20 ml), dried (MgSO4), and the product purified by
column chromatography using a gradient of hexane–EtOAc
(9:1–7:3).
4.3.6. 2-Isopropyl-6-((4-methoxyphenylamino)methyl)-
phenol (13). Yellow solid; mp 46–48 ꢀC; 1H NMR
(DMSO-d6): d¼1.15 (d, J¼4.4 Hz, 6H), 3.30 (m, 1H), 3.63
(s, 3H), 4.21 (s, 2H), 5.70 (br s, 1H), 6.61–6.65 (m, 2H),
6.70–6.79 (m, 3H), 7.04 (dd, J¼7.5, 1.7 Hz, 2H); 13C NMR
(DMSO-d6): d¼153.24, 152.43, 143.42, 135.89, 126.56,
126.46, 125.10, 120.25, 115.40, 56.12, 45.83, 26.77, 23.69;
HRMS calcd for (M+): 271.1572, found: 271.1578.
4.3.7. 2-tert-Butyl-6-((4-methoxyphenylamino)methyl)-
phenol (14). White solid; mp 80–82 ꢀC; 1H NMR
(DMSO-d6): d¼1.34 (s, 9H), 3.64 (s, 3H), 4.25 (d,
J¼5.6 Hz, 2H), 5.81 (br t, J¼5.6 Hz, 1H), 6.69–6.77 (m,
5H), 7.05–7.11 (m, 2H), 9.40 (br s, 1H); 13C NMR
(DMSO-d6): d¼155.69, 153.14, 142.93, 137.20, 127.11,
126.45, 125.86, 119.81, 116.50, 115.32, 56.10, 47.48,
35.21, 30.49; HRMS calcd for (M+): 285.1729, found:
285.1726.
4.3.1. 2-Bromo-6-((4-bromophenylamino)methyl)-phe-
4.3.8. 2-Chloro-6-((4-ethoxyphenylamino)methyl)-phe-
nol (15). White solid; mp 94–96 ꢀC; 1H NMR (DMSO-d6):
d¼1.23 (t, J¼6.9 Hz, 3H), 3.86 (q, J¼6.9 Hz, 2H), 4.21 (s,
2H), 5.70 (br s, 1H), 6.51 (d, J¼8.8 Hz, 2H), 6.68 (d,
J¼8.8 Hz, 2H), 6.78 (t, J¼7.7 Hz, 1H), 7.14–7.22 (m, 2H),
9.6 (br s, 1H); 13C NMR (DMSO-d6): d¼151.45, 151.19,
143.30, 129.91, 128.58, 127.73, 121.30, 121.03, 116.18,
114.59, 64.13, 44.19, 15.71; HRMS calcd for (M+):
277.0869, found: 277.0870.
1
nol (8). White solid; mp 98–99 ꢀC; H NMR (DMSO-d6):
d¼4.24 (s, 2H), 6.47–6.52 (m, 2H), 6.74 (t, J¼7.7 Hz,
1H), 7.11–7.20 (m, 3H), 7.36–7.39 (m, 1H), 9.22 (br s,
1H); 13C NMR (75 MHz, DMSO-d6): d¼152.14, 148.58,
132.25, 131.88, 129.64, 128.25, 121.93, 115.08, 112.10,
107.46, 43.00; HRMS calcd for (M+): 354.9207, found:
354.9192.
4.3.2. 2-(2-((4-Bromophenylamino)methyl))-6-chloro-
1
phenol (9). Pale yellow solid; mp 121–122 ꢀC; H NMR
4.3.9. 2-((Benzylamino)methyl)-6-chlorophenol (16).
Yellow liquid; H NMR (CDCl3): 3.86 (s, 2H), 4.03 (s,
1
(DMSO-d6): d¼4.24 (s, 2H), 6.50–6.53 (m, 2H), 6.80 (t,
J¼7.7 Hz, 1H), 7.11–7.25 (m, 4H), 9.40 (br s, 1H); 13C
NMR (DMSO-d6): d¼151.19, 148.60, 132.24, 129.52,
128.76, 127.61, 121.52, 121.16, 115.04, 107.40, 42.68;
HRMS calcd for (M+): 310.9712, found: 310.9722.
2H), 6.75 (t, J¼7.7 Hz, 1H), 6.94 (d, J¼7.3 Hz, 1H), 7.27–
7.38 (m, 6H); 13C NMR (CDCl3): d¼154.21, 137.41,
129.77, 129.22, 129.02, 128.34, 127.58, 123.49, 121.70,
119.94, 52.67, 51.39; HRMS calcd for (M+): 247.0764,
found: 247.0753.
4.3.3. 2-Bromo-6-((4-tert-butylphenylamino)methyl)-
1
phenol (10). Pale yellow solid; mp 84–86 ꢀC; H NMR
4.3.10. 2-((Benzylamino)methyl)-6-bromophenol (17).
1
(CDCl3): d¼1.20 (s, 9H), 4.24 (s, 2H), 5.9 (br s, 1H), 6.50
(d, J¼8.6 Hz, 2H), 6.73 (t, J¼7.7 Hz, 1H), 7.06 (d,
J¼8.6 Hz, 2H), 7.19 (m, 1H), 7.35 (m, 1H), 9.3 (br s, 1H);
13C NMR (CDCl3): d¼152.26, 146.76, 139.41, 131.67,
130.10, 128.37, 126.34, 121.85, 113.18, 111.84, 43.75,
34.31, 32.30; HRMS calcd for (M+): 333.0728, found:
333.0717.
White solid; mp 48–50 ꢀC; H NMR (DMSO-d6): d¼3.72
(s, 2H), 3.90 (s, 2H), 6.66 (t, J¼7.1 Hz, 1H), 6.90 (br s,
1H), 7.01 (d, J¼6.8 Hz, 1H), 7.28 (br s, 1H), 7.31–7.39
(m, 6H); 13C NMR (DMSO-d6): d¼156.09, 139.34,
132.01, 129.27, 129.14, 128.56, 128.04, 125.43, 120.27,
110.36, 52.11, 51.46; HRMS calcd for (M+): 291.0259,
found: 291.0251.
4.3.4. ((4-tert-Butylphenylamino)methyl)-6-chlorophenol
(11). Yellow solid; mp 82–84 ꢀC; 1H NMR (CDCl3): d¼1.30
(s, 9H), 4.43 (s, 2H), 6.77–6.85 (m, 3H), 7.30–7.26 (m, 1H),
7.11 (m, 3H); 13C NMR (CDCl3): d¼152.19, 144.55,
143.97, 129.36, 127.62, 126.59, 125.43, 121.41, 120.83,
115.83, 48.32, 34.47, 31.86; HRMS calcd for (M+):
289.1233, found: 289.1230.
4.3.11. 2-((Benzylamino)methyl)-6-methylphenol (18).
1
Yellow liquid; H NMR (DMSO-d6): d¼2.17 (s, 3H), 3.71
(s, 2H), 3.85 (s, 2H), 6.63 (t, J¼7.3 Hz, 1H), 6.83 (d,
J¼6.8 Hz, 1H), 6.83 (d, J¼7.3 Hz, 1H), 7.32–7.37 (m,
5H); 13C NMR (DMSO-d6): d¼156.98, 139.75, 130.04,
129.20, 129.12, 127.91, 126.96, 124.68, 123.03, 118.93,
52.29, 51.51, 16.50; HRMS calcd for (M+): 227.1310, found:
227.1308.
4.3.5. 2-Ethyl-6-((4-methoxyphenylamino)methyl)-phe-
nol (12). White solid; mp 65–66 ꢀC; 1H NMR (DMSO-d6):
d¼1.13 (t, J¼7.5 Hz, 3H), 2.58 (q, J¼7.5 Hz, 2H), 3.63 (s,
3H), 4.21 (d, J¼5.5 Hz, 2H), 5.66 (br t, J¼5.5 Hz, 1H),
6.61 (m, 2H), 6.7 (m, 3H), 6.75–7.05 (m, 2H), 8.78 (br s,
1H); 13C NMR (DMSO-d6): d¼153.74, 152.25, 143.51,
131.33, 128.16, 126.69, 120.12, 115.79, 115.36, 115.15,
56.13, 45.32, 23.47, 15.24; HRMS calcd for (M+):
257.1416, found: 257.1412.
4.3.12. 2-Methyl-6-((3-phenylpropylamino)methyl)-phe-
nol (19). Pale yellow liquid; 1H NMR (DMSO-d6): d¼1.88
(quintet, 2H), 2.26 (s, 3H), 2.69 (m, 4H), 3.96 (s, 2H),
6.70 (t, J¼7.3 Hz, 1H), 6.84 (d, J¼7.1 Hz, 1H), 7.06 (d,
J¼7.3 Hz, 1H), 7.18–7.32 (m, 5H); 13C NMR (DMSO-d6):
d¼152.06, 137.23, 125.55, 124.12, 124.04, 121.65, 121.56,
120.88, 117.52, 114.17, 48.41, 43.83, 29.07, 26.89, 11.38;
HRMS calcd for (M+): 255.1623, found: 255.1619.

H. F. Anwar et al. / Tetrahedron 63 (2007) 9997–10002
10001
4.3.13. 2-((4-Bromophenylamino)methyl)-4-methyl-phe-
nol (20). Yellow solid; mp115–116 ꢀC (lit.14 mp
2H), 5.48 (s, 2H), 6.77–6.83 (m, 3H), 7.03–7.07 (m, 2H),
7.11 (dd, J¼7.5, 2.0 Hz, 1H), 7.37 (dd, J¼7.9, 1.4 Hz,
1H); 13C NMR (DMSO-d6): d¼154.98, 151.38, 141.98,
131.81, 127.45, 124.21, 122.18, 120.39, 115.29, 110.31,
81.89, 56.04, 50.25; HRMS calcd for (M+): 319.0208, found:
319.0211.
1
115.5 ꢀC); H NMR (DMSO-d6): d¼2.28 (s, 3H), 4.30 (s,
2H), 5.75 (br s, 1H), 6.68 (d, J¼8.8 Hz, 2H), 6.78 (d,
J¼8.1 Hz, 1H), 6.99 (m, 2H), 7.31 (d, J¼8.8 Hz, 2H);
13C NMR (DMSO-d6): d¼149.50, 141.87, 127.79,
125.41, 125.17, 125.08, 118.01, 112.90, 112.00, 108.28,
43.80, 16.16; HRMS calcd for (M+): 291.0259, found:
291.0259.
4.4.3. 3-(4-Bromophenyl)-8-chloro-3,4-dihydro-2H-
benzo[e][1,3]oxazine (26). White solid; mp 139–140 ꢀC;
1H NMR (DMSO-d6): d¼4.70 (s, 2H), 5.58 (s, 2H), 6.88
(t, J¼7.78 Hz, 1H), 7.10–7.13 (m, 3H), 7.25 (dd, J¼7.8,
1.5 Hz, 1H), 7.39–7.42 (m, 2H); 13C NMR (DMSO-d6):
d¼150.34, 147.55, 132.69, 128.99, 126.92, 123.92, 121.75,
120.75, 120.36, 113.21, 80.24, 49.35; HRMS calcd for
(M+): 322.9712, found: 322.9711.
4.3.14. 2-((4-tert-Butylphenylamino)methyl)-4-methyl-
phenol (21). Yellow solid; mp 78–80 ꢀC; 1H NMR
(DMSO-d6): d¼1.19 (s, 9H), 2.18 (s, 3H), 4.11 (s, 2H),
5.72 (br s, 1H), 6.51 (d, J¼8.7 Hz, 2H), 6.62–6.70 (m,
1H), 6.80–6.84 (m, 1H), 7.00–7.08 (m, 3H), 9.30 (br s,
1H); 13C NMR (DMSO-d6): d¼153.53, 147.38, 138.69,
129.51, 128.57, 127.87, 126.61, 126.24, 115.57, 112.77,
42.50, 34.27, 32.34, 21.20; HRMS calcd for (M+):
269.1780, found: 269.1783.
4.4.4. 8-Chloro-3-(4-methoxyphenyl)-3,4-dihydro-2H-
benzo[e][1,3]oxazine (27). White solid; mp110–111 ꢀC;
1H NMR (DMSO-d6): d¼3.66 (s, 3H), 4.59 (s, 2H), 5.48
(s, 2H), 6.80–6.86 (m, 3H), 7.03–7.10 (m, 3H), 7.32 (dd,
J¼7.9, 1.5 Hz, 1H); 13C NMR (DMSO-d6): d¼154.97,
150.50, 141.99, 128.84, 126.81, 124.10, 121.49, 120.60,
120.39, 115.29, 81.73, 56.04, 50.17; HRMS calcd for
(M+): 275.0713, found: 275.0710.
4.3.15. 4-Chloro-2-((4-methoxyphenylamino)methyl)-
phenol (22). Pale yellow solid; mp 117–118 ꢀC (lit.15 mp
1
119.2 ꢀC); H NMR (DMSO-d6): d¼3.62 (s, 3H), 4.16 (d,
J¼5.2 Hz, 2H), 5.69 (br s, 1H), 6.50 (d, J¼8.9 Hz, 2H),
6.69 (d, J¼8.9 Hz, 2H), 6.82 (d, J¼8.5 Hz, 1H), 6.82 (dd,
J¼8.5, 2.6 Hz, 1H), 7.17 (d, J¼2.6 Hz, 1H), 9.82 (br s,
1H); 13C NMR (DMSO-d6): d¼154.73, 151.67, 143.51,
129.47, 128.25, 127.74, 123.27, 117.20, 115.48, 114.06,
56.11, 42.54; HRMS calcd for (M+): 263.0712, found:
263.0713.
Acknowledgements
Financial support to H.F.A. from the University of Oslo (The
Quota Scheme) is gratefully acknowledged.
4.3.16. 4-Bromo-2-((4-methoxyphenylamino)methyl)-
1
phenol (23). Pale yellow solid; mp 114–115 ꢀC; H NMR
References and notes
(CDCl3): d¼3.78 (s, 3H), 4.34 (s, 2H), 6.40 (br s, 1H),
6.77–6.83 (m, 5H), 7.25–7.32 (m, 2H); 13C NMR (CDCl3):
d¼156.78, 155.32, 140.16, 132.19, 131.44, 125.13, 118.87,
118.52, 115.24, 111.93, 56.03, 50.34; HRMS calcd for
(M+): 307.0198, found: 307.0208.
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2H-1,3-benzoxazines 24–27
A mixture of paraformaldehyde (0.30 g, 10 mmol) and
methanol (5 ml) was added to the salicylamines obtained
as described above, and the reaction mixture was refluxed
for 5–10 h. After complete conversion of the salicylamines,
the reaction mixture was extracted with Et2O (2ꢁ30 ml).
The organic layer was washed with brine (20 ml), dried
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dehyde and 2-bromo aniline at room temperature, <10% yield
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sponding polymeric material.
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4.4.1. 8-tert-Butyl-3-(4-methoxyphenyl)-3,4-dihydro-2H-
benzo[e][1,3]oxazine (24). Pale yellow liquid; H NMR
1
(DMSO-d6): d¼1.30 (s, 9H), 3.65 (s, 3H), 3.55 (s, 2H),
5.67 (s, 2H), 6.75–6.87 (m, 4H), 7.00–7.09 (m, 3H); 13C
NMR (DMSO-d6): d¼154.66, 153.50, 142.67, 137.37,
125.92, 125.27, 121.87, 120.51, 120.06, 115.17, 79.69,
56.02, 51.58, 35.11, 30.37; HRMS calcd for (M+):
297.1729, found: 279.1722.
4.4.2. 8-Bromo-3-(4-methoxyphenyl)-3,4-dihydro-2H-
benzo[e][1,3]oxazine (25). Pale yellow solid; mp 99–
100 ꢀC; 1H NMR (DMSO-d6): d¼3.66 (s, 3H), 4.59 (s,

10002
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