Synthesis of 3,4-dihydro-2H-1,3-benzoxazines by condensation of 2-hydroxyaldehydes and primary amines: Application to the synthesis of hydroxy-substituted and deuterium-labeled compounds

Article abstract of DOI:10.1080/00397910802138629

We report the synthesis of several substituted 3,4-dihydro-2H-1,3- benzoxazines by simple ring closure of 2-hydroxybenzylamines with paraformaldehyde. The facile synthesis of the benzylamine precursors from commercially available salicylaldehyde derivativ

Full text of DOI:10.1080/00397910802138629

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Synthesis of 3,4-
Dihydro-2H-1,3-benzoxazines
by Condensation of 2-
Hydroxyaldehydes and
Primary Amines: Application
to the Synthesis of Hydroxy-
Substituted and Deuterium-
Labeled Compounds
R. Andreu a & J. C. Ronda a
a Rovira i Virgili University, Analytical Chemistry
and Organic Chemistry Department, Faculty of
Chemistry, Tarragona, Spain
Version of record first published: 11 Jul 2008.
To cite this article: R. Andreu & J. C. Ronda (2008): Synthesis of 3,4-Dihydro-2H-1,3-
benzoxazines by Condensation of 2-Hydroxyaldehydes and Primary Amines:
Application to the Synthesis of Hydroxy-Substituted and Deuterium-Labeled
Compounds, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:14, 2316-2329
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Synthetic Communications1, 38: 2316–2329, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138629
Synthesis of 3,4-Dihydro-2H-1,3-benzoxazines by
Condensation of 2-Hydroxyaldehydes and
Primary Amines: Application to the
Synthesis of Hydroxy-Substituted and
Deuterium-Labeled Compounds
R. Andreu and J. C. Ronda
Rovira i Virgili University, Analytical Chemistry and Organic Chemistry
Department, Faculty of Chemistry, Tarragona, Spain
Abstract: We report the synthesis of several substituted 3,4-dihydro-2H-1,3-ben-
zoxazines by simple ring closure of 2-hydroxybenzylamines with paraformalde-
hyde. The facile synthesis of the benzylamine precursors from commercially
available salicylaldehyde derivatives affords a powerful general synthetic way to
prepare a variety of substituted benzoxazines, avoiding the formation of undesir-
able oligomeric species, thus leading to a simple workup and improving the yield
and purity of the final product. This straightforward method allows synthesis
of hydroxy-substituted and deuterium-labeled 1,3-benzoxazines that are not
attainable using other synthetic ways.
Keywords: Benzoxazine monomers; Deuterium labeling
INTRODUCTION
3,4-Dihydro-2H-1,3-benzoxazines are bicyclic heterocycles that are of
significant interest in the polymeric and pharmacological fields. 1,3-Ben-
zoxazines have long been recognized for their wide range of biological
activity with uses as herbicides and agricultural microbiocides, as well
Received in the USA March 23, 2008
Address correspondence to J. C. Ronda, Universitat Rovira i Virgili, Departa-
´
ment de Quımica Analıtica i Quımica Organica, Facultat de Quımica, Campus de
Sescelades, Carrer Marcellı Domingo s=n, E-43007 Tarragona, Catalonia, Spain.
´
´
`
´
´
E-mail: juancarlos.ronda@urv.cat
2316

3,4-Dihydro-2H-1,3-benzoxazines
2317
as bactericide, fungicide, antidepressive, anti-inflammatory, and antitumor
agents.[1–4] Moreover, 1,3-benzoxazine monomers were recently used to dev-
elop a new type of phenolic resin, namely polybenzoxazines, by the ring-
opening polymerization on thermal curing.[5–8] The resulting materials
possess typical characteristics of the traditional phenolic resins such as heat
resistance, good flame retardance, and electronic properties. Inaddition, they
provide unique characteristics such as low water absortion and excellent dim-
ensional stability, due to near-zero volumetric shrinkage upon curing.[9–12]
Other applications of these compounds are in supramolecular chemis-
try.[13,14] or the synthesis of metallic complexes with catalytic activity.[15]
Synthetic approaches for 3,4-dihydro-2H-1,3-benzoxazines include
Mannich condensation of phenol and a primary amine with formalde-
hyde,[16,17] condensation of o-hydroxybenzylamine with an aldehyde,[18–20]
rearrangement reactions of 2-(allyloxy)benzylamine with H2=CO in the
presence of rhodium catalyst,[21] condensation of 4-substituted phenols with
1,3,5-trimethyl-hexahydro-s-triazine in the presence of oxalyl chloride,[22]
reaction of 1-(bromomethyl)-2-(chloromethoxy)benzene with primary
amines,[23] dehydratation of N-(2-hydroxybenzyl)-3-aminopropanoic acid
with H2SO4,[24] and reaction of ortho-lithiated phenol dianions with N,N-
bis[(benzotriazol-1-yl)methyl]amines.[25]
By far the most extended method for the synthesis of these compounds
was described by Burke et al.[16] and consists of the reaction of a phenol, a
primary amine, and formaldehyde in 1:1:2 molar ratio. This reaction
involves the C-C formation by attack of the ortho phenol position on the
amine Mannich adduct. Many authors tested different modifications of this
basic method to optimize results. Solventless conditions reduce reaction
times and improve the yields.[26] The presence of water induces the benzox-
azine ring opening and leads to the formation of olygomeric species, so the
use of paraformaldehyde instead of aqueous formaldehyde and solvents of
low polarity also increase benzoxazine yields.[27,28]. Alternatively, water pro-
duced during the condensation can be reduced by using the corresponding
1,3,5-triazine instead of the aromatic amine and formaldehyde. Unfortu-
nately, this approach is limited to the case of stable aromatic triazines.[29]
In any case, the main drawback of this synthetic route is the extensive
formation of oligomers, which reduce the benzoxazine yield and make its
purification difficult. Moreover, the presence of some functional groups in
the benzoxazine is incompatible with the use of this direct synthetic meth-
odology. This is the case of the phenolic groups that are desirable to pre-
pare new polymeric materials with well-defined properties. This fact and
the aim to prepare deuterium-labeled benzoxazine monomers for mechan-
istic studies led us to explore the utility of alternative synthetic routes.
From all these synthetic methods, the condensation of substituted 2-
hydroxybenzylamines with formaldehyde seemed the most reliable for

2318
R. Andreu and J. C. Ronda
our purposes. The necessary 2-hydroxybenzylamines can be conveniently
synthesized by in situ reduction of the imines generated by condensation
of the readily available 2-hydroxybenzaldehydes and primary amines.
In this article, we report the application of this method to the syn-
thesis of high-purity 3,4-dihydro-2H-1,3-benzoxazines and a family of
their deuterated derivatives.
EXPERIMENTAL
Materials
Salicylaldehyde (Aldrich), 2,5-dihydroxybenzaldehyde (Aldrich), NaBH4
(Aldrich), paraformaldehyde (Probus), methylamine 40% (Probus),
benzylamine (Probus), aniline (Aldrich), 4-aminophenol (Fluka), phenol
(Probus), NaOD 40% in D2O (Aldrich), paraformaldehyde-d2 (Aldrich),
aniline-d5 (Aldrich), phenol-d6(Aldrich), NaBD4 (Aldrich), and CDCl3
(SDS) were used as received. Solvents were purified by standard procedures.
Instrumentation
Melting points were determined on an electrothermal Buchi 510 melting-
¨
1
point apparatus. H and 13C NMR spectra were registered on a Varian
Mercury-400 using TMS as an internal standard. Elemental analysis
was carried out on a Carlo Erba EA 1108 microanalyzer.
Synthesis of 2-Hydroxybenzylamines (2 in Scheme 1)
Salicylaldehyde or 2,5-hydroxybenzaldehyde (40 mmol) was added slowly
to a solution of amine (40 mmol) in EtOH (50 mL), and the mixture was
stirred at 60 ꢀC for 4–8 h. The resulting solution was cooled to room tem-
perature, and NaBH4 (0.76 g, 20 mmol) was added in small portions while
stirring. When the reduction was complete, 100 mL of water was added,
and the resulting product was extracted with diethyl ether, washed with
water, dried over anhydrous MgSO4, and concentrated to dryness. The
resulting 2-hydroxybenzylamines were colorless oils or white solids.
Data
2-Hydroxy-N-methylbenzylamine
Yield 90%, mp ¼ 39–41 ꢀC. 1H NMR (400 MHz, CDCl3, ppm): dH 7.20–
6.70 (4H, Ar-H), 6.35 (2H, OH and NH, broad), 3.91 (2H, Ar-CH2-N),
2.43 (3H, N-CH3). 13C NMR (100.5 MHz, CDCl3, ppm): dC 158.6

3,4-Dihydro-2H-1,3-benzoxazines
2319
Scheme 1. Synthetic pathway used in the preparation of benzoxazines B1 to B5.
(C-O), 128.9 (CH), 128.7 (CH), 122.6 (C), 119.3 (CH), 116.6 (CH), 54.9
(Ar-CH2-N), 35.5 (N-CH3).
2-Hydroxy-N-(benzyl)benzylamine
1
Yield 92%, viscous liquid. H NMR (400 MHz, CDCl3, ppm): dH 7.30–
6.70 (11H, Ar-H, OH and NH), 3.88 (2H, Ar-CH2), 3.70 (2H, Ar-
CH2). 13C NMR (100.5 MHz, CDCl3, ppm): dC 158.0 (C-O), 138.1
(C-N), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.3 (CH),
122.1 (C), 118.9 (CH), 116.1 (CH), 52.2 (Ar-CH2), 51.5 (Ar-CH2).
2-Hydroxy-N-phenylbenzylamine
ꢀ
1
Yield 95%, mp ¼ 113–115 C. H NMR (300 MHz, CDCl3, ppm): dH
8.42 (1H, OH), 7.30–6.80 (9H, Ar-H), 4.40 (2H, Ar-CH2-N), 3.95 (1H,
NH). 13C NMR (75.4 MHz, CDCl3, ppm): dC 156.7 (C-O), 147.2
(C-N), 129.3 (CH), 129.2 (CH), 128.6 (CH), 122.8 (C), 120.8 (CH),
120.0 (CH), 116.6 (CH), 115.8 (CH), 48.7 (Ar-CH2-N).

2320
R. Andreu and J. C. Ronda
2-Hydroxy-N-(4-hydroxyphenyl)benzylamine
ꢀ
1
Yield 86%, mp ¼ 123–125 C. H NMR (400 MHz, DMSO, ppm): dH
9.50 (1H, OH), 8.40 (1H, OH), 7.20–6.40 (8H, Ar-H), 5.33 (1H, NH),
4.11 (2H, Ar-CH2-N). 13C NMR (100.5 MHz, DMSO, ppm): dC 155.1
(C-O), 148.4 (C-O), 141.7 (C-N), 128.4 (CH), 127.4 (CH), 126.2 (C),
118.8 (CH), 115.6 (CH), 114.8 (CH), 113.7 (CH), 42.7 (Ar-CH2-N).
2,5-Dihydroxy-N-phenylbenzylamine
ꢀ
1
Yield 88%, mp ¼ 117–119 C. H NMR (400 MHz, DMSO, ppm): dH
8.80 (1H, OH), 8.59 (1H, OH), 7.03 (2H, Ar-H), 6.65–6.40 (6H, Ar-H),
6.00 (1H, NH), 4.12 (2H, Ar-CH2-N). 13C NMR (100.5 MHz, DMSO,
ppm): dC 149.9 (C-O), 148.9 (C-N), 147.3 (C-O), 128.9 (CH), 126.6
(C), 115.6 (CH), 115.5 (CH), 114.7 (CH), 113.6 (CH), 112.2 (CH), 41.4
(Ar-CH2-N).
Synthesis of Benzoxazines (3 in Scheme 1)
The necessary amounts of the corresponding 2-hydroxybenzylamine deriva-
tive (in all cases 30 mmol) and paraformaldehyde (0.9 g, 32 mmol) were
added to 50 mL of 1,4-dioxane, and the reaction mixture was stirred at
100 ꢀC for 18–24 h. The solvent was evapored, and the residue was dissolved
in diethyl ether and washed with 2 M NaOH solution (except B4 and B5).
The organic layer was dried over anhydrous MgSO4 and concentrated to
dryness. The obtained products were purified as described Table 1.
3-Methyl-3,4-dihydro-2H-1,3-benzoxazine (B1)
Yield 87%, liquid. 1H NMR (400 MHz, CDCl3, ppm): dH 7.15–6.70 (4H,
Ar-H), 4.76 (2H, O-CH2-N), 3.92 (2H, Ar-CH2-N), 2.56 (3H, N-CH3).
13C NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 153.6 (C-O), 127.5
(CH), 127.4 (CH), 120.4 (CH), 119.8 (C), 116.2 (CH), 83.6 (O-CH2-N),
52.0 (Ar-CH2-N), 39.5 (N-CH3). Elemental analysis: C9H11NO
(149.19). Calculated (%): C, 72.46; H, 7.43; N; 9.39. Experimental (%):
C, 72.38; H, 7.40; N, 9.35.
3-Benzyl-3,4-dihydro-2H-1,3-benzoxazine (B2)
Yield 92%, mp ¼ 71–72 ꢀC. 1H NMR (400 MHz, CDCl3, ppm): dH 7.35–
6.80 (9H, Ar-H), 4.85 (2H, O-CH2-N), 3.94 (2H, Ar-CH2), 3.90 (2H,

2321

2322
R. Andreu and J. C. Ronda
Ar-CH2). 13C NMR (100.5 MHz, CDCl3, ppm): dC 153.8 (C-O), 137.9 (C-
N), 128.7 (CH), 128.2 (CH), 127.5 (CH), 127.4 (CH), 127.1 (CH), 120.4
(CH), 119.8 (C), 116.2 (CH), 82.1 (O-CH2-N), 55.5 (CH2-Ar), 49.5
(Ar-CH2-N). Elemental analysis: C15H15NO (225.29). Calculated (%): C,
79.97; H, 6.71; N, 6.22. Experimental (%): C, 79.88; H, 6.93; N, 6.19.
3-Phenyl-3,4-dihydro-2H-1,3-benzoxazine (B3)
Yield 94%, mp ¼ 55–57 ꢀC. 1H NMR (400 MHz, CDCl3, ppm): dH 7.30–
6.70 (9H, Ar-H), 5.33 (2H, O-CH2-N), 4.61 (2H, Ar-CH2-N). 13C NMR
(100.5 MHz, CDCl3, ppm): dC 154.3 (C-O), 148.3 (C-N), 129.2 (CH),
127.8 (CH), 126.7 (CH), 121.4 (CH), 120.8 (C), 120.7 (CH), 118.2
(CH), 116.9 (CH), 79.4 (O-CH2-N), 50.4 (Ar-CH2-N). Elemental ana-
lysis: C14H13NO (211.26). Calculated (%): C, 79.59; H, 6.20; N, 6.63.
Experimental (%): C, 79.87; H, 6.55; N, 6.64.
3-(4-Hydroxyphenyl)-3,4-dihydro-2H-1,3-benzoxazine (B4)
Yield 92%, mp ¼ 70–72 ꢀC. 1H NMR (400 MHz, CDCl3, ppm): dH 7.15–
6.70 (8H, Ar-H), 5.27 (2H, O-CH2-N), 4.54 (2H, Ar-CH2-N), 4.49 (1H,
OH). 13C NMR (100.5 MHz, CDCl3, ppm): dC 154.1 (C-O), 150.8 (C-
O), 142.0 (C-N), 127.8 (CH), 126.7 (CH), 121.0 (CH), 120.8 (CH),
120.7 (C), 116.8 (CH), 116.0 (CH), 80.8 (O-CH2-N), 50.9 (Ar-CH2-N).
Elemental analysis: C14H13NO2 (227.26). Calculated (%): C, 73.99; H,
5.77; N, 6.16. Experimental (%): C, 73.79; H, 5.63; N, 6.31.
6-Hydroxy-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (B5)
ꢀ
1
Yield 95%, mp ¼ 102–103 C. H NMR (400 MHz, CDCl3, ppm): dH
7.25–6.40 (8H, Ar-H), 6.22 (1H, OH), 5.23 (2H, O-CH2-N), 4.44 (2H,
Ar-CH2-N). 13C NMR (100.5 MHz, CDCl3, ppm): dC 149.5 (C-O),
148.1 (C-O), 147.8 (C-N), 129.1 (CH), 121.5 (C), 121.4 (CH), 118.1
(CH), 117.5 (CH), 114.9 (CH), 112.8 (CH), 79.4 (O-CH2-N), 50.1 (Ar-
CH2-N). Elemental analysis: C14H13NO2 (227.26). Calculated (%): C,
73.99; H, 5.77; N, 6.16. Experimental (%): C, 74.46; H, 6.22; N, 6.09.
Synthesis of the Deuterated Benzoxazines (B3a, B3b, B3c, B3d in
Scheme 2)
Deuterium-labeled compounds were synthesized according the synthetic
sequence shown in Scheme 2.

3,4-Dihydro-2H-1,3-benzoxazines
2323
Scheme 2. Synthetic pathway used in the preparation of deuterated benzoxazines
B3a, B3b, B3c, and B3d.
2,2-Dideutero-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (B3a)
2-Hydroxy-N-phenylbenzylamine (2.0 g, 10.1 mmol) and paraformalde-
hyde-d2 (0.34 g, 10.1 mmol) were added to 50 mL of 1,4-dioxane and
heated at 100 ꢀC for 18 h. The residue obtained after concentration was
dissolved in diethyl ether and washed with 2 M NaOH solution. The
organic layer was dried over anhydrous MgSO4 and concentrated to dry-
ness, and the resulting product was purified by flash-chromatography
using hexane=dichloromethane 3:1 as eluant.
ꢀ
ꢀ
1
Yield 90%, mp 56–58 C. H NMR (400 MHz, CDCl3, 25 C, ppm):
dH 7.26–6.78 (9H, Ar-H), 4.60 (2H, Ar-CH2-N). 13C NMR (100.5 MHz,
CDCl3, 25 ꢀC, ppm): dC 154.3 (C-O), 148.3 (C-N), 129.2 (CH), 127.8
(CH), 126.7 (CH), 121.3 (CH), 120.8 (C), 120.7 (CH), 118.1 (CH), 116.8
(CH), 79.3 (O-CD2-N, low-intensity multiplet), 50.2 (Ar-CH2-N). Anal.
calcd. for C14H11D2NO (213.27): C, 78.84; H þ D, 7.09; N, 6.57. Found:
1
C, 79.45; H, 7.38; N, 6.58. Deuteration degree by H NMR 98%.
4,4-Dideutero-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (B3b)
Salicyladehyde-d1. Phenol (5.0 g, 53 mmol) was added to 20 mL of a 40%
solution of NaOD in D2O. The mixture was stirred for 30 min and heated

2324
R. Andreu and J. C. Ronda
up to 65–70 ꢀC. After the addition of a solution of benzyltrimethylammo-
nium chloride (61 mg, 0.21 mmol) in 8 ml of 1,4-dioxane, deuterated
chloroform (8.2 g, 70 mmol) was added dropwise, and the mixture was
stirred vigorously at 70 ꢀC for 1 h. The excess chloroform and the dioxane
were eliminated by distillation, and the aqueous layer was neutralized
with diluted hydrochloric acid. o-Hydroxybenzaldehyde and some
unreacted phenol were separated from the para isomer by steam distil-
lation. The crude product was purified by flash chromatography using
a mixture hexane=CH2Cl2 2:1 to give 2.6 g (40%) of a pale yellow liquid.
1H NMR (400 MHz, CDCl3, 25 ꢀC, ppm): dH 11.05 (1H, OH), 7.55–
7.00 (4H, Ar-H). 13C NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 196.2
(CDO), 161.6 (C-OH), 136.9 (CH), 133.6 (CH), 120.5 (C), 119.8 (CH),
1
117.5 (CH). Deuteration degree by H NMR: 94%.
a,a-Dideutero-2-hydroxybenzylamine. A mixture of salicylaldehyde-d1
(1.0 g, 8.12 mmol) and aniline (0.78 g, 8.37 mmol) in 5 mL of ethanol was
stirred for 1 h at room temperature. NaBD4 (0.1 g, 4.05 mmol) in 5 mL of
ethanol was added in small portions, and the reaction was monitored by
thin-layer chromatography (TLC) until complete disappearance of inter-
mediate imine. After pouring the mixture onto 150 mL of water, the
obtained solid product was separated by filtration and dried.
Yield 92%, mp 112–114 ꢀC. 1H NMR (400 MHz, CDCl3, 25 ꢀC,
ppm): dH 8.41 (1H, OH), 7.23–6.80 (9H, Ar-H), 3.95 (1H, NH). 13C
NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 156.6 (C-O), 147.1 (C-N),
129.3 (CH), 129.1 (CH), 128.6 (CH), 122.8 (C), 120.6 (CH), 120.0
(CH), 116.4 (CH), 115.7 (CH), 48.0 (Ar-CD2-N, low-intensity multiplet).
1
Deuteration grade by H NMR: 97%.
B3b. A mixture of a,a-dideutero-2-hydroxybenzylamine (0.95 g,
4.70 mmol) and paraformaldehyde (0.13 g, 4.70 mmol) in 30 mL of 1,4-
dioxane was stirred at 100 ꢀC for 16 h. The solvent was removed under
reduced pressure, and the crude product was purified by flash chromato-
graphy using a mixture of hexane=dichloromethane 3:1.
ꢀ
ꢀ
1
Yield 1.6g (88%), mp 55–57 C. H NMR (400 MHz, CDCl3, 25 C,
ppm): dH 7.40–6.80 (9H, Ar-H), 5.33 (2H, O-CH2-N). 13C NMR
(100.5 MHz, CDCl3, 25ꢀC, ppm): dC 154.3 (C-O), 148.3 (C-N), 129.2 (CH),
127.8 (CH), 126.7 (CH), 121.3 (CH), 120.8 (C), 120.7 (CH), 118.1 (CH),
116.8 (CH), 79.3 (O-CH2-N), 50.2 (Ar-CD2-N, low-intensity multiplet).
Anal. calcd. for C14H11D2NO (213.27): C, 78.84; H þ D, 7.09; N, 6.57.
Found: C, 79.24; H, 7.21; N, 6.43. Deuteration degre by 1H NMR: 97%.
3-(Pentadeuterophenyl)-3,4-dihydro-2H-1,3-benzoxazine (B3c)
2-Hydroxy-N-pentadeuterophenylbenzylamine. A mixture of salicylal-
dehyde (1.2 g, 10.2 mmol) and aniline-d5 (1.0 g, 10.1 mmol) in 10 mL of
ethanol was stirred for 1 h at room temperature. Then, NaBH4 (0.1 g,

3,4-Dihydro-2H-1,3-benzoxazines
2325
4.05 mmol) in 10 mL of ethanol was added in small portions, and the
reaction was monitored by TLC until complete disappearance of the
intermediate imine. After the addition of 250 mL of water, the resulting
white crystalline solid was colleꢀcted by filtration washed and dried.
ꢀ
1
Yield (94%), mp 112–114 C. H NMR (400 MHz, CDCl3, 25 C,
ppm): dH 8.41 (1H, OH), 7.26–6.80 (4H, Ar-H), 4.42 (2H, Ar-CH2-N),
3.95 (1H, NH). 13C NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 156.6
(C-O), 147.0 (C-N), 129.1 (CH), 128.8 (CD, triplet), 128.6 (CH), 122.9
(C), 120.2 (CD, triplet), 120.0 (CH), 116.5 (CH), 115.2 (CD, triplet),
1
48.5 (Ar-CH2-N). Deuteration degree by H NMR: 98%.
B3c. 2-Hydroxy-N-pentadeuterophenylbenzylamine (1.5 g, 7.3 mmol),
paraformaldehyde (0.23 g, 7.3 mmol), and 30 mL of 1,4-dioxane were
heated at 100 ꢀC for 18 h following the same procedure described for pro-
duct B3a to give a white crystalline.
Yield 87%, mp 55–57 ꢀC. 1H NMR (400MHz, CDCl3, 25ꢀC, ppm): dH
7.10–6.78 (4H, Ar-H), 5.33 (2H, O-CH2-N), 4.60 (2H, Ar-CH2-N). 13C NMR
(100.5 MHz, CDCl3, 25ꢀC, ppm): dC 154.3 (C-O), 148.2 (C-N), 128.7 (CD,
triplet), 127.8 (CH), 126.7 (CH), 120.8 (CD, triplet), 120.8 (C), 120.7 (CH),
117.8 (CD, triplet), 116.8 (CH), 79.4 (O-CH2-N), 50.3 (Ar-CH2-N). Anal.
calcd. for C14H8D5NO (216.29); C, 77.74; H þ D, 8.38; N, 6.48. Found: C,
78.34; H, 7.40; N, 6.35. Deuteration degree by 1H NMR: 98%.
5,6,7,8-Tetradeuterophenyl-3,4-dihydro-2H-1,3-benzoxazine (B3d)
Salicyladehyde-d4. Starting from phenol-d6 (2.5 g, 25 mmol) and chloro-
form (4.1 g, 35 mmol) and proceeding as for salicylaldehyde-d1, the result-
ing brown oil was purified by flash chromatography using a mixture
hexane=CH2Cl2 2:1 to give a pale yellow liquid.
Yield 38%. Deuteration degree by 1H NMR: 98%. 1H NMR
(400 MHz, CDCl3, 25 ꢀC, ppm): dH 11.05 (1H, OH), 9.82 (1H, CHO).
13C NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 196.4 (CHO), 161.5 (C-
OH), 136.7 (CD, triplet), 133.5 (CD, triplet), 120.5 (C), 119.6 (CD, trip-
let), 117.3 (CD, triplet).
2-Hydroxy-3,4,5,6-tetradeutero-N-Phenylbenzylamine. A mixture of
salicylaldehyde-d4 (1.0 g, 7.92 mmol) and aniline (0.75 g, 8.05 mmol) in
5 mL of ethanol was stirred for 1 h at room temperature. The resulting
imine was reduced using NaBH4 (0.1 g, 4.05 mmol) in 5 mL of ethanol.
After pouring the mixture onto 100 mL of water, the obtained solid pro-
duct was separated by filtration and dried.
ꢀ
1
Yield 92%, mp 111–113 C. H NMR (300 MHz, CDCl3, ppm): dH
8.40 (1H, OH), 7.30–6.80 (5H, Ar-H), 4.41 (2H, Ar-CH2-N), 3.95 (1H,
NH). 13C NMR (75.4 MHz, CDCl3, ppm): dC 156.7 (C-O), 147.2 (C-

2326
R. Andreu and J. C. Ronda
N), 129.0 (CD, triplet), 129.2 (CH), 128.4 (CD, triplet), 122.8 (C), 120.8
(CH), 119.8 (CD, triplet), 116.4 (CD, triplet), 115.8 (CH), 48.7
1
(Ar-CH2-N). Deuteration degree by H NMR:98%.
B3d.
2-Hydroxy-3,4,5,6-tetradeutero-N-phenylbenzylamine(1.5 g,
7.3 mmol), paraformaldehyde (0.23 g, 7.3 mmol), and 30 mL of 1,4-diox-
ane were heated at 100 ꢀC for 18 h. Following the same procedure
described for product B3a, a white solid was obtained.
ꢀ
ꢀ
1
Yield 80%, mp 56–58 C. H NMR (400 MHz, CDCl3, 25 C, ppm):
dH 7.30–6.80 (5H, Ar-H), 5.26 (2H, O-CH2-N), 4.53 (2H, Ar-CH2-N).
13C NMR (100.5 MHz, CDCl3, 25 ꢀC, ppm): dC 154.3 (C-O), 148.3
(C-N), 129.2 (CH), 127.3 (CD, triplet), 126.2 (CD, triplet), 121.3 (CH),
120.7 (C), 120.3 (CD, triplet), 118.2 (CH), 116.4 (CD, triplet), 79.4
(O-CH2-N), 50.3 (Ar-CH2-N). Anal. calcd. for C14H9D4NO (215.28):
C; 78.11; H þ D, 7.96; N, 6.51. Found: C, 78.54; H, 6.82: N, 6.72.
RESULTS AND DISCUSSION
The synthetic pathway checked in this work is depicted in Scheme 1. Con-
densation of salicylaldehyde or 2,5-dihydroxybenzaldehyde with different
amines was performed in ethanol at 60 ꢀC in absence of catalyst. After 4 to
8 h, the formation of the imine was complete and could be isolated upon
cooling if necessary. The reduction of the imine (1) was performed in the
same flask by the addition of an excess of NaBH4 to the warm ethanolic
solution. The crude product was isolated as a white powder by precipi-
tation with water and dried under vacuum. In all cases, the corresponding
2-hydroxybenzylamines (2) were obtained in good to excellent yields and
1
were pure enough by H NMR to be used in the following step without
further purification. The benzoxazine ring formation was achieved by
reacting the corresponding 2-hydroxybenzylamine with 1 equivalent of
paraformaldehyde in refluxing dioxane for 18 to 24 h. The pure 3,4-dihy-
dro-2H-1,3-benzoxazines (3) were isolated simply by dissolving the dry
crude in ethyl ether, washing with 2 M NaOH to remove traces of
unreacted phenol, and crystallizing the obtained product after concen-
tration in the appropriate solvent. In the case of hydroxyl-substituted
benzoxazines, the treatment with aqueous NaOH was obviously omitted.
This synthetic procedure and simple workup yield the desired benzoxa-
zines with high purity and yields ranging from 87 to 95%, which are
higher than those reported using conventional methods. Moreover, under
the assayed conditions, no significant amounts of oligomeric species or
by-products were detected by TLC, indicating the selectivity of this
three-step pathway. It must be pointed out that this methodology allows
synthesis of the hydroxy-substituted derivatives 4-[2H-1,3-benzoxazin-

3,4-Dihydro-2H-1,3-benzoxazines
2327
3(4H)-il]phenol B4 and 3-phenyl-3,4-dihydro-2H-1,3-benzoxazin-6-ol B5,
which were described for the first time and are not attainable using other
synthetic methods.
The sequential incorporation of the aromatics and the benzoxazine
ring methylene units used in this synthetic approach is the key to obtain
deuterium-labeled benzoxazine derivatives and gives the possibility of
preparing other labeled target compounds, with 13C or 15N for instance.
We used this methodology to prepare different 3-phenyl-3,4-dihydro-
2H-1,3-benzoxazines deuterated selectively in both methylene carbons
and in both aromatic rings. As shown in Scheme 2, the appropriate use
of deuterated paraformaldehyde or sodium borodeuteride allow labeling
easily the methylene positions. To obtain the other compounds, readily
available deuterated aniline-d5 or phenol-d5 were used. The necessary
intermediates salicylaldehyde-d1 and salicylaldehyde-d4 were con-
veniently prepared by the Riemer–Tiemann reaction[30] from deuterated
phenol and chloroform or deuterated chloroform as reported in the
experimental section. These deuterated salicylaldehyde derivatives are
obtained with moderate yields by this single-step procedure, but obtained
products are pure and their deuterium content is very high (94 to 98%).
The procedure used to prepare these compounds was the same as
that for the nondeuterated equivalents, but a smaller scale was used
and the final purification was performed by column chromatography.
Yields and purity were also satisfactory in all cases.
Table 1 summarizes the experimental conditions and yields for all the
synthesized benzoxazines. It must be pointed out that the procedure has
been scaled up to 100 g of compound with reproducible results. Moreover,
we have also synthesized 3-phenyl-3,4-dihydro-2H-1,3-benzoxazines with
different substituents (CH3, Cl, OCH3, NO2) in the 6 or 8 positions or in
the para position of the N-phenyl group, with the same satisfactory results,
thus proving that this methodology is of general application.
ACKNOWLEDGMENTS
ꢀ
The authors express their thanks to CICYT (Comision Interministerial de
Ciencia y Tecnologıa) (MAT2005-01593) for financial support for this work.
´
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