Synthesis of chiral 1,4,2-Oxazaphosphepines

Article abstract of DOI:10.3390/molecules200813794

Synthesis and structural characterization of 1,4,2-oxazaphosphepines is described. The 1,4,2-oxazaphosphepines were obtained from reaction of chiral 1,3-benzoxazines with dichlorophenylphosphine or triethyl phosphite. The configuration of some of these co

Full text of DOI:10.3390/molecules200813794

Molecules 2015, 20, 13794-13813; doi:10.3390/molecules200813794
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Chiral 1,4,2-Oxazaphosphepines
Oscar Salgado-Escobar †, Leticia Chavelas-Hernández †, Blanca E. Domínguez-Mendoza †,
Irma Linzaga-Elizalde * and Mario Ordoñez *
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos,
Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico; E-Mails: ose@uaem.mx (O.S.-E.);
letychh@gmail.com (L.C.-H.); bed@uaem.mx (B.E.D.-M.)
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: linzaga@uaem.mx (I.L.-E.);
palacios@uaem.mx (M.O.); Tel./Fax: +52-777-329-7997 (I.L.-E.).
Academic Editor: Jean Jacques Vanden Eynde
Received: 11 June 2015 / Accepted: 22 July 2015 / Published: 29 July 2015
Abstract: Synthesis and structural characterization of 1,4,2-oxazaphosphepines is described.
The 1,4,2-oxazaphosphepines were obtained from reaction of chiral 1,3-benzoxazines with
dichlorophenylphosphine or triethyl phosphite. The configuration of some of these compounds
was stablished by X-ray analysis.
Keywords: 1,4,2-oxazaphosphepines; 1,3-benzoxazines; chiral o-hydroxybenzylamines;
aminophenols
1. Introduction
The 2-arylmorpholinol 1 and 2 possess a strong specific affinity toward the noradrenergic system
with application in the treatment of depression and attention deficit hyperactivity disorder (ADHD).
On the other hand, the α-aminophosphonic and α-aminophosphinic acids are currently attracting interest
in organic and medicinal chemistry, as well as in agriculture, due to their important biological and
pharmacological properties, and have been used as key synthetic intermediates for the preparation of
more complex compounds [1–6]. The great importance of this type of compounds has allowed organic
chemists to report numerous procedures regarding their racemic or stereoselective synthesis [7–12]. The
phosphorus heterocycles type 3 can be considered as analogues of 2-arylmorpholinol 1, and may be

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useful as intermediates in the synthesis of α-aminophosphinic acids [13,14]. We described [15] in
previous publications the synthesis of enantiopure (2S,5S)-4-benzyl-2-ethoxy-2-oxo-5-phenyl-1,4,2-
oxazaphosphinane 4 from (S)-phenylglycinol [16]; however, to the best of our knowledge, the synthesis
of 1,4,2-oxazaphosphepine 2-oxides type 5 has been less explored [17] (Figure 1). These benzo derivatives
could be considered as a restructured ring system of 3 with possible applications in medicinal chemistry
and organic synthesis.
Figure 1. 2-Arylmorpholinols, α-aminophosphonic and α-aminophosphinic derivatives.
As a part of our ongoing efforts in the discovery and synthesis of new phosphorus heterocycles
conformational constraints [18,19], we report herein the preparation and conformational study of
several [1,2,4] oxazaphosphepine 2-oxides.
2. Results and Discussion
For the synthesis of 1,4,2-oxazaphosphepine 2-oxides, initially we carried out the preparation of
chiral o-hydroxybenzylamines 6. Following the procedure described in the literature, the reaction of
o-salycilaldehyde and o-hydroxyacetophenone with (S)-α-methylbenzylamine in toluene at reflux gave
the corresponding imines, which without additional purification were reacted with NaBH4 in methanol
at room temperature, obtaining the o-hydroxybenzylamines (S)-6a [20] and (S,S)-6b [21] in excellent
yield and >99:1 diastereoisomeric ratio (Scheme 1).
Me
R
R
1. (S)- -MBA
Ph
PhMe,
N
H
O
2. NaBH4
OH
OH
MeOH, r.t.
(S)-6a; R = H, 100%
(S,S)-6b; R = Me, 88%, >99:1 d.r.
Scheme 1. Synthesis of the compounds 6a and 6b.
On the other hand, the “one-pot” three-component reaction of phenol with aryl aldehydes and
(S)-α-methylbenzylamine under heating and solvent-free conditions afforded the o-hydroxybenzylamines

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6c,d and 7c,d. In all cases, the diastereoisomeric ratio was similar to those obtained in the nucleophilic
addition of other reagents onto imines bearing (S)-α-methylbenzylamine [22]. The “one-pot”
three-component reaction of phenol with benzaldehyde and (S)-α-methylbenzylamine, gave the
o-hydroxybenzylamines (S,S)-6c and (R,S)-7c in 45% yield and 72:28 diastereoisomeric ratio, with
predominance of the (S,S)-6c diastereoisomer. The reaction of phenol with 2-chlorobenzaldehyde and
(S)-α-methylbenzylamine, produced the o-hydroxybenzylamines (R,S)-6d and (S,S)-7d in 47% yield
and 64:36 diastereoisomeric ratio, now with a predominance of the (R,S)-6d diastereoisomer, derived
of the priority change of the substituents on the new stereogenic center, and not by the nucleophilic
attack on the intermediate imine (Scheme 2). The pure diastereoisomers (S,S)-6c, (R,S)-7c, (R,S)-6d and
(S,S)-7d were obtained after purification and separation by column chromatography.
Scheme 2. Synthesis of the compounds 6c, 7c, 6d and 7d.
The diastereoselectivity in the synthesis of o-hydroxybenzylamine (S,S)-6b considering that in the
Schiff bases the C-H bond of the chiral amine in the most stable conformation is eclipsed with the
N-C-H fragment, as would be expected from the 1,3-allylic strain model [23], and the conformations
with C-Ph and C-Me eclipsed with N-C-H were appreciably higher in energy, and the nucleophilic
attack of hydride or the phenol on the imines should take place at the re face (less hindered side) to
afford the (S,S)-diastereoisomers as the principal product (Figure 2).
H:
Me
Me
Me
Me
Me
si
H
Ph
Ph
Ph
S
N
H
N
H
S
S
R
N
re
S
Me
H
OH
OH
O
H:
6b
7b
(S,S)- ; principal
(S,R)- ; minor
derived from
derived from
re-face attack
si-face attack
Me
R
Me
R
Nu:
H
si
H
Ph
Ph
Ph
N
N
N
R
re
S
Me
H
H
OH
OH
Nu:
7c,d
; minor
6c,d
; major
derived from
si-face attack
derived from
re-face attack
OH
Nu: =
Figure 2. Proposed mechanism for nucleophilic attack of NaBH4 and phenol onto imines.
Once the o-aminophenols 6a–d and 7c,d derivatives were synthesized, the next step was the reaction
with formaldehyde in order to obtain the 1,3-benzoxazines 8 and 9. Following a similar procedure to that
described in the literature [24], initially, the reaction of o-aminophenol (S)-6a with formaldehyde in

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dichloromethane at reflux, afforded the 1,3-benzoxazine (S)-8a in 85% yield, whereas the reaction of
o-aminophenol (S,S)-6b under identical conditions, produced the 1,3-benzoxazines (S,S)-8b in 90%
yield. In a similar way, the o-aminophenols 6c,d and 7c,d were reacted with formaldehyde, obtaining
the 1,3-benzoxazines 8c,d and 9c,d in 59% to 81% yield (Scheme 3).
Scheme 3. Synthesis of the compounds 8a–d and 9c,d.
The absolute configuration of the stereogenic center at C16 of the 1,3-benzoxazines (S,S)-8b
and (S,S)-8c was determined by comparison with the enantiomers (R,R) previously reported in the
literature [25], whereas the absolute configuration of the stereogenic center at C16 of the 1,3-benzoxazine
9d was determined as (S,S) by single crystal X-ray analysis for the minor diastereoisomer [26], which
show that the 2-chlorophenyl substituent has an anti-disposition to the (α)-methylbenzyl fragment
(Figure 3). On these bases, we assumed that the stereochemistry for the major 1,3-benzoxazine is (R,S).
Figure 3. X-ray structure for 1,3-benzoxazine (S,S)-9d.

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With the 1,3-benzoxazines 8a–d in hand, the next step was carried out for the reaction with
phosphorus nucleophilic reagents. Initially, the 1,3-benzoxazine (S)-8a was reacted with triethyl
phosphite in dichloromethane at room temperature for 2 h, obtaining the α-aminophosphonate (S)-10a in
quantitative yield. On the other hand, the reaction of 1,3-benzoxazine (S,S)-8c with triethyl phosphite in
dichloromethane at room temperature did not give the desired product, and when the reaction was
carried out at 40 °C for 72 h, the phosphonate rac-11c was obtained in 20% yield (Scheme 4).
Scheme 4. 1,3-Benzoxazines reaction with triethyl phosphite.
The formation of 11c can be explained through the formation of enone intermediate A, which by
nucleophilic reaction with triethyl phosphite gives rise to the formation of intermediate B. Finally, the
phenolate is protonated generating ethylene and diethylphenyl phosphonate like Michaelis-Arbuzov
reaction (Scheme 5) [27,28].
Scheme 5. Proposed reaction mechanism for the formation of phosphonate 11c.
On the other hand, the reaction of the 1,3-benzoxazine (S)-8a with triethyl phosphite in the presence
of BF3·OEt2 (0.2 eq) in dichloromethane at room temperature, gave the α-aminophosphonate (S)-10a
and the 1,4,2-oxazaphosphepine 12a in 32 and 15% yield, respectively (Table 1, entry 1). The reaction
of 1,3-benzoxazine (S,S)-8b under identical conditions gave the 1,4,2-oxazaphosphepines 13b and 14b
in 7 and 15% yield, respectively (Table 1, entry 2). In a similar way, the reaction of (S,S)-8c afforded
the 1,4,2-oxazaphosphepines 13c and 14c in 11 and 16% yield, respectively (Table 1, entry 3). However,
the reaction of (R,S)-8d gave the 1,4,2-oxazaphosphepine 13d in only 6% yield (Table 1, entry 4).

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When other Lewis acids such as SnCl4 and TiCl4 were used as catalyst, the reaction did not proceed or very
low yields were obtained. Additionally, after several attempts it was not possible to increase the yields.
Table 1. Reaction of 8a–d with (EtO)3P catalyzed with BF3·OEt2.
Entry
R
a: H
b: Me
10; Yield (%) 12; Yield (%) 13; Yield (%) 14; Yield (%)
1
2
3
4
32
--
15
--
--
7
--
15
16
--
c: C6H5
d: 2-ClC6H4
--
--
--
--
11
6
13
1H-, C-NMR and X-ray analysis [29] for the compound 13c allowed assigning the configuration
as (2R,5S,1ʹS). Additionally this seven-membered ring has a chair-conformation with the phenyl and
the ethoxy groups in trans-diaxial disposition (Figure 4).
Figure 4. X-ray crystallographic structure of (2R,5S,1ʹS)-13c.
On the other hand, the reaction of chiral 1,3-benzoxazines 8a–d with dichlorophenylphosphine as
phosphorus source and triethylamine in dichlorometane at room temperature afforded the diastereoisomeric

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mixture of 1,4,2-oxazaphosphepines 15a–d and 16a–d in 50:50 to 0:100 diastereoisomeric ratio. In a
similar way, the reaction of 9c,d gave the 1,4,2-oxazaphosphepines 17c,d and 18c,d in 26:74 and 16:84
diastereoisomeric ratios, respectively. Most of the compounds were obtained as diastereoisomeric pairs,
due to the formation of a new chiral center by the insertion of phosphorus atom (Scheme 6). The
1
compound 15b could be observed by H-NMR after purification, but this compound could not be
fully characterized. Compounds 17d and 18d could not be separated by chromatographic procedure,
however, good diastereoselectivity was obtained.
Me
Me
R
R
Me
R
N
P
Ph
N
P
Ph
PhPCl2, CH2Cl2
Et3N, 25 oC 72 h
N
Ph
+
Ph
O
O
O
O
O
Ph
8a-d
15a-d
a; R = H; 7%, 0:100 d.r.
16a-d
b
; R = Me; 29%, 48:52 d.r.
c
; R = C6H5; 52%, 14:86 d.r.
d
; R = 2-ClC6H5; 8%, 50:50 d.r.
Me
Me
O
Me
R
R
R
N
P
Ph
N
P
Ph
N
Ph
PhPCl2, CH2Cl2
Et3N, 25 oC 72 h
+
Ph
O
O
O
O
Ph
18c,d
; R = C6H5; 22%, 26:74 d.r.
9c,d
17c,d
c
d
; R = 2-ClC6H5; 8%, 16:84 d.r.
Scheme 6. Synthesis of 1,4,2-oxazaphosphepines.
The X-rays analysis of the compounds 16a, 16b, 15d and 18c allowed the assignment of the
configuration [30–33], and it was found that the chair conformation is the most stable (Figure 5). The
compounds 16a, 16b and 18c exhibit an axial distribution for the P=O moiety. Additionally a syn-diaxial
distribution was observed between P=O and methylbenzyl fragment. For the compound 15d, the X-ray
structure showed a boat conformation with a 33.7° O-P-C-N angle.
(2S,1′S)-16a
(2S,5S,1′S)-16b
Figure 5. Cont.

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(2R,5R,1′S)-18c
(2S,5R,1′S)-15d
Figure 5. Chair conformations for 16a, 16b, and 18c. Boat conformation for 15d [34]. The
methylbenzyl group was removed to allow for a better appreciation of the conformations.
3. Experimental Section
3.1. General Comments
Reagents were obtained from commercial suppliers and were used without further purification.
Melting points were determined in a Fischer Johns apparatus and are uncorrected. NMR spectra were
1
13
recorded on Varian System instrument (400 MHz for H and 100 MHz for C) and Varian Gemini
1
13
200 MHz (200 MHz for H and 50 MHz for C). The spectra were obtained in CDCl3 solution using
TMS as internal reference. High resolution CI+ and FAB+ mass experiments were done in a JEOL
HRMStation JHRMS-700. X-ray diffraction studies were performed on a Bruker-APEX diffractometer
with a CCD area detector at 100 K (λMo Kα = 0.71073 Å, monochromator: graphite). Specific rotations
were measured in a Perkin-Elmer 341 polarimeter at room temperature and λ = 589 nm. The purification
of compounds was carried out by column chromatography utilizing (silica gel, 230–400 and 70–230)
and chromatotron (silica gel Merck 60 PF254 and gypsum) and neutral alumina. The dichloromethane
was refluxed on phosphorous pentoxide. Spectroscopic data for 6a [20] were identical to those reported
13
in the literature. 1H- and C-NMR data for the compound 8a are identical with those described in the
literature for the (R) enantiomer [24].
3.2. Preparation of Aminophenols
3.2.1. Preparation of 2-{(1S)-1-{[(1S)-1-Phenyethyl]amino}ethyl}phenol (6b)
A mixture of 2-hydroxyacetophenone 1.0 g, 1.37 mL (7.3 mmol), (S)-α-methylbenzylamine 0.89 g,
0.93 mL (7.3 mmol) and toluene (25 mL), was heated for 1 h under azeotropic removal of water.
The solvent was evaporated under reduced pressure; the crude product was dissolved in methanol (21 mL)
and treated with cerium trichloride heptahydrate 1.36 g (3.7 mmol). The solution was cooled at −78 °C,
and sodium borohydride 0.55 g (1.5 mmol) was added. The reaction mixture was allowed the room
temperature and stirred for 16 h. The solvent was removed under vacuum, the crude product was

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dissolved in dichloromethane (175 mL), treated with a saturated solution of ammonium chloride (35 mL),
and extracted with dichloromethane (3 × 30 mL). The organic layers were dried over anhydrous
Na2SO4, filtered and evaporated under reduced pressure, obtaining (1.72 g, 97%) as a mixture of two
diastereoisomers (90:10 d.r.). The mixture was dissolved in ethyl ether (50 mL), washed with 1.5 M
hydrochloric acid (5 mL), 1.0 M sodium hydroxide (7 mL), and extracted with ethyl acetate (3 × 30 mL).
The organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure,
to give the (S,S)-diastereoisomer (6b) [21] (1.55 g, 88%) as a colorless oil. [α]D = −70.9° (c = 0.0127,
CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.34 (d, J = 7.0 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H), 3.64
(q, J = 6.7 Hz, 1H), 3.70 (q, J = 6.7 Hz, 1H), 6.75–7.38 (m, 9H). 13C-NMR (CDCl3, 50 MHz): δ 23.0,
23.6, 55.5, 56.3, 116.9, 119.3, 126.4, 127.6, 128.4, 128.8, 143.5, 157.6.
3.2.2. Preparation of Aminophenols (6c) and (7c)
A mixture of benzaldehyde 3.0 g, 2.8 mL (28.3 mmol), phenol 3.2 g (33.9 mmol) and
(S)-α-methylbenzylamine 3.4 g, 3.6 mL (28.3 mmol), was heated at 60–70 °C for 48 h. The reaction
mixture was percolated on a column chromatography, eluting with hexane:EtOAc (98:2), obtaining
(6c) and (7c) (3.85 g, 45%) as a diastereoisomeric mixture 72:28 d.r., which was separated by column
chromatography eluting with hexane:EtOAc (99:1), to give both aminophenols (6c) as viscous oil
(2.8 g, 32%) and (7c) as viscous oil (1.1 g, 13%).
2-[(S)-Phenyl-{[(1S)-1-phenylethyl]amino}methyl]phenol (6c). [α]D = +132.8° (c = 0.0179, CHCl3).
1H-NMR (CDCl3, 200 MHz): δ 1.47 (d, J = 6.8 Hz, 3H), 3.85 (q, J = 6.8 Hz, 1H), 4.70 (s, 1H),
6.77–7.45 (m, 14H). 13C-NMR (CDCl3, 50 MHz): δ 23.0, 56.3, 64.9, 117.3, 119.7, 126.8, 127.7, 128.1,
129.1, 129.6, 142.1, 142.4, 157.8.
2-[(R)-Phenyl-{[(1S)-1-phenylethyl]amino}methyl]phenol (7c). [α]D = −102.1° (c = 0.010, CHCl3).
1H-NMR (CDCl3, 200 MHz): δ 1.42 (d, J = 6.6 Hz, 3H), 3.71 (q, J = 6.6 Hz, 1H), 4.83 (s, 1H),
6.46–7.41 (m, 14 H). 13C-NMR (CDCl3, 50 MHz): δ 23.2, 55.2, 63.2, 117.0, 119.1, 125.9, 127.3,
128.0, 128.1, 128.3, 129.0, 129.1, 129.2, 140.2, 142.3, 157.8.
3.2.3. Preparation of Aminophenols (6d) and (7d)
A mixture of phenol 3.0 g (31.9 mmol), o-chlorobenzaldehyde 4.48 g (31.9 mmol) and
(S)-α-methylbenzylamine 3.86 g, 4.05 mL (31.9 mmol), was heated at 60–70 °C for 24 h. After this
time, the reaction mixture was purified by column chromatography eluting with hexane:EtOAc (98:2),
to give (3.4 g, 47%) as a diastereoisomeric mixture 64:36 d.r., which was separated by column
chromatography using a mixture of hexane:EtOAc (99:1) as eluent, obtaining the aminophenols (6d)
as viscous oil (2.2 g, 30%) and (7d) as viscous oil (1.2 g, 17%).
2-[(R)-2-Chlorophenyl-{[(1S)-1-phenylethyl]amino}methyl]phenol (6d). [α]D = +125.95° (c = 0.010,
1
CHCl3). H-NMR (CDCl3, 400 MHz): δ 1.49 (d, J = 6.8 Hz, 3H), 3.85 (q, J = 6.7 Hz, 1H), 5.23
13
(s, 1H), 6.73–7.41 (m, 14H). C-NMR (CDCl3, 100 MHz): δ 22.2, 56.6, 61.3, 117.4, 119.8, 123.5,
127.2, 127.7, 128.1, 128.8, 129.3, 129.4, 130.0, 130.3, 131.1, 133.4, 137.0, 138.5, 142.5, 158.6. HRMS
(CI+): m/z calculated for C21H20ClNO [M + H] 337.1233; found for [M + H]+, m/z 338.1325.

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2-[(S)-2-Chlorophenyl-{[(1S)-1-phenylethyl]amino}methyl]phenol (7d). [α]D = −63.81° (c = 0.0118,
1
CHCl3). H-NMR (CDCl3, 200 MHz): δ 1.46 (d, J = 6.6 Hz, 3H), 3.75 (q, J = 6.6 Hz, 1H), 5.34
13
(s, 1H), 6.48–7.46 (m, 14H). C-NMR (CDCl3, 50 MHz): δ 22.8, 55.8, 61.0, 117.1, 119.3, 124.1,
127.3, 127.7, 128.0, 128.6, 129.0, 129.2, 129.4, 130.6, 130.8, 134.1, 137.1, 142.4, 158.0. HRMS (CI+):
m/z calculated for C21H20ClNO [M + H] 337.1233; found for [M + H]+, m/z 338.1325.
3.3. Preparation of 1,3-Benzoxazines
3.3.1. (4S)-4-Methyl-3-[(1ʹS)-1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (8b)
A mixture of (6b) 1.5 g (5.9 mmol), formaldehyde 0.23 g, 0.6 mL (7.7 mmol) and dichloromethane
(25 mL), was heated for 1 h under azeotropic removal of water. The solvent was evaporated under
reduced pressure and the crude product was purified by column chromatography on neutral alumina,
using hexane as eluent, obtaining the compound (8b) (1.4 g, 90%) as viscous oil. [α]D = +39.18°
(c = 0.012, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.36 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 6.6 Hz, 3H),
3.60 (q, J = 6.6 Hz, 1H), 3.88 (q, J = 6.6 Hz, 1H), 5.00 (AB system, J = 11.0 Hz, 1H), 5.15 (AB
13
system, J = 11.0 Hz, 1H), 6.78–7.32 (m, 9H). C-NMR (CDCl3, 50 MHz): δ 22.6, 24.5, 52.4, 59.3,
74.5, 116.7, 120.6, 125.7, 127.3, 127.5, 128.7, 128.8, 145.9, 154.6. HRMS (CI+): m/z calculated for
C17H19NO [M + H] 253.1467; found for [M + H]+, m/z 254.1474.
3.3.2. (4S)-4-Phenyl-3-[(1ʹS)-1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (8c)
A mixture of (6c) 0.5 g (1.6 mmol), formaldehyde 60 mg, 0.16 mL (2.1 mmol) and dichloromethane
(15 mL), was heated for 1 h under azeotropic removal of water. The solvent was evaporated under
reduced pressure and the crude product was purified by recrystallization from cold methanol, to give
the compound (8c) (420 mg, 81%) as a white solid, mp = 98–100 °C. [α]D = +37.3° (c = 0.010,
1
CHCl3). H-NMR (CDCl3, 200 MHz): δ 1.51 (d, J = 6.6 Hz, 3H), 3.96 (q, J = 6.6 Hz, 1H), 4.70
(s, 1H), 4.80 (AB system, J = 11.0 Hz, 1H), 5.05 (ABX system, J = 10.8, 2.0 Hz, 1H), 6.77–7.45
13
(m, 14H). C-NMR (CDCl3, 50 MHz): δ 21.6, 59.0, 59.4, 74.5, 116.6, 120.3, 120.4, 127.2, 127.6,
127.9, 128.1, 128.3, 128.5, 128.8, 129.0, 130.4, 143.8, 145.3, 154.6. HRMS (CI+): m/z calculated for
C22H21NO [M + H] 315.1623; found for [M + H]+, m/z 316.1694.
3.3.3. (4R)-4-(2-Chlorophenyl)-3-[(1ʹS)-1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (8d)
A mixture of (6d) 1.7 g (4.9 mmol), formaldehyde 180 mg, 0.5 mL, (6.3 mmol) and
dichloromethane (25 mL), was heated for 1 h under azeotropic removal of water. The solvent was
evaporated under reduced pressure and the crude product was purified by column chromatography
using a mixture of hexane:EtOAc (99:1) as eluent, obtaining the compound (8d) (1.2 g, 59%) as a
1
colorless highly viscous liquid. [α]D = +66.65° (c = 0.0108, CHCl3). H-NMR (CDCl3, 200 MHz): δ
1.53 (d, J = 6.6 Hz, 3H), 4.34 (q, J = 6.7 Hz, 1H), 4.71 (AB system, J = 11.0 Hz, 1H), 4.78 (AB
system, J = 11.0 Hz, 1H), 5.30 (s, 1H), 6.77–7.40 (m, 14 H). 13C-NMR (CDCl3, 50 MHz): δ 18.4, 58.2,
60.3, 74.4, 116.8, 120.6, 122.0, 126.3, 127.5, 127.8, 128.2, 128.4, 128.6, 128.8, 128.9, 129.2, 130.0,
132.0, 134.6, 141.3, 142.6, 155.4. HRMS (CI+): m/z calculated for C22H20ClNO [M + H] 349.1233;
found for [M + H]+, m/z 350.1321.

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3.3.4. (4R)-4-Phenyl-3-[(1ʹS)-1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (9c)
A mixture of (7c) 0.5 g (1.6 mmol), formaldehyde 60 mg, 0.16 mL, (2.1 mmol) in dichloromethane
(15 mL), was heated for 1 h under azeotropic removal of water. The solvent was evaporated under
reduced pressure and the crude product was purified by recrystallization from cold methanol obtaining
1
(9c) (0.42 g, 77%) as a white solid, mp = 79–81 °C. [α]D = −68.3° (c = 0.010, CHCl3). H-NMR
(CDCl3, 400 MHz): δ 1.57 (d, J = 6.0 Hz, 3H), 4.11 (q, J = 6.4 Hz, 1H), 4.37 (ABX system, J = 10.4,
2.4 Hz, 1H), 4.57 (AB system, J = 10.8 Hz, 1H), 5.24 (s, 1H), 6.88–7.43 (m, 14H). 13C-NMR (CDCl3,
100 MHz): δ 21.5, 57.1, 57.9, 76.1, 116.7, 119.9, 120.4, 127.0, 127.3, 127.7, 128.0, 128.3, 128.4,
128.9, 129.7, 143.7, 144.0, 154.8.
3.3.5. (4S)-4-(2-Chlorophenyl)-3-[(1ʹS)-1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (9d)
A mixture of (7d) 0.63 g (1.8 mmol), formaldehyde 70 mg, 0.19 mL, (2.3 mmol) and dichloromethane
(25 mL) was heated for 1 h under azeotropic removal of water. The solvent was evaporated under
reduced pressure and crude was purified by column chromatography using hexane:EtOAc (99:1) as
eluent, obtaining the compound (9d) (340 mg, 66%) as a white solid, mp = 100–104 °C. [α]D = −118.26°
(c = 0.0108, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.63 (d, J = 6.6 Hz, 3H), 4.10 (q, J = 6.7 Hz, 1H),
4.34 (ABX system, J = 10.6, 1.4 Hz, 1H), 4.64 (AB system, J = 10.8 Hz) 5.66 (s, 1H), 6.80–7.47
13
(m, 14H). C-NMR (CDCl3, 50 MHz): δ 21.3, 56.1, 58.7, 75.6, 116.6, 120.0, 120.5, 126.3, 127.4,
127.7, 128.5, 128.8, 129.2, 130.3, 132.5, 134.6, 140.9, 144.5, 154.9. HRMS (CI+): m/z calculated for
C22H20ClNO [M + H] 349.1233; found for [M + H]+, m/z 350.1349.
3.4. Reaction of 1,3-Benzoxazines with Triethyl Phosphite
3.4.1. Synthesis of (S)-Diethyl-{[(2-hydroxybenzyl)(1-phenylethyl)amino]methyl}phosphonate (S)-10a
A mixture of benzoxazine (8a) 0.5 g (2.1 mmol), triethyl phosphite 0.34 g, 0.35 mL, (2.1 mmol) and
dry dichloromethane (10 mL), was reacted under nitrogen atmosphere at room temperature for 2 h. The
solvent was evaporated under reduced pressure. The compound was characterized without purification.
The compound (S)-10a) (0.78 g, 100%) as a colorless oil. [α]D = −33.10° (c = 0.010, CHCl3). 1H-NMR
(CDCl3, 400 MHz): δ 1.27 (t, J = 6.8 Hz, 3H), 1.42 (d, J = 7.2 Hz, 1H), 2.67 (ABX system, J = 15.6,
12.4 Hz, 1H), 2.94 (ABX system, J = 15.6, 11.6 Hz, 1H), 3.89 (AB system, J = 14.0 Hz, 1H), 3.95 (AB
13
system, J = 14.0 Hz, 1H), 4.00–4.07 (m, 4H), 4.19 (q, J = 7.2 Hz, 1H), 6.78–7.37 (m, 9H). C-NMR
(CDCl3, 100 MHz): δ 13.6, 16.5 (d, JC/P = 5.9 Hz), 44.2 (d, JC/P = 163.9 Hz), 55.0 (d, JC/P = 4.4 Hz),
57.4 (d, JC/P = 11.7 Hz), 62.3 (d, JC/P = 5.9 Hz), 62.4 (d, J = 5.9 Hz), 116.5, 119.4, 122.0, 127.8, 128.4,
31
128.5, 128.6, 129.2, 129.7, 139.7, 157.7. P-NMR (CDCl3, 80.95 MHz): δ 26.78. HRMS (CI+): m/z
calculated for C20H28NO4P [M + H] 377.1756; found for [M + H]+, m/z 378.1819.
3.4.2. Synthesis of Diethyl-[(2-hydroxyphenyl)(phenyl)methyl]phosphonate (11c)
A mixture of benzoxazine (8c) 200 mg (0.6 mmol) and triethyl phosphite 100 mg, 0.10 mL, (0.6 mmol)
in dry dichloromethane (5 mL) was reacted under nitrogen atmosphere at reflux for 72 h. The solvent
was evaporated under reduced pressure. The mixture was purified by column chromatography using

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hexane:EtOAc (80:20). The compound (11c) (40 mg, 20%) was obtained as a white solid, mp =
1
156–159 °C. [α]D = 0° (c = 0.010, CHCl3). H-NMR (CDCl3, 400 MHz): δ 1.12 (t, J = 7.0 Hz, 3H),
1.15 (t, J = 6.8 Hz, 3H), 3.86–4.08 (m, 4H), 4.72 (AB system, JH/P = 26.6 Hz, 1H), 7.00–7.52 (m, 9H),
8.89 (br, 1H). 13C-NMR (CDCl3, 100 MHz): δ 16.3, 47.0 (d, JC/P = 136.15 Hz), 63.5 (d, JC/P = 7.0 Hz),
64.0 (d, JC/P = 7.4 Hz), 118.1, 119.1, 121.0, 127.3, 127.5, 128.6, 128.8, 129.1, 129.8 (d, JC/P = 8.1 Hz),
31
131.0 (d, JC/P = 7.7 Hz), 136.5 (d, JC/P = 4.35 Hz), 155.0 (d, JC/P = 5.85 Hz). P-NMR (CDCl3,
80.95 MHz): δ 28.43. HRMS (CI+): m/z calculated for C17H21O4P [M + H] 320.1177; found for
[M + H]+, m/z 321.1033.
3.5. General Procedure for the Preparation of 1,4,2-Oxazaphosphepines (12), (13) and (14)
Under anhydrous conditions, the corresponding benzoxazine in dry dichloromethane was treated with
boron trifluoride etherate and triethyl phosphite. The reaction mixture was stirred at room temperature
for 72 h. The solvent was evaporated under reduced pressure, and the crude was dissolved in ethyl
acetate, and treated with a saturated solution of ammonium chloride and stirred for 15 min. The organic
phase was extracted with ethyl acetate, and the organic extracts were dried over anhydrous Na2SO4,
and evaporated under reduced pressure. The crude product was purified by column chromatography.
3.5.1. (S)-2,2,2-Triethoxy-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1,4,2λ5-benzoxazaphosphepine (12a)
A mixture of benzoxazine (8a) 0.75 g (3.1 mmol) boron trifluoride etherate 80 mg, 0.08 mL
(0.6 mmol) and triethyl phosphite 0.52 g, 0.53 mL, (3.1 mmol) in dry dichloromethane (10 mL), was
reacted at room temperature for 72 h. The solvent was eliminated and the crude product was purified
by column chromatography using hexane: i-PrOH (98:2) as eluent, obtaining the compound (12a)
(155 mg, 15%), as colorless. The compound (10a) was also obtained (377 mg, 32%). [α]D = −28.4°
(c = 0.011, CHCl3). 1H-NMR (CDCl3, 400 MHz): δ 1.24 (t, J = 6.8 Hz, 3H), 1.25 (t, J = 6.8 Hz, 3H),
1.39 (t, J = 6.8 Hz, 3H), 1.41 (d, J = 7.2 Hz, 3H), 2.80 (ABX system, JH/P = 15.4, 12.6 Hz, 1H), 2.97
(ABX system, JH/P = 15.6, 8.4 Hz, 1H), 3.71 (AB system, J = 14.8 Hz, 1H), 3.91 (AB system, J = 14.8 Hz,
1H), 3.96 (q, J = 7.2 Hz, 2H), 4.00 (q, J =6.8 Hz, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.19 (q, J = 6.8 Hz, 1H)
13
6.80–7.56 (m, 9H). C-NMR (CDCl3, 100 MHz): δ 14.1, 15.1, 16.60, 16.66, 45.5 (d, JC/P = 162.5 Hz),
48.6 (d, JC/P = 7.3 Hz), 58.3 (d, JC/P = 10.2 Hz), 61.7 (d, JC/P = 7.3 Hz), 61.8 (d, J = 7.3 Hz), 63.7,
111.3, 120.5, 126.9, 127.8, 128.1, 128.4, 130.7, 142.6, 157.2. 31P-NMR (CDCl3, 80.95 MHz): δ 10.24.
HRMS (CI+): m/z calculated for C22H32NO4P [M + H] 405.2069; found for [M + H]+, m/z 406.2128.
3.5.2. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (13b) and (14b)
A mixture of benzoxazine (8b) 1.0 g (3.9 mmol), boron trifluoride etherate 110 mg, 0.09 mL,
(0.8 mmol) and triethyl phosphite 0.65 g, 0.67 mL, (3.9 mmol) in dry dichloromethane (20 mL), was
reacted at room temperature for 72 h. The solvent was eliminated and the crude product was purified
by column chromatography using hexane:EtOAc (80:20) as eluent, obtaining the compounds (13b)
(96 mg, 7% and (14b) (204 mg, 15%), both as colorless oil.
(2R,S)-2-Ethoxy-(5S)-5-methyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (13b). [α]D = −2.2° (c = 0.013, CHCl3). 1H-NMR (CDCl3, 400 MHz): δ 1.41 (d, J = 6.8 Hz, 3H),

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1.43 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 6.8 Hz, 3H), 3.67 (ABX system, JH/P = 16.4, 5.8 Hz, 1H), 3.74
(ABX system, JH/P = 16.4, 6.0 Hz, 1H), 3.79 (dq, J = 7.2, 5.3 Hz, 2H), 4.31 (q, J = 7.2 Hz, 1H), 4.33
13
(q, J = 7.2 Hz, 1H), 6.56–7.35 (m, 9H). C-NMR (CDCl3, 100 MHz): δ 16.4, 16.5, 18.7, 22.7, 41.3
(d, JC/P = 125.9 Hz), 59.0, 60.1, 62.1 (d, JC/P = 8.8 Hz), 122.5, 122.6, 124.9, 126.9, 127.1, 128.4, 129.3,
31
131.3, 134.1, 145.6, 147.9. P-NMR (CDCl3, 80.95 MHz): δ 15.52. HRMS (CI+): m/z calculated for
C19H24NO3P [M + H] 345.1494; found for [M + H]+, m/z 346.1557.
(2R,S)-2-Ethoxy-(5S)-5-methyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide, (14b). [α]D = +5.40° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 400 MHz): δ 1.23 (d, J = 7.0 Hz, 3H),
1.32 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 3.60 (dq, J = 6.8, 6.8 Hz, 1H), 3.75 (q, 7.2 Hz, 1H),
3.82 (ABX system, JH/P = 16.8, 1.6 Hz, 1H), 3.85 (ABX system, JH/P = 16.8, 3.6 Hz, 1H), 4.05–4.15
(m, 2H), 4.29–4.39 (m, 2H), 6.57–7.35 (m, 9H). 13C-NMR (CDCl3, 100 MHz): δ 16.3, 16.4, 18.4, 22.7,
41.3 (d, JC/P = 123.0 Hz), 58.6, 60.0, 61.5 (d, JC/P = 8.8 Hz), 121.9, 122.0, 124.7, 127.0, 127.1, 128.5,
129.0, 131.5, 134.1, 145.5, 148.4. 31P-NMR (CDCl3, 80.95 MHz): δ 18.75. HRMS (CI+): m/z
calculated for C19H24NO3P [M + H] 345.1494; found for [M + H]+, m/z 346.1553.
3.5.3. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (13c) and (14c)
A mixture of benzoxazine (8c) 0.68 g (2.2 mmol), boron trifluoride etherate 60 mg, 0.05 mL,
(0.4 mmol) and triethyl phosphite 0.36 g, 0.37 mL, (2.2 mmol) in dry dichloromethane (5 mL) was
reacted at room temperature for 72 h. The solvent was eliminated and the crude product was purified
by column chromatography using hexane:EtOAc (80:20) as eluent, obtaining the less polar compound
(13c) (100 mg, 11%) as yellow oil, and the more polar compound (14c) (138 mg, 16%) as a white solid
mp = 164–170 ºC. The compound (14c) was recrystallized from dichloromethane–hexane to give
a crystal for X-ray studies.
(2S)-2-Ethoxy-(5S)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (13c). [α]D = +74.90° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.28 (t, J = 7.0 Hz, 3H),
1.51 (d, J = 6.6 Hz, 3H), 3.32 (ABX system, JH/P = 16.2, 8.4 Hz, 1H), 3.57 (ABX system, JH/P = 16.2,
3.8 Hz, 1H), 3.99–4.23 (m, 3H), 4.96 (s, 1H), 6.67–7.71 (m, 14H). 13C-NMR (CDCl3, 50 MHz): δ 16.5
(d, JC/P = 5.85 Hz), 21.9, 40.2 (d, JC/P = 128.15 Hz), 59.9, 62.4 (d, JC/P = 7.3 Hz), 67.8, 123.1, 123.2,
125.5, 127.4, 127.5, 128.1, 128.5, 128.8, 130.3, 130.8, 133.2, 139.7, 145.5. 31P-NMR (CDCl3,
80.95 MHz): δ 10.97. HRMS (CI+): m/z calculated for C24H26NO3P [M + H] 407.1650; found for
[M + H]+, m/z 408.1710.
(2R)-2-Ethoxy-(5S)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (14c). [α]D = +79.62° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.25 (t, J = 7.0 Hz, 3H),
1.42 (d, J = 6.8 Hz, 3H), 3.54 (ABX system, JH/P = 16.8, 6.8 Hz, 1H), 3.70 (ABX system, JH/P = 16.0,
5.2 Hz, 1H), 3.80 (q, J = 6.8 Hz, 1H), 4.03–4.45 (m, 2H), 4.92 (s, 1H), 6.66–7.39 (m, 14H). 13C-NMR
(CDCl3, 50 MHz): δ 16.5 (d, JC/P = 5.95 Hz), 22.6, 41.7 (d, JC/P = 123.3 Hz), 59.9, 61.6 (d, JC/P = 7.95 Hz),
67.2, 122.3, 122.4, 125.3, 127.3, 127.5, 127.6, 128.0, 128.7, 128.9, 130.0, 130.6, 130.7, 138.7, 145.4,
31
149.1 (d, JC/P = 7.2 Hz). P-NMR (CDCl3, 80.95 MHz): δ 13.52. HRMS (CI+): m/z calculated for
C24H26NO3P [M + H] 407.1650; found for [M + H]+, m/z 408.1710.

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3.5.4. Synthesis of (2R,S)-2-Ethoxy-(5R)-5-(2-chlrophenyl)-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro
-1,4,2-benzoxazaphosphepine 2-oxide (13d)
A mixture of benzoxazine (8d) 0.56 g (1.6 mmol), boron trifluoride etherate 40 mg, 0.04 mL
(0.3 mmol) and triethyl phosphite 0.26 g, 0.27 mL, (1.6 mmol) in dry dichloromethane (10 mL) was
reacted at room temperature for 72 h. The solvent was eliminated and the crude product was purified
by column chromatography using hexane:EtOAc (80:20) as eluent, obtaining the compound (13d)
(47 mg, 6%). [α]D = +163.41° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 400 MHz): δ 1.28 (t, J = 7.0 Hz, 3H),
1.48 (d, J = 6.8 Hz, 3H), 3.11 (AB system, J = 16.4 Hz, 1H), 3.20 (AB system, J = 15.6 Hz, 1H), 3.89
(dq, J = 6.6, 3.2 Hz, 1H), 4.22 (m, 2H), 5.66 (s, 1H), 7.07–7.44 (m, 13H). 13C-NMR (CDCl3,
100 MHz): δ 13.8, 16.5, 16.6, 41.3 (d, JC/P = 153.75 Hz), 59.3 (d, JC/P = 11.7 Hz), 62.0, 65.8, 105.2,
123.0, 123.1, 125.9, 127.7, 127.8, 128.2, 128.3, 128.9, 129.6, 129.7, 131.3, 131.8, 132.1, 140.0, 141.8.
31P-NMR (CDCl3, 80.95 MHz): δ 21.21. HRMS (CI+): m/z calculated for C24H25ClNO3P [M + H]
441.1261; found for [M + H]+, m/z 442.1361.
3.6. General Procedure for the Preparation of 1,4,2-Oxazaphosphepines (15), (16), (17) and (18)
Under anhydrous conditions, the corresponding benzoxazine dissolved in dry dichloromethane was
treated with dichlorophenylphosphine followed by the slow addition of triethylamine, and the reaction
mixture was stirred at room temperature for 72 h. After this time, the solvent was evaporated under
reduced pressure, and the residue was treated with a minimum amount of water and extracted with ethyl
acetate. The combined organic layers were dried over anhydrous Na2SO4, evaporated under reduced
pressure, and the crude product was purified by column chromatography.
3.6.1. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (16a)
The benzoxazine (8a) 1.0 g (4.4 mmol) was reacted at room temperature with
dichlorophenylphosphine 0.78 g, 0.6 mL, (4.4 mmol) and triethylamine 0.89 g, 1.22 mL, (8.8 mmol) in
dichloromethane (25 mL). The solvent was evaporated under reduced pressure and the crude was
purified by column chromatography using a mixture of hexane:EtOAc (8:2), obtaining the compound
(16a) (110 mg, 7%) as a white solid, mp = 204–206 °C.
(2S)-2-Phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine 2-oxide (16a).
1
[α]D = +22.48° (c = 0.010, CHCl3). H-NMR (CDCl3, 400 MHz): δ 1.46 (d, J = 6.4 Hz, 3H), 3.51
(AB system, J = 15.2 Hz, 1H), 3.75 (ABX system, J = 15.2, 3.2 Hz, 1H), 3.81 (AB system, J = 14.4 Hz,
1H), 3.99 (dq, J = 7.0, 4.0 Hz, 1H), 4.09 (ABX system, J = 14.8, 1.6 Hz, 1H), 6.75–8.02 (m, 14H).
13C-NMR (CDCl3, 100 MHz): δ 21.7, 53.4 (d, JC/P = 89.5 Hz), 55.3, 61.3, 122.4 (d, JC/P = 3.0 Hz),
125.1, 127.4, 127.6, 128.6, 128.7, 128.8, 129.7, 130.7, 131.4, 131.5, 131.7, 133.0, 144.3, 150.1 (d,
31
JC/P = 6.1 Hz). P-NMR (CDCl3, 80.95 MHz): δ 34.87. HRMS (CI+): m/z calculated for C22H22NO2P
[M + H] 363.1388; found for [M + H]+, m/z 364.1454.

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3.6.2. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (15b) and (16b)
The benzoxazine (8b) 0.85 g (3.4 mmol) was reacted at room temperature with
dichlorophenylphosphine 0.6 g, 0.46 mL, (3.4 mmol) and triethylamine 0.68 g, 0.94 mL, (6.8 mmol) in
dichloromethane (25 mL). The solvent was evaporated under reduced pressure and the crude was
31
analyzed by P-NMR, observing the two diastereoisomers with a 48:52 ratio, which was purified by
column chromatography using a mixture of hexane:EtOAc (8:2), obtaining the compound (16b)
(190 mg, 15%) as a white solid mp = 168–172 °C. The compound (16b) was recrystallized from
dichloromethane-hexane to give a crystal for X-ray studies. The diastereoisomer (15b) was obtained as
unstable colorless oil (14 %) and only the 1H-NMR spectrum was obtained.
(2R)-2-Phenyl-(5S)-5-methyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (15b). [α]D = +36.17° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.48 (d, J = 6.8 Hz, 3H),
1.51 (d, J = 7.6 Hz, 3H), 3.58 (ABX system, J = 15.4, 10.6 Hz, 1H), 3.67 (ABX system, J = 15.8, 7.8 Hz,
1H), 4.22 (q, J = 6.8 Hz, 1H), 4.36 (q, J = 7.2 Hz, 1H), 6.90–7.84 (m, 14H).
(2S)-2-Phenyl-(5S)-5-methyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (16b). [α]D = +71.55° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.48 (d, J = 6.6 Hz, 3H),
1.58 (d, J = 7.0 Hz, 3H), 3.56 (AB system, J = 16 Hz, 1H), 3.67 (AB system, J = 16.4 Hz, 1H), 3.91
(q, J = 6.9 Hz, 1H), 4.04 (q, J = 6.5 Hz, 1H), 6.8–7.94 (m, 14H). 13C-NMR (CDCl3, 50 MHz): δ 20.5,
20.6, 45.1 (d, JC/P = 87.9 Hz), 60.2, 60.6, 123.6, 125.3, 127.0, 127.3, 128.4, 128.5, 128.8, 129.4, 131.1,
131.5 (d, JC/P = 9.1 Hz), 132.8, 135.2, 144.9, 148.7 (d, JC/P = 7.6 Hz). 31P-NMR (CDCl3, 161.8 MHz):
δ 37.23. HRMS (CI+): m/z calculated for C23H24NO2P [M + H] 377.1545; found for [M + H]+,
m/z 378.1612.
3.6.3. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (15c) and (16c)
The benzoxazine (8c) 0.30 g (0.9 mmol) was reacted at room temperature with
dichlorophenylphosphine 0.17 g, 0.13 mL, (0.9 mmol) and triethylamine 0.19 g, 0.26 mL, (1.9 mmol)
in dichloromethane (5 mL). The solvent was evaporated under reduced pressure and the crude product
was purified by column chromatography using a mixture of hexane:EtOAc (80:20) as eleuent, obtaining
the compounds (15c) as a colorless high viscosity oil (7%) and (16c) as a white solid (45%) mp =
166–172 °C.
(2R,S)-2-Phenyl-(5S)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (15c). [α]D = +88.4° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.29 (d, J = 6.8 Hz, 3H),
3.35 (ABX system, J = 16.4, 14.6 Hz, 1H), 3.49 (ABX system, J = 16.4, 6.4 Hz, 1H), 4.09 (dq, J = 6.8,
13
6.4 Hz, 1H), 5.29 (s, 1H), 6.70–7.59 (m, 19H). C-NMR (CDCl3, 50 MHz): δ 15.9, 29.8, 45.3 (d,
JC/P = 95.2), 60.0 (d, J = 7.3 Hz), 69.1, 123.6, 123.7, 125.8, 127.6, 127.7, 127.9, 128.5, 128.6, 128.7,
128.8, 129.4, 131.4, 131.5, 132.0, 132.8, 132.9, 142.4 (d, JC/P = 99.5 Hz). 31P-NMR (CDCl3,
161.8 MHz): δ 36.74. HRMS (CI+): m/z calculated for C23H24NO2P [M + H] 439.1701; found for
[M + H]+, m/z 440.1774.

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(2R,S)-2-Phenyl-(5S)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (16c). (0.19 g, 45%) [α]D = +146.78° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 200 MHz): δ 1.56
(d, J = 6.4 Hz, 3H), 3.40 (AB system, J = 16.4 Hz, 1H), 3.58 (AB system, J = 16.4 Hz, 1H), 4.14 (q,
13
J = 6.0 Hz, 1H), 5.05 (s, 1H), 7.12–7.57 (m, 19H). C-NMR (CDCl3, 50 MHz): δ 21.3, 20.6, 45.9
(d, JC/P = 84.9 Hz), 60.3, 68.5, 123.9, 125.6, 127.4, 127.5, 127.6, 128.2, 128.6, 128.7, 130.2, 131.3,
131.4, 132.7, 132.9, 149.22. 31P-NMR (CDCl3, 161.8 MHz): δ 32.57. HRMS (CI+): m/z calculated for
C23H24NO2P [M + H] 439.1701; found for [M + H]+, m/z 440.1783.
3.6.4. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (15d) and (16d)
The benzoxazine (8d) 1.0 g (2.9 mmol) was reated at room temperature with
dichlorophenylphosphine 0.5 g, 0.39 mL, (2.9 mmol) and triethylamine 0.57 g, 0.80 mL, (5.7 mmol) in
dichloromethane (15 mL). The solvent was evaporated under reduced pressure and the crude product
was purified by column chromatography using a mixture of hexane:EtOAc (80:20) as eluent, obtaining
the compounds (15d) (50 mg, 4%) as an orange solid, mp = 65–68 °C and (16d) (50 mg, 4%) as
a white solid mp = 220–224 °C with a diastereoisomeric ratio 50:50.
(2R)-2-Phenyl-(5R)-5-(2-chlorophenyl)-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-
1
benzoxazaphosphepine 2-oxide (15d). [α]D = +116.74° (c = 0.0036, CHCl3). H-NMR (CDCl3,
200 MHz): δ 1.44 (d, J = 7.0 Hz, 3H), 3.15 (ABX system, J = 15.2, 15.2 Hz, 1H), 3.43 (ABX system,
13
J = 16.1, 9.9 Hz, 1H), 4.02 (q, J = 6.6 Hz, 1H), 5.90 (s, 1H), 6.70–8.54 (m, 18H). C-NMR (CDCl3,
50 MHz): δ 12.6, 43.7 (d, JC/P = 104.9 Hz), 59.5, 65.5, 124.2, 126.0, 127.7, 128.0, 128.3, 128.5, 128.9,
31
129.3, 131.7, 131.9, 132.7, 141.2, 148.3. P-NMR (CDCl3, 81 MHz): δ 38.60. HRMS (CI+): m/z
calculated for C28H25ClNO2P [M + H] 473.1311; found for [M + H]+, m/z 474.1437.
(2S)-2-Phenyl-(5R)-5-(2-chlorophenyl)-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-
1
benzoxazaphosphepine 2-oxide (16d). [α]D = +223.83° (c = 0.0072, CHCl3). H-NMR (CDCl3,
400 MHz): δ 1.54 (d, J = 6.8 Hz, 3H), 3.37 (ABX system, J = 16.0, 6.4 Hz, 1H), 3.42 (ABX system,
13
J = 16.0, 8.4 Hz, 1H), 3.93 (bs, 1H), 5.85 (s, 1H), 6.94–8.11 (m, 18H). C-NMR (CDCl3, 50 MHz):
δ 11.4, 44.0 (d, JC/P = 107.9 Hz), 58.8, 66.9, 124.7, 126.3, 127.3, 127.7, 127.9, 128.1, 128.3, 128.5,
129.0, 129.8, 130.0, 130.7, 131.2, 131.4, 132.1, 132.4, 133.3, 140.9, 147.2. 31P-NMR (CDCl3,
81 MHz): δ 42.36. HRMS (CI+): m/z calculated for C28H25ClNO2P [M + H] 473.1311; found for
[M + H]+, m/z 474.1390.
3.6.5. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (17c) and (18c)
The benzoxazine (9c) 0.25 g (0.8 mmol) was reacted at room temperature with
dichlorophenylphosphine 0.14 g, 0.10 mL, (0.8 mmol) and triethylamine 0.16 g, 0.22 mL, (1.6 mmol)
in dichloromethane (5 mL). The solvent was evaporated under reduced pressure and the crude product
was purified by column chromatography using a mixture of hexane:EtOAc (80:20) as eluent, obtaining
the compounds (17c) (18 mg, 5%) as a white solid mp = 60–65 °C, and (18c) which is unstable in
solution, (60 mg, 17%) as a white solid mp = 193–195 °C.

Molecules 2015, 20
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(2S)-2-Phenyl-(5R)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
1
2-oxide (17c). H-NMR (CDCl3, 200 MHz): δ 1.30 (d, J = 6.6 Hz, 3H), 3.36 (ABX system, J = 16.0,
12.2 Hz, 1H), 3.52 (ABX system, J = 16.1, 5.1 Hz, 1H), 4.11 (dq, J = 7.0, 2.2 Hz, 1H), 5.30 (s, 1H),
13
6.91–7.63 (m, 19H). C-NMR (CDCl3, 50 MHz): δ 15.9, 45.3 (d, JC/P = 95.5 Hz), 59.9, 69.1, 123.5,
31
125.7, 127.6, 127.8, 128.4, 128.6, 128.6, 129.3, 131.3, 131.5, 132.0, 132.7, 141.8, 142.7. P-NMR
(CDCl3, 80.95 MHz): δ 36.7. HRMS (CI+): m/z calculated for C23H24NO2P [M] 439.1701; found for
[M + H]+, m/z 439.1772.
(2R)-2-Phenyl-(5R)-5-phenyl-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-benzoxazaphosphepine
2-oxide (18c). [α]D = −95.35° (c = 0.010, CHCl3). 1H-NMR (CDCl3, 400 MHz): δ 1.20 (d, J = 6.6 Hz, 3H),
3.04 (ABX system, J = 16.1, 4.7 Hz, 1H), 3.48 (ABX system, J = 16.1, 3.7 Hz, 1H), 4.16 (q, J = 7.0 Hz,
13
1H), 5.35 (s, 1H), 7.14–7.86 (m, 19H). C-NMR (CDCl3, 50 MHz): δ 21.3, 46.1 (d, JC/P = 98.7 Hz),
60.3, 69.7, 124.3, 126.1, 127.7, 127.8, 128.2, 128.5, 128.6, 128.9, 130.2, 131.9, 132.0, 132.1, 133.0,
31
142.3, 148.0. P-NMR (CDCl3, 161.8 MHz): δ 37.84. HRMS (CI+): m/z calculated for C23H24NO2P
[M] 439.1701; found for [M + H]+, m/z 439.1639.
3.6.6. Synthesis of 1,4,2-Oxazaphosphepine 2-oxide (17d) and (18d)
The benzoxazine (9d) 300 mg (0.9 mmol) was reacted at room temperature with
dichlorophenylphosphine 150 mg, 0.11 mL, (0.85 mmol) and triethylamine 170 mg, 0.24 mL,
(1.7 mmol) in dichloromethane (10 mL). The solvent was evaporated under reduced pressure and the
crude product was purified by column chromatography using a mixture of hexane:EtOAc (80:20) as
eluent, obtaining (430 mg, 9%) of diastereoisomeric mixture as high viscosity oil, the two compounds
1
were identified by H- and 31P-NMR with a 16:84 diastereoisomeric ratio, which the separation
was not possible.
(2R,S)-2-Phenyl-(5S)-5-(2-chlorophenyl)-4-[(1ʹS)-1-phenylethyl]-2,3,4,5-tetrahydro-1,4,2-
benzoxazaphosphepine 2-oxide (17d) and (18d). The asterisk denotes the minor diastereoisomer.
1H-NMR (CDCl3, 200 MHz): δ 1.06* (d, J = 7.0 Hz, 3H), 1.49 (d, J = 7.0 Hz, 3H), 2.99*
(ABX system, J = 16.2, 4.2 Hz, 1H), 3.25 (ABX system, J = 16.3, 5.8 Hz, 1H), 3.42* (ABX system,
J = 16.4, 5.4 Hz, 1H), 3.56 (ABX system, J = 16.5, 4.4 Hz, 1H), 3.96* (q, J = 6.9 Hz, 1H), 3.97 (q,
J = 6.9 Hz, 1H), 5.76* (s, 1H), 5.85 (s, 1H), 6.72–8.45 (m, 36H). 31P-NMR (CDCl3, 81 MHz):
δ 40.35*, 41.51. HRMS (FAB+): m/z calculated for C28H25ClNO2P [M + H] 473.1311; found for
[M + H]+, m/z 474.1389.
4. Conclusions
In conclusion, we have developed a method for the diastereoisomeric synthesis of
1,4,2-oxazaphosphephines by nucleophilic addition of dichlorophenylphosphine or trimethyl phosphite
to chiral 1,3-benzoxazines, which were easily prepared from chiral o-aminophenols. The X-ray
analysis shows that these heterocycles adopt a chair and boat conformation. Additionally, these
compounds represent an opportunity for more detailed studies and applications.

Molecules 2015, 20
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Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/08/13794/s1.
Acknowledgments
The authors thank CONACyT of México, for their financial support via Projects 181816 and
Laboratorio Nacional de Estructura de Macromoléculas (LANEM, CONACyT 251613). We thank to
P. Román-Bravo and V. Labastida-Galván for the determination of the X-ray structure and HRMS.
O. S. E. also thank CONACYT for a Graduate Scholarship.
Author Contributions
I.L.-E. and M.O., designed research and wrote de paper; O.S.-E. and L.C.-H. made the synthesis of
the compounds, B.E.D.-M. measured and analyzed the NMR spectra. All authors read and approved
the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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26. Crystal data for C22H20ClNO (S,S)-9d. Mr = 349.84 g·mol−1, 0.47 × 0.36 × 0.17 mm3, orthorhombic,
space group P2(1)2(1)2(1), a = 7.3447(9) Å, b = 8.2949(11) Å, c = 29.909(4) Å, α = 90°, β = 90°,
γ = 90°, V = 1822.2(4) Å3. Z = 4, ρ = 1.275 g·cm−3, θmax = 24.99°, 3202 independent reflections,
R1 = 0.0639 with I > 2 σ(I), wR2 = 0.1661 for all data, 227 parameters. (CCDC 1048109, the data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html).
27. Franzen, V.; Joschek, H.I.; Mertz, C. Untersuchungen über Carbene, IX. Carbene aus
Sulfoniumsalzen. Chem. Ber. 1961, 94, 2942–2950.
28. Griffin, C.E.; Mitchell, T.D. Phosphonic Acids and Esters. IX. Thermal Reactions of Trialkyl
Phosphites with Nonactivated Acetylenes. J. Org. Chem. 1965, 30, 1935–1939.
29. Crystal data for C24H26NO3P (2R,5S,4ʹS)-13c. Mr = 407.43 g·mol−1, 0.43 × 0.32 × 0.23 mm3,
monoclinic, space group P2(1), a = 9.7938(11) Å, b = 9.3756(10) Å, c = 11.3313(13) Å, α = 90°,
β = 94.193(2)°, γ = 90°, V = 1037.7(2) Å3. Z = 2, ρ = 1.304 g·cm−3, θmax = 25°, 3662 independent
reflections, R1 = 0.0265 with I > 2 σ(I), wR2 = 0.0682 for all data, 264 parameters. (CCDC 1048111).
30. Crystal data for C22H22NO2P (2S,1ʹS)-16a. Mr = 363.38 g·mol−1, 0.49 × 0.16 × 0.07 mm3,
orthorhombic, space group P2(1)2(1)2(1), a = 5.6501(8) Å, b = 15.203(2) Å, c = 21.959(3) Å,
α = 90°, β = 90º, γ = 90°, V = 1886.3(5) Å3. Z = 4, ρ = 1.280 g·cm−3, θmax = 24.99°, 3327
independent reflections, R1 = 0.0434 with I > 2 σ(I), wR2 = 0.0973 for all data, 236 parameters.
(CCDC 1048108).
31. Crystal data for C23H24NO2P (2S,5R,1ʹS)-16 b. Mr = 377.40 g·mol−1, orthorhombic, space group
P2(1)2(1)2(1), a = 6.2631(9) Å, b = 14.995(2) Å, c = 21.591(3) Å, α = 90°, β = 90º, γ = 90°,
V = 2027.7(5) Å3. Z = 4, ρ = 1.236 g·cm−3, θmax = 25.0°, 3575 independent reflections, R1 = 0.0449
with I > 2 σ(I), wR2 = 0.1076 for all data, 246 parameters. (CCDC 1049455).
32. Crystal data for C28H26NO2P (2R,5R,1ʹS)-18c. Mr = 439.47 g·mol−1, 0.49 × 0.37 × 0.25 mm3,
orthorhombic, space group P2(1)2(1)2(1), a = 8.0683(10) Å, b = 8.4445(11) Å, c = 34.421(4) Å,
α = 90°, β = 90º, γ = 90°, V = 2345.2(5) Å3. Z = 4, ρ = 1.245 g·cm−3, θmax = 25.0°,
4125 independent reflections, R1 = 0.0591 with I > 2 σ(I), wR2 = 0.1318 for all data, 290
parameters. (CCDC 1048107).
1
33. Crystal data for C28H25ClNO2P (2S,5R,1′S)-15d. Mr = 473.91 g·mol− , 0.41 × 0.32 × 0.23 mm3,
monoclinic, space group P2(1), a = 8.9832(13) Å, b = 10.3750(16) Å, c = 13.492(2) Å, α = 90°,
3
β = 108.333(3)º, γ = 90°, V = 1193.7(3) Å3. Z = 2, ρ = 1.319 g·cm− , θmax = 25.0°, 4212
independent reflections, R1 = 0.0571 with I > 2 σ(I), wR2 = 0.1383 for all data, 299 parameters.
(CCDC 1048110).
34. For 18c and 15d, the phenyl group joined to phosphorus atom has been deleted for a major
appreciation of the conformation.
Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).