One-pot synthesis of new 6-(alkylamine)dibenzo[c,e][1,2]oxaphosphinine-6-oxides

Article abstract of DOI:10.1080/00397911.2016.1265651

Several new 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides were prepared through a one-pot reaction, starting with 2-phenylphenol, phosphorus trichloride, and a Zn catalyst, to form 6-chloro-6H-dibenz[c,e][1,2]oxaphosphine. The alkylamine derivatives were subsequently prepared through a nucleophilic substitution reaction involving aliphatic amines and H₂O₂oxidation under soft conditions. This method has the advantages that it is a one-pot synthesis, does not require an inert atmosphere, and involves in situ catalyst formation.

Full text of DOI:10.1080/00397911.2016.1265651

One-Pot Synthesis of New 6-(Alkylamine)Dibenzo[c,e][1,2]Oxaphosphinine-6-
Oxides
Ávila-Zárraga, José Gustavo1,, Pérez, Ignacio1, Beristain, Erick1, Gavilan, Irma1, Moises
Romero2
1Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán, México,
D. F., México2Facultad de Química, Universidad del Estado de México, PaseoColón,
Paseo, Tollocan
Corresponding author Ávila-Zárraga, José Gustavo E-mail: gavila@unam.mx
Abstract
Several new 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides were prepared
via a one-pot reaction, starting with 2-phenylphenol, phosphorus trichloride, and a Zn
catalyst, to form 6-chloro-6H-dibenz[c,e][1,2]oxaphosphine. The alkylamine derivatives
were subsequently prepared via a Nucleophilic Substitution (SN) reaction involving
aliphatic amines and H2O2 oxidation under soft conditions. This method has the
advantages that it is a one-pot synthesis, does not require an inert atmosphere, and
involves in-situ catalyst formation.
Graphical Abstract
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KEYWORDS: oxaphosphine oxides, one-pot synthesis, alkylamine, in-situ catalyst
Introduction
Derivatives of 6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides are of great interest due to
their potential applications as flame retardants in polymer systems.[1–3] Among these
compounds, the 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides are of
particular interest on account of their low toxicity compared with polyhalogenated
compounds used as flame retardants.[4] Despite the interesting properties of 6H-
dibenz[c,e][1,2]oxaphosphinine-6-oxides, only a few methods for synthesizing these
compounds have been reported in the literature.[5–7] One synthesis starts with 6-chloro-
dibenzo[c.e][1,2]oxaphosphorine (CDOP)[5,6] and, after two steps, the 6-diethylamino-
dibenz[c,e][1,2]oxaphosphinine-6-oxide is obtained in good yield; the disadvantage of
this method is that a series of steps are required to prepare the CDOP starting materials.
Another method starts from 6H-dibenz[c,e][1,2]oxaphosphinine-6-oxide (DOPO),[7]
which is commercially available. This method uses the Atherton-Todd reaction[8] and
offers good results; however it has not been extensively explored. Here we describe the
first one-pot synthesis of 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides,
starting from the commercially available and inexpensive compound, 2-phenylphenol.
RESULTS AND DISCUSSION
Taking into account that CDOP and DOPO (the starting materials for the previously
reported syntheses of our target compounds) can be obtained from 2-phenylphenol, we
considered the possibility of obtaining the 6-(alkylamine)-6H-
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dibenz[c,e][1,2]oxaphosphinine-6-oxides 2 (Scheme 1) in a one-pot process from 2-
phenylphenol 1. In our first attempt at this synthesis, 2-phenylphenol was first reacted
with PCl3 at 50°C[5] without solvent. After 3 h, 40 mol % of ZnCl2 was added and the
temperature was increased to 150°C and the mixture was stirred for 2 h. Then, the
solution was cooled to R.T. and a solution of diethylamine in toluene was added and the
mixture was stirred for 3 h. The solution was then cooled to 0°C, hydrogen peroxide was
added, and the solution was stirred for 1 h. After workup and flash chromatography, the
product 2 was obtained in 12% yield. In an effort to improve the yield, we applied the
same procedure but with a higher temperature for the first two steps (100 and 180°C
respectively); this new protocol resulted in a 52% yield after purification. Next we
examined the effect of adding the ZnCl2 at the first step in order to keep the flask closed
throughout all steps in the synthesis; this change increased the yield to 57%. Finally, we
found that replacing the ZnCl2 with a 30% mol of Zn precluded the need for a constant
flux of nitrogen to evacuate the hydrogen chloride that formed during the reaction, as
hydrogen chloride reacts with zinc to form the ZnCl2 catalyst in situ; this change did not
affect the results.
Having determined the best methodology, we sought to synthesize various 6-
(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides (2) by changing diethylamine
to other primary and secondary aliphatic amines; the results are presented in Figure 1.
The use of secondary cyclic amines allowed us to obtain the desired product in 48–54%
yield (2b-2d). The steric effect of diisopropylamine was reflected in a decreased yield of
41% (2e), which was lower than that obtained with isopropylamine (47%, 2f) or
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butylamine (49%, 2g). Use of cyclohexylamine also caused a decrease in the yield (43%,
2h), whereas cyclopropylamine afforded the best yield (69%, 2i). Finally, the reaction
was successful even with (S)-methylbenzylamine (41, 2j). We believe that the key step is
the nucleophilic substitution of the chloride in the CDOP intermediate by the amine,
because the oxidation of the CDOP without the addition of the nucleophile affords DOPO
in 85% yield after purification. In all cases we obtained 6-(biphenyl-2-yloxy)-6H-
dibenz[c,e][1,2]oxaphosphinine-6-oxide 3 as a by-product in 7% yield; this species is
formed by the SN of 2-phenylphenol in CDOP and subsequent oxidation.
In conclusion, we have developed a straightforward one-pot method for synthesizing 6-
(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides (2). We used the proposed
method to obtain six new compounds in good yield, and demonstrated that it is a general
method for obtaining primary and secondary alkylamine derivatives.
EXPERIMENTAL
All chemicals were purchased from commercial sources and were used without
purification. Solvents were purified using standard laboratory techniques. Infrared spectra
were recorded on a Perkin Elmer Spectrum RX1 spectrometer. 1H, 13C and 31P NMR
were performed on a Varian Unity Inova 300 spectrometer at 300, 75 and 120 MHz in
CDCl3 using TMS as an internal standard. Mass spectra were recorded on a Leco
Pegasus 4D in positive ESI mode.
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General procedure for the synthesis of 6-(alkylamine)-6H-
dibenz[c,e][1,2]oxaphosphinine-6-oxides 2.
1.3 mmol of 2-phenylphenol and 25 mg of Zn (30% mol) were placed in a flask with a
magnetic stirrer under an inert atmosphere, and then 1.4 mmol of phosphorus trichloride
was added via a cannula. The reaction mixture was heated at 100°C for 4 h with stirring,
after which the temperature was raised to 180°C and the stirring was continued for 3 h.
The reaction mixture was then cooled to R.T. and a solution of 1.9 mmol of the aliphatic
amine in 10 mL of toluene was added via a cannula, and the mixture was stirred 3 h.
After this period the reaction was cooled to 0°C and 0.4 mL of 30% hydrogen peroxide
solution was added dropwise and the mixture was stirred for 1 h. The mixture was then
extracted with brine (3 x 5 mL) and the organic phase was dried with anhydrous sodium
sulfate and filtered, after which the solvent was evaporated. The crude product was
purified by flash chromatography using Hex/AcOEt (1:1).
6-(Pyrrolidin-1-Yl)-6H-Dibenzo[C,E][1,2]Oxaphosphinine 6-Oxide (2b).
31P NMR (120 MHz, CDCl3) δ: 13.0. 1H NMR (300 MHz, CDCl3) δ: 1.86 – 1.91 (q. J=
3.2 Hz, 4H), 3.16 – 3.33 (m, 4H) 7.20 – 8.02 (m, 8H). 13C NMR (75 MHz, CDCl3) δ:
150 .4 (d, J= 7.4 Hz), 137.1 (d, J=7.0 Hz), 132.6 (d, J= 2.4 Hz), 130.2 (s), 129.74 (d, J=
9.1 Hz), 128.2 (d, J= 14.4 Hz), 124.9 (d, J= 1.0 Hz), 124.6 (d, 164.1 Hz), 124.1 (s), 123.7
(d, J= 11.3 Hz), 122.1 (d, J= 11.6 Hz), 120.5 (d, J= 6.3 Hz), 46.8 (d, J= 4.9 Hz), 26.5 (d,
J= 8.7 Hz). HRMS (ESI+): m/z calcd for C16H16NO2P [M+]:285.0919, found: 285.0897.
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SUPLEMENTARY DATA
Full experimental detail, 1H, 13C and HRMS data for the new compounds can be found
via the ‘‘Supplementary Content’’ section of this article’s webpage.
ACKNOWLEDGEMENTS
We thank to the PAIP-5000:9060 program of Faculty of Chemistry at UNAM, E. B. is
grateful to CONACYT (387012) for a postgraduate scholarship. I. P. is grateful to
DGAPA-UNAM for a postdoctoral fellowship. We are grateful to Adrián Vázquez,
Georgina Duarte, Margarita Guzmán, Rosa I. del Villar, Maricela Gutiérrez for their
assistance in acquiring spectral data.
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Scheme 1. One-pot synthesis of 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-
oxides 2.
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Figure 1. 6-(alkylamine)-6H-dibenz[c,e][1,2]oxaphosphinine-6-oxides 2 obtained. 2a, 2c,
2g and 2j,(6, 8) were previously reported, all other compounds are new.
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