Stereoselective synthesis of phosphoryl derivatives

Article abstract of DOI:10.1080/10426500802591655

The reaction of dialkylphosphonites with N-(bromomethyl)phthalimide furnishes alkyl phenyl hydrogenphosphinates, dialkyl phenylphosphonates, and N-[(bromomethyl)phthalimido)]-phosphinates. The stereoselectivity of the primary product of the reaction appea

Full text of DOI:10.1080/10426500802591655

Phosphorus, Sulfur, and Silicon, 184:2902–2909, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802591655
Stereoselective Synthesis of Phosphoryl Derivatives
H. D. Durst,1 D. K. Rohrbaugh,1 and S. Munavalli2
1U.S. Army, Edgewood Chemical Biological Center, Aberdeen Proving
Ground, Maryland, USA
2SAIC, Gunpowder Branch, Aberdeen Proving Ground, Maryland, USA
The reaction of dialkylphosphonites with N-(bromomethyl)phthalimide fur-
nishes alkyl phenyl hydrogenphosphinates, dialkyl phenylphosphonates, and N-
[(bromomethyl)phthalimido)]-phosphinates. The stereoselectivity of the primary
product of the reaction appears to increase with the increasing size of the groups
attached to the phosphorus atom.
Keywords Alkylphosphinates; dialkylphosphites; mass spectral characterization;
Michaelis–Arbuzov reaction; stereoselectivity
INTRODUCTION
In connection with another ongoing project dealing with the synthe-
sis of biologically active chiral phosphorus compounds, the reaction of
dialkylphosphonites with N-(bromomethyl)phthalimide was examined
and the mass spectral characterization of the compounds formed during
the course of the reaction, are presented in this article. In this context,
it should be stated that the reaction of N-(bromomethyl)phthalimide
with trialkylphosphites has been previously employed in the prepara-
tion of novel antibiotics and other synthetically useful reagents.1
The classical Michaelis–Arbuzov reaction permits the transforma-
tion of tervalent P-compounds into pentavalent compounds containing
the P=O (phosphoryl) moiety via the decomposition of the phospho-
nium salt intermediate formed from the nucleophilic attack by the
phosphorus atom.2,3 The attack by the tervalent P has been described
to follow the mechanism of the SN2 process.4 The mechanism of the re-
action with cyclic tervalent phosphorus compounds, in particular, has
attracted a great deal of interest.4 The transformation of the five- and
six-membered cyclic phosphonites into phosphonates has been stated
Received 14 May 2008; accepted 16 October 2008.
Address correspondence to S. Munavalli, SAIC, P.O. Box 68, Gunpowder Branch,
Aberdeen Proving Ground, MD 21010, USA. E-mail: shekar.munavalli@yahoo.com
2902

Stereoselective Synthesis of Phosphoryl Derivatives
2903
to follow a highly stereospecific course.5a–5d This has been found to be
true even in the free radical–catalyzed Michaelis–Arbuzov reaction.5d
Thus, a stereochemical approach has been employed to delineate the
reaction pathways.6,7
RESULTS AND DISCUSSION
Dimethyl phenylphosphonite (1) was subjected to the Michaelis–
Arbuzov reaction in the presence of N-(bromomethyl)phthalimide (2)
at 115–120◦C for 4 h. After cooling the reaction mixture to room tem-
perature, the volatile alkyl halide formed during the course of the re-
action was removed under house vacuum. The residue solidified after
being kept overnight in the refrigerator. The GC-MS analysis of the re-
action mixture showed the presence of eight components, two of which
were the staring materials, namely 1 and 2 (Scheme 1). There is noth-
ing new about the formation of phenyl hydrogenphosphinate (3) and
dimethylphenylphosphonate (4) from 1.2g Component 5 was identified
as N-(methoxymethyl)phthalimide. Its formation apparently involves
the displacement of the halogen of N-(bromomethyl)phthalimide (2) by
the methoxyl group, which itself is formed during the course of the
Michaelis–Arbuzov reaction. This inference is supported by previous
observations.8 Compound 6 is present in trace amounts and could not
be completely identified, as it undergoes extensive disintegration in the
mass spectrometer before its molecular ion peak is registered. As evi-
denced by the presence of the most prominent peak (m/e = 160) in its
mass spectrum, this compound carries the phthalimodomthylene moi-
ety in its structure. Methyl (phthalimidomethyl) phenylphosphinate
SCHEME 1 Reaction of dimethyl phenylphosphonite.

2904
H. D. Durst et al.
TABLE I Mass Spectral Fragmentation of Compounds Cited in
Scheme 1
1. Hydrogen methyl phenylphosphinate (3): M+ = 156 (r.t. = 7.22 min, 2.1%) 155 (M-H,
99%); 141 (M-CH3); 126 (M-OCH3); 91 (C7H7); 79 (M-C6H5, 100%); 77 (C6H5); 65
(PH2O3) and 51 (C4H3).
2. Dimethyl phenyphosphinate (1): M+ = 170 (r.t. = 7.54 min, 12.8%); 169 (M-H); 155
(M-CH3,100%); 140 (M-OCH2); 125 [C6H5P(O)H]; 77 (C6H5); 63 (PO3) and 51
(C4H3).
3. Dimethyl phenyphosphonate (4): M+ = 186 (r.t. = 7.60 min, 2.0%); 185 (M-H, 97%);
169 (185-2H-CH3); 155 (M-OCH3); 141 (M OCH2-CH3); 125 [C6H5P(O)H]; 109
(M-C6H5); 91 (C7H7, 98%); 77(C6H5, 100%); 63 (PO3) and 51 (C4H3).
4. N-Methoxymethyl)phthalimide (5): M+ = 191 (not seen, r.t. = 9.48.min, 1.0%); 190
(M-H); 176(191-CH3); 160 (M-OCH3); 148 (M-OC2H3); 133 (148-NH); 117 (133-O);
104 (C6H4CO); 77(C6H5, 100%); and 51 (C4H3).
5. Unknowm (6): M+ = (not seen recorded); (r.t. = 9.97.min, 02%). This is a
phthalimide derivative.The wavy line represents the unknown part of the molecule.
6. N-(Bromomthyl)phthalimide (2): M+ = 279 (r.t. = 10..46.min,2.5%); 160 (M-HBr,
100%); 133[C6H4(CHO)(CO)]; 104 (C6H4CO); 76 (C6H4); 56 (CONCH3) and 44
(CONH2).
7. Methyl (phthalimidomethyl) phenylphosphinate (7): M+ = 315 (r.t. =
16.09.min,76.09%); 300 (M-CH3); 237 (M-C6H5-2H); 219 (237-H2O); 189
(219-OCH2); 160 (M-C6H4(CO)2NCH2, 100%);133 [C6H4(CHO)(CO)]; 104
[C6H4(CO)]; 91 (C7H); 77 (C6H5); 65 (PH2O3) and 51 (C4H3).
8. Methyl (phthalimidomethyl) phenylphosphinate (8): M+ = 315 (r.t. =
16..38.min,2.5%); 300 (M-CH3); 237 (M-C6H5-2H); 219 (237-H2O); 189 (219-OCH2);
160 (M-C6H4(CO)2NCH2, 100%);133 [C6H4(CHO)(CO)]; 104 [C6H4(CO)]; 91 (C7H);
77 (C6H5); 65 (PH2O3) and 51 (C4H3).
(7) turned out to be the major product of the reaction (76.9%). It is
interesting to note the characterization of its diastereomer, 8, which is
present in small amounts (2.5%). This may be due to the steric influ-
ence of the phenyl moiety. The mass spectral fragmentation data of the
above-mentioned compounds are given in Table I.
This reaction was repeated but with one difference: the substrate
1 was substituted with diethyl phenylphosphite (9) in the reaction.
In this case, the reaction product, a viscous, oily material, was found
to contain six components, namely diethyl phenylphosphite (9), ethyl
phenyl hydrogenphosphinate (10), diethyl phenylphosphonate (11),
an unknown compound (12), N-(bromomethyl)phthalimide (2), and
ethyl (phthalimidomethyl) phenylphosphinate (13) (Scheme 2). Here
again, the unknown compound contains the (phthalimidomethyl) moi-
ety. This compound degrades extensively before its molecular ion peak
is recorded. Compound 13 was the desired product, which formed about
88.2% of the reaction mixture. Table II furnishes the details of the
characterization of the compounds using their GC-MS breakdown

Stereoselective Synthesis of Phosphoryl Derivatives
2905
SCHEME 2 Reaction of diethyl phenylphosphonite.
behavior. Next, di-isopropyl phenyl-phosphonite (14) was used as
the substrate. This reaction was found to be the cleanest of
the three reactions, for only trace amounts of two impurities ac-
companied the expected compound, namely isopropyl (phthalim-
idomethyl)phenylphosphinate (17), and its yield was almost quanti-
tative (98.9%). The two compounds in question are: (i) isopropyl phenyl
hydrogenphosphinate (15) and (ii) di-isopropyl phenylphosphonate (16)
(cf. Scheme 3). Table II furnishes the details regarding the mass spec-
tral fragmentation behavior of the compounds cited above.
In the three reactions described above, the presence of the alkyl
phenyl hydrogenphosphinates, namely 3, 10, and 15, was detected. This
observation suggests that during the course of the reaction, OCH2-,
OC2H4-, and OC3H6- fragments are expelled from their precursor moi-
eties. There are precedents for this inference.8a,9
Also, characterized were the respective phosphonates 4, 11, and 16,
which obviously arise from the oxidation reactions. Again, there are
precedents for this suggestion.8,10,11 It is interesting to note the in-
creasing yields of the expected Michaelis–Arbuzov reaction products
with the increasing size of the groups attached to the phosphorus atom
of the substrates. The third reaction appears to be highly stereoselec-
tive, in that it furnishes 98.9% of the desired product. Only in the case
SCHEME 3 Reaction of diiisopropyl phenylphosphonite.

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H. D. Durst et al.
TABLE II Mass Spectral Fragmentation of Compounds Cited in
Schemes 2 and 3
1. Diethyl phenylphosphonite (9): M+ = 198(r. t. = 8.24 min, 2.3%); 170 (M-C2H4); 141
(C6H5P(O)OH,100%);125 [C6H5PH(O)]; 93[P(O)OC2H5]; 77 (C6H5); 51 (C4H3) and
43 (OC2H3).
2. Hydrogen ethyl phenylphosphinate (10): M+ = 170 (r. t. = 7.42 min, 4.2%); 169
(M-H); 142 (M-C2H4); 125(142-OH, 100%); 91 (C7H7 or P(OH)(OC2H5); 78
([P(O)(OCH3]. 77 (C6H5); 65 (PH2O2); 51 (C4H3) and 43(OC2H3).
3. Diethyl phenylphosphonate (11): M+ = 214 (r. t. = 8.12 min, 3.1%); 186 (M-C2H4);
158 [C6H5P(O)(OH)2,100%]; 141 (158-OH, 98%); 124 [C6H5P(O)]); 94
[P(O)H2(OC2H5); 77 (C6H5); 65 (PH2O2); 51 (C4H3) and 43(OC2H3).
4. Unknown (12): M+ = not known (r. t. = 9.61 min, 3.5%); has a phthalimido moiey.
5. Ethyl (phthalimidomethyl)phenylphosphonate (13): M+ = 329 (r. t. = 15.84 min,
88.2%); 284 (M-OC2H5); 237(M-C6H5-CH3); 219 (238-H2O); 189(219-OCH2); 160
(M-P(O)(OC2H5)); 141 [C6H5P(O)(OH), 100%[;104 (C6H5CO); 91 (P(OH)(OC2H5); 77
(C6H5) and 51 (C4H3).
6. Hydrogen isopropyl phenylphosphinate (15): M+ = 184 (r. t. = 8.53min, 1.1%); 183
(M-H); 169 (M-CH3);143 (M-C3H5100%); 125 [C6H5P(O)OH]; 78 ([P(O)(OCH3]. 77
(C6H5) and 65 (PH2O2).
7. Diisopropyl phenylphosphonate (16): M+ = 242 (r. t. = 9.23min, 0.9%); 227 (M-CH3);
201 (M-C3H5); 183 (201 -H2O); 159 (201-C3H6,: 100%);, 141 [C6H5P(O)(OH)], 119
[CH3P(O) (OC3H7)]; 84 (201-OC3H5); 77 (C6H5) and 59(OC3H7).
8. Isopropyl (phthalimidomethyl)phenylphosphinate (17): M+ = 343 (r. t. = 19..01
min,98.9%); 301 (M-C3H6);284(301-OH); 237 [C7H5N(COP(O)(OC3H7)]; 219
(237-H2O); 183 (C6H5 P(O)(OC3H7); 160 (M-P(O)(OC3H7);141 [C6H5P(O)(OH),
100%); 104 (C6H5CO); 91 (P(OH)(OC2H5); 77 (C6H5) and 65 (PH2O2).
of dimethyl phenylphosphonite (1) was the presence of the diastere-
omer (8) of the expected product (7) detected. Attempts are underway
to transform these compounds, namely phthalimidophosphinates (7,
13, and 17), into bioactive phosphorus-containing compounds.
In summary, the yields of the products of the reaction of N-
(bromomethyl)phthalimide (2) with dimethyl phenylphosphonite (1),
diethyl phenylphosphonite (9), and diisopropyl phenylphosphonite (14)
are 76.8%, 88.2%, and 98.9% respectively (cf. Figure 1). This clearly
implies the importance of the steric bulk of the alkoxy group attached
to the phosphorus atom.
FIGURE 1 Percentage of yields of the products.

Stereoselective Synthesis of Phosphoryl Derivatives
2907
EXPERIMENTAL
All solvents were dry and freshly distilled prior to use. Mass spectra
were obtained using a Finnigan TSQ-7000 GC/MS/MS equipped with
a 30 m × 0.25 mm, i.d. DB-5 capillary column (J and W Scientific,
Folsom, CA) or a Finnigan 5100 GC/MS equipped with a 15 m × 0.25
mm, i.d. Rtx-5 capillary column (Restek, Bellefonte, PA). The conditions
on the 5100 were oven temperature 60–270◦C at 10◦C/min, injection
temperature was 210◦C, interface temperature 230◦C, electron energy
70 eV, emission current 500 µA, and scan time 1 sec. The conditions on
the TSQ-7000 were oven temperature 60–270◦C at 15◦C/min, injection
temperature 220◦C, interface temperature 250◦C, source temperature
150◦C, electron energy 70 eV (EI) or 200 eV (CI), emission current
400 µA (EI) or 300 µA (CI), and scan time 0.7 sec. Data were obtained
in both the electron ionization mode (range 45–450 da) and chemical
ionization mode (mass range 60–450 da). Ultrahigh purity methane
was used as the CI agent gas with a source pressure of 0.5 Torr (5100)
or 4 Torr (TSQ-7100). Routine GC analyses were accomplished with
a Hewlett-Packard 5890A gas chromatograph equipped with a J and
W Scientific 30 m × 0.53 mm, i.d. DB-5 column (J and W Scientific,
Folsom, CA).
General Procedure
Reaction of Dimethyl Phenylphosphonite (1) with
N-(Bromomethyl)phthalimide (2)
A mixture containing dimethyl phenylphosphonite (1, 5 mmol) and
N-(bromomethyl)-hthalimide (2, 5 mmol) was heated with stirring and
under nitrogen for 4 h at 115–120◦C. The reaction mixture was cooled
to ambient temperature, and the volatile material was distilled off in
vacuo. The residue was first analyzed by gas chromatography. Then,
it was heated again under house vacuum and reanalyzed using GC.
When no additional peaks appeared in the chromatogram, the reaction
product was then subjected to GC-MS analysis (using both the EI and
CI modes). The following compounds were thus identified: (i) hydrogen
methyl phenylphosphinate (3), (ii) dimethyl phenylphosphinite (1); (iii)
dimethyl phenylphosphonate (4), (iv) N-(methoxymethyl)phthalimide
(5), (v) unknown (6), (vi) N-bromomethylphthalimide (2), (vii) methyl
(phthalimidomethyl) phenylphosphinate (7), and (viii) methyl (phthal-
imidomethyl) phenylphosphinate (8, isomer of 7), and their mass spec-
tral data are given in Table I.

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H. D. Durst et al.
Reaction of Diethyl Phenylphosphonite (9) with
N-(Bromomethyl)phthalimide (2)
The reaction was carried out in an analogous manner as de-
scribed above, except 1 was replaced with diethyl phenylphospho-
nite (9). The GC-MS analysis permitted the characterization of (i)
diethyl phenylphosphite (9), (ii) hydrogen ethyl phenyl-phosphinate
(10), (iii) diethyl phenylphosphonate (11), (iv) unknown (12), (v)
N-bromomethyl(phthalimide (2), and (vi) ethyl (phthalimidomethyl)
phenylphosphinate (13) (cf. Scheme 2). Here again, the unknown com-
pound possesses the phthalimido moiety, and its molecular ion peak
could not be ascertained due to its premature extensive degradation.
The desired product, namely ethyl (phthalimidomethyl) phenylphos-
phinate (13), was formed in 88.2% yields. Table II provides the mass
spectral information.
Reaction of Diisopropyl Phenylphosphonite (14) with
N-(Bromomethyl)phthalimide (2)
The reaction was conducted in a similar manner as described
above, except 1 was replaced with diisopropyl phenylphosphonite (14).
The GC-MS analysis enabled the identification of the three compo-
nents, namely (i) hydrogen isopropylphenylphosphinate (15), (ii) diiso-
propyl phenylphosphonate (16), and (iii) isopropyl (phthalimidomethyl)
phenylphosphinate (17). The last compound was obtained in 98.9%
yields. The mass spectral breakdown of the three compounds is given
in Table II.
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