Phospha-Michael reactions involving P-heterocyclic nucleophiles

Article abstract of DOI:10.1002/hc.20421

P-heterocyclic γ-ketophosphonates were synthesized by the Michael reaction of methyl vinyl ketone with dibenzo-1,2-oxaphosphorine 2-oxide, 1,3,2-dioxaphosphorine 2-oxide and benzo1,3,2-dioxaphospholane 2-oxide, respectively. In the first two cases, 50% of

Full text of DOI:10.1002/hc.20421

Heteroatom Chemistry
Volume 19, Number 3, 2008
Phospha-Michael Reactions Involving
P-Heterocyclic Nucleophiles
Gyo¨rgy Keglevich,1 Melinda Sipos,1 Daniella Taka´cs,1
and Krisztina Luda´nyi2,3
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2Semmelweis University, Faculty of Pharmacy, Department of Pharmaceutics,
1092 Budapest, Hungary
3Hungarian Academy of Sciences, Chemical Research Center, 1525 Budapest, Hungary
Received 12 July 2007; revised 17 October 2007
19:288–292, 2008; Published online in Wiley InterScience
ABSTRACT: P-heterocyclic γ-ketophosphonates
(www.interscience.wiley.com). DOI 10.1002/hc.20421
were synthesized by the Michael reaction of methyl
vinyl ketone with dibenzo-1,2-oxaphosphorine
2-oxide, 1,3,2-dioxaphosphorine 2-oxide and benzo-
1,3,2-dioxaphospholane 2-oxide, respectively. In the
first two cases, 50% of 1,8-diazabicyclo[5.4.0]undec-
INTRODUCTION
The phospha-Michael reaction is an evergreen
method for the synthesis of γ-ketophosphonates,
-phosphinates, and -phosphine oxides, as well as,
that of related compounds [1–3]. In our labora-
tory, the possible accomplishments of the phospha-
Michael reaction were studied on simple model
reactions [4]. The addition of >P(O)H species
to α-methyleneglutaric esters was performed to
make available potential NAALADase inhibitors
useful in the treatment of stroke [5]. The re-
action of a series of 1,2-dihydrophosphinine ox-
ides with dialkyl phosphites, diphenylphosphine
oxide, and ethyl phenyl-H-phosphinate gave valu-
able 3-phosphonato-, 3-phosphinoxido-, and 3-
phosphinato-1,2,3,6-tetrahydrophosphinine oxides
[6–9], whose twist-boat conformation was stabilized
by special intramolecular H-bonds. The 3-P(O)Ph2-
1-Ph-tetrahydrophosphinine 1-oxide was a useful
bidentate P-ligand after double deoxygenation [10].
In this paper, the Michael addition of hetero-
cyclic >P(O)H species, such as oxaphosphorine-,
7-ene had to be used that was also required in
the addition of dibenzooxaphosphorine oxide to
cyclohexenone to result in the formation of the
corresponding γ-ketophosphonate. The addition
of dibenzooxaphosphorine oxide to less reactive
1,2-dihydrophosphinine oxide was accomplished
after activation by an equimolar amount of
trimethylaluminum to afford a 3-P(O)<-1,2,3,6-
tetrahydrophosphinine oxide, which was subjected
to catalytic hydrogenation to provide the corre-
sponding 1,2,3,4,5,6-hexahydrophosphinine oxide.
ꢀ
C
2008 Wiley Periodicals, Inc. Heteroatom Chem
Correspondence to: Gyo¨rgy Keglevich; e-mail: keglevich@mail.
bme.hu.
Contract grant sponsor: Joint funds from the European Union
and the Hungarian State.
Contract grant number: GVOP-3.2.2.-2004-07-0006/3.0.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA T 067679.
2008 Wiley Periodicals, Inc.
c
ꢀ
288

Phospha-Michael Reactions Involving P-Heterocyclic Nucleophiles 289
dioxaphosphorine-, and dioxaphospholane deriva-
tives to unsaturated ketones and an unsaturated
cyclic phosphine oxide is described.
RESULTS AND DISCUSSION
SCHEME 2
The first model reaction studied was the addition
of dibenzo-1,2-oxaphosphorine oxide (DBOP) 1 to
methyl vinyl ketone (MVK). It was found that species
1 was added easily on the double bond of MVK under
microwave conditions in the absence of any solvent.
This was in accord with the observation of Stockland
et al. [3]. An accomplishment in the presence of 50%
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chlo-
roform at reflux was a suitable alternative (Scheme
1). The addition of DBOP on the electron-poor dou-
ble bond of cyclohexenone could not, however, be
accomplished under microwave, only in the pres-
ence of DBU, in boiling chloroform (Scheme 1). The
50% quantity of the DBU was critical from the point
of view efficiency of the addition. The use of less DBU
led to low conversions, whereas the application of an
equimolar amount resulted in complex mixtures. Af-
ter column chromatography, adduct 3 was obtained
in a 54% yield. Owing to the existing and the newly
formed stereogenic centers, 3 was formed as a 64:36
mixture of two diastereomers.
ner. Sensitivity of a five-membered hetero ring of
7 toward moisture did not allow its purification by
column chromatography (Scheme 3). Benzo-1,3,2-
dioxaphospholane 6 seemed to be of enhanced reac-
tivity toward MVK than 1,3,2-dioxaphosphorine 4.
Finally, the reaction of DBOP 1 with 1,2-
dihydrophosphinine oxide 8 was studied. It was
found that neither microwave activation nor DBU
catalyst promoted the reaction. The suppressed re-
activity of the model under discussion was overcome
by the activation of DBOP (1) with trimethylalu-
minum. In this way, the Michael reaction resulting
in the 3-P(O)<-tetrahydrophosphinine oxide (9) took
place and adduct 9 was obtained as a mixture of a
major (83%) and a minor (17%) isomer, in a 78%
yield after purification by column chromatography
(Scheme 4).
Reduction of tetrahydrophosphinine oxide 9 by
catalytically activated hydrogen resulted in hexahy-
drophosphinine oxide 10 as a 8:2 mixture of a major
(82%) diastereomer and two minor (13% and 5%)
isomers (Scheme 4). Obviously, hydrogenation of the
major diasteromer (83%) of 9 provided the major
isomer (82%) of 10, whereas that of the minor com-
ponent (17%) of 9 led to the formation of two minor
(13% and 5%) isomers of 10.
The reaction of 1,3,2-dioxaphosphorine oxide 4
with MVK was performed in a similar way to fur-
nish γ-ketophosphonate 5 with a yield of 74% after
column chromatography (Scheme 2).
The Michael addition of benzo-1,3,2-dioxaphos-
pholane oxide (6) on the double bond of MVK
could be carried out without the use of any DBU
yielding ketophosphonate 7 in a quantitative man-
All new products (3, 5, 7, 9, and 10) were char-
1
acterized by 31P, 13C, and H NMR, as well as, mass
spectral data.
To summarize our results, new phospha-Michael
reactions were performed in the sphere of P-
heterocyclic >P(O)H species. The reaction condi-
tions had to be tuned to the reactivity of the given
model compounds. The γ-ketophosphonates could
be well obtained in the presence of 50% of DBU at
61◦C, but in one case there was no need for catalyst.
The synthesis of a bis(P O species) required activa-
tion by trimethylaluminum.
SCHEME 1
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

290 Keglevich et al.
SCHEME 4
EXPERIMENTAL
6-(Butan-3-on-1-yl)-dibenzo[c,e][1,2]oxaphospho-
rin 2-Oxide (2). Yield: 0.50 g (52%). 31P NMR (CDCl3)
δ 37.4 (δlit 37.0) [3].
The 31P, 13C, and 1H NMR spectra were obtained on
a Bruker DRX-500 spectrometer operating at 202.4,
125.7, and 500 MHz, respectively. Chemical shifts
are downfield relative to 85% H3PO4 or TMS. FAB
measurements were performed on a ZAB-2SEQ in-
strument using 3-nitrobenzyl alcohol as the matrix.
The >P(O)H reactants were purchased from
Aldrich (Schnelldorf, Germany) (6), or prepared ac-
cording to known procedures (1) [11] and (4) [12].
1,2-Dihydrophosphinine oxide 8 was synthesized as
described earlier [13].
2-(Cyclohexan-3-on-1-yl)-dibenzo[c,e][1,2]oxaphos-
phorin 2-Oxide (3). Yield: 0.54 g (54%); (M +
+
1
H)found = 313.0979, C18H18O3P requires 313.0994; H
NMR (CDCl3) δ 1.56–1.70 (m, 1H, CH), 1.86–2.64
(m, 8H, CH2), 7.10–8.02 (m, 8H, Ar).
Major: 31P NMR (CDCl3) δ 36.6 (64%); 13C NMR
(CDCl3) δ 23.2 (J = 2.8, CH2), 26.1 (J = 17.5, CH2),
37.6 (J = 97.1, PCH), 39.2 (CH2), 41.1 (CH2), 120.2
(J = 6.2, Ar), 122.1 (J = 10.4, Ar), 122.5 (J = 117.4,
PC), 124.1 (J = 9.4, Ar), 124.8 (Ar), 125.3 (Ar), 128.6
(J = 12.8, Ar), 130.9 (J = 9.8, Ar), 131.0 (Ar), 133.8
(J = 2.2, Ar), 136.2 (J = 6.4, Ar), 149.1 (J = 8.2, POC),
208.3 (J = 14.9, C O).
Minor: 31P NMR (CDCl3) δ 36.8 (36%); 13C NMR
(CDCl3) δ 23.3 (J = 4.3, CH2), 26.0 (J = 17.0, CH2),
38.1 (J = 97.2, PCH), 39.2 (CH2), 41.1 (CH2), 120.1
(J = 6.2, Ar), 122.4 (J = 117.0, PC), 124.0 (Ar), 124.8
(Ar), 125.3 (Ar), 128.6 (J = 12.7, Ar), 131.0 (Ar), 131.0
(J =∼9.8, Ar), 133.8 (J = 2.2, Ar), 149.3 (J = 8.2,
POC), 208.2 (J = 14.8, C O).
Synthesis of 6-(butan-3-on-1-yl)-dibenzo[c,e]
[1,2]oxaphosphorin-6-oxide (2) by the reaction
of methyl vinyl ketone and dibenzo-1,2-oxaphos-
phorine oxide (1) under microwave irradiation. The
mixture of 38.6 µL (0.46 mmol) of methyl vinyl
ketone and 0.10 g (0.46 mmol) of dibenzo-1,2-
oxaphosphorine oxide (1) was heated at 130◦C
in a CEM Discovery microwave reactor (applying
maximum of 30 W) for 1 h. The product was
recrystallized from hexane/ether (6:1) to give 0.10 g
(72%) of product 2; 31P NMR (CDCl3) δ 37.6 (δlit
37.0) [3].
2-(Butan-3-on-1-yl)-1,3,2-dioxaphosphorin
2-
Oxide (5). Yield: 0.35 g (74%), 31P NMR (CDCl3)
δ 27.9; 13C NMR (CDCl3) δ 17.6 (J = 144.2, PCH2),
26.3 (J = 7.6, CH2), 29.4 (CH3), 35.6 (J = 3.8, CH2),
66.2 (J = 6.4, OCH2), 205.6 (J = 13.6, C O); 1H
NMR (CDCl3) δ 2.00–2.05 (m, 2H, CH2), 2.05–2.14
(m, 2H, PCH2), 2.18 (s, 3H, CH3), 2.76–2.84 (m,
2H, C(O)CH2), 4.21–4.29 (m, 2H, OCH2), 4.45–4.54
(m, 2H, OCH2); (M + H)+found = 193.0621, C7H14O4P
requires 193.0630.
General Procedure for the Preparation of
Adducts 2, 3, and 5 by the Reaction of
α,β-Unsaturated Ketones and Cyclic >P(O)H in
the Presence of DBU
The mixture of 3.0 mmol of methyl vinyl ketone (0.25
mL) or cyclohexene-2-one (0.29 g), 2.86 mmol of
cyclic >P(O)H species 1 or 4 (0.62 and 0.35 g, respec-
tively) and 0.10 mL (1.43 mmol) of DBU in 2 mL of
chloroform was kept at reflux for 3 h. Then, the mix-
ture was washed with 5% HCl solution, the organic
phase dried, and the crude product was purified by
column chromatography (silica gel, 3% methanol in
chloroform) to give the corresponding products (2,
3, or 5).
2-(Butan-3-on-1-yl)-benzo-1,3,2-dioxaphospholane
2-Oxide (7). 7 was prepared measuring in 0.44 g
(2.86 mmol) of 6 and 0.35 mL (4.29 mmol) of methyl
vinyl ketone as described above, but without the use
of any DBU. Owing to the sensitivity of 7, the crude
Heteroatom Chemistry DOI 10.1002/hc

Phospha-Michael Reactions Involving P-Heterocyclic Nucleophiles 291
product was not purified by chromatography. Evap-
oration of the volatile components afforded 0.66 g
(98%) of product 7 in a purity of 95%. 31P NMR
(CDCl3) δ 51.8; 13C NMR (CDCl3) δ 20.2 (J = 134.3,
PCH2), 29.1 (CH3), 35.5 (J = 4.5, C(O)CH2), 112.5
(3 J = 10.2, CH), 123.7 (CH), 144.4 (CO), 204.4
(J = 13.4, C(O)); 1H NMR (CDCl3) δ 2.20 (s, 3H,
CH3), 2.40–2.54 (m, 2H, PCH2), 2.80–2.94 (m, 2H,
CH2), 6.90–7.20 (m, 4H, Ar); (M + H)+found = 227.0461,
C10H12O4P requires 227.0473.
and 0.08 g of 10% Pd/C in 30 mL of methanol was
hydrogenated in an autoclave at 50◦C and 3.5 bar
for 48 h on stirring. The suspension was filtered,
and the solvent was evaporated. Purification of the
crude product so obtained by column chromatogra-
phy (silica gel, 3% methanol in chloroform) afforded
hexahydrophosphinine oxide 10 as an 82%–13%–5%
mixture of three diastereomers.
Yield: 0.09 g (90%); (M + H)+found = 423.1263,
C24H25O3P2 requires 423.1279.
Major: 31P NMR (CDCl3) δ 34.1 (P2) and 36.5 (P1),
3 JPP = 56.6 (82%); 13C NMR (CDCl3) δ 23.9 (1 J = 15.8,
2 J = 2.1, C5 CH3), 24.1 (1 J = 63.0, 2 J = 4.2, C2), 31.2
Synthesis of 3-(Dibenzo[c,e][1,2]oxaphos-
phorinoxido)-4-chloro-5-methyl-1-phenyl-1,2,3,6-
Tetrahydrophosphinine 1-Oxide (9)
2
(1 J = 3.3, 2 J = 18.0, C5), 32.2 (1 J = J = 2.9, C4), 34.4
(2 J = 93.3, 1 J = 1.5, C3), 34.8 (1 J = 64.0, C6), 120.1
(2 J = 6.2, Ar), 122.2 (2 J = 10.3, Ar), 122.4 (1 J = 116.6,
2 J = 2.2, PC), 124.2 (2 J = 9.6, Ar), 124.9 (Ar), 125.5
To 0.20 g (1.01 mmol) of the dibenzooxaphospho-
rine oxide 1 in 10 mL of dry chloroform, 0.50 mL
(1.01 mmol) of 2 M trimethylaluminum in hexane
at 0◦C was added. After a period of 20 min, 0.24 g
(1.06 mmol) of the dihydrophosphinine oxide (8) in
5 mL of chloroform was added dropwise. After com-
plete addition, the cooling bath was removed and
the contents of the flask were stirred for 20 h. Then,
the mixture was hydrolyzed by the addition of 0.5
mL of conc. hydrochloric acid in 4.5 mL of water.
After filtration, the organic phase was separated and
dried (Na2SO4). The crude product was purified by
column chromatography (silica gel, 3% methanol in
chloroform) to afford compound 9.
2
1
ꢁ
(Ar), 128.5 ( J = 12.6, Ar), 129.0 ( J = 5.6, C3 )*, 129.1
1
2
ꢁ
ꢁ
( J = 3.5, C2 )*, 130.6 ( J = 9.6, Ar), 130.9 (C4 ), 132.0
(2 J = 2.5, Ar), 133.8 (2 J = 2.0, Ar), 136.2 (2 J = 6.5,
Ar), 149.0 (2 J = 8.1, POC), *may be reversed; 1H
NMR (CDCl3) δ 1.03 (1 J = 6.3, 2 J = 2.9, 3H, C5 CH3),
1.24–1.44 (m, 2H, CH2), 1.80–2.06 (m, 3H, C3H and
CH2), 2.06–2.20 (m, 1H, C5H), 2.46–2.72 (m, 2H,
CH2), 7.28–7.58 and 7.70–8.00 (m, 13H, Ar).
Minor1: 31P NMR (CDCl3) δ 33.6 (P2) and 35.9
(P1), 3 JPP = 58.8 (13%).
Yield: 0.87 g (78%); (M + H)+found = 455.0712,
Minor2: 31P NMR (CDCl3) δ 32.5 (P2) and 37.3
C24H22ClO3P2 requires 455.0733 for the 35Cl isotope.
(P1), 3 JPP = 54.7 (5%).
Major: 31P NMR (CDCl3) δ 31.6 (P2) and 32.8
3
(P1), JPP = 17.0 (83%); 13C NMR (CDCl3) δ 23.8
2
2
(1 J = 6.9, J = 2.6, C5 H3), 24.4 (1 J = 70.9, J = 3.7,
C2), 34.6 (1 J = 61.9,2 J = 2.1, C6), 43.8 (1 J = 4.9,
2 J = 90.8, C3), 120.3 (2 J = 6.4, Ar), 121.9 (1 J = 7.2,
2 J = 16.5, C5), 122.5 (2 J = 10.5, Ar), 123.0 (1 J = 120.5,
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2
1
ꢁ
PC), 124.0 ( J = 10.2, Ar), 125.3 ( J = 16.1, C3 )*,
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1
ꢁ
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ꢁ
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