Synthesis of multifunctionalized phosphonic acid esters via opening of oxiranes and azetidinium salts with phosphoryl-substituted carbanions

Article abstract of DOI:10.1039/b009720i

Ring-opening of N,N-diethyl-3-benzyloxyazetidinium salt 1b and N,N-dibenzyl-2,3-epoxypropylamine 6 by phosphoryl-substituted carbanions generated from phosphonates 2a-e furnishes the multifunctional phosphonates 3a-e and 7a, 7b, 7e bearing the same carbon skeleton. The reaction of the heterocyclic electrophiles 1b and 6 with the P-allyl anion generated from 2f demonstrates the strong dependence of the α/γ-regioselectivity on the reaction conditions. Depending on the character of the electrophile and/or the reaction medium the regioselective synthesis of both a α- and γ-regioisomers is realized.

Full text of DOI:10.1039/b009720i

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Synthesis of multifunctionalized phosphonic acid esters via opening
of oxiranes and azetidinium salts with phosphoryl-substituted
carbanions
1
Agata Bakalarz-Jeziorna, Jan Heli n´ ski and Bo z˙ ena Krawiecka*
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Łód z´ ,
Sienkiewicza 112, Poland
Received (in Cambridge, UK) 4th December 2000, Accepted 20th February 2001
First published as an Advance Article on the web 21st March 2001
Ring-opening of N,N-diethyl-3-benzyloxyazetidinium salt 1b and N,N-dibenzyl-2,3-epoxypropylamine 6 by
phosphoryl-substituted carbanions generated from phosphonates 2a–e furnishes the multifunctional phosphonates
a–e and 7a, 7b, 7e bearing the same carbon skeleton. The reaction of the heterocyclic electrophiles 1b and 6 with
3
the P-allyl anion generated from 2f demonstrates the strong dependence of the α/γ-regioselectivity on the reaction
conditions. Depending on the character of the electrophile and/or the reaction medium the regioselective synthesis
of both α- and γ-regioisomers is realized.
Introduction
formed products. Therefore, the experiments were carried out
using the benzylated salt 1b as a suitable starting material. The
carbanions derived from diethyl methylphosphonate 2a and its
substituted analogues 2b–2e were used as phosphoryl-stabilized
nucleophiles. The example of phosphonate 2f, in which R =
Oxirane ring-opening with various nucleophiles is well recog-
nized as a useful starting point for the synthesis of multi-
functionalized organic compounds. Azetidines are not as
highly strained systems as their three-membered analogues—
aziridines. However, a considerable part of their chemistry
involves ring-opening reactions, which renders them useful
1
–
CH᎐CH (i.e. allylphosphonate), requires special discussion
᎐
2
and will be described in a separate section.
2
Reaction of 1b with 2a–2e leads to ring opening of the hetero-
cyclic system and C–C bond formation to give derivatives of
phosphonic acids bearing the functional groups at the α-,
γ- and δ- positions of the butylphosphonic acid skeleton. The
reactions illustrated in Scheme 1 occurred readily in most cases
synthetic intermediates in some transformations. It was
3
demonstrated that the presence of positive charge on the
nitrogen atom of this heterocyclic system supports ring-
opening reactions. Therefore, quaternary azetidinium salts and
their substituted derivatives react according to this pattern.
In this paper we report the synthesis of 4-(N,N-dialkyl-
amino)-3-hydroxy- and 4-(N,N-dialkylamino)-3-benzyloxy-
butylphosphonates 3 and 7 containing other functionality [e.g.
–
Ph, –CN, –COOEt, –P(O)(OEt) ] and 6-(N,N-dialkylamino)-
2
4
-hydroxy- and 6-(N,N-dialkylamino)-4-benzyloxyhex-1-enyl-
phosphonates 8 and 9 using the ring-opening reactions of two
heterocyclic systems: N,N-diethyl-3-benzyloxyazetidinium salt
1
b and N,N-dibenzyl-2,3-epoxypropylamine 6. The results of
these both strategies are complementary.
Multifunctionalized phosphonic acids are of importance
because of their potential biological activity and utility as
4
,5
versatile intermediate reagents for organic synthesis.
Results and discussion
Reactions of heterocyclic systems 1b and 6 with carbanions
generated from phosphonates 2a–2e
N,N-Dialkyl-3-hydroxyazetidinium chlorides 1, readily access-
6
ible according to Gaertner from 1-chloro-2,3-epoxypropane
and dialkylamines were recently applied in this laboratory to
the synthesis of (3-dialkylamino-2-hydroxy)propylphosphonic
Scheme 1
7,8
acids and their structural analogues. The reaction involved
the ring-opening reaction of salts 1 via nucleophilic attack of
phosphorus nucleophiles on the carbon atom with resultant
C–P bond formation. In this work N,N-diethyl-3-hydroxy-
azetidinium chloride 1a was chosen as a model starting hetero-
in high yields. The carbanions were generated from the corre-
sponding phosphonates by the action of sodium hydride (for
phosphonates 2b–2e) or butyllithium (for phosphonates 2a and
2f). The representative procedure is a one-pot reaction, which
was carried out in the temperature range 25–60 ЊC (when
NaH was used) or Ϫ78–25 ЊC (for BuLi) within 3–10 h. It is
noteworthy that when R ≠ H a second stereogenic centre is
generated, and therefore, phosphonates 3b–3d were formed as a
8
cyclic reagent. Our experience from the previous studies
showed that the hydroxy group of the salt 1a should be pro-
tected in order to avoid secondary reactions of the initially
1
086
J. Chem. Soc., Perkin Trans. 1, 2001, 1086–1090
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009720i

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Table 1 Reaction of azetidinium salt 1b with phosphonates 2
Reaction
time/h
Yield
(%)
Diastereomeric
ratio of 3
Starting phosphonate
Base
Solvent(s)
T/ЊC
2
2
2
2
2
a (R = H)
BuLi
NaH
NaH
NaH
NaH
DME
DME–DMSO
DME
DME
Toluene
Ϫ78→20
60
60
60
60→110
6
10
10
10
25
69
83
83
77
11
—
b (R = Ph)
12 : 10
15 : 10
27 : 10
—
c (R = COOEt)
d (R = CN)
e [R = P(O)(OEt)2]
1
0–12
mixture of diastereomers as shown by the presence of two
phosphonates.
This approach to the synthesis of functional-
31
chemical shifts in their P NMR spectra. The two diastereo-
mers were usually formed in unequal amounts (Table 1).
Unfortunately, we were not able to separate the diastereomers
by column chromatography. However, the phosphonate 3b
ized phosphonates of type 3 using 6 (R = Bn) as the starting
material proved to be a complementary method to that using
azetidinium salts as electrophiles. The reaction of phosphoryl-
substituted carbanions 2 with epoxide 6 (R = Bn) has the
following advantages: it proceeds under relatively mild condi-
tions (at Ϫ78 to 20 ЊC) and avoids the steps of protection and
deprotection of the hydroxy group.
(
R = Ph) was separated by gas chromatography into its
31
diastereomers. Phosphonate 3e [R = P(O)(OEt) ] shows two
P
2
NMR signals because of the diastereotopy of the phosphorus
atom. The results of the reactions described in Scheme 1 are
collected in Table 1.
The described procedure requires protection of the OH
group in the 3-hydroxyazetidinium salt 1a. The alternative
procedure, avoiding this inconvenience, appears to be the ring-
opening reaction of corresponding epoxides with the above-
mentioned phosphorus nucleophiles.
Reactions of heterocyclic compounds 1b and 6 with the
phosphoryl-stabilized allylic system
The allylphosphonate 2f (R = –CH᎐CH ) may react with elec-
trophiles at α- or γ-position of the carbon chain leading to 7f
α-attack) or 8 (γ-attack) (Scheme 4). The reaction of electro-
᎐
2
(
A convenient starting material would be the aminomethyl
epoxides 6, which are readily available from 1-chloro-2,3-
epoxypropane 4. As the model epoxide we have chosen
N,N-dibenzyl-2,3-epoxypropylamine 6 (R = Bn), prepared by
the sequence of the reactions shown in Scheme 2. The amino
Scheme 2
alcohol 5 (R = Bn), in contrast to the analogous compounds, in
which R N– = Me N–, Et N–, morpholino-, piperidino-, does
2
2
2
not undergo the cyclization to the corresponding N,N-dibenzyl-
-hydroxyazetidinium chloride under the conditions described
3
6
by Gaertner. However, the amino alcohol 5 (R = Bn) can be
Scheme 4
readily transformed into the amino epoxide 6 (R = Bn) by
the conventional procedure. The use of epoxide 6 (R = Bn) in
the reaction with carbanions derived from phosphonates 2
allowed us to obtain phosphonates 7, which possess the same
basic structure as the phosphonates 3, but bear a free hydroxy
group. Epoxide 6 (R = Bn) was regioselectively attacked by the
nucleophiles at the less hindered site (Scheme 3).
9
philes with allylic anions, stabilized by a phosphoryl group, is
a well-studied area of organophosphorus chemistry.
sense of α-/γ-selectivity has been found to be highly dependent
on a number of factors, particularly, the structure of the
electrophile and the nature of the reaction medium. The
regioselective reactions of allylic anions with electrophiles pro-
12–24
The
1
5,21,22
vide access to a variety of useful synthetic intermediates.
Investigations have been concentrated on such electrophiles
1
3
14,15
13–19
as alkyl
enones
and silyl halides,
carbonyl compounds,
2
0,21
22
and heteroatom electrophiles. Relatively less inter-
est has been devoted to the reaction of epoxides.
23,24
Azetidin-
ium salts, to our knowledge, have not been investigated, not
7
counting the preliminary studies in our laboratory.
The reaction of N,N-dibenzylamino-2,3-epoxypropylamine 6
with lithiated allylphosphonate 2f was carried out at Ϫ78 ЊC in
THF or toluene in the presence of BF ؒEt O, as described
3
2
above in the reactions of phosphonates 2a,b,e. The chemo-
selectivity of the reaction depended strongly on the solvent
(
Scheme 4). When the reaction was performed in THF (Scheme
4
3
, pathway A) the only product was the 4-(N,N-dibenzylamino)-
-hydroxy-1-vinylbutylphosphonate 7f (δ : 29.4, 30.0, mixture
P
of diastereoisomers in the ratio 12 : 10), the result of the
exclusive α-attack of the nucleophile. When toluene was used as
the reaction medium, a drastic shift to γ-attack by the anion
generated from 2f was observed, giving predominantly the
Scheme 3
N,N-Dibenzyl-2,3-epoxypropylamine 6 was reacted with the
lithio carbanions generated from 2 in the presence of BF ؒEt O,
as reported for the syntheses α-, β- and γ-hydroxyalkyl-
3
2
product of γ-attack (60%), the phosphonate 8 (δ : ϩ18.5 ppm)
P
J. Chem. Soc., Perkin Trans. 1, 2001, 1086–1090
1087

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1
(
Scheme 4, pathway B). In either solvent the monosubstituted
300 spectrometers, operating at 200.13 and 300.13 MHz for H,
13
epoxide 6 was regioselectively attacked by the nucleophile at
the less hindered site. The E-configuration of the vinyl double
bond in phosphonate 8 was established from its H NMR
50.288 and 75.17 MHz for C and 80.96 and 121.49 MHz for
31
P, were used for recording NMR spectra. Chemical shifts are
1
reported in ppm (δ) using TMS as internal and H PO4 as
3
spectral data. A similar shift of the regioselectivity induced by a
change of solvent was observed by Ergüden and Schaumann
external standard. Coupling constants are given in Hz.
24
for the reaction of lithiated diphenylallylphosphine oxide
with a variety of functionalized epoxides. The phosphonate
Reaction of N,N-diethyl-3-benzyloxyazetidinium bromide 1b
with phosphonate 2 in the presence of sodium hydride. General
procedure
9
of similar structure to 8 was obtained in the reaction of
N,N-diethyl-3-benzyloxyazetidinium bromide 1b with diethyl
lithioallylphosphonate, generated from the allylphosphonate 2f
and BuLi at Ϫ78 ЊC during 10 h in mixture of DME–DMF
8
To a suspension of azetidinium bromide 1b (60 mmol) in a
3
solvent (100 cm ) were added successively the corresponding
phosphonate 2b–2e (72 mmol) and sodium hydride (72 mmol).
The reaction mixture was stirred at room temperature until the
hydrogen evolution had ceased. Then it was stirred at 60 ЊC
for 10 h. The reaction was quenched by pouring the mixture
3
into water (150 cm ). The reaction product was extracted with
3
chloroform (3 × 100 cm ), dried, evaporated and purified by
column chromatography (eluent: CHCl –MeOH). According
3
to this procedure the following functionalized phosphonates
were prepared.
Diethyl
4-(N,N-diethylamino)-3-benzyloxy-1-phenylbutyl-
phosphonate 3b. (Reaction solvent: DME–DMSO, 1 : 1.) Pale
yellow oil (yield: 83%); R 0.4 (CHCl –MeOH, 20 : 1); ν
max
f
3
Scheme 5
Ϫ1
(
(
neat)/cm : 3428 (br), 2971, 2931, 2870, 1661, 1454, 1383, 1110
P᎐O), 1060, 1028, 963, 738, 699, 562; MS (FAB): 397.5 (M ϩ
᎐
ϩ
(
1 : 1, v/v). 6-(N,N-Diethylamino)-5-benzyloxyhex-1-enylphos-
phonate 9 was the only reaction product. The crude reaction
mixture and the product purified by column chromatography
1
); δ (121.5 MHz, CDCl ): 28.75, 29.26 (12 : 10); δ (300 MHz,
P
3
H
CDCl ): 0.84–1.38 (2 × m, 12H, CH CH N, CH CH O), 2.35–
3
3
2
3
2
2
.67 [m, 9H, (CH CH ) NCH , CH CHPh], 3.37–3.64 (m, 4H,
3 2 2 2 2
31
showed the same picture: one signal in the P NMR at ϩ21.5
ppm. This chemical shift, characteristic of vinyl phosphonates,
has been ascribed to the phosphonate 9, which had to be
formed as the result of 100% γ-attack of the allyl anion
generated from 2f on the electrophile—azetidinium salt 1b.
One can speculate that the observed difference in α-/γ-
regioselectivity has been produced by the difference in the
solvation effect of the lithium cation in apolar (toluene) and
polar (THF) solvents. However, the result of the reaction of
azetidinium salt 1b with phosphoryl allyl anion, carried out in a
polar solvent mixture (DME–DMF) indicates that the course
of the reaction depends on a variety of factors that influence
the α-/γ-regioselectivity of the reactions.
CH CH O), 3.72–4.07 [2 × m, 1H, CH(OBn)], 4.60–4.70 (m,
3
2
2
H, CH Ph), 7.20–7.34 (m, 10H, aromatic); δC (75.5 MHz,
2
CDCl ): 12.47, 12.72 (CH CH N), 16.86, 16.94, 17.04, 17.12
3
3
2
1
(
CH CH O), 34.52 (CH CHPh), 41.54 [d, JC–P 138.1,
3 2 2
1
CH(Ph)P], 41.71 [d, J
119.5, CH(Ph)P(O)], 48.63, 48.68
C–P
(
CH CH N), 55.30, 55.41, 57.47, 58.16, 58.26 ( NCH ),
3
2
2
6
2.35–63.18 (2 × m, CH CH O), 71.95–72.66 (m, 6 lines, CH -
3 2 2
Ph), 75.53 [d, J 15.5, CH(OBn)], 76.30 [d, J 13.2, CH(OBn)],
27.68, 128.05, 128.13, 128.25, 128.38, 128.90, 128.97, 129.46
aromatic), 130.04 (d, J 6.6, Ph, C-ipso), 130.29 (d, J 6.4, Ph,
C-ipso).
1
(
Single diastereoisomer: δP (121.5 MHz, CDCl ): 29.56;
3
δH (300 MHz, CDCl ): 0.99 (t, J 7.1, 6H, CH CH N), 1.21 (t,
3
3
2
J 7.0, 6H, CH CH O), 2.42–2.58 [m, 9H, (CH CH ) NCH ,
3
2
3
2
2
2
CH CH(Ph)], 3.47–3.65 (m, 4H, CH CH O), 3.83–4.02 [2 × m,
2
3
2
Conclusions
1
H, CH(OBn)], 4.65 and 4.74 (AB, JAB 12.0, 2H, CH Ph), 7.22–
2
This paper describes two complementary methods giving
easy access to multifunctionalized phosphonates using as start-
ing materials simple, readily available heterocyclic systems:
azetidinium salts and aminomethyl epoxides. The ring-opening
reaction of electrophiles 1b and 6 (R = Bn) by the P-allyl anion
generated from 2f proved to be strongly dependent on the reac-
tion conditions. The α- and γ-regioisomers are accessible by
selection of the appropriate electrophile and reaction medium.
Further studies using optically active heterocyclic systems as
starting materials are in progress.
7.45 (m, 10H, aromatic); δ (50.3 MHz, CDCl ): 10.14, 10.88
C
3
(CH CH N), 14.68, 15.77 (CH CH O), 33.04 (CH CHPh),
3
2
3
2
2
40.33 [d, JC–P 137.1, CH(Ph)P], 47.35, 47.08 (CH CH N),
3
2
53.85, 56.52 ( NCH ), 61.50, 61.64, 62.34, 62.49 (CH CH O),
2
3
2
71.12, 71.42 (CH Ph), 74.82 [d, J 14.2, CH(OBn)], 126.48,
2
126.86, 127.08, 127.38, 127.83, 128.08, 128.47 (aromatic),
128.89 (d, J 6.7, Ph, C-ipso).
Diethyl 4-(N,N-diethylamino)-3-benzyloxy-1-ethoxycarbonyl-
butylphosphonate 3c. (Reaction solvent: DME.) Pale yellow oil
(
yield: 83%); R 0.31 (CHCl –MeOH, 30 : 1); NMR spectra
f 3
7
were given in the preliminary paper.
Experimental
All air- and moisture-sensitive reactions were carried out under
an atmosphere of argon. All solvents were purified by standard
procedures and freshly distilled prior to use. All reactions were
Diethyl
4-(N,N-diethylamino)-3-benzyloxy-1-cyanobutyl-
phosphonate 3d. (Reaction solvent: DME.) Pale yellow oil
(yield: 77%); R 0.31 (CHCl –MeOH, 30 : 1); ν (neat)/cm :
max
3400 (br), 2980, 1661, 1455, 1229 (P᎐O), 1075, 1048, 947, 795,
749, 701, 570. MS (FAB): 397.5 (M ϩ 1), 369.5 (M Ϫ HCN);
Ϫ1
f
3
31
monitored by P NMR spectroscopy and/or by thin layer
chromatography (TLC) using Merck Kieselgel 60 (F254) analyt-
ical plates. Spots were detected under UV light or visualized
with iodine vapour. Column chromatography was performed
using Merck silica gel 60 (230–400 mesh). All organic extracts
were dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. IR spectra were recorded using an ATI
Mattson Infinity FTIR instrument. Bruker AC-200 and MSL
ϩ
δP (121 MHz, CDCl ): 19.14, 19.50 (27 : 10); δH (300 MHz,
3
CDCl ): 0.99–1.09 (m, 6H, CH CH N), 1.36–1.42 (m, 6H,
3
3
2
CH CH O), 1.82–2.38 [2 × m, 2H, CH CH(CN)], 2.41–
3
2
2
2.74 [3 × m, 6H, (CH CH ) NCH ], 3.27–3.60 [2 × m, 1H,
3
2
2
2
CH(CN)], 3.70–3.78 [m, 1H, CH(OBn)], 4.16–4.33 (m, 4H,
CH CH O), 4.52–4.87 (m, 2H, CH Ph), 7.28–7.42 (m, 5H,
3
2
2
1
088
J. Chem. Soc., Perkin Trans. 1, 2001, 1086–1090

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aromatic); δC (75.5 MHz, CDCl ): 12.56, 12.73 (CH CH N),
C H NOCl requires: C, 70.46; H, 6.96; N, 4.83; Cl, 12.23%;
17 20
3
3
2
1
1
2
4
6
1
6.93, 17.06 (CH CH O), 27.02 [d, JC–P 143.13, C(CN)P],
M, 289.8; δ (300 MHz, CDCl ): 2.28–2.46 (m, 2H, NCH ),
3
2
H
3
2
1
7.40 [d, J
145.24, C(CN)P], 32.06, 32.40 [CH CH(CN)],
2.91 (s, 1H, OH), 3.06–3.26 (m, 2H, CH Cl), 3.20 and 3.46 (AB,
C–P
2
2
8.50, 48.70 (CH CH N), 57.70, 58.13 [NCH CH(OBn)],
JAB 13.47, CH Ph), 3.60–3.72 [m, 1H, CH(OH)], 7.03–7.19 (m,
3
2
2
2
4.34, 64.64 (CH CH O), 72.47, 72.78, 73.31, 75.50 (CH Ph),
10H, aromatic); δ (75.5 MHz, CDCl ): 48.65 (CH Cl), 57.70
3
2
2
C
3
2
16.90, 117.01 (CN), 128.50–138.97 (5 lines, aromatic).
(
NCH ), 59.64 (CH Ph), 69.10 [CH(OH)], 128.22, 128.75,
2
2
1
29.24, 129.39, 130.00, 139.67 (aromatic).
Tetraethyl 4-(N,N-diethylamino)-3-benzyloxybutan-1-ylidene-
bis(phosphonate) 3e. The reaction was carried out according
to the above procedure in toluene at 60 ЊC (20 h) and under
N,N-Dibenzyl-2,3-epoxypropylamine 6
To a solution of N,N-dibenzyl-3-chloro-2-hydroxypropylamine
reflux (5 h). Pale yellow oil (yield: 11%); MS (CI): 508.5
3
5
(14.00 g, 0.048 mol) in tert-butyl alcohol (60 cm ) was added
ϩ
(
2
M ϩ 1). C H NO P requires M 507.5. δ (81 MHz, CDCl ):
28
43
7
2
P
3
potassium hydroxide (3.00 g, 0.054 mol) dissolved in a minimal
volume of water. The reaction mixture was stirred at room tem-
perature for 24 h. Then the precipitate of KCl was filtered off,
the filtrate evaporated and purified by column chromatography.
The epoxide 6 was obtained as a pale yellow oil (10.00 g, 83%).
4.75, 24.95; δH (200 MHz, CDCl ): 0.99 (t, J 7.1, 6H,
3
CH CH N), 1.20–1.41 (m, 12H, CH CH O), 1.92–2.73 [2 × m,
3
2
3
2
8
2
(
H, CH CH N, NCH CH(OBn)CH ], 2.82 [dddd, J 3.7, 8.7,
3 2 2 2
4.3, 1H, CHP(O)], 3.83–3.95 [m, 1H, CH(OBn)], 4.51 and 4.75
AB, JAB 11.4, 2H, CH Ph), 7.21–7.35 (m, 5H, aromatic); δ (50
2
C
R 0.38 (MeCOOEt–hexane, 1 : 10). Found: C, 80.94; H, 7.65;
f
MHz, CDCl ): 11.72 (CH CH N), 16.28 (CH CH O), 29.87
3
3
2
3
2
N, 5.48%. C H NO (253.23) requires: C, 80.60; H, 7.56; N,
1
7
19
[
CH(OBn)CH CHP], 32.54 {t, J
132.0, CH[P(O)(OC2-
2
C–P
ϩ
5
1
2
.53%. MS (FAB): 254.2 (M ϩ 1); δH (300 MHz, CDCl ):
3
H ) ] }, 47.54 (CH CH N), 57.71 [ NCH CH(OBn)], 62.10–
5
2 2
3
2
2
.97–2.01 (m, 1H), 2.16–2.26 (m, 2H), 2.54–2.62 (m, 1H), 2.77–
.85 [(m, 1H, CH(ring)], 3.42 and 3.71 (AB, JAB 13.7, 4H,
6
2.48 (m, OCH CH ), 71.63 (CH Ph), 75.40–75.55 [m,
2 3 2
CH(OBn)], 127.28, 127.59, 128.15, 138.55 (aromatic).
CH Ph), 7.06–7.37 (m, 10H, aromatic); δ (CDCl , 75.5 MHz):
2
C
3
4
4.94 [OCH (ring)], 51.43 (CHO), 56.66 ( NCH ), 59.77
2
2
Reaction of N,N-diethyl-3-benzyloxyazetidinium bromide 1b
with diethyl methylphosphonate 2a and diethyl allylphosphonate
(
(
CH Ph), 127.97, 128.27, 128.75, 129.25, 129.84, 140.52
aromatic).
2
2
f in the presence of butyllithium. General procedure
To a stirred suspension of N,N-diethyl-3-benzyloxyazetidinium
Reaction of the lithiated phosphonates 2 with N,N-dibenzyl-2,3-
bromide 1b prepared from 1a (60 mmol) and phosphonate 2a or
epoxypropylamine 6. General procedure
3
2
f (72 mmol) in a solvent (200 cm ) was added portionwise
To a stirred solution of phosphonate 2 (30 mmol) in a solvent
(
(
from a syringe) a solution of n-BuLi (72 mmol) in hexane
1.6 M) at Ϫ78 ЊC. The reaction mixture was stirred at Ϫ78 ЊC
3
(
50 cm ) was added portionwise (from a syringe) butyllithium
(
32 mmol) in hexane (1.6 M) at Ϫ78 ЊC. After the mixture had
for 10 h, then was allowed to warm to room temperature. A
been stirred for 30 min, it was transferred by stainless steel
3
saturated aqueous solution of NH Cl (150 cm ) was added
4
needle to a stirred solution of epoxide 6 (30 mmol) in a solvent
to a stirred mixture. The reaction product was extracted with
3
(
50 cm ) at Ϫ78 ЊC. The reaction mixture was stirred for an
3
CHCl (3 × 50 cm ), dried, evaporated and purified by column
3
additional 15 min, then BF ؒEt O (33 mmol) was introduced by
3
2
chromatography. According to this procedure the following
functionalized phosphonates were prepared.
syringe at a temperature of below Ϫ78 ЊC. The stirring was
continued for 10 h at the same temperature. The reaction was
3
quenched with saturated aq. NH Cl solution (70 cm ). The
4
Diethyl 4-(N,N-diethylamino)-3-benzyloxybutylphosphonate
temperature was allowed to reach room temperature, and
3
0
a. (Reaction solvent: DME.) Pale yellow oil (yield: 69%); R
f
31 1 13
the solvent was evaporated in vacuo. The residue was extracted
.35 (CHCl –MeOH, 30 : 1); P, H and C NMR spectra were
3
7
3
with AcOEt (3 × 50 cm ), the organic layers were washed with
described in the preliminary paper.
3
water (2 × 20 cm ), dried, evaporated and purified by column
chromatography. According to this procedure the following
phosphonates 7 were prepared.
Diethyl
(E)-6-(N,N-diethylamino)-5-benzyloxyhex-1-enyl-
phosphonate 9. (Reaction solvent DME–DMF, 1 : 1.) Pale yel-
low oil (yield: 67%); R 0.35 (CHCl –MeOH, 20 : 1); ν (neat)/
f
3
max
Diethyl 4-(N,N-dibenzylamino)-3-hydroxybutylphosphonate
Ϫ1
cm : 3404 (br), 2960, 1653, 1455, 1228 (P=O), 1075, 1048, 948,
7
0
2
a. (Reaction solvent: DME.) Pale yellow oil (yield: 63%); R
f
Ϫ1
ϩ
7
95, 749, 701, 570; MS (FAB): 398.5 (M ϩ 1); δ (81 MHz,
P
.60 (CHCl –MeOH, 20 : 1); ν (neat)/cm : 3378 (OH), 3028,
3
max
CDCl ): 21.25; δ (300 MHz, CDCl ): 1.025 (t, J 7.1, 6H,
3
H
3
982, 2801, 1494, 1453, 1239 (P᎐O), 1052, 1027, 747, 699;
᎐
CH CH N), 1.29 and 1.30 (each t, J 7.1, 6H, CH CH O), 1.81–
3
2
3
2
ϩ
MS (FAB): 406.2 (M ϩ 1); δ (127.5 MHz, CDCl ): 32.93;
P
3
1
.85 (m, 4H, CH CH N), 2.47–2.66 (m, 6H
NCH CH -
3
2
2
2
δ (300 MHz, CDCl ): 1.29 (t, J 7.0, 6H, CH CH O), 1.35–2.16
H
3
3
2
CH CH᎐), 3.85–3.98 [m, CH(OBn)], 3.99–4.14 (m, 4H,
2
[
3
3
m, 4H, CH CH P(O)], 2.44 (d, J 6.6, 2H, NCH ), 3.41 and
2
2
2
CH CH O), 4.56 and 4.66 (AB, J 11.49, 2H, CH Ph), 6.78
3
2
AB
2
.81 (AB, JAB 13.4, 4H, NCH Ph), 3.66–3.74 [m, 1H, CH(OH)],
2
(
ddt, degenerated to dq, J 6.9, 23.7, 1H, ᎐CHP), 7.23–7.34 (m,
᎐
.98–4.13 (m, 4H, CH CH O), 7.22–7.38 (m, 10H, aromatic);
3
2
6
H, CH᎐CHP and aromatic); δC (75.5 MHz, CDCl ): 12.41
᎐
3
1
δ (50.3 MHz, CDCl ): 16.31, 16.42 (CH CH O), 21.66 (d, J
C
3
3
2
C–P
(
CH CH N), 15.28, 15.54 (CH CH O), 31.92, 32.07 (CH -
3 2 3 2 2
1
5
1
42.3, CH P), 27.38 (CH ), 58.43 (NCH Ph), 58.70 ( NCH ),
2 2 2 2
CH᎐CH), 48.20 (CH CH N), 58.04 ( NCH ), 61.79, 61.86,
᎐
3
2
2
9.05, 59.53, 61.37, 61.49 (CH CH O), 66.7, 67.06 [CH(OH)],
3
2
6
1.92 (CH CH O), 72.72 (CH Ph), 128.02 (d, J
178.5,
3
2
2
C–P
27.24, 128.38, 128.95 (aromatic), 138.33 (aromatic ipso).
᎐
CHP), 127.70, 128.13, 128.57, 139.62 (aromatic), 144.53 (d,
᎐
3
JC–P 11.1, CH᎐CHP).
᎐
Diethyl
4-(N,N-dibenzylamino)-3-hydroxy-1-phenylbutyl-
phosphonate 7b. (Reaction solvent: DME.) Pale yellow oil (yield:
N,N-Dibenzyl-3-chloro-2-hydroxypropylamine 5
Ϫ1
7
1%); R 0.63 (CHCl –MeOH, 20 : 1); ν (neat)/cm : 3388
f 3 max
Dibenzylamine (15.00 g, 0.076 mol) and 1-chloro-2,3-epoxy-
(OH), 3062, 3028, 2982, 2931, 2906, 2800, 1495, 1453, 1369,
propane 4 (7.00 g, 0.76 mol) were dissolved in methanol (100
cm ) and stirred at room temperature for 24 h. The reaction
1234 (P᎐O), 1056, 1028, 795, 751, 700. Found: N, 2.70; P,
᎐
3
ϩ
6.40%; (M ϩ 1) 482.6. C H O NP requires: N, 2.91; P,
28
36
4
mixture was concentrated under vacuum and the residue
was purified by column chromatography to give 5 as a pale
yellow oil (yield: 15.00 g, 68%); R 0.6 (CHCl –hexane, 5 : 1)
6.43%; M, 481.6; δ (81 MHz, CDCl ): 30.07, 29.04 (11 : 10);
P
3
δH (200.13 MHz, CDCl ): 1.01–1.33 (2 × m, 6H, CH CH O),
3
3
3
1.78–2.51 [m, 5H, NCH CH CH(Ph)], 3.33 and 3.71 (AB, J
f
3
2
2
AB
ϩ
Found: C, 70.06; H, 6.87; N, 4.83; Cl, 12.68%; M , 289.8.
13.3, 4H, NCH Ph), 3.79–3.88 [m, 1H, CH(OH)], 3.99–4.07 (m,
2
J. Chem. Soc., Perkin Trans. 1, 2001, 1086–1090
1089

View Article Online
4
H, CH CH O), 7.21–7.29 (m, 15H, aromatic); δ (75.5 MHz,
CH(OH)], 3.37 and 3.85 (AB, JAB 13.4, 4H, CH Ph), 3.44–3.76
3
2
C
2
CDCl ): 15.84, 15.99, 16.12 (CH CH O), 34.76 [CH CH(Ph)],
[m, CH(OH)], 4.03–4.15 (m, 4H, CH CH O), 5.67 (ddt, J 17.1,
3
3
2
2
3
2
3
5
9.93 [d, JC–P 137.12, CH(Ph)], 40.27 [d, JC–P 139.15, CH(Ph)],
1.6, JH–P 20.9, 1H, ᎐CHP), 6.76 (ddt, J 17.1, 6.5, JH–P 22.0, 1H,
CH᎐CHP), 7.21–7.44 (m, aromatic); δ (50.32 MHz, CDCl ):
8.16 and 58.27 (NCH Ph), 59.67 ( NCH ), 61.57–62.45
2
2
᎐
C
3
(
6 lines, CH CH O), 63.82 [d, J 15.4, CH(OH)], 65.18 [d,
16.43, 30.08, 30.53, 32.71, 58.46, 59.49, 61.55, 66.17, 117.07 (d,
3
2
C–P
JC–P 11.6, CH(OH)], 126.92, 128.67, 128.77, 128.91, 129.12,
29.25, 129.42, 129.56, 135.25 (d, J 6.8, Ph, C-ipso), 136.26
JC–P 187.0, ᎐CHP), 127.38, 128.49, 129.05, 138.38 (aromatic),
1
153.30 (CH᎐CHP).
᎐
(
d, J 6.8, Ph, C-ipso), 138.19 (C-ipso PhCH N).
2
Acknowledgements
Tetraethyl 4-(N,N-dibenzylamino)-3-hydroxybutan-1-ylidene-
bis(phosphonate) 7e. (Reaction solvent: THF.) Pale yellow
The work was supported (in part) by the Polish State Com-
mittee for Scientific Research Nr 3T09A 038 09. The authors
are grateful to Professor Jan Michalski for his continuous
interest in this study and fruitful discussions.
oil (yield: 32%); Rf 0.34 (CHCl –MeOH, 20 : 1). Found:
3
C, 57.44; H, 7.72; N, 2.37; P, 10.57%. C H P O N (541.55)
26
41
2
7
requires: C, 57.67; H, 7.63; N, 2.59; P, 11.44%; MS (FAB): 542.3
ϩ
ϩ
Ϫ1
(
M ϩ 1), 512.2 (M Ϫ C H ); ν (neat)/cm : 3402 (OH),
2 5 max
2
983, 2933, 2909, 2800, 1651, 1451, 1495, 1452, 1392, 1242
᎐
References
(
P᎐O), 1165, 1028, 974, 800, 750, 700, 526; δP (127.5 MHz,
CDCl ): 24.43, 24.71; δH (500 MHz, CDCl ): 1.21–1.36 (m,
1 J. Gorzynski-Smith, Synthesis, 1985, 629; R. M. Hanson, Chem.
Rev., 1991, 91, 437 and references cited therein.
3
3
1
2H, CH CH O), 1.71–2.11 (m, 2H, CH CHP), 2.40–2.50 (m,
3
2
2
2
J. Almena, F. Foubelo and M. Yus, Tetrahedron, 1994, 50, 5775 and
references cited therein.
R. H. Higgins, W. J. Faircloth, R. G. Baughman and Q. L. Eaton,
J. Org. Chem., 1994, 59, 2172.
2
H, NCH CH), 2.61–2.73 [m, 1H, CHP(O)], 3.51 and 3.72
2
(
AB, J 13.5, 4H, CH Ph), 3.56 (s, 1H, OH), 4.03–4.11 [m, 1H,
2
3
CH(OH)], 4.13–4.18 (m, 8H, CH CH O), 7.23–7.35 (m, 10H,
3
2
aromatic); δ (125.77 MHz, CDCl ): 16.72, 16.77 (CH CH O),
C
3
3
2
4 P. Kafarski and B. Lejczak, Phosphorus Sulfur Silicon Relat. Elem.,
1991, 63, 193; W. K. Sietsema and F. H. Ebetino, Expert Opin.
Invest. Drugs, 1994, 3, 1255.
3
1.38 (CH CHP), 33.29 (t, J
133.2), 58.94 (PhCH ), 59.87
C–P 2
2
[
NCH CH(OH)], 62.85–63.42 (m, CH CH O), 66.34–66.39
2
3
2
5
For examples see: G. Lavielle and G. Sturtz, Bull. Soc. Chim. Fr.,
[m, CH(OH)].
1970, 1369; S.-K. Chung and D.-H. Kang, Tetrahedron: Asymmetry,
997, 5, 3027; J. K. Myers and E. N. Jacobsen, J. Am. Chem. Soc.,
1
Reaction of the lithiated allylphosphonate 2f with N,N-dibenzyl-
,3-epoxypropylamine 6
1999, 121, 8959.
2
6 V. R. Gaertner, Tetrahedron Lett., 1964, 141; V. R. Gaertner, J. Org.
Chem., 1967, 32, 2972.
According to the above general procedure, lithiated diethyl
allylphosphonate 2f was reacted in two different solvents.
7
8
9
J. Heli n´ ski, Z. Skrzypczy n´ ski and J. Michalski, Tetrahedron Lett.,
1995, 36, 9201.
A. Bakalarz, J. Heli n´ ski, B. Krawiecka, J. Michalski and M. J.
Potrzebowski, Tetrahedron, 1999, 55, 12211.
(
a) Reaction in THF. Diethyl 4-(N,N-dibenzylamino)-3-
M. Karikomi, T. Yamazaki and T. Toda, Tetrahedron Lett., 1993, 34,
hydroxy-1-vinylbutylphosphonate 7f was obtained as a mixture
1
787.
of two diastereoisomers. Pale yellow oil (yield: 66%); R 0.58
10 H. Tanaka, M. Fukui, K. Haraguchi, M. Masaki and T. Miyasaka,
f
(
CHCl –MeOH, 20 : 1). Found: N, 3.25; P, 7.18%. C H NO P
Tetrahedron Lett., 1989, 30, 2567.
3
14 34
4
ϩ
requires: N, 3.26; P, 7.00%; MS FAB 432.4 (M ϩ 1); νmax(neat)/
cm : 3393 (OH), 2982, 2932, 2908, 2801, 1636, 1494, 1452,
1
1
1 S. Racha, Z. Li, H. El-Sabbagh and E. Abushanab, Tetrahedron
Lett., 1992, 33, 5491; Z. Li, S. Racha, L. Dan, H. El-Sabbagh and
E. Abushanab, J. Org. Chem., 1993, 58, 5779.
Ϫ1
240 (P᎐O), 1055, 1027, 965, 749, 700, 645; δ (121.49 MHz,
᎐
P
1
2 P. Page, C. Blonski and J. Perié, Tetrahedron, 1996, 52, 1557.
CDCl ): 30.03, 29.38 (11 : 10); δH (300.13 MHz, CDCl ): 1.27,
3
3
13 (a) M. Maleki, J. A. Miller and O. W. Lever, Tetrahedron Lett., 1981,
22, 3789; (b) A. M. M. M. Phillips and T. A. Modro, Phosphorus,
Sulfur Silicon Relat. Elem., 1991, 55, 41.
1
2
3
.29, 1.30 (3 × t, J 7.1, 7.1, 5.3, 6H, CH CH O), 1.55–1.98 [m,
3 2
H, CH CH(CH᎐CH )P], 2.35–2.54 (m, 2H, NCH ), 2.59–
2
2
2
.00 [m, 1H, CH(CH᎐CH )P], 3.23 and 3.97 (AB, J 13.4, 4H,
1
4 D. A. Evans, J. M. Takacs and K. M. Hurst, J. Am. Chem. Soc.,
979, 101, 371.
᎐
2
AB
1
NCH Ph), 4.03–4.18 (m, 4H, CH CH O), 5.07–5.26 (m, 2H,
CH᎐CH ), 5.53–5.84 (m, 1H, H C᎐CHC), 7.15–7.39 (10H,
aromatic); δ (50.3 MHz, CDCl ): 15.95, 16.06 (CH CH OP),
2
3
2
1
5 H. Al-Badri, E. About-Jaudet, J. C. Combret and N. Collignon,
Synthesis, 1995, 1401; H. Al-Badri, E. About-Jaudet, J. C. Combret
and N. Collignon, Synthesis, 1994, 1972; H. Al-Badri, E. About-
Jaudet, J. C. Combret and N. Collignon, Tetrahedron Lett., 1995, 36,
393.
6 C. Y. Yuan, J. C. Yao and S. S. Li, Phosphorus, Sulfur Silicon Relat.
Elem., 1990, 53, 21; C. Y. Yuan, J. C. Yao and S. S. Li, Phosphorus,
Sulfur Silicon Relat. Elem., 1991, 55, 121.
᎐
2
2
C
3
3
2
3
2.98 and 33.26 [2 × d, J 3.4, CH CH(CH᎐CH )], 38.75 [d,
2 2
1
1
JC–P 135.0, (CH ᎐CH)CHP], 38.79 [d, JC–P 135.8, (CH ᎐
2
᎐
2
᎐
CH)CHP], 58.15, 58.29 (NCH Ph), 59.60 ( NCH ), 61.05–
6
1
1
2
2
1.89 (m, CH CH O), 63.78 [d, J 15.0, CH(OH)], 65.29
3 2
[d, J 12.4, CH(OH)], 118.00 (d, J 13.1, HC᎐CH ), 119.30
᎐
2
7 (a) A. M. M. M. Phillips and T. A. Modro, J. Chem Soc., Perkin
Trans. 1, 1991, 1875; (b) E. L. Muller, H. M. Roos and T. A. Modro,
J. Phys. Org. Chem., 1993, 64; (c) K. P. Gerber, H. M. Roos and
T. A. Modro, J. Mol. Struct., 1993, 296, 85.
(
(
(
d, J 13.9, HC᎐CH ), 126.77, 127.95, 128.57 (aromatic), 132.18
᎐
2
d, J 9.7, CH᎐CH ), 133.31 (d, J 10.3, CH᎐CH ), 138.24
aromatic ipso).
᎐
2
2
1
8 K. Kondo, A. Negishi and D. Tunemoto, Angew. Chem., 1974, 86,
4
15.
(
b) Reaction in toluene. Diethyl (E)-6-(N,N-dibenzylamino)-
1
9 A. H. Davidson, C. Earnshaw, I. Grayson and S. Warren, J. Chem.
Soc., Perkin Trans. 1, 1977, 1452.
20 D. H. Hua, R. Chan-Yu King, J. A. McKie and L. Myer, J. Am.
Chem. Soc., 1987, 109, 5026 and references cited therein.
5
-hydroxyhex-1-enylphosphonate 8 (60%) was obtained in a
mixture with phosphonate 7f (40%). δ (50.3 MHz, CDCl ): 7f:
2
of 7f : 8 was 10 : 15. From this mixture the pure phosphonate 8
was separated by repeated development of the mixture on a
preparative chromatographic plate. δ (121.49 MHz, CDCl ):
P
3
9.01, 28.62 (mixture of diastereoisomers), 8: 18.47. The ratio
2
1 S. Hanessian, D. Andreotti and A. Gomtsyan, J. Am. Chem. Soc.,
995, 117, 10393.
1
2
2 J. I. Grayson, S. Warren and A. T. Zaslona, J. Chem. Soc.,
Perkin Trans. 1, 1987, 967.
23 G. Sturtz, B. Corbel and J. P. Paugam, Tetrahedron Lett., 1976, 47.
24 J. K. Ergüden and E. Schaumann, Synthesis, 1996, 707.
P
3
1
1
8.47; δ (200.13 MHz, CDCl ): 1.25–1.38 (m, 6H, CH CH O),
H
3
3
2
.39–1.49 (m, 2H,
NCH ), 2.18–2.50 [m, 4H, CH CH -
2
2
2
1
090
J. Chem. Soc., Perkin Trans. 1, 2001, 1086–1090