A concise synthesis of 4-vinylphencyphos

Article abstract of DOI:10.1055/s-0032-1318453

A fast and clean procedure has been found to prepare the 4-vinyl derivative of enantiomerically pure 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphinan- 2-oxide, commonly known as phencyphos. This cyclic phosphoric acid is a popular acidic resolving agent. Functionalization opens a route to attachment to surfaces. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318453

770▌
LETTER
lAetteCr oncise Synthesis of 4-Vinylphencyphos
A Concise Synthesis of 4-Vinylphencyphos
Maarten W. van der Meijden,a Klaus Wurst,b Richard M. Kellogg*a
a
Syncom BV, Kadijk 3, 9747 AT Groningen, The Netherlands
Fax +31(50)5757399; E-mail: r.m.kellogg@syncom.nl
b
Institut für Allgemeine Anorganische und Theoretische Chemie, Universität Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
Received: 10.01.2013; Accepted after revision: 21.02.2013
duction of the carbon framework of 1 (see further). Intro-
duction of the vinyl group at a late stage by cross-coupling
with a suitable derivative of 1 was seen as the best ap-
proach. We chose to prepare a 4-bromo-substituted deriv-
Abstract: A fast and clean procedure has been found to prepare the
4-vinyl derivative of enantiomerically pure 2-hydroxy-5,5-dimeth-
yl-4-phenyl-1,3,2-dioxaphosphinan-2-oxide, commonly known as
phencyphos. This cyclic phosphoric acid is a popular acidic resolv-
ing agent. Functionalization opens a route to attachment to surfaces. ative. The synthesis of enantiomerically pure brocyphos 5
is illustrated in Scheme 1.
Key words: Hiyama coupling, resolving agent, phosphoric acid,
chiral
Bromobenzaldehyde 2 was allowed to react under strong-
ly basic conditions with isobutyraldehyde (3) to give diol
4, the result of a Claisen condensation followed by Can-
nizzaro reaction.1 The product 4 was treated with POCl3
and the resulting acid chloride was hydrolyzed to provide
5 after acidification. This compound has not been de-
scribed previously in the literature but was prepared ac-
cording to experimental conditions described for similar
compounds.1 Resolution was performed using quinine as
a resolving agent. Compound 5 was enantiomerically pure
as established by chiral HPLC (see experimental).
The conformationally rigid cyclic phosphoric acid, phen-
cyphos 1, and derivatives thereof in enantiomerically pure
form are known to be excellent resolving agents for vari-
ous basic compounds.1,2
O
O
OH
O
P
An X-ray crystal structure determination was performed
on the obtained (+)-enantiomer of compound 5. The com-
pound crystallizes as a monohydrate in the orthorhombic
space group P212121 and is therefore likely a conglomer-
ate. The absolute configuration was confirmed by the
Flack parameter19 of 0.01(1), which allows assignment of
5 as S (see Figure 1). Figure 2 shows also the hydrogen
bonding scheme, which forms a column along the crystal-
lographic a-axis with O–O distances between 246–273
pm (246 pm for O5–O3 and 268 or 273 pm between O5
and O4A or O4B). The six-membered ring adopts the ex-
pected chair conformation.
1
Figure 1 Phencyphos
We have been particularly interested in the development
of derivatives of 1 that lend themselves for attachment to
solids.3–6 A vinyl substituent is particularly attractive. At-
tachment strategies include coupling to a thiol-functional-
ized silicon surface7–9 or preparation of polymer-bound
materials that might be used both for resolutions or as cat-
alysts. We also note that chiral phosphoric acids, especial-
ly those derived from bisnaphthol, are known to catalyze
a wide range of reactions.10–18
Somewhat surprisingly, only the enantiomerically pure
form crystallizes as a hydrate whereas the racemate crys-
tallizes in non-hydrated form. The crystal structure of the
racemate has not been determined. We note that both ra-
Early introduction of a vinyl substituent is not attractive
owing to the rather rigorous conditions required for pro-
1) POCl3, CH2Cl2
reflux
2) NaOH, H2O
95 °C
OH
O
O
P
KOH
EtOH
50 °C
O
O
O
OH OH
+
3) HCl, H2O
r.t.
89% over 3 steps
4) resolution with quinine
IPA
29%
Br
Br
Br
2
3
4
(S)-5
32% yield, >98% ee
Scheme 1 Synthesis of brocyphos 5
SYNLETT 2013, 24, 0770–0772
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318453; Art ID: ST-2013-B0033-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Concise Synthesis of 4-Vinylphencyphos
771
cemic 1 as well as the pure enantiomers can occur as
monohydrates and that racemic 1 has been shown to be a
conglomerate that may be resolved by preferential crystal-
lization.20
O
OH
O
O
OH
O
P
P
MgBr
ZnCl2
O
O
X
PdCl2(dppf)2⋅CH2Cl2
Br
THF
r.t.
5
6
Scheme 3 Attempted Negishi coupling of brocyphos 5 with divinyl-
zinc
1,1′-Bis(diphenylphosphino)ferrocene palladium(II)di-
chloride dichloromethane complex [PdCl2(dppf)2
CH2Cl2] was used as catalyst.26 A mixture of mainly start-
ing material and ca. 20% of an unidentified side product
was obtained.
Figure 2 X-ray crystal structure of (S)-(+)-brocyphos monohydrate
Introduction of the vinyl group via a vinyltin reagent in a
Stille coupling was another possibility (Scheme 4).
Cross-coupling with 5 with a vinyl equivalent was expect-
ed to provide the desired product 6. This proved to be less
easy than expected. Kumada coupling of (S)-5 (see
Scheme 2) using vinyl Grignard reagent was first ex-
plored.
O
OH
O
O
OH
O
P
P
O
O
Bu3Sn
Pd(PPh3)4
DMF
60 °C
Br
6
5
O
OH
O
O
OH
O
<50% conversion
P
P
O
O
Scheme 4 Stille coupling to prepare vinylphencyphos 6
MgBr
PdCl2(dppf)2⋅CH2Cl2
THF
–78 °C to r.t.
or
–78 °C to reflux
or
r.t. to reflux
or
Unfortunately, Stille coupling using tributyl(vinyl)tin and
Pd(PPh3)427 led to less than 50% conversion. Purification
problems similar to those encountered in Kumada cou-
pling were encountered. In addition, the toxicity of the tri-
alkyltin compounds formed as product makes this
alternative less attractive.
Br
5
6
r.t.
These disappointing results led to consideration of other
alternatives. We felt that the phosphoric acid embedded in
5 might be the source of many of the problems. Hiyama
coupling,28 which involves the use of a vinyl silane under
basic conditions, was a particularly interesting alternative.
Our attention was drawn to a paper in which the reaction
of a trialkoxyvinyl silane with, for example, 4-bromoben-
zoic acid is reported.29 As shown in Scheme 5, the reac-
tion with 5 was carried out (in a pressure tube) in aqueous
sodium hydroxide, under which conditions the phosphoric
acid segment would be in a neutral salt form before any re-
action began. In fact, this reaction of 5 (racemate or pure
enantiomer) catalyzed by Pd(OAc)2 proceeded in virtually
quantitative yield with complete retention of enantiopuri-
ty as established by chiral HPLC. The absolute configura-
tion of the product should be S, identical to starting
material 5. This approach is clearly a very effective way
to prepare 4-vinylphencyphos 6, which was obtained pure
after extraction. The reaction has been carried out on 6-
mmol scale. Further scale-up is not expected to be a prob-
lem. The reagents are cheap and the reaction conditions
quite simple.
max. ca. 50% conversion
Scheme 2 Kumada coupling of brocyphos (S)-5
Kumada coupling, although not described for phosphoric
acids, has been reported for an unprotected carboxylic ac-
id.21 In fact, there are very few cross-coupling reactions
described for molecules containing an unprotected phos-
phoric acid. Unfortunately, Kumada coupling with 5 stops
at maximally ca. 50% conversion. Addition of extra
equivalents of Grignard reagent, change of catalyst to
NiCl2(PPh3)2, PdEnCat, Pd(di-tert-BP-ferrocene) or
PdCl2(MeCN)2/combiphos, change of temperature, or ad-
dition of tris(acetylacetonato) iron(III) [Fe(acac)3]22 in
THF did not improve the conversion. Purification of 6 was
troublesome: crystallization was not effective and use of
preparative HPLC led to loss of most material despite the
promising peak separation seen in the HPLC trace.
Negishi coupling to introduce the vinyl group23–26 (see
Scheme 3) was attempted using brocyphos 5 with a zinc
reagent, prepared in situ from vinylmagnesium bromide
and ZnCl2.26
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 770–772

772
M. W. van der Meijden et al.
LETTER
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O
OH
O
O
OH
O
P
P
O
O
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NaOH, H2O
140 °C
Br
(S)-6
(S)-5
3 h
quant.
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Scheme 5 Hiyama coupling of (S)-(+)-brocyphos 5
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Enantiomerically pure (S)-vinylphencyphos 6 is a remark-
ably stable compound, obtained as a white solid. It can be
readily handled and stored for long periods without de-
composition or polymerization. This stability of a styrene
derivative that contains also a strong acid stands in con-
trast to observations made, for example, with 4-vinylben-
zoic acid and 4-vinylphenylacetic acid30 as well as 4-
vinylbenzylphosphonic acid.31 The latter compound is
stabilized by addition of a radical inhibitor. These styrene
derivatives are reported to be quite sensitive to polymer-
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Acknowledgment
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The analytical department at Syncom BV carried out the analysis.
The research leading to these results has received funding from the
European Community’s Seventh Framework Programme under
grant agreement no. NMP4-SL-2008-214340, project RESOLVE.
Supporting Information for this article is available online at
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Synlett 2013, 24, 770–772
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