Stereospecific addition of H-P bond to alkenes: A simple method for the preparation of (RP)-phenylphosphinates

Article abstract of DOI:10.1021/jo051582b

A variety of functionalized optically pure (R_p)- alkylphenylphosphinates are readily prepared by stereospecific radical or base-catalyzed additions of the easily available (R_p)-menthyl phenylphosphinate to alkenes.

Full text of DOI:10.1021/jo051582b

by using radical5f or base-catalyzed reactions to give a
variety of (-)-menthyl (RP)-alkylphenylphosphinates 2 in
good yields (eq 1). Although Mislow and co-workers
briefly reported that a diastereomerically rich 1 added
stereospecifically to cyclohexene in the presence of diben-
zoyl peroxide,5f applications of this kind of radical reac-
tion for the synthesis of optically active alkylphenylphos-
phinates have not been investigated. In addition, the
base-catalyzed stereospecific addition of (RP)-1 to alkenes
appears to be new.
Stereospecific Addition of H-P Bond to
Alkenes: A Simple Method for the
Preparation of (RP)-Phenylphosphinates
Li-Biao Han* and Chang-Qiu Zhao
National Institute of Advanced Industrial Science and
Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
libiao-han@aist.go.jp
Received July 29, 2005
A variety of functionalized optically pure (RP)-alkylphen-
ylphosphinates are readily prepared by stereospecific radical
or base-catalyzed additions of the easily available (RP)-
menthyl phenylphosphinate to alkenes.
AIBN-Induced Stereospecific Radical Additions
of (RP)-1 to Alkenes. In the presence of AIBN, (RP)-1
can add stereospecifically to monosubstituted alkenes to
give the corresponding adducts in high yields. Thus, as
shown by 1H NMR spectroscopy, though non-addition
products could be detected from an equimolar mixture
of (RP)-1 (1.0 mmol) with 1-octene (1.0 mmol) in benzene-
d6 (0.5 mL) after heating at 80 °C for 16 h, when a trace
amount of AIBN (10 mol %) was added, the addition
proceeded efficiently to give menthyl octylphenylphos-
phinate 2a in 78% yield as a single diastereomer (which
has an RP configuration at phosphorus as deduced from
the experiment described below) (eq 2). On the other
hand, a similar addition using a diastereomeric mixture
of 1 (RP/SP ) 55/45) gave a diastereomeric mixture of 2a
with a ratio of RP/SP ) 55/45, confirming that this AIBN-
initiated radical addition proceeds stereospecifically.3
Note that the stereochemistry of (RP)-1 was maintained
intact when it was heated in benzene at 80 °C for 16 h.
In the presence of 10 mol % AIBN, however, ca. 2% of
(SP)-1 was detected under similar conditions. The fact
that only (RP)-2a was formed and no racemization of
(RP)-1 could be observed during the addition may indicate
that, although there are two possible competing routes
for the P-centered radical intermediate (i.e., racemization
and stereospecific addition to alkene), the latter was
preferentially favored.6,7
Optically active -stereogenic compounds have attracted
growing attention because of their novel applications in
organic synthesis and bioorganic chemistry.1 However,
their preparation usually requires tedious procedures.1e,2
By adopting a modified procedure of Mislow and co-
workers,3 pure (-)-menthyl (RP)-phenylphosphinate 1
(RP/SP > 99/1) can be easily prepared on a large scale.4,5
We have revealed that a palladium-catalyzed addition
of (RP)-1 to alkynes took place stereospecifically to give
high yields of (RP)-alkenylphosphinates.4 However, at-
tempts to extend this strategy to alkenes failed. As a
complement of the palladium-catalyzed additions to al-
kynes,4 herein we report that highly stereospecific addi-
tion of (RP)-1 to alkenes can be alternatively achieved
(1) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-
Interscience: New York, 2000. (b) Sasaki, M. In Chirality in Agro-
chemicals; Kurihara, N., Miyamoto, J., Eds.; Wiley & Sons: Chichester,
1998; pp 85-139. (c) Imamoto, T. In Handbook of Organophosphorus
Chemistry; Engel, R., Ed.; Marcel Dekker: New York, 1992; Chapter
1. (d) Kagan H. B.; Sasaki, M. In Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; Wiley & Sons: New York, 1990; Vol.
1, Chapter 3. (e) Dubrovina, N. V.; Bo¨rner, A. Angew. Chem., Int. Ed.
2004, 43, 5883.
(2) (a) Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94, 1375.
(b) Haynes, R. K.; Au-Yeung, T.-L.; Chan, W.-K.; Lam, W.-L.; Li, Z.-
Y.; Yeung, L.-L.; Chan, A. S. C.; Li, P.; Koen, M.; Mitchell, C. R.;
Vonwiller, S. C. Eur. J. Org. Chem. 2000, 3205. (c) Free Man, R. N.;
Mitchell, C. R.; Vonwiller, S. C. J. Org. Chem. 1994, 59, 2919.
(3) Farnham, W. B.; Murray, R. K.; Mislow, K. J. Am. Chem. Soc.
1970, 92, 5809.
(4) Han, L.-B.; Zhao, C.-Q.; Onozawa, S.; Goto, M.; Tanaka, M. J.
Am. Chem. Soc. 2002, 124, 3842. (RP)-1 is available on request (Fax:
+81-29-861-4511).
(5) Known transformations of diastereomeric 1. Stereospecific meth-
ylation with MeI: (a) Reference 3. Addition to aldehydes: (b) Imamoto,
T.; Oshilki, T.; Onozawa, T.; Matsuo, M.; Hikosaka, T.; Yanagawa, M.
Heteroatom Chem. 1992, 3, 563. (c) Cai, J.; Zhou, Z.; Zhao, G.; Tang,
C. Heteroatom Chem. 2003, 14, 312. Addition to cyclohexene in the
presence of dibenzoyl peroxide: (d) Benschop, H. P.; Platenburg, D.
H. J. M. J. Chem. Soc., Chem. Commun. 1970, 1098. (e) Berg, G. R. V.
D.; Platenburg, D. H. J. M.; Benschop, H. P. J. Chem. Soc., Chem.
Commun. 1971, 606. (f) Farnham, W. B.; Murray, R. K.; Mislow, K. J.
Chem. Soc., Chem. Commun. 1971, 146.
10.1021/jo051582b CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/20/2005
J. Org. Chem. 2005, 70, 10121-10123
10121

TABLE 1. Stereospecific Radical Addition of (RP)-1 to
This radical addition is highly affected by the concen-
trations of the substrates, and a high concentration of
the substrates accelerates the reaction. Thus, as deter-
mined by 1H NMR spectroscopy, while 68% yield of
(RP)-2a was obtained at 0.5 M concentration of the sub-
strates, 78 and 92% yields of the adduct were obtained
at concentrations of 1 and 2 M, respectively.
Alkenesa
The configuration at phosphorus of the adduct 2a is
determined to be RP on the basis of the following reaction.
Thus, 45% yield of 2b was obtained by a similar radical
addition of (RP)-1 to an enantiomerically pure vinylphos-
phinate (RP)-3 (eq 3). The 31P NMR spectroscopy of 2b
displays only one signal, indicating that the two phos-
phorus atoms have the same RP configuration.
This stereospecific radical addition can be successfully
applied to other alkenes to produce valuable optically
pure phosphinates in good yields (Table 1). It is note-
worthy that a variety of functionalities such as hydroxyl,
alkoxy, acetoxyl, thio, phosphino (PR2), phosphinoyl
(Ph2P(O)), silyl, and stannyl groups were tolerant under
the reaction conditions, and the corresponding multi-
functionalized adducts were obtained in good yields.
Compared to terminal alkenes, the additions to simple
internal alkenes proceeded slowly. Thus, the reaction
with a large excess amount of cyclohexene, for example,
required 40 h of heating to get an acceptable yield of the
adduct (run 15). This difference in reactivity between
terminal and internal alkenes, however, enables the
selective introduction of the phosphinoyl group to the
terminal carbon-carbon double bond when a terminal
and an internal carbon-carbon double bond coexist in a
substrate. For example, the reaction of 3-cyclohex-
enylethene with (RP)-1 (run 10) gave the addition product
to the terminal CdC bond selectively.8 Expecting good
diastereoselectivities when new chiral carbon centers are
generated,9 we also conducted reactions with 2,3-dihy-
drofuran and others (runs 11-14). However, the diaste-
reoselectivities were not satisfactory under the present
conditions.9 As generally seen in radical additions of
P(O)-H bonds to alkens,10 1 did not add to aromatic
alkenes such as styrene and alkenes with an electron-
withdrawing group (vide infra), where polymerization of
the alkenes took place.
a R ) (-)menthyl; unless otherwise noted, an equimolar (RP)-1
and an alkene were heated at 80 °C in the presence of 10 mol %
AIBN under the conditions shown in the table. b Yields refer to
isolated yields. c H2O2 was added to the reaction mixture to convert
2f to 2g. The yield refers to that of 2g. d A 46/54 diastereomer
mixture. e A 47/53 diastereomer mixture. f A 35/65 diastereomer
mixture. g A 48/52 diastereomer mixture. h Run in a sealed tube
with 5 equiv of the alkene.
(6) A careful analysis of the reaction mixtures revealed that ca. 3%
of a byproduct was also formed (estimated from 31P NMR spectroscopy).
This byproduct, however, is not (SP)-2a, but appears to be that
generated by the addition dimerization of 1-octene with (RP)-1.
(7) As expected, when the alkene was consumed, racemization of
(RP)-1 took place. For example, (SP)-1 was observed in the remaining
1 for a reaction using an excess of (RP)-1 (1.2 equiv to 1-octene) under
the reaction conditions of eq 2.
(8) Although not distinguishable on 1H or 31P NMR spectroscopy,
compound 2l is assumed to be a diastereomeric mixture because of
the chiral carbon at the cyclohexene ring.
Stereospecific Michael Additions of (RP)-1 to
Electron-Deficient Alkenes. As described above, the
radical additions of (RP)-1 to electron-deficient alkenes
such as methyl acrylate or acrylonitrile, which produce
more valuable functionalized phosphorus compounds,
hardly proceed. Since a base-catalyzed Michael addition
of P(O)-H bonds to electron-deficient alkenes is well-
(9) For stereoselective radical additions, see: Sibi, M. P.; Manyem,
S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263 and references therein.
Improved diastereoselectivies are expected if the current reactions can
be performed under milder conditions. Optimization of the reaction
conditions is now in progress.
(10) Organic Phosphorus Compounds; Kosolapoff, G. M., Maier, L.,
Eds.; Wiley-Interscience: New York, 1972; Vol. 4, p 297.
10122 J. Org. Chem., Vol. 70, No. 24, 2005

SCHEME 1
phosphines by stereospecific reductions with LiAlH4 or
silanes,1a 2b is a versatile precursor for a variety of C2-
symmetric bidentate phosphorus compounds. In conclu-
known,10 we decided to investigate the addition of (RP)-1
in the presence of a base catalyst. However, since a rapid
racemization of (RP)-1 takes place under basic condi-
tions,11 the initial attempts were disappointing. Thus, the
t-BuONa-catalyzed addition of (RP)-1 to diethyl vinylphos-
phonate only gave a diastereomer mixture of 2h in 51%
yield (determined by 1H NMR) (Scheme 1). Accidentally,
however, we found that alkoxymagnesium halides are
excellent catalysts for this Michael addition of (RP)-1 to
produce the corresponding adducts efficiently and highly
stereospecifically. Thus, the EtOMgCl-catalyzed addition
of (RP)-1 to ethyl vinylphosphonate gave 2h in 87% yield
with an RP/SP ratio of 94/6. The diastereoselectivity was
further improved as bulky alkoxymagnesium chlorides
were used as the catalysts (i.e., ROMgCl/diastereoselec-
tivity: i-PrOMgCl/92% and t-BuOMgCl/ca. 99%). A sepa-
rate experiment confirmed that the exchange of the
alkoxy group of EtOMgCl with menthoxy of 1, but not
that of 2h, could take place to give a racemic EtO(Ph)-
P(O)H under the reaction conditions in the absence of
ethyl vinylphosphonate. As expected, similar transes-
terification was slow with bulky i-PrOMgCl, and no
transesterification was observed with t-BuOMgCl. The
formation of a trace amount of side products (EtO)2-
P(O)(CH2)2P(O)Ph(OR) (R ) Et, i-Pr) (ca. 3-5% yield) in
the addition reactions is in agreement with the above
observation. We assumed that this transesterification
process (i.e., the attack of alkoxy group at P(O)) might
cause, to some extent, the racemization of 1,1a and
therefore the bulky t-BuOMgCl gave the best selectivity.
Since t-BuOMgCl is not soluble in THF, handling of the
catalyst is somehow difficult. This, however, could be
overcome by employing (-)-MenOMgCl (Men represents
menthyl group) as the catalyst that is soluble in THF
and can give excellent yields and selectivity of the
addition product.
sion, a variety of (RP)-menthyl alkylphenylphosphinates
can be conveniently prepared by highly stereospecific
radical and/or base-catalyzed Michael additions of (RP)-1
to alkenes. This stereospecific addition of (RP)-1 to
alkenes is a complement to our previous reported metal-
catalyzed stereospecific additions to alkynes and fulfills
the strategy for the preparation of optically pure phos-
phinates by using the now readily available (RP)-1.
Experimental Section
AIBN-Induced Free Radical Addition of (RP)-(-)-Men-
thyl Phenylphosphinate 1a to 1-Octene: A Representative
Procedure for the Radical Additions. (RP)-1a (280 mg, 1.0
mmol), 1-octene (112 mg, 1.0 mmol,) and AIBN (16 mg, 0.1
mmol) were dissolved in 0.5 mL of dry benzene under nitrogen.
The resulting solution was heated at 80 °C for 16 h. The solvent
was evaporated under a reduced pressure to give an oil that was
subjected to purification on a preparative GPC instrument
(Japan Analytical Industry LC-908 equipped with 1H and 2H
columns) using CHCl3 as solvent to give pure 2a in 87% yield
(341 mg) as a colorless oil.
(-)-Menthoxy Magnesium Chloride Catalyzed Michael
Addition of (RP)-(-)-Menthyl Phenylphosphinate 1a to
Diethyl Vinylphosphonate: A Representative Procedure
for the Base-Catalyzed Michael Additions. To a mixture of
(RP)-1a (280 mg, 1.0 mmol) and diethyl vinylphosphonate (1.1
mmol, 180 mg) in THF (1 mL) was added menthoxy magnesium
chloride (0.1 mL, 1 M solution in THF). The resulting solution
was stirred at room temperature for 12 h. The solvent was
evaporated under a reduced pressure to give an oil that was
subjected to purification on a preparative GPC instrument
(Japan Analytical Industry LC-908 equipped with 1H and 2H
columns) using CHCl3 as solvent to give pure 2h in 87% yield
(387 mg) as a colorless oil.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (B) (Kakenhi
16350027) from Japan Society for the Promotion of
Science (JSPS). We thank Dr. Dae-Yon Lee for helping
arranging this manuscript.
As illustrated by eq 4, by using this strategy, a C2-
symmetric bidentate P-stereogenic phosphorus com-
pounds can be readily obtained. Thus, the (-)-MenOMgCl-
catalyzed addition of (RP)-1 to 3 gave (RP,RP)-2b selectively
in 87% isolated yield. Since 2b can be converted ste-
reospecifically into phosphine oxides12 and these phos-
phine oxides can be further converted to C2-symmetric
Supporting Information Available: Spectral and ana-
lytical data and copies of 1H NMR spectra of the addition
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051582B
(11) For a related base-induced racemization of optical active
P(O)-H compounds, see: Emmick, T. L.; Letsinger, R. L. J. Am. Chem.
Soc. 1968, 90, 3459.
(12) Koide, Y.; Sakamoto, A.; Imamoto, T. Tetrahedron Lett. 1991,
32, 3375.
J. Org. Chem, Vol. 70, No. 24, 2005 10123