CsOH-promoted epoxide ring-opening with phosphines: Mild and efficient synthesis of monohydroxyphosphines

Article abstract of DOI:10.1016/j.tetlet.2003.08.068

A mild and convenient synthesis of monohydroxyphosphines has been achieved by epoxide ring-opening using primary or secondary phosphines in the presence of cesium hydroxide, 4 ? molecular sieves and DMF at room temperature. These reaction conditions were

Full text of DOI:10.1016/j.tetlet.2003.08.068

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7579–7582
CsOH-promoted epoxide ring-opening with phosphines: mild and
efficient synthesis of monohydroxyphosphines
Daniel L. Fox, Ashlee A. Robinson, James B. Frank and Ralph Nicholas Salvatore*
Department of Chemistry, Western Kentucky University, 1 Big Red Way, Bowling Green, KY 42101-3576, USA
Received 9 July 2003; revised 16 August 2003; accepted 18 August 2003
Abstract—A mild and convenient synthesis of monohydroxyphosphines has been achieved by epoxide ring-opening using primary
,
or secondary phosphines in the presence of cesium hydroxide, 4 A molecular sieves and DMF at room temperature. These
reaction conditions were found to be highly regio- and stereoselective producing various monohydroxyphosphines exclusively in
moderate to high yields.
© 2003 Elsevier Ltd. All rights reserved.
Epoxides are versatile intermediates that serve as pre-
eminent building blocks in organic synthesis.1 Epoxides
can be opened under a variety of conditions, although,
the most practical and widely employed strategy for the
synthesis of 1,2-bifunctional compounds is via nucle-
ophilic ring-opening using a Lewis acid promoter or a
strong base.2 Epoxide ring-opening reactions with
carbanions3, alcohols,4 amines,5 and thiols6 have been
extensively studied, since they provide a suitable route
for the formation of CꢀC, CꢀO, CꢀN, and CꢀS s-
bonds, respectively. However, ring-opening reactions
with phosphorus nucleophiles (e.g. phosphines) have
received little attention. In conjunction with the ongo-
ing work in our laboratory toward the synthesis of
bidentate ligands as transition-metal-based catalysts,
monodenate hydroxyphosphines are of particular inter-
est.7 We found that pre-existing ring-opening protocols
using phosphines are hampered by the use of harsh
reagents,8 low reaction temperature,9 and result in
unsatisfactory yields.10 In this context, we herein dis-
close our results regarding a mild and convenient epox-
ide to monohydroxyphosphine ring-opening procedure
using primary and secondary phosphines.
dimethylformamide (DMF) in an inert nitrogen
atmosphere, various epoxides underwent facile ring-
opening using primary and secondary phosphines
(Scheme 1). The reaction was begun at 0°C and gradu-
ally allowed to warm to room temperature. We propose
that the reaction proceeds via the phosphide anion
weakly coordinated with the cesium cation (e.g. ‘naked
anions’), thereby exhibiting enhanced nucleophilicity
without the aid of a Lewis-acid promoter as a trigger
for the reaction.11 Moreover, these conditions were
found to be highly regio- and stereoselective, affording
various structurally diverse b-hydroxyphosphines in
moderate to high yields.
Initially, structurally diverse epoxides were probed to
test the feasibility of ring-opening reactions using a
secondary phosphine. Several examples illustrating this
simple and practical methodology are summarized in
Table 1. As a typical procedure, the preparation of
trans-2-PPh2(C6H10OH) was performed at 0°C by drop-
wise addition of cyclohexene oxide (1) (1.2 equiv.) to a
stirred solution of diphenylphosphine (1 equiv.), CsOH
(1 equiv.), in the presence of molecular sieves and
DMF. After the addition of 1 was complete, the dark
red-orange color immediately disappeared and turned
yellow. The reaction was quenched with water
In the presence of cesium hydroxide, activated pow-
,
dered 4 A molecular sieves, and anhydrous N,N-
Scheme 1.
Keywords: epoxides; phosphines; monohydroxyphosphine; cesium hydroxide; bidentate ligands.
* Corresponding author. Tel.: +1-270-745-3271; fax: +1-270-745-5361; e-mail: ralph.salvatore@wku.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.068

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D. L. Fox et al. / Tetrahedron Letters 44 (2003) 7579–7582
Table 1. CsOH-promoted epoxide ring-opening of various
epoxides using Ph2PH
dal ether (8) reacted efficiently offering similar yield
(entry 8). Epoxides containing heterocyclic groups also
proved successful. For example, furfuryl glycidal ether
(9) was subjected to ring-opening in the presence of
diphenylphosphine generating the appropriate b-phos-
phino-alcohol smoothly in good yield (entry 9).
Whereas the reaction of the in situ generated
diphenylphosphide anion with commercially available
(+)-limonene oxide (10), which is a mixture of cis- and
trans-epoxides, delivered only one (+)-trans-isomer as
an air-sensitive white solid after 24 h (entry 10).14
Interestingly, (−) a-pinene oxide, a crowded epoxide,
was subjected to this methodology, however, failed to
react with the phosphide anion, even under heating
conditions.
With acceptable results in hand for ring-opening reac-
tions using a secondary phosphine, we next turned our
focus to performing similar reactions with a primary
phosphine, phenylphosphine. Due to the tendency of
primary phosphorus compounds to rapidly oxidize, we
were pleased to find that our protocol described for
secondary phosphines was viable for the primary as
well. Therefore, several epoxides were reacted with
phenylphosphine to determine the synthetic utility of
the conditions. As delineated in Table 2, reaction of
phenylphosphine with numerous epoxides gave the
desired monohydroxyphosphine in moderate to excel-
lent yields. In the case of cyclopentene oxide (11), a
meso-epoxide, ring-opened products were completely
anti-stereoselective giving only the trans isomers after
23 h (Table 2, entry 1). Comparatively, cyclohexene
oxide (1) reacted efficiently to generate products which
were obtained as a single diastereomer also possessing
trans-stereochemistry (entry 2). An epoxide containing
an aliphatic chain, 1,2-epoxyhexane (2), likewise under-
went ring-opening producing the preferred result in a
high yield (entry 3). Coming full circle, epoxides con-
taining different functionality and steric constraints
were again examined to observe whether the existing
protocol was effective. Isopropyl glycidal ether (5) was
reacted with phenyl phosphine to give rise to the corre-
sponding monohydroxyphosphine in moderate yield
(entry 4). Similarly, 6 underwent the desired ring-open-
(degassed with nitrogen), extracted with dichloro-
methane, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The residue was subse-
quently purified by recrystallization (THF/hexane),
affording trans-2-(diphenylphosphino)cyclohexanol as
the sole reaction product in moderate yield (Table 1,
entry 1).12 To our delight, cis-2-(diphenylphos-
phino)cyclohexanol was not detected, demonstrating
the high stereoselectivity embedded in this protocol. To
test issues of regioselectivity, several epoxides were
studied. In each case, as expected, nucleophilic ring-
opening occurred at the less substituted carbon (entries
2–3). With this data in hand, epoxides with additional
functionality were next investigated in order to provide
a more complete picture of the substrate versatility of
the epoxide partner. Similarly, reaction of
diphenylphosphine with both 1,2-epoxy-7-octene (4)
and allyl glycidal ether (5) generated the coupled prod-
ucts in yields of 62 and 50%, respectively (entries 4–5).
In each example, the terminal alkene was left intact.
Furthermore, no side products stemming from elimina-
tion, rearrangements, or oxidation of phosphorus were
detected in any example.13 Next, several epoxides con-
taining the ether moiety were examined to further
probe the limits of the proposed conditions. Isopropyl
glycidal ether (6) underwent facile ring-opening with
Ph2PH to afford the desired product in high yield after
72 h (entry 6). Reaction with styrene oxide (7) produced
the b-monohydroxyphosphine as the major product in
shorter reaction time (entry 7). Likewise, phenyl glyci-
Table 2. CsOH-promoted epoxide ring-opening of various
epoxides using PhPH2

D. L. Fox et al. / Tetrahedron Letters 44 (2003) 7579–7582
7581
References
ing to afford the product in a 42% yield after 43 h
(entry 5). Styrene oxide (7) also opened to produce the
coupled product in a moderate yield (entry 6). Finally,
(+)-limonene oxide (10) reacted with PhPH2 generating
the (+)-trans-isomer of PhPH(C6H10OH) in a 50% yield
after hydrolysis and purification (entry 7). All of the
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membered rings have traditionally proven more resis-
tant to opening than epoxides. Thus, the established
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strategy (Scheme 2).
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In conclusion, we report a mild and efficient method
for the preparation of monohydroxyphosphines using
cesium hydroxide monohydrate as the base of choice.
These improved procedures not only offer a novel
synthetic route to monohydroxyphosphines, but do so
regio- and stereospecifically. Furthermore, the mild,
near neutral reaction environment is an improvement
over the use of Lewis acid or strong base typically
needed to perform these ring-openings. Additionally,
the experimental conditions set forth herein show a
broad scope, as they proved equally useful for both
primary and secondary phosphines. Furthermore, the
ring-opening of oxetanes also proved successful using
the aforementioned experimental conditions. Applica-
tions of this methodology toward the preparation of
additional monohydroxyphosphines via use of chiral
epoxides are underway and their direct use in the
synthesis of coordination compounds are currently in
progress and will be reported in due course. Further-
more, ring-opening of azirdines with phosphines for the
synthesis of P,N-ligands will next be explored.
10. Quin, L. D. A Guide to Organophosphorus Chemistry;
Wiley-Interscience: New York, 2000.
11. It is plausible the reaction proceeds via the diphenylphos-
phide anion, which is prepared in situ by reaction of
Ph2PH and CsOH. The anion, presumably is weakly
coordinated to the cesium cation, hence, a ‘naked anion’
demonstrating enhanced nucleophilicity, as defined by the
‘cesium effect’. Preliminary observations during the
course of the reaction are consistent with previously
reported examples using other alkali metal counterparts.
However, since the cesium cation is weakly coordinated
to the phosphide anion, we cannot discount the role the
cesium cation may play in the ring-opening. Currently,
the mechanism is under investigation and these results
will be reported in due course. For formation of ‘naked
Acknowledgements
Financial support from the National Science Founda-
tion-Kentucky EPSCoR (596166) is gratefully acknowl-
edged, as is support from Western Kentucky
University. Also, we wish to thank Chemetall for their
generous supply of cesium bases.

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D. L. Fox et al. / Tetrahedron Letters 44 (2003) 7579–7582
anions’ by solvation of cesium ions which has been
186, 183, 108. Anal. calcd for C18H21OP: C, 77.08; H,
7.39. Found: C, 76.61; H, 7.44.
previously postulated and studied extensively in other
systems, see: (a) Dijkstra, G.; Kruizinga, W. H.; Kellogg,
R. M. J. Org. Chem. 1987, 52, 4230. (b) For reviews on
the ‘cesium effect’, see: Ostrowicki, A.; Vogtle, F. Topics
in Current Chemistry; 1991; Vol. 161. For formation of
alkyl metal diphenylphosphides, see: (c) Aguiar, A. M.;
Greenberg, H. J.; Rubenstein, K. E. J. Org. Chem. 1963,
28, 2091; (d) Fisher, C.; Mosher H. S. Tetrahedron Lett.
1977, 18, 2487; (e) Chatt, J.; Hart, F. A. J. Chem. Soc.
1960, 1378. (f) For Ph2PCs, see: Fluck, E.; Issleib, K. Z.
Naturforsch. B 1965, 20, 1123.
13. 31P NMR spectra were obtained for both crude and
purified products substantiating the claim for complete
specificity and purity of each monohydroxyphosphine
product. Side products stemming from elimination and
oxidation of the phosphine were not detected in an
example.
14. Commercially available (+)-limonene oxide is assumed to
1
be a 1:1 mixture of (+)-cis- and (+) trans-isomers, but H
NMR suggests a greater proportion of the trans-isomer.
For a similar result using LiPPh2, see: Newhall, W. F. J.
Org. Chem. 1964, 29, 185 and Ref. 9a.
12. For trans-2-(diphenylphosphino)cyclohexanol (Table 1,
entry 1): Air-sensitive white solid; mp: 144–146°C; 1H
NMR (270 MHz, CDCl3) l 0.90 (m, 1H), 1.20 (m, 2H),
1.40 (m, 1H), 1.62 (m, 1H), 1.71 (m, 2H), 2.08 (m, 1H),
2.34 (m, 1H), 2.68 (br s, 1H, OH), 3.47 (m, 1H), 7.32–
7.37 (m, 6H), 7.52 (m, 2H), 7.45 (m, 2H). 13C NMR (70
MHz, CDCl3) l 24.2, 25.8, 27.0, 35.1, 43.5, 71.9, 127.6,
127.9, 128.0, 132.5, 134.0, 137.3, 138.4. 31P NMR (121.5
MHz, CDCl3): l −7.6. MS (m/z): 284 (M+), 267, 229,
15. All the reported ring-opened products gave analytical and
spectroscopic data in agreement with the proposed struc-
tures. 1H, 13C, 31P NMR, GC/MS and IR spectra were
taken and compared with the known compounds. Ele-
mental analyses were obtained by the Materials Charac-
terization Center at WKU. The stereochemistry of the
products have been assigned trans configuration by com-
parison with the known compounds. See Ref. 9a.