In situ phosphine oxide reduction: A catalytic appel reaction

Article abstract of DOI:10.1002/chem.201101563

Several important reactions in organic chemistry thrive on stoichiometric formation of phosphine oxides from phosphines. To avoid the resulting burden of waste and purification, cyclic phosphine oxides were evaluated for new catalytic reactions based on in situ regeneration. First, the ease of silane-mediated reduction of a range of cyclic phosphine oxides was explored. In addition, the compatibility of silanes with electrophilic halogen donors was determined for application in a catalytic Appel reaction based on in situ reduction of dibenzophosphole oxide. Under optimized conditions, alcohols were effectively converted to bromides or chlorides, thereby showing the relevance of new catalyst development and paving the way for broader application of organophosphorus catalysis by in situ reduction protocols. Copyright

Full text of DOI:10.1002/chem.201101563

DOI: 10.1002/chem.201101563
In Situ Phosphine Oxide Reduction: A Catalytic Appel Reaction
Henri A. van Kalkeren, Stefan H. A. M. Leenders, C. Rianne A. Hommersom,
Floris P. J. T. Rutjes, and Floris L. van Delft*[a]
Abstract: Several important reactions
in organic chemistry thrive on stoichio-
metric formation of phosphine oxides
from phosphines. To avoid the resulting
burden of waste and purification, cyclic
phosphine oxides were evaluated for
new catalytic reactions based on in situ
regeneration. First, the ease of silane-
mediated reduction of a range of cyclic
phosphine oxides was explored. In ad-
dition, the compatibility of silanes with
electrophilic halogen donors was deter-
mined for application in a catalytic
Appel reaction based on in situ reduc-
tion of dibenzophosphole oxide. Under
optimized conditions, alcohols were ef-
fectively converted to bromides or
chlorides, thereby showing the rele-
vance of new catalyst development and
paving the way for broader application
of organophosphorus catalysis by in
situ reduction protocols.
Keywords: Appel reaction · halo-
genation · homogeneous catalysis ·
phosphorus heterocycles · synthetic
methods
Introduction
gorized into strategies involving recycling either by activa-
tion or by reduction of the phosphine oxide. In the former,
the oxidation state of the phosphorus species remains con-
stant during the whole sequence (Figure 1a, left), while in
the latter case phosphorus is shuttled from PV to PIII
throughout the catalytic cycle (Figure 1a, right).
Phosphorus-containing compounds play an important role in
chemical and biochemical sciences.[1] Apart from being an
essential element of natural products, phosphorus-containing
reagents are of indispensable value in organic synthesis, in
particular by virtue of three specific features: 1) the high nu-
cleophilicity of phosphines, 2) the ability to adopt different
oxidation states, and 3) the strong phosphorus–oxygen bond.
Representative examples of the value of phosphorus-based
À
chemistry include the Appel reaction (formation of C X
bonds),[2] Mitsunobu reaction (formation of C O or C N
bonds)[3] and Wittig-type reactions (formation of C=C
bonds).[4] Unfortunately, although formation of phosphine
oxide ensures good conversions, it also often hampers purifi-
cation.[5] Moreover, most phosphorus-based conversions
suffer from poor atom economy, leading to substantial
amounts of residual waste. During the last decade in partic-
ular, new methods have emerged to overcome these draw-
backs. For instance, phosphines have been incorporated into
polymers[6] to enable easier purification of the product.
However, immobilization clearly does not solve the problem
of waste, and subsequent separate regeneration of the non-
cyclic phosphines still requires harsh conditions.[7] Ideally, a
phosphorus species is used in catalytic amounts.[8] Studies
aiming at catalytic applications of phosphorus can be cate-
À
À
Figure 1. a) Organophosphorus catalysis strategies involving activation or
reduction of phosphine oxide. b) Examples of organophosphorus cata-
lysts.
The first report of organophosphorus catalysis by activa-
tion of phosphine oxides dates back to 1962, when Campbell
et al. reported the use of catalytic phosphine oxide for pro-
duction of carbodiimides from isocyanates by the activation
mechanism.[9] The key to this methodology is reaction of
phosphine oxide 1a (Figure 1b) with an isocyanate, leading
to CO2 and a phosphorane imine intermediate that reacts
with a second isocyanate. Thereafter, it took more than 40
years before a similar formation of an imine with a catalytic
phosphorus reagent was reported by Marsden et al. Using
1b as catalyst, they showed that intramolecular trapping of
[a] H. A. van Kalkeren, S. H. A. M. Leenders, C. R. A. Hommersom,
Prof. Dr. F. P. J. T. Rutjes, Dr. F. L. van Delft
Institute for Molecules and Materials
Radboud University Nijmegen
Heyendaalseweg 135, 6525 AJ Nijmegen (The Netherlands)
Fax : (+31)24-365-3393
E-mail: f.vandelft@science.ru.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101563.
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Chem. Eur. J. 2011, 17, 11290 – 11295

FULL PAPER
a phosphorane imine with an aldehyde in a catalytic aza-
Wittig reaction can be applied in the synthesis of heteroaro-
matic compounds.[10] While isocyanates activate only cyclic
phosphine oxides at a reasonable rate, the more reactive
oxalyl chloride is able to activate readily available and
cheap triphenylphosphine oxide by formation of a phoshoni-
um species with extrusion of CO and CO2. Denton et al.
successfully applied such oxalyl-mediated phosphonium re-
generation for chlorination of compounds in a catalytic
Appel reaction[11] and epoxide opening.[12] So far, reactions
seem to be limited to oxalyl chloride, which makes the intro-
duction of other nucleophiles difficult.
Recently, an in situ reduction approach was introduced by
OꢁBrien et al. in the first catalytic Wittig reaction.[13] To this
end, the key cyclic phosphine oxide 2 was reduced in situ to
the corresponding phosphine, followed by conversion to an
ylide and subsequent Wittig reaction. Remarkably, diphenyl-
silane (Ph2SiH2) or trimethoxysilane ((MeO)3SiH) reduced
the phosphoryl compound selectively, without affecting the
aldehyde and other reagents.
Figure 2. Conversion of phosphine oxides 2–6 over time as determined by
GC with tetradecane as an internal standard.
Although the number of applications of catalytic phos-
phorus chemistry is still limited at this moment, we recog-
nized that the concept of in situ reduction offers great po-
tential for broad applicability. Here we report the synthesis
of a variety of new organophosphorus catalysts, which were
evaluated for ease of reduction and successfully applied in
the bromination and chlorination of alcohols in a catalytic
Appel reaction.
As expected, the remote 3-methyl substituent on 2 had little
influence, as both 1-phenylphospholane oxide (3) and 3-
methyl-1-phenylphospholane oxide (2) are equally effective-
ly reduced. Six-membered phosphine oxide 4 was also re-
duced, albeit very slowly, with less than 20% conversion
after 3 h. Neither saturated nor unsaturated seven-mem-
bered heterocycle 5 and 6, respectively, showed any reaction
under these conditions. These results underline the proposed
correlation between relief of ring strain and susceptibility to
reduction by silanes.[13,18] The trend furthermore suggests
that five-membered rings are the preferred candidates for
an in situ reduction strategy.
Despite the proven effective reduction of aliphatic five-
membered phosphine oxides, we sought to widen the scope
of phospholane-type reagents for potentially catalytic trans-
formations. We envisioned that aromatic phospholes could
be interesting candidates in this respect, due to increased
ring strain and recovery of aromaticity after reduction. An
important additional advantage of phospholes is the tunabil-
ity of electronic properties by introduction of substituents.
Therefore, we turned our attention to dibenzophospholes
and the corresponding oxides (Scheme 1, compounds 10–12
and 13–15, respectively), which are stable at room tempera-
Results and Discussion
Catalyst design: To determine the effect of ring size on the
rate of reduction by silanes, as well as the influence of a 3-
methyl substituent and the degree of saturation of seven-
membered rings, we synthesized cyclic phosphine oxides 2–
6. Phosphacycloalkanes with three- and four-membered
rings were also synthesized, but the corresponding phos-
phine oxides were found to be too unstable for application
in catalysis.[14] Compounds 2, 4, and 6 were prepared as re-
ported.[13,15] Phospholane oxide 3 was obtained by a known
synthesis of the phosphine[16] followed by oxidation with
H2O2; phosphepane 5 was obtained by Pd/C-catalyzed hy-
drogenation of 6.
Having the set of cyclic phosphines at hand, we explored
the efficiency of reduction by diphenylsilane. Thus, the con-
sumption of phosphine oxide by diphenylsilane (1.5 equiv,
1,4-dioxane, 1008C) was monitored over time by GC analy-
sis (Figure 2).[17] First, rapid reduction of five-membered
phosphine oxides 2 and 3 was observed, leading to complete
formation of the corresponding phosphines over 200 min.
Scheme 1. Synthesis of dibenzophospholes. a) nBuLi (2 equiv), Et2O, RT,
3.5 h, then PPhCl2, Et2O, reflux, 1 h; 55% 10, 30% 11, 20% 14, 57% 12;
b) H2O2 (4 equiv), Et2O, 2 h, 85 % 13, 83% 14, 86% 15.
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F. L. van Delft et al.
ture in air. Phospholes lacking fused aromatic rings were
also considered but not pursued, because PV-containing
phospholes are known to dimerize by Diels–Alder reac-
tion.[19] To investigate the effect of electron donation or
withdrawal on the reactivity of the phosphorus atom, we
synthesized three different phospholes with H, CH3O, or
CF3 groups at the C2 and C8 positions (Scheme 1). Phosp-
holes 10–12 were readily obtained from biphenyl precursors
7–9 by a literature procedure involving generation of the
dianion followed by quenching with dichlorophenylphos-
phine.[20] The requisite methoxy-substituted biphenyl precur-
sor 8 was synthesized by bromination of 2,2’-dibromo-1,1’-
biphenyl.[21] Precursor 9 was prepared by modified Ullmann
coupling of 1-bromo-2-iodo-4-(trifluoromethyl)benzene,
after several attempts at Suzuki or Kumada cross-coupling
reactions had failed. Finally, all three phospholes were oxi-
dized with H2O2 to oxides 13–15 in high yields.
action of silanes.[23] With respect to rate of reduction, there
is only a small difference between phospholanes and phosp-
holes: reduction of 13 was approximately 1.5 times slower
than that of 2, based on 66% conversion after 3 h in 0.3m
dioxane (not shown).
Catalytic Appel reaction: To evaluate the applicability of
phospholes 10–12 as catalysts for synthetic transformations,
we aimed at a new catalytic Appel reaction.[2] Although sev-
eral other procedures are known to convert alcohols to the
corresponding halides, the Appel reaction is of particular
value due to the mild conditions and stereospecificity. How-
ever, formation of stoichiometric amounts of phosphine
oxide is still a major drawback. We therefore attempted a
catalytic Appel reaction through in situ reduction of the
concomitantly formed oxide (Scheme 2).
Although there was no precedent for mild reduction of di-
benzophosphole oxide, compounds 13–15 were readily re-
duced by diphenylsilane, under similar conditions to phos-
pholanes 2 and 3. Due to the low volatility of 13 and 14,
conversions were monitored by 31P NMR spectroscopy
(Figure 3) instead of GC.[19b] Lower concentrations than
before (0.1 versus 0.3m) were used to minimize the influ-
ence of temperature fluctuations during reaction and analy-
sis.[22] From the NMR spectra, clean conversion plots with
variable rates were obtained as an indication of the effect of
electron-donating
and
-withdrawing
substituents
(Figure 3).[17] Electron-withdrawing substituents (R=CF3)
significantly reduce the reduction rate with respect to unsub-
stituted phosphole (R=H), but a much smaller influence
was found for enhancement of electron density (R=OMe).
Thus, the Lewis basicity of the phosphoryl group is of im-
portance for the reduction potential, at least under the
Scheme 2. Appel reaction with in situ phosphine regeneration.
Figure 3. Left: Stacked 31P NMR spectra of the reduction of 13 over time. Oxide 13 (29.1 ppm) is reduced to dibenzophosphole 10 (À11.1 ppm). Right:
Conversion of dibenzophosphole oxides 13–15 over time.
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Catalytic Appel Reaction
FULL PAPER
We focused explicitly on catalysis of the Appel reaction
with aromatic phosphines, because 3-methyl-1-phenylphos-
pholane oxide (2) was expected to be unsuitable for achiev-
ing good conversions, due to alkylation of the phosphine by
the halogenated product formed in situ. Indeed, 2 reacted
with (2-bromoethyl)benzene at elevated temperatures (not
shown). In contrast, no alkylation occurred with dibenzo-
phosphole 10, and this was taken as a clear indication of its
potential to give catalytic turnovers.
and DEBM (1.5 equiv) to alcohol 18 in dioxane at 1008C
led to a conversion of 65% over 66 h (Table 1, entry 1). To
increase the reaction rate, the reaction was performed at
higher concentrations, but a lower yield of (2-bromoethyl)-
benzene was obtained due to side reactions (Table 1, en-
tries 2 and 3). A more beneficial effect was obtained by
switching the solvent to acetonitrile, which is known to sta-
bilize ionic intermediates for Appel reactions with tetra-
chloromethane, and this led to faster conversion and higher
yields.[2] Indeed, a good yield in a much shorter time was ob-
tained in acetonitrile (82% in 19 h; Table 1, entry 4), and
even a catalyst loading of only 5 mol% still gave reasonable
conversion (Table 1, entry 9). The reaction also proceeded
at 608C, but required prolonged reaction times (Table 1,
entry 6). As an alternative reducing agent, triethylsilane was
evaluated but was not strong enough to reduce 13, and thus
only 9% of the bromide was obtained (Table 1, entry 7). In
contrast, trimethoxysilane was able to reduce 13, but in this
case silylation of starting alcohol 18 resulted in low conver-
sion (Table 1, entry 8). 3-Methyl-P-phenylphospholane
oxide (2) led to a poor yield of bromide (Table 1, entry 13),
mainly due to alkylation of the phosphine generated in situ
by the bromide product. The same alkylation, albeit much
slower, thwarted a high yield for the more electron-rich di-
methoxydibenzophosphole 11, although the yield of the cat-
alytic Appel reaction was acceptable (Table 1, entry 12).
The catalytic involvement of dibenzophosphole10 was corro-
borated by performing the reaction in the absence of diben-
zophosphole 10 (Table 1, entry 10) or silane (Table 1,
entry 11), which gave 6% or no conversion, respectively.
To establish the potential general usefulness of the cata-
lytic Appel reaction, the optimized reaction conditions were
We began our investigations of potential dibenzophosp-
hole-catalyzed Appel reaction by utilizing the established
bromonium donor tetrabromomethane. To this end, we
treated phenylethyl alcohol with tetrabromomethane
(1.5 equiv) in the presence of Ph2SiH2 (1.1 equiv) and 10
(10 mol%) in dioxane at 1008C. No more than 18% conver-
sion could be observed by GC, while 31P NMR analysis
showed many phosphorus signals as an indication of catalyst
decomposition. We therefore used the alternative bromoni-
um donor N-bromosaccharine (16).[24] With this donor more
catalyst turnovers could be obtained leading to 60% conver-
sion, but multiple additions of diphenylsilane and 16 (total
addition of 3.5 equiv in four additions) were required to
drive the reaction towards completion. The large amount of
diphenylsilane suggests a competitive reaction with the bro-
monium donor. Nevertheless, the good conversion implies
that clean regeneration of dibenzophosphole takes place, in
contrast to the reaction with tetrabromomethane. The ma-
jority of alternative reagents (i.e., bromine,[25] N-bromosuc-
cinimide,[26] N-bromoacetamide, 2,4,4,6-tetrabromocyclo-
hexa-2,5-dienone)[27] reacted quickly with diphenylsilane
(Figure 4). However, diethyl bromomalonate (DEBM, 17)
reacted only slowly with diphenylsilane and was therefore
selected for further investigations.[28]
Since there is no precedent for Appel reactions involving
DEBM, we started investigating this donor by a classic reac-
tion with an excess of PPh3 (1.5 equiv). In the presence of
DEBM (1.5 equiv) in dioxane at room temperature, 2-phe-
nylethanol (18) was converted to the corresponding bromide
in 83% yield, which served as a stimulus to perform a cata-
lytic Appel reaction. Thus, addition of a catalytic amount
(10%) of dibenzophosphole 10, diphenylsilane (1.1 equiv),
Table 1. Optimization of the catalytic Appel reaction by variation of catalyst,
solvent, silane, and temperature.
Entry Cat.
Silane
Cat.
[mol%]
Solvent
c
T
t
Yield
AHCTUNGTRENNUNG
[m] [8C] [h] [%][a]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
–
11
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Et3SiH
10
10
10
10
10
10
10
dioxane 0.1 100 66
65
28
16
82
–
62
9
5
dioxane 0.5 100
dioxane 1.0 100
4
4
MeCN 0.1
82 19
DMF[b] 0.1 100
–
MeCN 0.1
MeCN 0.1
MeCN 0.1
MeCN 0.1
MeCN 0.1
MeCN 0.1
MeCN 0.1
60 39
82 46
82 23
82 72
82 20
82 20
82 19
A
9
Ph2SiH2
–
Ph2SiH2
Ph2SiH2
5
10
–
69
6
0
10
11
12
10
68
(R=OMe)
2
13
Ph2SiH2
10
MeCN 0.1
82 20
17
(OꢁBrien[13]
)
[a] Yield determined by GC with tetradecane as internal standard; reaction
was terminated after full consumption of alcohol. [b] Diphenylsilane immedi-
ately reacted with DMF.
Figure 4. Compatibility of bromonium donors with Ph2SiH2.
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F. L. van Delft et al.
Table 2. Substrate scope of catalytic Appel reaction.
simply replacing DEBM by diethyl chloromalonate
in the reaction as performed in Table 2, no conver-
sion of 2-phenylethyl alcohol was observed, even at
higher temperatures (1008C). Tetrachloromethane
as chloronium donor also gave no reaction. It was
postulated that this lack of reactivity could be due
to an impractically slow reaction of dibenzophosp-
hole with either of the chlorinating agents. Indeed,
when dibenzophosphole 10 was mixed with CCl4 in
deuterated acetonitrile in the presence of water
(10 equiv), no oxidation product was observed by
31P NMR spectroscopy, that is, the phosphorus atom
is insufficiently nucleophilic to react. However, 2,8-
dimethoxy-substituted dibenzophosphole 11 did
react with tetrachloromethane. As a consequence,
11 was able to give catalyst turnovers in an Appel
reaction; phenylethyl alcohol was converted to (2-
chloroethyl)benzene by 11 and CCl4 at 1008C in
acetonitrile. However, although the starting material
was fully consumed, only a low conversion was ob-
served (Scheme 3). The lower nucleophilicity of
chloride might be the cause of side reactions with
the phosphonium intermediate, such as elimination
or nucleophilic displacement by silanol. In similar
reactions with 1-decanol, a significant amount of the
silyl ether (decyloxy)diphenylsilane was observed by
GC-MS.[31]
Entry
1
Substrate
Product
Yield[a]
[%]
72 (73)
2
3
55 (80)
45 (75)
4
5
71
63
6
72
7
8
9
20
0[b]
NR[c]
Conclusion
10
NR[c]
A range of phosphines and phospholes, as well as
the corresponding oxides, was synthesized, and the
ease of reductive interconversion explored. From
the reduction of the cyclic phosphine oxides, it
became clear that five-membered rings are the pre-
[a] Yield of isolated compound (yield determined by GC with tetradecane as internal
standard). [b] Full conversion but decomposition on loading onto silica gel. [c] NR=
no reaction. Only about 10% consumption of starting material; all components re-
mained unconverted, except for 10, which was isolated as its oxide 13.
applied to a range of substrates (Table 2). In most cases,
conversion of the alcohol to bromide was high, and the de-
sired products were isolated in moderate to good yields
(Table 2, entries 1 and 4–6). Somewhat lower yields were
obtained for highly reactive bromides (Table 2, entries 2, 3,
and 8), while other sterically demanding secondary alcohols
showed poor reactivity (Table 2, entry 7, 9, and 10). These
results show that when SN2 substitution is difficult for steric
reasons, conversion is limited. However, good conversion of
the secondary alcohol b-cholesterol was obtained (Table 2,
entry 6), most likely through neighbouring-group participa-
tion of the double bond, as earlier observed for bromide in-
troduction into the corresponding b-mesylate.[29] The high
stereoselectivity observed is a remarkable advantage of the
previously mentioned poor reactivity in a sterically demand-
ing SN2 reaction, especially considering the fact that forma-
tion of 3-bromocholest-5-ene by a classic Appel reaction
normally gives mixtures of stereoisomers.[30]
Scheme 3. Chlorination with dibenzophosphole 10 or 2,8-dimethoxydi-
benzophosphole 11.
ferred candidates for catalytic applications. Dibenzophosp-
holes were added to the class of organophosphorus catalysts
for functional-group conversion by using the strategy of in
situ reduction of the resulting phosphorus oxides. These cat-
alysts can be used for catalytic Appel reactions, with the ad-
vantage that the electron density of the dibenzophosphole
ring, and the nucleophilic properties of both the oxidized
and reduced forms, can be conveniently modified. Electron-
withdrawing substituents decrease the rate of reduction of
the phosphole oxides, while electron-donating groups in-
After establishing the optimal conditions for bromination,
we turned our attention to the introduction of chloride. On
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Catalytic Appel Reaction
FULL PAPER
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Furthermore, the nucleophilicity of the phosphine is impor-
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Experimental Section
General procedure for catalytic Appel reaction: 5-Phenyldibenzophosp-
hole (10, 10 mol%) was added to a dry two-neck flask equipped with a
stirring bar and a condenser. Then acetonitrile (0.1m), diphenylsilane
(1.1 equiv), and the alcohol (1 equiv) were added though a septum. Final-
ly diethyl bromomalonate (1.5 equiv) was slowly added and the reaction
mixture was heated to reflux for the indicated time. After full conversion
(as determined by GC) the reaction mixture was extracted with pentane
(5ꢂ). After evaporation of the pentane, the crude product was purified
by column chromatography (silica gel, EtOAc:heptane or pentane).
Acknowledgements
This research has been performed within the framework of the CatchBio
program. The authors gratefully acknowledge the support of the Smart
Mix Program of the Netherlands Ministry of Economic Affairs and the
Netherlands Ministry of Education, Culture and Science.
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Received: May 20, 2011
Published online: August 25, 2011
Chem. Eur. J. 2011, 17, 11290 – 11295
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11295