Phosphine-boronates: Efficient bifunctional organocatalysts for Michael addition

Article abstract of DOI:10.1039/c2cc30399j

Phosphine-boronates R₂P(o-C₆H₄) B(OR′)₂ have been evaluated as bifunctional organocatalysts for the Michael addition of malonate pronucleophiles to methylvinylketone. The presence of the Lewis acidic boron center adjacent to phosphorus significantly improves catalytic performance. Isolation and complete characterization of a key intermediate, namely a β-phosphonium enolate, substantiate the role of the Lewis acidic moiety in the catalytic process.

Full text of DOI:10.1039/c2cc30399j

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Frontiers in Molecular
Main Group Chemistry
web themed issue
Guest editors: Manfred Scheer and Richard
Layfield
All articles in this issue will be gathered together
online at
www.rsc.org/cc/maingroup

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 4495–4497
www.rsc.org/chemcomm
COMMUNICATION
Phosphine-boronates: efficient bifunctional organocatalysts for Michael
additionwz
ab
Olivier Basle,y Susana Porcel,zab Sonia Ladeira,c Ghenwa Bouhadir*ab and
´
Didier Bourissou*ab
Received 17th January 2012, Accepted 14th March 2012
DOI: 10.1039/c2cc30399j
Phosphine-boronates R2P(o-C6H4)B(OR0)2 have been evaluated as
bifunctional organocatalysts for the Michael addition of malonate
pronucleophiles to methylvinylketone. The presence of the Lewis
acidic boron center adjacent to phosphorus significantly improves
catalytic performance. Isolation and complete characterization of a
key intermediate, namely a b-phosphonium enolate, substantiate
the role of the Lewis acidic moiety in the catalytic process.
PB derivatives towards catalytic CC coupling reactions. Herein
we report our first catalytic results and mechanistic investigations
in this area.
Phosphines have been recognized quite early on as competent
organocatalysts for the Michael addition of active methylene
compounds to electron-poor olefins.9 For this study, the reaction
of dimethylmalonate 1 with methylvinylketone (MVK) 2 was
chosen as model reaction (Scheme 1). Our investigations began
with the recently described phosphine-boronate Ph2PBpin
(Fig. 1).10 All catalytic tests were performed at room temperature
with a catalyst loading of 10 mol%. The influence of the
solvent was studied and the molar ratio of the substrates was
varied (Table S1, ESIz). The best results were obtained in
acetonitrile, using two equivalents of MVK with respect to
dimethylmalonate. Accordingly, the desired addition product
3 was obtained in 67% yield within 9 h. Notably, Ph2PBin
performs slightly better than PPh3 indicating some positive
influence of the boronate moiety.
In recent years, cooperation between Lewis acids and Lewis bases
has attracted considerable interest, and so-called Frustrated Lewis
Pairs and ambiphilic derivatives have been shown to exhibit
unique chemical behavior.1,2 In this context, our group has been
particularly interested in phosphine-boranes connected by an
ortho-phenylene bridge, the close proximity of the two reactive
sites being anticipated to amplify their cooperativity. In addition
to possessing original and versatile ligand properties,2,3 R2P-
(o-C6H4)BR02 derivatives have been found to efficiently stabilize
reactive intermediates derived from phosphines.4,5
Phosphines have emerged over the past few decades as
powerful nucleophilic catalysts for a variety of CC coupling
reactions.6 Taking into account the great potential of cooperative
multi-center organocatalysis,7 a few bifunctional phosphine
catalysts have also been applied to the formation of carbon–
carbon bonds.8 Essentially protic moieties (such as phenolic OH
groups) have been involved as ancillary activating sites, but to the
best of our knowledge, the association of phosphines with Lewis
acidic boron centers has not been considered thus far in this
area. With the aim of further extending the synthetic interest
of ambiphilic compounds, we became interested in evaluating
Then, the nature of the boronate group was varied and its
influence on the catalytic performance was evaluated (Fig. 1,
Table 1). Not surprisingly, reducing the steric demand of the
boronate ester was found to increase the activity of the PB
derivatives. The phosphine-boronate Ph2PBNeo exhibited the
highest activity (97% conversion of the malonate was achieved
a
´
Universite de Toulouse, UPS, LHFA, 118 route de Narbonne,
F-31062 Toulouse, France. E-mail: dbouriss@chimie.ups-tlse.fr
b CNRS, LHFA UMR 5069, F-31062 Toulouse, France.
Fax: +33 5 6155 8204; Tel: +33 5 6155 6803
´
118 route de Narbonne, 31062 Toulouse Cedex 9, France
w This article is part of the ChemComm ‘Frontiers in Molecular Main
Group Chemistry’ web themed issue.
Scheme 1 Catalytic Michael addition of dimethylmalonate 1 to
methylvinylketone 2.
c
Universite Paul Sabatier, Institut de Chimie de Toulouse (FR 2599),
z Electronic supplementary information (ESI) available: Experimental
details and characterization data, including crystallographic data for
8. See DOI: 10.1039/c2cc30399j
y Current address: Ecole Nationale Supe
Avenue du General Leclerc – CS 50837, 35700, Rennes cedex 7, France
and CNRS, UMR 6226, Rennes, France.
z Current address: Instituto de Quımica, Universidad Nacional
Autonoma de Mexico, Circuito Exterior s/n, Ciudad Universitaria,
04510 Me
´
rieure de Chimie de Rennes,
´
´
´
Fig. 1 Phosphine-boronates evaluated as organo-catalysts for the
´
´
´
xico D.F., Mexico.
Michael addition.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4495–4497 4495

Table 1 Catalyst survey for the Michael addition of dimethylmalonate
1 to MVKa
Entry Ratio 1 : 2 Catalyst
Time/h Convb 3c (%) 4/5c (%)
Scheme 2 Catalytic Michael addition of the substituted malonate 6
to methylvinylketone 2.
1
2
3
4
5
6
7
8
9
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 1
1 : 1
1 : 1
1 : 1
Ph2PBNeo 3.5
Ph2PBGly 3.5
97
75
61
32
98
77
82
77
62
57
65
49
28
29
58
69
60
50
28/12
7/ndd
5/1
Ph2PBPin
PPh3
3.5
3.5
1
double adducts upon reacting 1 with 2. Compounds Ph2PBGly
and Ph2PBNeo featuring non-sterically hindered boronate
moieties significantly outperformed Ph2PBPin and PPh3,
affording the desired product 7 in 82 and 95% yields, respectively,
after 62 h. The corresponding dimethylphosphine-boronates also
proved to be efficient catalysts for the Michael addition of the
substituted malonate 6, and as expected, the reaction proceeds
much faster than with the diphenylphosphine-boronates. The
steric demand for the boronate moiety seems to play a pivotal
role. Indeed, after 5 h at room temperature, the Michael adduct 7
was obtained in up to 95% yield with Me2PBNeo, but only 50%
with Me2PBpin. These results further emphasize the participation
and beneficial influence of the boronate moiety in the catalytic
transformation. And preliminary studies substantiate the ability
of the PB compounds to catalyze the Michael addition of other
substrates.z
o5
Me2PBGly
Me2PBGly
Me2PBNeo
Me2PBPin
Me2PPh
17/52
7/ndd
2/10
7/7
1
1
1
1
5/6
a
Reactions were carried out with 1 (0.2 mmol) at 25 1C in acetonitrile
(0.4 mL). Determined by 1H NMR. Yields determined by
1H NMR using mesitylene as internal standard. Not detected.
b
c
d
in only 3 h 30 min), but led to poor selectivity (40% of the
double Michael adducts 4 and 5, resulting from intramolecular
aldol reaction9a). A much better compromise was met with
Ph2PBGly, compound 3 being obtained in 65% yield within
3h30, with minimal amounts of the side-products 4/5 (o10%
overall). Comparatively, Ph2PBpin and PPh3 afforded 3 in
only 49% and 28% yields, respectively. These results confirm
that the introduction of a boronate moiety can improve the
catalytic performance of the phosphine, and thereby substantiate
some cooperative behavior of the nucleophilic and Lewis acidic
moieties of the PB organocatalyst.11
To try to get some insight into the role of the bifunctional
phosphine-boronate, stoichiometric reactions were then performed.
According to in situ NMR monitoring in deuterated acetonitrile,
Ph2PBpin reacts readily with MVK 2 at room temperature. The
diagnostic signals for Ph2PBpin (d 31P ꢀ5.4 and 11B 33.7 ppm)
disappear progressively in favor of two new signals (d 31P 34.2 and
11B 6.6 ppm), suggesting the quaternarization of both the
phosphorus and boron atoms. Side-reactions and decomposi-
tion prevent gaining more information about the formed
compound, but pleasingly, a cleaner reaction was observed
with Me2PBpin. Addition of MVK induced the instantaneous
With the aim of further increasing the catalytic activity of
the phosphine-boronates, we then envisioned to replace the
Ph substituents at phosphorus for alkyl groups. The known
(o-bromophenyl)-dimethylphosphine Me2P(o-C6H4)Br12 was
used as a key precursor. Halogen–lithium exchange followed by
electrophilic trapping with trimethoxyborate and subsequent
transesterification with the appropriate diol afforded the desired
compounds Me2PBpin, Me2PBNeo and Me2PBGly. These new
phosphine-boronates were isolated in pure form and characterized
by multi-nuclear NMR and HRMS.z
formation of a new compound 8. Its 31P (d 31.5 ppm) and 11
B
(d 6.6 ppm) NMR data are very similar to those observed with
Ph2PBpin, and consistent with the presence of phosphonium
and borate moieties. In addition, signals clearly attributable to
a P–CH2–CHQCq skeleton were identified by 1H [d 3.56 ppm
(m, 2H, PCH2), 4.20 (pseudo-quartet, 3JH–H = 3JH–P = 7.3 Hz,
Compound Me2PBGly was first evaluated in the catalytic
Michael addition (Table 1, entry 5). Complete conversion was
achieved within only 1 h at room temperature, but at the expense
of selectivity. The major products are actually the double adducts
4 and 5 rather than the monoadduct 3. To circumvent this
limitation, an equimolar ratio of methylvinylketone 2 was used
with respect to malonate 1. Gratifyingly, all dimethylphosphine-
boronates were found to efficiently promote the Michael reaction
under these conditions with good selectivity in favor of the
monoadduct 3 (entries 6–8). Here Me2PBNeo provided the best
results, affording 3 in 69% yield and only 12% of side-products
4 and 5 (entry 7). A comparable selectivity, but significantly lower
yield was obtained using Me2PPh as catalyst (entry 9).
3
CH =)] and 13C NMR [d 160.6 (d, JC–P = 10.6 Hz, C =),
2
87.6 (d, JC–P = 12.6 Hz, CH)]. X-Ray diffraction analysis
unambiguously confirmed the molecular structure of
8
(Scheme 3).z Formal 1,4-addition of the PB derivative to
MVK results in an eight-membered ring system. In other
words, nucleophilic attack of the phosphorus atom of Me2PBpin
on MVK forms a b-phosphonium enolate which is stabilized
intramolecularly by the boronate moiety. Strong interaction
The fact that the double adducts 4 and 5 were obtained as
major products in the presence of two equivalents of MVK
indicates that the dimethylphosphine-boronate Me2PBGly is able
to effectively promote Michael addition with unsubstituted as well
as substituted malonate derivatives. This prompted us to evaluate
the catalytic performance of PB compounds towards a more
challenging Michael addition, namely the reaction of methyl
diethylmalonate 6 with MVK 2 (Scheme 2; Table S2, ESIz). Long
reaction times were required with the diphenylphosphine-boronate
catalysts, in line with the formation of only small amounts of
Scheme 3 Synthesis, X-ray structure (ellipsoid drawing at 50% prob-
ability; hydrogen atoms omitted for clarity) and protonation of the b-
phosphonium enolate 8.
c
4496 Chem. Commun., 2012, 48, 4495–4497
This journal is The Royal Society of Chemistry 2012

between the enolate moiety and the boron center is apparent from
the short O1B bond [1.509(2) A] and from the pyramidalization of
the boron environment (the sum of bond angles for the CBpin
fragment = 326.251). Compound 8 stands as a very rare example
of a b-phosphonium enolate. Such zwitterionic derivatives are
usually unstable and exist as cyclic pentavalent phosphoranes.
To the best of our knowledge, the only unambiguously
characterized precedents were reported recently by Kwon et al.
from three-component reactions involving triphenyl, trimethyl or
tributyl-phosphine, methylpropionate and 4-pyridinecarbox-
aldehyde.13,14 Note also that the formation of 8 from Me2PBpin
and MVK nicely complements the results observed recently
by Erker and co-workers upon reacting the ethylene-bridged
phosphine-borane Mes2PCH2CH2B(C6F5)2 with a,b-unsaturated
carbonyl derivatives.15
Notes and references
1 For recent reviews dealing with metal-free organocatalysis, see:
(a) D. W. Stephan, Chem. Commun., 2010, 46, 8526;
(b) D. W. Stephan and G. Erker, Angew. Chem., Int. Ed., 2010,
49, 46.
2 For recent reviews dealing with transition metal complexes, see:
(a) I. Kuzu, I. Krummenacher, J. Meyer, F. Armbruster and
F. Breher, Dalton Trans., 2008, 5836; (b) F.-G. Fontaine,
J. Boudreau and M.-H. Thibault, Eur. J. Inorg. Chem., 2008,
5439; (c) G. Bouhadir, A. Amgoune and D. Bourissou, Adv.
Organomet. Chem., 2010, 58, 1.
3 For recent evaluations in transition metal-mediated catalytic reac-
tions, see: (a) M. W. P. Bebbington, S. Bontemps, G. Bouhadir,
M. J. Hanton, R. P. Tooze, H. van Rensburg and D. Bourissou,
New J. Chem., 2010, 34, 1556; (b) R. Malacea, N. Saffon,
D. Bourissou and M. Gomez, Chem. Commun., 2011, 47, 8163.
´
4 (a) M. W. P. Bebbington, S. Bontemps, G. Bouhadir and
D. Bourissou, Angew. Chem., Int. Ed., 2007, 46, 3333;
(b) S. Moebs-Sanchez, G. Bouhadir, N. Saffon, L. Maron and
D. Bourissou, Chem. Commun., 2008, 3435.
After nucleophilic attack at the electron-poor alkene, phos-
phine-catalyzed Michael additions are supposed to proceed via
acid–base exchange with the malonate derivative.9 To check the
ability of the b-phosphonium enolate 8 to participate in such
acid–base reaction, it was treated in situ with HBF4. The
corresponding g-keto phosphonium 9 was readily and cleanly
formed and its structure was unambiguously established spectro-
scopically.16 Note that traces of 9 are also detected upon reaction
of Me2PBPin with MVK, probably as a result of protonation of
the b-phosphonium enolate 8 with adventitious proton sources.
To verify that derivative 8 can be effectively considered as an
intermediate in the catalytic cycle, it was evaluated itself for the
coupling of dimethylmalonate 1 and MVK 2. Within the margin
of error, the MVK adduct 8 and phosphine-boronate Me2PBpin
gave identical catalytic results in terms of activity and selectivity
(with 8, products 3, 4 and 5 were obtained in 61, 15 and 10%
yields, respectively, as to compare with entry 8, Table 1).
In conclusion, introduction of a boronate moiety in the
ortho-position of phenylphosphines was shown to enhance
their catalytic performance towards Michael addition. The
role of the Lewis acidic moiety is supported by the isolation of
a key b-phosphonium enolate intermediate upon reaction of
the phosphine-boronate Me2P(o-C6H4)Bpin with methyl-
vinylketone. Following the seminal contribution of D. W.
Stephan and G. Erker, PB derivatives and related Frustrated
Lewis Pairs have been successfully applied to metal-free
hydrogenation of a variety of organic substrates.1 The results
reported here extend the scope of such bifunctional organo-
catalysts to the formation of carbon–carbon bonds. Future
work will aim at evaluating PB derivatives in other CC bond-
forming reactions, including in asymmetric versions.17
5 For HF scavenging with a PB derivative, see: S. Moebs-Sanchez,
N. Saffon, G. Bouhadir, L. Maron and D. Bourissou, Dalton
Trans., 2010, 39, 4417.
6 (a) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008,
37, 1140; (b) J. L. Methot and W. R. Roush, Adv. Synth. Catal.,
2004, 346, 1035; (c) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res.,
2001, 34, 535.
7 (a) M. Shibasaki, M. Kanai and K. Funabash, Chem. Commun.,
2002, 1989; (b) J.-A. Ma and D. Cahard, Angew. Chem., Int. Ed.,
2004, 43, 4566; (c) D. H. Paull, C. J. Abraham, M. T. Scerba,
E. Alden-Danforth and T. Lectka, Acc. Chem. Res., 2008, 41, 655;
(d) S. J. Connon, Chem. Commun., 2008, 2499.
8 Y. Wei and M. Shi, Acc. Chem. Res., 2009, 43, 1005.
9 (a) D. A. White and M. M. Baizer, Tetrahedron Lett., 1973,
14, 3597; (b) T. Yoshida and S. Saito, Chem. Lett., 1982, 1587;
(c) E. Gomez-Bengoa, J. M. Cuerva, C. Mateo and
´
A. M. Echavarren, J. Am. Chem. Soc., 1996, 118, 8553;
(d) M. Lumbierres, C. Marchi, M. Moreno-Manas,
R. M. Sebastian, A. Vallribera, E. Lago and E. Molins, Eur. J.
´
Org. Chem., 2001, 2321; (e) C. Gimbert, M. Lumbierres,
C. Marchi, M. Moreno-Manas, R. M. Sebastian and
A. Vallribera, Tetrahedron, 2005, 61, 8598.
10 o-Phenylene-bridged phosphine-boronates readily split singlet
oxygen to give stable peroxoboronates: S. Porcel, N. Saffon,
G. Bouhadir, L. Maron and D. Bourissou, Angew. Chem., Int.
Ed., 2010, 49, 6186.
11 Comparison of Ph2PBin and PPh3/PhBPinsupports some coopera-
tivity effect between the phosphine and boronate moietiesz.
12 D. Werner and L. Dahlenburg, Z. Naturforsch., 1987, 42, 1110.
13 X.-F. Zhu, C. E. Henry and O. Know, J. Am. Chem. Soc., 2007,
129, 6722.
14 On the basis of NMR data, the reaction of a hydroxyl-functionalized
naphthyl-phosphine with MVK was proposed to give a b-phos-
phonium enolate intramolecularly stabilized by Oꢁ ꢁ ꢁH–O hydrogen
bonding: M. Shi, L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc., 2005,
127, 3790.
15 (a) C. M. Momming, S. Fromel, G. Kehr, R. Frohlich, S. Grimme
¨
and G. Erker, J. Am. Chem. Soc., 2009, 131, 12280; (b) B.-H. Xu,
¨
¨
This communication is dedicated to the memory of Prof.
Marcial Moreno-Manas. This work has been supported by the
Centre National de la Recherche Scientifique (CNRS) and
G. Kehr, R. Frohlich, B. Wibbeling, B. Schirmer, S. Grimme and
¨
G. Erker, Angew. Chem., Int. Ed., 2011, 50, 7183.
16 For rare precedents of g-keto phosphonium salts, see ref. 14 and
(a) M. E. Krafft, T. F. N. Haxell, K. A. Seibert and K. A. Abboud,
J. Am. Chem. Soc., 2006, 128, 4174; (b) C. Gimbert, M. Moreno-
the Universite
(PhoSciNet) is also acknowledged. S.P. thanks the Ministry of
Ciencia e Innovacion of Spain for a Postdoctoral Fellowship.
´
Paul Sabatier (UPS). COST action CM0802
Manas, E. Perez and A. Vallribera, Tetrahedron, 2007, 63, 8305.
´
17 For FLP-catalyzed asymmetric hydrogenation, see: (a) D. Chen
and J. Klankermayer, Chem. Commun., 2008, 2130; (b) D. Chen,
Y. Wang and J. Klankermayer, Angew. Chem., Int. Ed., 2010,
49, 9475.
´
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4495–4497 4497