"Clickphine": A novel and highly versatile P,N ligand class via click chemistry

Article abstract of DOI:10.1021/ol061015q

A novel P,N-type ligand family (ClickPhine) is disclosed that is easily accessible using the Cu(I)-catalyzed azide-alkyne "click" cycloaddition. A diverse set of ligands was made in just three steps from readily available starting materials to give several homogeneous and a heterogeneous catalyst. Preliminary experiments show the efficacy of these ligands in the Pd-catalyzed allylic alkylation reaction.

Full text of DOI:10.1021/ol061015q

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3227-3230
“Clickphine”: A Novel and Highly
Versatile P,N Ligand Class via Click
Chemistry
Remko J. Detz, Silvia Are´valo Heras, R. de Gelder,† Piet W. N. M. van Leeuwen,
Henk Hiemstra, Joost N. H. Reek,* and Jan H. van Maarseveen*
Van’t Hoff Institute for Molecular Sciences, Faculty of Science, UniVersity of
Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands, and
Molecular Materials, Institute for Molecules and Materials, Radboud UniVersity
Nijmegen, ToernooiVeld 1, 6525 ED Nijmegen, The Netherlands
jVm@science.uVa.nl; reek@science.uVa.nl
Received April 27, 2006
ABSTRACT
A novel P,N-type ligand family (ClickPhine) is disclosed that is easily accessible using the Cu(I)-catalyzed azide
−alkyne “click” cycloaddition.
A diverse set of ligands was made in just three steps from readily available starting materials to give several homogeneous and a heterogeneous
catalyst. Preliminary experiments show the efficacy of these ligands in the Pd-catalyzed allylic alkylation reaction.
Transition metal catalysis is increasingly important both for
industry and academia, since it provides new efficient and
sustainable routes for organic synthesis and the production
of fine chemicals.1 Ligand variation is the most powerful
tool in transition metal catalysis, and key features of transition
metal catalysts such as activity, selectivity, and stability are
dictated by the steric and electronic properties of ligands that
are coordinated to the metal.2 It is therefore no surprise that
most effort in the area of catalysis is put into the design of
novel ligands. Besides the development of new catalysts by
ligand design and combinatorial approaches,3 much research
is devoted to catalyst recycling. Various elegant concepts
for homogeneous catalyst separation and recycling have been
developed4 such as the use of ionic liquids,5 supercritical
fluids,6 supported aqueous phase catalysis,7 and fluorous
phase catalysis.8 A widely studied approach to facilitate
catalyst-product separation is the attachment of homoge-
neous catalysts to dendritic,9 polymeric organic, inorganic,
or hybrid supports.10 Here the ligand requires a group that
enables anchoring to such a support.
Sharpless and co-workers recently introduced click-
chemistry as a new way of categorizing organic reactions
(3) (a) Hoveyda, A. In Handbook of Combinatorial Chemistry; Nicolaou,
K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim, 2002; Vol.
2, pp 991-1016. (b) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284.
(c) Gennari, C.; Piarulli, U. Chem. ReV. 2003, 103, 3071-3100.
(4) (a) Cole-Hamilton, D. J. Science 2003, 299, 1702. (b) Chem. ReV.
2002, 102, issue 10 thematic issue.
† Radboud University Nijmegen.
(1) (a) Nicolaou, K. C.; Bulger, P. C.; Sarlah, D. Angew. Chem., Int.
Ed. 2005 44, 4442. (b) Clarke., P. A.; Cridland, A. P. Annu. Rep. Prog.
Chem., Sect. B 2004 100, 91.
(2) (a) Chaloner, P. A.; Esteruelas, M. A.; Joo´, F.; Oro, L. A.
Homogeneous Hydrogenation; Kluwer: Dordrecht, 1994. (b) Brown, J. M.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1. (c) Parshall, G. W.;
Ittel, S. D. Homogeneous Catalysis, Wiley: New York, 1992; (d) van
Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem.
ReV. 2000, 100, 2741.
(5) (a) Wasserscheid, P.; Welton, T. In Ionic Liquids in Synthesis; Wiley-
VCH Verlag: Weinheim, 2003. (b) Welton, T. Chem. ReV. 1999, 99, 2071.
(6) (a) Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. ReV. 1999, 99, 475.
(b) Darr, J. A.; Poliakoff, M. Chem. ReV. 1999, 99, 495.
(7) (a) Arhanchet, J. P.; Davis, M. E.; Merola, J. S.; Hanson, B. E. Nature
1989, 339, 454. (b) Sandee, A. J.; Slagt, V. F.; Reek, J. N. H.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M. Chem. Commun. 1999, 17, 1633.
(8) (a) Horva´th, I. T.; Ra´bai, J. Science 1994, 266, 72. (b) Horva´th, I. T.
Acc. Chem. Res. 1998, 31, 641. (c) Barthel-Rosa, L. P.; Gladysz, J. A. Coord.
Chem. ReV. 1999, 190-192, 587.
10.1021/ol061015q CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/27/2006

that are modular in nature, highly efficient, mild, and
selective and require only simple reaction and workup
procedures.11 We anticipated that the implementation of a
click-reaction in the synthetic scheme of a ligand should
automatically lead to a novel versatile ligand that is easy to
vary. In addition, it might also provide a handle to attach
the ligand to various supports.
We were especially interested in the Cu(I)-catalyzed 1,3-
dipolar “click” azide-alkyne cycloaddition,12 since the
resulting 1,4-disubstituted 1,2,3-triazoles can be part of a
bidentate P,N-type ligand. P,N ligands represent an important
class of ligands that have been applied in various catalytic
transformations.13
In this paper, we report the preparation of a series of P,N
ligands using click chemistry, and we show that this strategy
allows facile immobilization of these ligands on soluble
(dendrimers, poly(ethylene glycol)) and insoluble supports
(polystyrene resin). Preliminary results show that the pal-
ladium catalysts are highly active and regioselective in the
allylic alkylation of cinnamyl acetate and that the im-
mobilized catalyst can indeed be recycled.
The synthesis of the first ligand commences with the
treatment of commercially available borane-protected diphen-
ylphosphine 1 with n-BuLi followed by addition of propargyl
bromide providing propynyl phosphine 2 (Scheme 1).
Recently, a triazole-based monophosphine, ClickPhos, was
reported showing high activity in the Pd-catalyzed Suzuki-
Miyaura coupling and amination reactions of aryl chlorides.14
Also, the triazole itself has already shown its good metal-
coordination properties.15 Surprisingly, the use of triazoles
as nitrogen donors in P,N ligands has, as far as we know,
no literature precedent yet. This novel class of P,N ligands
might be attractive because of the easy and highly modular
synthetic accessibility, which enables facile tuning of their
steric and electronic properties for catalyst optimization
(Figure 1). In addition, several commonly used supports have
Scheme 1. Synthesis of Ligand Derivatives 4a-e
The acetylene moiety was subjected to Cu(I)-catalyzed
azide-alkyne cycloaddition providing the P-protected Click-
Phine derivatives 3a-e in high yields. Throughout the
sequence, the phosphine must be protected to prevent
unwanted iminophosphorane formation (Staudinger reaction)
during the “click” reaction. The unprotected ligands 4a-d
were obtained after liberation of the phosphine by treatment
with DABCO.
Azidophosphine 6 was prepared starting from the previ-
ously reported hydroxyphosphine 5.16 Although the subse-
quent azide-alkyne cycloaddition was slower than the
reversed one, several acetylenes could be coupled providing
7a-c. Borane removal with DABCO provided ligands 8a-
c, which will be slightly different from 4 because these
ligands will coordinate with N(2) instead of N(1) when the
ligand functions as a bidentate ligand (Scheme 2).
Figure 1. P,N ligands obtained by the Cu(I)-catalyzed azide-
alkyne cycloaddition reaction.
azide or acetylene moieties facilitating a complete system
approach including a catalyst-separation step underscoring
their versatility.
(9) (a) van Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Reek, J. N. H. Chem. ReV. 2002, 102, 3717. (b) Kreiter, R.; Kleij, A. W.;
Klein Gebbink, R. J. M.; van Koten, G. In Dendrimers IV: Metal
Coordination, Self-Assembly, Catalysis; Vo¨gtle, F., Schalley, C. A., Eds.;
Springer-Verlag: Berlin, 2001; Vol. 217, p 163. (c) Oosterom, G. E.; Reek,
J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Angew. Chem., Int.
Ed. 2001, 40, 1828. (d) Astruc, D.; Chardac, F. Chem. ReV. 2001, 101,
2991.
(10) Reviews on polymer immobilized catalysts include: (a) Hartley,
F. R.; Vezey, P. N. AdV. Organomet. Chem. 1977, 15, 189. (b) Hartley, F.
R. In Supported Metal Complexes. A New Generation of Catalysts; Reidel:
Dordrecht, 1985. (c) Iwasawa, Y. In Tailored Metal Catalysts; Ugo, R.,
James, B. R., Eds.; Reidel: Dordrecht, 1986. (d) Keim, W.; Driessen-
Ho¨lscher, B. In Handbook of heterogeneous catalysis; Ertl, G., Kno¨zinger,
H., Weitkamp, J., Eds.; Wiley-VCH: Weinhein, 1997; Vol. 1. (e) Lindner,
E.; Schneller, T.; Auer, F.; Mayer, H. A. Angew. Chem., Int. Ed. 1999, 38,
2154. (f) Thomas, J. M. Angew. Chem., Int. Ed. 1999, 38, 3588.
(11) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Kolb, H. C.; Sharpless, K. B. Drug Discuss. Today
2003, 8, 1128. (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur.
J. Org. Chem. 2006, 1, 51-68.
To demonstrate that the approach indeed also works to
arrive at supported ligands, both a dendrimer and a poly-
styrene resin were decorated with the ligands. The previously
reported second-generation carbosilane dendrimer 9 employ-
ing an azide group at the focal point was attached to
(12) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornoe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(13) (a) Bell, S.; Wu¨stenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.;
Pfaltz, A. Science 2006, 311, 642. Review article: (b) Guiry, P. J.;
Saunders: C. P. AdV. Synth. Catal. 2004, 346, 497.
(14) Liu, D.; Gao, W.; Dai, Q.; Zhang, X. Org. Lett. 2005, 7, 4907.
(15) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853.
(16) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett. 2004,
6, 4479.
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Org. Lett., Vol. 8, No. 15, 2006

corresponding phosphine oxide (13%), two minor phosphorus
signals (19%) of unidentified species were also detected.
Upon mixing ligands 4a-d or dendritic ligand 11 with
[Pd(allyl)Cl]2 in dichloromethane the corresponding neutral
metal complexes are formed, according to NMR experiments
Scheme 2. Synthesis of Ligand Derivatives 8a-c
1
(Scheme 5). The H NMR spectra show broad signals for
Scheme 5. Synthesis of Palladium Complexes
phosphine 2 using standard click conditions.17 Deprotection
of the phosphine with DABCO gave dendritic ligand 11 in
very high yield (Scheme 3).
the allylic protons (except for the central proton) indicating
isomerization via π rotation or π,σ-rearrangement. The 31P
NMR spectrum shows a broad signal at 20.6 ppm. Crystals
suitable for X-ray analysis were obtained for complex 17b,
revealing monodentate binding of the ligand (Figure 2) with
Scheme 3. Synthesis of the Dendritic Ligand 11
The polystyrene-supported azide was prepared by treat-
ment of Merrifield resin 12 with sodium azide according to
literature procedures (Scheme 4).18 The resulting resin 13
Figure 2. X-ray diffraction structure of complex 17b. Hydrogen
atoms have been ommited for clarity.
Scheme 4. Synthesis of the Polystyrene-Supported Complex 14
the chloride still coordinated to the palladium.19
The corresponding cationic palladium-allyl complexes
were prepared from the palladium chloride by addition of
1
AgBF4. The H NMR signal of the triazole proton shifted
0.71 ppm to lower field (from 8.15 to 8.86 ppm) after ion-
exchange, and the CH2 group gave rise to an AB pattern
showing that these protons became inequivalent. In addition,
the signal in the 31P NMR spectrum shifted from 20.6 to
40.5 ppm and became sharper. These data all point to the
formation of a palladium-allyl complex in which the ligand
shows bidentate P,N coordination. Unfortunately, all crystal-
lization attempts of these complexes failed.
was subjected to the Cu(I)-catalyzed cycloaddition with
propynylphosphine 2 using tris(benzyltriazolylmethyl)amine
(TBTA) as the ligand to accelerate the reaction.15 The
polystyrene-supported ligand complex 16 was obtained after
DABCO-mediated phosphine liberation and subsequent com-
plexation with palladium. 31P MAS-NMR analysis revealed
a yield of 68% of the supported complex. Next to the
Many efforts have been made in enantioselective allylic
alkylation with P,N-ligands;20 the subject of regioselectivity
(19) CCDC 603618 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK.; fax:
(+44)1223-336-033; or deposit@ccdc.cam.ac.uk). The crystallographic data
are also available in the CIF file in the Supporting Information.
(20) For a seminal example, see: Pretot, R.; Pfaltz, A. Angew. Chem.,
Int. Ed. 1998, 37, 323.
(17) Amore, A.; van Heerbeek, R.; Zeep, N.; van Esch, J.; Reek, J. N.
H.; Hiemstra, H.; van Maarseveen, J. H. J. Org. Chem. 2006, 71, 1851
(18) Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org Lett. 2003, 5,
1753.
Org. Lett., Vol. 8, No. 15, 2006
3229

has been less studied.21 Our initial experiments show that
the palladium complexes of the novel ligands described are
active in the Pd-catalyzed allylic alkylation of cinnamyl
acetate applying sodium methyl diethylmalonate as nucleo-
phile. The palladium complexes are highly active and
selective for the trans product a (Table 1), and all reactions
and we found that large bite angle ligands resulted in
preferential formation of the branched product.22 The ligands
that are reported here have small bite angles and provide
very high selectivities for the linear product (up to 98%).23
Interestingly, within the small ligand series investigated we
already observed a large effect in the reactivity. The catalysts
based on ligands 4d and 11 (the dendritic ligand), with more
electron-rich triazole rings, were considerably more active
(entries 4 and 5). It was also observed that the cationic
palladium complexes generally gave higher initial rates than
the neutral analogues.
Table 1. Pd-Catalyzed Allylic Alkylation of Cinnamyl Acetate
Preliminary experiments with polystyrene-supported cata-
lyst 16 showed that the supported catalyst retained its activity
and was easy to recycle. A small decrease in activity upon
recycling had to be accepted; the fourth run still gave 54%
conversion of the cinnamyl acetate after 1 h reaction time,
whereas the first run showed 72% conversion (Table 1,
entries 6 and 7), which is not uncommon for palladium
catalysts.
conversiona (%)
selectivitya,b (%)
In conclusion, we have shown the versatility of a new class
of P,N-ligands that is accessible via the robust Cu(I)-
catalyzed alkyne-azide cycloaddition enabling facile tailor-
made modification for optimization or other (e.g., ligand
immobilization) purposes. The efficacy of these ligands is
shown for Pd-catalyzed alkylation reactions.
ligand
X
35 min
1 h
a
b
1
2
3
4
5
6c
7c,d
4a
4b
4c
4d
11
15
15
BF4
BF4
BF4
BF4
BF4
Cl
55
54
65
68
78
90
91
72
54
97
97
97
98
98
96
96
3
3
3
2
2
4
4
78
80
64
Acknowledgment. The NRSC-C is kindly acknowledged
for financial support of this project.
Cl
a Conversion of cinnamyl acetate and regioselectivity were determined
by GC using decane as internal standard and in select cases confirmed by
NMR. All reactions gave full conversion. b No cis product (c) was observed.
c Approximately 2 mol % of catalyst and 1:0.7 cinnamyl acetate/Nu ratio.
d The reaction was carried out with the 15-Pd complex recovered after
three previous runs without further addition of [PdallylCl]2.
Supporting Information Available: The crystallographic
CIF file of 17b and full experimental details and compound
characterization data for 2, 3a-e, 4a-d, 6, 7a-c, 8a-c,
10, 11, and 13-15. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL061015Q
went to completion after prolonged reaction. We previously
studied the effect of the bite angle of P,N-type ligands on
the selectivity in the palladium-catalyzed allylic alkylation,
(22) van Haaren, R. J.; Druijven, C. J. M.; van Strijdonck, G. P. F.;
Oevering, H.; Reek, J. N. H,; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
J. Chem. Soc., Dalton Trans. 2000, 1549.
(23) The “memory effect” might also contribute to the high regioselec-
tivity for the trans product; see also: (a) Loyd-Jones, G. C.; Stephen, S.
C.; Murray, M.; Butts, C. P.; Vyskocil, S.; Kocovsky, P. Chem. Eur. J.
2000, 6, 4348. (b) Loyd-Jones, G. C.; Stephen, S. C. Chem. Eur. J. 1998,
4, 2539.
(21) (a) Kondo, K.; Kazuta, K.; Saitoh, A.; Murakami, Y. Heterocycles
2003, 59(1), 97. (b) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai,
L.-X. J. Am. Chem. Soc. 2001, 123, 7471.
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