Synthesis of hemilabile P,N-ligands with a pentane-2,4-diyl backbone

Article abstract of DOI:10.1016/j.tetlet.2014.05.091

A general and convenient two-step synthetic method has been developed for the preparation of a novel class of aminoalkyl-phosphine type compounds, which involves nucleophilic ring-opening of cyclic sulfate esters. The ring-opening step was performed using several different aliphatic and aromatic amines to produce aminoalkyl sulfates that were reacted with LiPPh₂ to give the corresponding P,N-ligands. The desymmetrization procedure affords an easy route to synthesize enantiomerically pure pentane-2,4-diyl based P,N-ligands with a highly tunable structure. The ligands derived from primary amines have a stereogenic N-atom that can be useful in asymmetric catalytic syntheses.

Full text of DOI:10.1016/j.tetlet.2014.05.091

Accepted Manuscript
Synthesis of hemilabile P,N-ligands with a pentane-2,4-diyl backbone
Gergely Farkas, Zsófia Császár, Szabolcs Balogh, Imre Tóth, József Bakos
PII:
S0040-4039(14)00912-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.091
TETL 44682
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 April 2014
13 May 2014
22 May 2014
Please cite this article as: Farkas, G., Császár, Z., Balogh, S., Tóth, I., Bakos, J., Synthesis of hemilabile P,N-ligands
with a pentane-2,4-diyl backbone, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.091
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Synthesis of hemilabile P,N-ligands with a pentane-2,4-diyl backbone
Gergely Farkas,a Zsófia Császár,a Szabolcs Balogh,b Imre Tóth,a József Bakosa*
aDepartment of Organic Chemistry, University of Pannonia, H-8200 Veszprém, Egyetem u. 10,
Hungary
bNMR Laboratory, University of Pannonia, Egyetem u. 10, H-8200 Veszprém, Hungary
*E-mail: bakos@almos.vein.hu, Tel: +36 88 624 544, Fax: +36 88 624 469
Abstract
A general and convenient two-step synthetic method has been developed for the preparation of a
novel class of aminoalkyl-phosphine type compounds, which involves nucleophilic ring-opening
of cyclic sulfate esters. The ring-opening step was performed using several different aliphatic
and aromatic amines to produce aminoalkyl sulfates that were reacted with LiPPh2 to give the
corresponding P,N-ligands. The desymmetrization procedure affords an easy route to synthesize
enantiomerically pure pentane-2,4-diyl based P,N-ligands with a highly tunable structure. The
ligands derived from primary amines have a stereogenic N-atom that can be useful in asymmetric
catalytic syntheses.
Graphical Abstract
Keywords
P,N-ligands, Cyclic sulfates, Asymmetric synthesis, Azetidine, Stereogenic N-atom

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The design of chiral ligands plays a key role in the development of metal-catalyzed asymmetric
reactions. Many recent studies have addressed the development of novel chiral ligands.1 Despite
impressive progress in this field, the design of suitable chiral ligands for a particular application
can be a formidable task. From the thousands of ligands prepared so far, only a few classes stand
out because of their versatility and unique catalytic properties. Interestingly, some of them
originate from the first period of the development of chiral ligands and yet they are capable of
holding their position amongst many other newly developed efficient compounds.2
BDPP [2,4-bis(diphenylphosphino)pentane] belongs to the first generation of effective chiral
diphosphine ligands in asymmetric hydrogenation and in other enantioselective transformations.3
Numerous additional ligands based on the pentane-2,4-diyl backbone have been prepared and
have also proved to be successful in asymmetric catalysis.4 Furthermore, ligands possessing a
pentane-2,4-diyl framework can be easily synthesized starting from the corresponding diols,
ditosylates or cyclic sulfates.
In complexes containing BDPP the formation of a chiral skew conformation may be preferred
that can put terminal groups in a chiral array.5 Furthermore, Bosnich et al. emphasized the
importance of chiral conformations stabilized by chiral centers at the ring backbone.6
The use of different donor atoms is one of the most effective ways of desymmetrizing chiral
bidentate ligands. To date, a large number of heterodonor ligands having P and N coordinating
functionalities have been synthesized and investigated in catalytic processes.7,8 The success of
these ligand classes is due to the fact that they have a combination of coordination sites with
different σ-donor and π-acceptor properties. The weak coordination of the nitrogen to the metal
center allows easy dissociation and gives a hemilabile character to the ligand.9 Additionally,
there are several classes amongst P,N-ligands having a chiral N-donor atom.10 The special
feature of these ligands is attributed to the formation of a configurationally stable nitrogen in
cyclometallated species that can ensure an efficient transfer of chirality from the catalyst to the
substrate.
Combining the unique pentanediyl-based chiral conformation and the stereoelectronic features of
P and N functionalities, we envisaged the synthesis of a new class of C1-symmetric hemilabile
aminoalkyl phosphine ligands. Furthermore, this type of compound can also be used as valuable
building blocks for certain highly modular phosphine-phosphoramidite ligands.4h,i Our synthetic
approach is based on a desymmetrization procedure involving nucleophilic ring-opening of

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chiral sulfate esters.11,4c More recently, a general and efficient method was described for the
preparation of chiral and achiral P,N- and P,S-ligands from 1,2-cyclic sulfates using C-
nucleophiles.12
In our approach, 1,3-cyclic sulfates were obtained by a simple one-pot reaction from the
corresponding diols, following the procedure developed for 1,2-cyclic sulfates by Gao and
Sharpless.13 This involves the treatment of diols with SOCl2 followed by oxidation with NaIO4 in
the presence of a catalytic amount of RuCl3.
The novel ligands were synthesized in two simple steps (Scheme 1). At first, enantiomerically
pure (4R,6R)-4,6-dimethyl-1,3,2-dioxathiane-2,2-dioxide (1) and the corresponding primary
amine were mixed neat or in THF leading to the aminoalkyl sulfate 2.14 A remarkable feature of
the methodology is that the use of strong bases as deprotonating agents for the amine can be
avoided. The addition of three equivalents of LiPPh2 in THF provided the aminoalkylphosphines
3 in good yields. Both the ring-opening reaction of the cyclic sulfate with the amine and the
second substitution reaction take place with complete inversion at the stereogenic centers
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providing the product with (2S,4S) configuration. The P{1H} NMR spectra of compounds 3
exhibited one singlet indicating the formation of one single diastereomer. Ligands 3a-e have a
stereogenic N-atom that will be configurationally stable upon coordination to the metal due to
the endocyclic stereogenic centers in the chelate ring.10b
Scheme 1 Synthesis of P,N-ligands by nucleophilic ring-opening with primary amines
According to this procedure, aminoalkyl phosphines can be easily synthesized in pure form
without any subsequent purification. The product of the first step was isolated by a simple
filtration from an ethereal suspension. In the second step the HPPh2 by-product was removed by

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extraction with diethyl ether after acidifying the solution. On adjusting the pH back to basic, the
next ethereal extraction provided the product in pure form.
In the case of treatment of 2e with LiPPh2 we observed the formation of a by-product
(approximately 20%) that was identified as N-phenylazetidine 4. The route leading to this
valuable intermediate 4 is a competitive reaction to the formation of aminophosphine 3e and
presumably occurs by the same mechanism as the formation of aziridines (Scheme 2). It is
known, that treatment of vicinal sulfate esters with primary amines in THF at reflux can afford
aziridines by deprotonation under basic conditions.15 As far as we are aware, ring-opening of
cyclic sulfates of optically pure 1,3-diols with primary amines followed by nucleophilic
substitution with LiPPh2 has hitherto not been reported as a possible synthetic route to chiral,
symmetrically substituted arylazetidines. Chiral C2-symmetric N-arylazetidines have been
prepared before from optically pure anti-1,3-diols via bis(methanesulfonates).16 The ring-
opening of N-phenyl azetidine by LiPPh2, as another route that would lead to the other
diastereomer (R,S), did not occur under the reaction conditions applied.17
Scheme 2 Formation of N-phenylazetidine 4 under basic conditions
In order to widen the applicability of this convenient methodology, cyclic amines were also
investigated as nucleophiles for the ring-opening step. Despite the fact that cyclic amines are
stronger nucleophilic agents compared to primary amines no double substitution was observed.
The reaction was completely chemo- and stereoselective according to the NMR data. In the
second step, only two equivalents of LiPPh2 were used.

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Scheme 3 Synthesis of P,N-ligands by nucleophilic ring-opening with secondary cyclic amines
The application of this methodology can be extended to other mixed P,N-ligands (e.g.,
phosphine-oxazoline, phosphine-imidazole). The modular design of the ligand synthesis would
allow a correlation between the ligand-metal structure and the enantioselectivity of the reaction.
According to our preliminary results the scope of our methodology can also be applied to mixed
P,S-ligands.
In conclusion, we have reported the synthesis of a novel class of enantiomerically pure pentane-
2,4-diyl-based ligands. The unique conformational features expressed by the chiral backbone and
the different donor abilities of the coordination sites might give useful catalytic properties to the
ligands. The developed synthetic strategy offers a convenient, two-step route and can be
extended to the synthesis of other P,N-type ligands. Moreover, the procedure allows the
preparation of compounds with a highly modular structure as a useful tool in efficient catalyst
design.
Acknowledgements
We thank Ms Ágnes Kripli and Mr Béla Édes for skillful assistance in analytical measurements
and synthetic experiments. This research was supported by the European Union and the State of
Hungary, co-financed by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-
11/1-2012-0001 ‘National Excellence Program’. This article was partly supported under the
projects TÁMOP-4.2.2/A 11/1/KONV-2012-0071.
Supplementary data

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Supplementary information including synthetic and spectroscopic data for compounds 2, 3 and 4
associated with this article can be found in the online version.
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