Atropisomeric phosphinines: Design and synthesis

Article abstract of DOI:10.1039/b715197g

The first atropisomeric phosphinine was designed and prepared by introducing substituents into specific positions of the heterocyclic framework; the presence of axial chirality was predicted by means of DFT calculations and experimentally verified by chir

Full text of DOI:10.1039/b715197g

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Atropisomeric phosphinines: design and synthesis†‡
Christian Mu¨ller,*a Evgeny A. Pidko,a Daniel Totev,a Martin Lutz,b Anthony L. Spek,b Rutger A. van Santena
and Dieter Vogta
Received 2nd October 2007, Accepted 3rd October 2007
First published as an Advance Article on the web 10th October 2007
DOI: 10.1039/b715197g
The first atropisomeric phosphinine was designed and pre-
pared by introducing substituents into specific positions of
the heterocyclic framework; the presence of axial chirality
was predicted by means of DFT calculations and exper-
imentally verified by chiral HPLC analysis, derivatization
axial chirality within the heterocyclic framework and close to
the phosphorus center, without changing the properties of these
ligands by additional chiral auxilliaries.4,8 We anticipated that the
original phosphinine-synthesis described by Ma¨rkl would provide
the opportunity to introduce substituents into specific positions of
the heterocycle, due to their modular synthesis and the necessity to
maintain the axial chirality. Thus, as a first approach we aimed for
the preparation of the axially chiral phosphinine1. This compound
resembles the molecular structure of 2,2ꢀ-3,3ꢀ-tetramethyl biphenyl
2 (Fig. 1; only one isomer is shown) and is at the same time
expected to be synthetically accessible. The enantiopure biphenyl
2 has indeed a considerable optical stability due to the Buttressing-
effect as well as the relatively large negative racemization entropy
as reported previously in the literature.9,10 In order to estimate
the barriers for rotation around the Ca–Cb-bond in compounds 1
and 2, we performed DFT calculations.11 In fact, it has recently
been shown that the rotational barriers of various biphenyls
can be reliably predicted by theoretical calculations and are in
good agreement with the experimentally determined values.13 As
anticipated for compounds with structural analogy, the calculated
1
experiments as well as temperature dependent 31P{ H} NMR
spectroscopy.
k3-Phosphinines (phosphabenzenes, phosphorins), the higher ho-
mologues of pyridines, have been known for many decades, due
to the pioneering work of Ma¨rkl and Ashe III in the late 1960s.1
These heterocycles are planar, aromatic systems in which one –
CH– group of the aryl moiety is substituted by a low-coordinated,
trivalent phosphorus atom.
While atropisomeric pyridines have recently been prepared by
Heller et al. via enantioselective Co-catalyzed cyclotrimerization
of bulky acetylenes and nitriles, their phosphorus containing
analogues still remain elusive because the introduction of chirality
into these flat systems is intrinsically difficult to achieve.2 Only a
few examples of chiral phosphinines exist in the literature, but they
are based on chiral auxilliaries, such as oxazoline or binaphthol
groups, which are attached to the heterocyclic framework.3,4
On the other hand, chiral phosphinines could be highly interest-
ing ligands for asymmetric homogeneous catalysis. Monodentate
triarylphosphinines, for example, have shown to be efficient
ligands for the Rh-catalyzed hydroformylation of internal and
less reactive alkenes, due to their special steric and electronic
properties.3,5 Moreover, phosphinines are precursors for the
preparation of phosphabarrelenes.6,7 These bicyclic systems have
also been successfully applied as ligands in the Rh-catalyzed
hydroformylation of internal alkenes, showing basically no iso-
merization activity towards 1-alkenes.7 The preparation of chiral
phosphinines and phosphabarrelenes could therefore lead to
ligand systems, which are suitable for the efficient enantioselective
functionalization of internal alkenes with relevance for both
intermediates and the fine-chemicals industry.
values§ for 1 and 2 are thus very similar and in the order of DG‡
=
298
110 5 kJ mol−1 (Table 1, entry 1 and 2).
Motivated by these findings, we continued with the experimental
procedure for the synthesis of phosphinine 1, having a barrier for
internal rotation, which is expected to be high enough for further
separation of the enantiomers at ambient conditions.
The key-intermediate for the preparation of triaryl-substituted
phosphinines with the substitution pattern as depicted in Fig. 1
is 2,3-dimethylpropiophenone 3 (Scheme 1). The use of a pro-
piophenone rather than an acetophenone ultimately results in
locating a methyl-group in the 3-position of the heterocycle,
necessary for maintaining the axial chirality.14 Compound 3 was
Table 1 Calculated rotational barriers for 1, 2 and 9
Entry
Compound
DE‡/kJ mol−1
DG‡298/kJ mol−1
1
2
3
1
2
9
106
101
92
116
109
100
During the course of our investigations on functionalized
phosphinines, we started to investigate the possibility of generating
aSchuit Institute of Catalysis, Department of Chemical Engineering and
Chemistry, Eindhoven University of Technology, 5600 MB Eindhoven, The
Netherlands. E-mail: c.mueller@tue.nl; Fax: +31 40 245 5054; Tel: +31 40
247 3040
bBijvoet Center for Biomolecular Research, Department of Crystal and Struc-
tural Chemistry, Utrecht University, 3584 CH Utrecht, The Netherlands
† CCDC reference number 659766. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b715197g
‡ Electronic supplementary information (ESI) available: A detailed list
of all experimental procedures, cif file and crystallographic data for
compound 8. See DOI: 10.1039/b715197g
Fig. 1 Axial chirality in 1 and 2.
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Scheme 1 Synthesis of substituted pyrylium salts.
synthesized in high yield, starting from commercially available
bromoxylene, according to a literature procedure.15 Reaction of
3 with two equivalents of the benzylidene-acetophenones 4 or 5,
respectively, and in the presence of HBF4·Et2O yields a racemic
mixture of the corresponding pyrylium salts 6 (R = H) and 7 (R =
OMe) as yellow–orange solids in moderate yields. 6 and 7 were
1
1
1
fully characterized by means of H, 13C{ H} and 19F{ H} NMR
spectroscopy as well as elemental analysis.
In order to gain structural information on the pyrylium
salts as well, we anticipated that hydroxy-functionalized com-
pounds would be ideal candidates for obtaining single-crystals
as demonstrated before by us.4 Consequently, compound 7 was
quantitatively converted into the yellow pyrylium salt 8 by reaction
with excess BBr3 in CH2Cl2 and subsequent aqueous workup (see
Scheme 2).
Fig. 2 Molecular structure of 8 in the crystal. Displacement ellipsoids are
shown at the 50% probability level. The O–H · · · Br hydrogen bond is drawn
˚
with dashed lines. Selected bond lengths (A): C1–O1: 1.358(2), O1–C5:
1.346(3), C5–C21: 1.452(3), C1–C6: 1.484(3), O2 · · · Br1: 3.1438(18).
Torsion angle (◦): C7–C6–C1–C2: +73.0(3).
17
trile, or alternatively by reaction with P(CH2OH)3 in refluxing
pyridine. Compound 1 was obtained as a yellow powder after
column chromatography in 34% yield and fully characterized
1
1
1
by means of H, 13C{ H} and 31P{ H} NMR spectroscopy and
elemental analysis. In the 31P{ H} NMR spectrum of 1 the single
1
resonance at d = 190.5 ppm (C6D6) is characteristic for the
aromatic phosphinine.
A very good separation to a 1 : 1 mixture of enantiomers
was achieved by analytical HPLC on a chiral stationary phase,
Scheme 2 Preparation of pyrylium salt 8.
R
using n-hexane as eluent (Chiralcelꢀ OD–H, t1 = 19.31 min, t2 =
◦
23.81 min, T = 25 C, flow-rate 1 mL min−1, see ESI‡), which
The complete removal of the –CH3 group was confirmed by
1H NMR spectroscopy. At the same time, the reaction with H2O
produced substantial amounts of HBr which led to the anion
exchange of BF4− for Br− during aqueous workup as indicated by
confirms that the barrier of internal rotation is indeed reasonably
high as expected.
In order to additionally verify that phosphinine 1 is a racemate
we transformed 1 into the corresponding phosphabarrelene 9 by
reaction with in-situ generated benzyne, according to a procedure
described by Ma¨rkl and Breit et al. (Scheme 3).6,7 Compound
9 was obtained as a yellow solid in 35% yield after flash
chromatography and was fully characterized. The reaction of a
racemic mixture of a phosphinine with benzyne should lead to
four stereoisomers, because a stereogenic phosphorus center is
additionally established upon formation of the phosphabarrelene
(Scheme 3).
1
the lack of any resonance in the 19F{ H} NMR spectrum.
Red crystals of 8, suitable for X-ray crystallography, were indeed
obtained by slow crystallization from methanol and the molecular
structure is illustrated in Fig. 2, along with selected bond lengths
and angles. It confirms not only the expected substitution pattern
and the formation of the hydroxy-functionalized pyrylium salt,
−
but also the presence of a Br−, rather than a BF4 anion with
additional hydrogen bonding. 8 crystallizes as a racemate in
the centrosymmetric space group P21/c. The torsion angle of
+73.0(3)◦ shows that the xylyl-substituent in the 2-position is
situated almost perpendicular to the plane, which is formed by
the oxygen-containing heterocycle, due to the expected restricted
rotation around the C1–C6 bond. In contrast, the planes of the
hydroxy-functionalized aryl-moiety in the 6-position and of the
heterocycle are almost parallel to one another as observed before
for several pyrylium salts.4,8
The two enantiomeric pairs should consequently give rise to two
1
different signals in the 31P{ H} NMR spectrum, if axial chirality
is maintained in the molecule. Indeed, we could observe two
1
resonances for 9 by 31P{ H} NMR spectroscopy at d = −65.0 ppm
and d = −66.4 ppm (C6D6), respectively, in a diastereomeric ratio
of 2 : 3 (see ESI‡).
The presence of four stereoisomers was further confirmed in
situ by reaction of 9 with the enantiomerically pure chiral Pd
18
Pyrylium salt 6 was further converted into the corresponding
complex (S)-[PdCl{C6H4CH(Me)NMe2}]2 in C6D6 (Scheme 4).
16
phosphinine 1 by reaction with excess P(SiMe3)3 in acetoni-
Four resonances at d = 6.0, 4.9, 2.2 and 0.0 ppm were observed by
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presence of axial chirality was verified by chiral HPLC analysis and
derivatization experiments towards atropisomeric phosphabarre-
lenes. The rotational barrier for racemization was estimated both
theoretically by DFT calculations and experimentally by tempera-
1
ture dependent 31P{ H} NMR spectroscopy. Future investigations,
which are out of the scope of this communication, will focus on
the isolation of the enantiomers as well as their application in
asymmetric homogeneous catalysis.
Notes and references
§ The activation energies reported correspond to the low-energy clockwise
rotation path of the isomers shown in Fig. 1.
1 (a) G. Ma¨rkl, Angew. Chem., 1966, 78, 907; (b) A. J. Ashe, III, J. Am.
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153; (d) K. Dimroth, Top. Curr. Chem., 1973, 38, 1–147; (e) G. Ma¨rkl,
in Multiple Bonds and Low Coordination in Phosphorus Chemistry,
ed. M. Regitz, O. J. Scherer, Thieme Verlag, Stuttgart, 1990, pp. 220;
(f) P. Le Floch in Phosphorus–Carbon Heterocyclic Chemistry: The Rise
of a New Domain, ed. F. Mathey, Pergamon, Palaiseau, 2001, pp. 485–
533; (g) F. Mathey, Angew. Chem., Int. Ed., 2003, 42, 1578; (h) F. Mathey
and P. Le, Floch, Sci. Synth., 2005, 15, 1097.
Scheme 3 Synthesis of phosphabarrelene 9 from 1. e: enantiomeric pair,
d: diastereomeric pair.
2 A. Gutnov, B. Heller, C. Fischer, H.-J. Drexler, A. Spannenberg, B.
Sundermann and C. Sundermann, Angew. Chem., Int. Ed., 2004, 43,
3795.
3 (a) B. Breit, Chem. Commun., 1996, 2071; (b) B. Breit, J. Mol. Catal. A:
Chem., 1999, 143, 143.
4 C. Mu¨ller, L. Guarrotxena-Lope´z, H. Kooijman, A. L. Spek and D.
Vogt, Tetrahedron Lett., 2006, 47, 2017.
5 (a) B. Breit, R. Winde and K. Harms, J. Chem. Soc., Perkin Trans. 1,
1997, 2681; (b) B. Breit, R. Winde, T. Mackewitz, R. Paciello and K.
Harms, Chem.–Eur. J., 2001, 7, 3106.
Scheme 4 Reaction of 9 with a chiral Pd-complex.
6 G. Ma¨rkl, Tetrahedron Lett., 1971, 12, 1249.
7 (a) B. Breit and E. Fuchs, Chem. Commun., 2004, 694; (b) E. Fuchs, M.
Keller and B. Breit, Chem.–Eur. J., 2006, 12, 6930.
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2006, 36, 869; (b) C. Mu¨ller, D. Wasserberg, J. J. M. Weemers,
E. A. Pidko, S. Hoffmann, M. Lutz, A. L. Spek, S. C. J. Meskers,
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5384.
1
31P{ H} NMR spectroscopy and in the expected ratio of 3 : 2 : 2 :
3 (see ESI‡).
DFT calculations additionally revealed, that the calculated
rotational barrier DG‡ around the Ca–Cb-bond in compound
9 equals 100 kJ mol−1298and is therefore comparable to that in
phosphinine 1 (Table 1, entry 3). Unlike for compound 1, the
mixture of stereoisomeric phosphabarrelenes also now provides
the opportunity of determining experimentally the rotational
barrier in compound 9. Upon heating, rotation around the Ca–
Cb is anticipated, leading to fast exchange on the NMR-time scale
and consequently to the formation of enantiomers with a single
11 DFT calcualtions were all performed at B3LYP/6–31G(d) level using
the Gaussian 03 program.12 The activation energies DE‡ reported were
corrected for zero-point energy. Activation Gibbs free energies DG‡
298
were calcualted using the ideal gas approximation at a pressure of 1
atm and a temperature of 298.15 K.
resonance in the 31P{ H} NMR spectrum.
1
12 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N.
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We therefore performed temperature dependent 31P{ H} NMR
1
spectroscopy of compound 9 in xylene. At T = 150 ◦C, coalescence
of the two signals starts to occur. Due to the experimental
conditions, measurements at even higher temperatures could not
be performed. Nevertheless, an experimental rotational barrier of
at least DG‡A(rot) ≥ 85 5 kJ mol−1 was estimated from the obtained
data,19 which agrees well with the above theoretical results. Due
to the similar structure of phosphabarrelene 9 and phosphinine
1 as well as due to the slightly higher calculated rotational
barrier for the latter compound, we believe that the experimental
value determined for 9 can be adequately extrapolated to phos-
phinine 1.
In summary, we demonstrated the design and the synthesis of
the first atropisomeric monodentate phosphinine by introducing
methyl-substituents into specific positions of the heterocyclic
moiety. The phosphinine was obtained as a racemate and the
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