A Highly Diastereoselective Recognition Process as the Basis for the

Communication pubs.acs.org/Organometallics

A Highly Diastereoselective Recognition Process as the Basis for the Resolution of Palladatricyclo[4.1.0.02,4]heptanes A. Stephen K. Hashmi,*,†,‡ Marc A. Grundl,‡ Dominic Riedel,† Matthias Rudolph,† and Jan W. Bats

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Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany § Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität Frankfurt, Max-von-Laue-Straße 7, 60438 Frankfurt, Germany

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S Supporting Information *

ABSTRACT: The synthesis of palladatricyclo[4.1.0.02,4]heptane diastereomers by positional selective transesterification with (1R,2S,5R)(−)-menthol is used for the resolution of these chiral organometallic compounds. The separation process of the two diastereomers is simplified by an unprecedented aggregation phenomenon. In a molecular recognition process the highly diastereoselective formation of dimers of strongly differing stability allows an efficient separation by normal column chromatography. The stereoselective dimerization was proven by IR and mass spectroscopic studies as well as 1H NMR techniques and X-ray crystal structure analysis.

5-Palladatricyclo[4.1.0.02,4]heptanes (PdTHs) are interesting chiral scaffolds, which are easily accessible by oxidative cyclometalation of two cyclopropenes at Pd(0). They are stable to both oxygen and water and possess two vacant coordination sites on palladium, which give rise to a rich coordination chemistry.1 Recently we published the formation of the diastereomeric complexes 2a,b, which could be separated by HPLC (Scheme 1). The removal of the corresponding

ligand with copper(II) acetate allowed the first access to enantiomerically pure PdTHs.2 A great disadvantage of this procedure is the low overall yield over the two steps and the high costs caused by the use of stoichiometric amounts of expensive, enantiomerically pure ligands such as the DIOP ligand. Next we investigated a diastereoselective oxidative cyclometalation using alkyl lactate groups on the esters of the cyclopropenes in the reaction with Pd(0).3 This was quite successful, as dr values of up to 97:3 could be achieved, but the major drawback was the tedious synthesis of the corresponding cyclopropenes. For an easier access to nonracemic chiral palladacycles, we turned our focus to classical chiral resolution strategies. By transesterification of rac-1 with commercially available (1R,2S,5R)-(−)-menthol,4 the easily separable, enantiomerically pure diastereomers 3a,b were obtained in high yields up to a gram scale (Scheme 2).5 Most remarkably, the separation succeeded with a normal silica gel column: 3a eluted first, followed by 3b. The relative configuration of the known stereocenters in the (−)-menthol unit and the four stereocenters in the PdTH framework could be assigned for both diastereomers by two independent crystal structure analyses, one of each diastereomer of 3. Here we report our results on the origin of this unexpectedly simple chromatographic separation of the two diastereomers of 3.

Scheme 1. Complexation of rac-1 with DIOP

Received: October 16, 2011 Published: January 9, 2012 © 2012 American Chemical Society

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dx.doi.org/10.1021/om2009952 | Organometallics 2012, 31, 523−526

Organometallics

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Scheme 2. Transesterification of rac-1

Figure 2. Solid-state structure of dimeric 4.

palladium(II) species.8 To explore the nature of these aggregates, we conducted several analytic investigations on isolated 3a,b and racemic 1. Mass spectrometric studies (FAB+) of caref ully dried 3a revealed a peak at m/z 1446.6 (24%), indicating a dimeric unit of 3a in addition to the peak at m/z 722.2 (37%), which refers to the monomer. A similar observation was found during mass spectrometric studies on diastereomer 3b, whereas for racemic compound 1 no dimer was detected. To investigate the participation of the ester moieties in the formation of these aggregates, IR spectra of the dried compounds were analyzed. For 3a two strong carbonyl bands at 1594 and 1715 cm−1 were detected. Addition of acetonitrile led to slow decrease of the signal intensity at 1594 cm−1, while a new signal at 1681 cm−1 appeared. No change could be observed for the signal at 1715 cm−1. Similar results were obtained for 3b and for rac-1. In consistence with reported IR data of structurally related palladium ester enolates (which showed a carbonyl band of 1595 cm−1), a coordination over the carbonyl moieties close to the metal center as in complex 4 seemed likely.7 Due to the partial enolate character (Pd in α position of the ester groups), these are known to absorb at lower wavenumbers. In the presence of additional ligands, the coordinated ester group is replaced, which leads to IR values shifted in the region of the free, uncoordinated ester. This reaction was also monitored by in situ 1H NMR spectroscopy (Figure 3). For dried compounds 3a,b higher

Results and Discussion. Upon purification of the 1:1 mixture of 3a,b by column chromatography on silica, a third compound could be detected by TLC. “Two dimensional TLC”, i.e. eluting in one direction first and then turning the TLC plate by 90° clockwise and eluting once more (in orthogonal direction to the first elution), indicated that this component was an aggregate of 3a which under the condition of the TL chromatography slowly converted to monomeric 3a (Figure 1; this method of elution should place all spots on a

Figure 1. Two-dimensional TLC of the mixture of diastereomers 3a,b (eluent hexanes/acetonitrile/dichloromethane 7/2/5).

diagonal traceif a spot is not on the diagonal, it must be formed by a chemical reaction). Notably, no similar aggregate of 3b or mixed aggregate of 3a/3b could be detected in TLC. Due to the significant difference in Rf values for the aggregate and its monomer, separation of the two diastereomers was much easier than expected and led to the isolation of 3a,b in excellent yield. On the other hand, at first glance it is puzzling that an aggregate of 3a would possess a higher Rf value than 3a. We assumed the formation of a higher aggregate consisting of monomeric units of 3a that are bound to each other via intermolecular coordination of ester groups to palladium. The reason for the lower polarity of the aggregate with respect to the monomeric units would be the blocking of coordination sites in the course of the aggregation process. This assumption is supported by reports on structurally related palladole compounds 4 (Figure 2)7 as well as ester enolates of

Figure 3. 1H NMR monitored reaction of oligomeric (3a)n in deuterated benzene (475 μL) after addition of deuterated acetonitrile (25 μL).

oligomers were obtained in benzene as solvent. After addition of acetonitrile, a well-defined new product was detectable for (3a)n which slowly converted to its corresponding monomer. In sharp contrast to the behavior of 3a, in the case of (3b)n only a fast transformation to the monomer was visible (Figure 4). From these data we concluded that, in the case of (3a)n, first the C2-symmetric dimer (3a)2 is formed in a fast reaction from higher aggregates of 3a, while the subsequent formation of the 524

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consisting of 3a,b which then, like the aggregates of 3b, would be cleaved quickly by the solvent. To investigate a possible diastereoselective formation of the corresponding dimers, a 1:1 mixture of 3a,b was dissolved in acetonitrile and carefully dried. The reaction course was also investigated by NMR techniques (Figure 5). Shortly after the

Figure 4. 1H NMR monitored reaction of oligomeric (3b)n in deuterated benzene (475 μL) after addition of deuterated acetonitrile (25 μL).

monomer 3a seemed to be the slow, rate-limiting step (Scheme 3). Considering these results, one can assume that oligomeric Scheme 3. Mechanistic Rationale for the Formation of 3a from Its Oligomers Figure 5. Reaction of a dried 1/1 mixture of 3a,b in deuterated benzene (475 μL) after addition of deuterated acetonitrile (25 μL) monitored by 1H NMR.

addition of acetonitrile, only monomeric 3b and dimeric (3a)2 were detected. As the amount of monomeric 3a was the same for the pure diasteromer, as well as for the mixture after the same reaction time, one can exclude formation of mixed but unstable dimers or oligomers. Hence, a high diastereoselectivity is likely for the formation of the dimers. Attempts to determine the solid-state structure of dimeric 3a failed, but fortunately we could obtain the desired X-ray crystal structure analysis when conducting control experiments with the enantiomeric (+)-menthol and starting from the tetraethyl ester analogue of the PTH 1, leading to the product 5 (Figure 6).6 The results of the solid-state structure analysis clearly supported the previous assumptions. Each of the palladium atoms is bound to oxygen (Pd−O = 2.1794(15) and 2.1766(15) Å). One of the palladium atoms is bound to nitrogen exclusively (Pd−N = 2.0808(19) Å); the ligand at the other palladium atom is disordered and can be coordinated to acetonitrile or a water molecule (Pd−O = 2.141(2) Å). The CO bond lengths are 0.03 Å longer compared to those of a free carbonyl group, which is reflected by IR data as well. The two Pd centers show a distorted-square-planar coordination. The angle between the C/Pd/C plane and the O/Pd/N(or O) plane at one palladium center is 9.9°; for the other palladium center the value is 10.6°. The six-membered rings of the menthyl groups have chair conformations, with all side groups in equatorial positions. The high density of substituents on the central core of the dinuclear organometallic compound shows that the correct relative configuration of the stereocenters is crucial to allow the formation of the kinetically stabilized dimer of 3a; 3b prefers a different conformation, which does not allow the formation of stabilized dimeric units. Conclusion. Overall, this unprecedented aggregation phenomenon forms the basis of the easy separation of the two diastereomers of 3 by column chromatography. As the

(3a)n consists of dimeric sub units (3a)2, wherein the noncoordinating ester moieties of these units are coordinated to other building blocks. Together with the IR data it seemed likely that only the ester moieties adjacent to the metal center are involved in the aggregation process. Complex 3b forms similar higher aggregates consisting of dimeric subunits. The kinetics of the steps leading to monomeric complexes in the presence of acetonitrile, however, are much faster. On the basis of the simple TLC results alone, we could not completely rule out the formation of mixed complexes 525

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Figure 6. Molecular formula and two different views of the solid-state structure of 5. The solid-state structure is shown with an acetonitrile molecule bonded to one Pd atom and a water molecule bonded to the other Pd atom. Acta Crystallogr., Sect. C 2000, 56, 814−817. (d) Hashmi, A. S. K.; Rivas Nass, A.; Bats, J. W.; Bolte, M. Angew. Chem. 1999, 111, 3565− 3567; Angew. Chem., Int. Ed. Engl. 1999, 38, 3370−3373. (e) Hashmi, A. S. K.; Naumann, F.; Rivas Nass, A.; Degen, A.; Bolte, M.; Bats, J. W. Chem.Eur. J. 1999, 5, 2836−2844. (f) Hashmi, A. S. K.; Bats, J. W.; Naumann, F.; Berger, B. Eur. J. Inorg. Chem. 1998, 131, 1987−1990. (g) Hashmi, A. S. K.; Naumann, F.; Bolte, M.; Rivas Nass, A. J. Prakt. Chem. 1998, 340, 240−246. (h) Hashmi, A. S. K.; Naumann, F.; Bats, J. W. Chem. Ber./Recl. 1997, 130, 1457−1459. (i) Hashmi, A. S. K.; Schwarz, L. Chem. Ber./Recl. 1997, 130, 1449−1456. (2) Hashmi, A. S. K.; Naumann, F.; Probst, R.; Bats, J. W. Angew. Chem. 1997, 109, 127−130; Angew. Chem., Int. Ed. Engl. 1997, 36, 104−106. (3) Hashmi, A. S. K.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385−2387. (4) Brunner, H.; Schmidt, E. J. Organomet. Chem. 1973, 50, 219−225. (5) Hashmi, A. S. K.; Riedel, D.; Grundl, M.; Wittel, B.; Föll, A.; Lubkoll, J.; Traut, T.; Hewer, R.; Rominger, F.; Frey, W.; Bats, J. W. Chem. Eur. J. 2011, 17, 6407−6414. (6) CCDC 847658 (5) contains supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (7) Brown, L. D.; Itoh, K.; Suzuki, H.; Hirai, K.; Ibers, J. A. J. Am. Chem. Soc. 1978, 100, 8232−8238. (8) Tian, G.; Boyle, P. D.; Novak, B. M. Organometallics 2002, 21, 1462−1465.

stereochemically pure products can be functionalized by another positional selective transesterification, this use of the readily available (−)-menthol auxiliary can easily be embedded into longer synthetic sequences of more complex enantiopure organopalladium compounds.5 In the context of the biological applications of the PTHs,5 it is crucial to use enantiomerically pure compounds, and the diastereoselective dimerization process described here will allow this for similar palladacycles as well. As the stereodifferentiation for other metal centers with similar coordination geometries should be similar, this principle should be extendable to other organometallic compounds.

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ASSOCIATED CONTENT

S Supporting Information *

Text and figures giving details of the syntheses and a CIF file giving crystallographic data for 5. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +49(0)6221-548413. Fax: +49(0)6221-544205. E-mail: [email protected].

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ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft (Ha 1932/7-2). Palladium salts were donated by Umicore AG & Co. M.A.G. is grateful for a fellowship of the Fonds der Chemischen Industrie.

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REFERENCES

(1) (a) Hashmi, A. S. K.; Grundl, M. A.; Bats, J. W.; Bolte, M. Eur. J. Org. Chem. 2002, 1263−1270. (b) Hashmi, A. S. K. Trends Organomet. Chem. 2003, 33−45. (c) Bats, J. W.; Rivas Nass, A.; Hashmi, A. S. K. 526

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