Synthesis of new bioorganometallic Ir- and Rh-complexes having β-lactam containing ligands.

Organic & Biomolecular Chemistry View Article Online

Published on 28 October 2013. Downloaded by Columbia University on 01/10/2014 08:11:57.

PAPER

Cite this: Org. Biomol. Chem., 2014, 12, 286

View Journal | View Issue

Synthesis of new bioorganometallic Ir- and Rh-complexes having β-lactam containing ligands† Jaime G. Muntaner, Luis Casarrubios* and Miguel A. Sierra* The synthesis (and full spectroscopic and crystallographic characterization) of new classes of bioorganometallic Ir- and Rh-complexes having β-lactam containing ligands has been achieved in three steps starting from simple precursors. The procedure for preparing these bioorganometallic compounds uses β-lactams having a phenylpyridyl moiety attached to the C4, N1 or C4 and N1 positions simultaneously, and a directed C–H metal-insertion, in the presence of (MCp*Cl2)2 (M = Ir, Rh). Enantiomerically pure 2-azetidinones can be transformed into diastereomeric (at the metal) mixtures of enantiopure metalla-

Received 2nd July 2013, Accepted 22nd October 2013 DOI: 10.1039/c3ob41354c www.rsc.org/obc

2-azetidinones. Bimetallic 2-azetidinones are also accessible by this approach. The insertion of electronpoor alkynes into the M–C bond of the bioorganometallic complex occurs regioselectively and in excellent yields. Overall, the sequence imine-β-lactam–metalla-β-lactam is a versatile and efficient full methodology to prepare and functionalize unprecedented, novel Ir- and Rh-complexes having β-lactam containing ligands.

Introduction β-Lactam antibiotics are crucial for the treatment of bacterial infections as they have been for nearly 75 years. The social and economic importance of these compounds makes research in this field a priority fuelled by the continuous appearance of pathogens having multidrug resistance,1 in particular those having enzymes capable of hydrolysing the four membered ring of these antibiotics (metallo-β-lactamases or mβs),2 which renders the antibiotic inactive. Lately, the discovery of the New Delhi mβs (NDM-1) conferring nearly complete resistance to most of the standard β-lactam antibiotics has triggered worldwide alarm.3 So far there are no known inhibitors of these class B β-lactamases as these enzymes are named. Hence the quest for unprecedented structures having a β-lactam nucleus.4 One potential solution to these problems is the incorporation of organometallic moieties as substituents of the 2-azetidinone ring through the functionalization of an adequately preformed organic 2-azetidinone. These compounds would be new unprecedented bioorganometallic entities,5 which may

Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain. E-mail: [email protected], [email protected]; http://www.ucm.es/info/biorgmet/; Fax: (+34)913944310 † Electronic supplementary information (ESI) available: Experimental details of all the compounds synthesized in this paper including copies of the 1H and 13 C NMR spectra. CCDC 944670 (23a), 944671 (30b) and 944672 (35a). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41354c

286 | Org. Biomol. Chem., 2014, 12, 286–297

have antibacterial or other biological activities. In fact, it is known that 2-azetidinone-derived drugs show biological properties of interest apart from their antibacterial activity. Thus, their strong activity as inhibitors of mammalian serine proteases,6 cholesterol absorption inhibitors,7 inhibitors of the human cytomegalovirus (HCMV, a β-herpes virus),8 neuroprotectors,9 and antitumorals10 has been reported. Moreover, true bioorganometallic β-lactams are nearly unknown and they are mainly metallocene-derived 2-azetidinones.11 In fact, most of the compounds derived from natural or synthetic β-lactam antibiotics are coordination complexes of well-known antibacterial agents.12 Our own interest in the synthesis of bioorganometallic β-lactams has resulted, to date, in the preparation of ferrocenyl-2-azetidinones, 1 and 2,11d and the first example of a 6-ruthenocenylpenicillin 3 (Fig. 1).11e Macrocyclic bis-β-lactams 4 having the metal moiety embedded in the macrocycle, which can also be considered as bioorganometallic derivatives, have been reported from these laboratories.11f Chromium carbene penicillin and cephalosporin derivatives have also been synthesized by us.11g Following the idea of functionalizing an adequately preformed organic 2-azetidinone with an organometallic moiety, building a M–C bond in the process, we examined the possibility of using a N-directed C–H insertion reaction to fulfil these requirements.13 In fact, we have succeeded recently in using efficient C–H insertion reactions to prepare metal-modified nucleotides and nucleosides.14 Described in this paper is a general approach to the preparation of monocyclic 2-azetidinones having Ir or Rh nuclei in their structures through a N-directed C–H insertion reaction. To the best of our

This journal is © The Royal Society of Chemistry 2014

View Article Online


Organic & Biomolecular Chemistry

Fig. 1

Paper

Examples of metalla-β-lactams.

knowledge the resulting structures are unprecedented in β-lactam or related chemistry and could be of interest both as bioactive substrates15 and as synthetic intermediates, an aspect of β-lactam chemistry that is of substantial interest.16

Scheme 1 Reaction conditions: mmol amine–mmol aldehyde (1 : 1). Method A: CH2Cl2, Na2SO4, rt, 15 h. Method B: MeOH, 50 °C, 3 h. Method C: anh. toluene, 110 °C, 15 h, sealed tube, activated molecular sieves.17

Results and discussion Substituted aryl pyridines 5 and 7 were synthesized through metal catalyzed coupling reactions. Imines 6a–c were obtained by condensation of the corresponding aldehydes 5 and p-anisidine, while imines 8a–c and 9 were prepared by condensation of amines 7 with p-anisaldehyde (compounds 8) and aldehyde 5b (imine 9). In all cases yields were nearly quantitative (Scheme 1). Compound 6b was reacted with phenoxy-, methoxyacetyl chloride and Evans’ oxazolidinone derived acetyl chloride 10 at −78 °C in DCM as solvent yielding the desired 2-azetidinones 11, 12 and 13 in 78%, 60% and 70% isolated yields, respectively. Compounds 11 and 12 were single cis-diastereomers while β-lactam 13 was a single cis-enantiomer (Scheme 2). Reaction of compounds 11 and 12 with (IrCp*Cl2)2 or (RhCp*Cl2)2 in the presence of NaOAc using DCM as the solvent at rt yields the β-lactams 14 and 15, respectively, in essentially quantitative yields and as diastereomeric mixtures due to the introduction of the new chiral center at the metal. As expected, the selectivity in the newly formed chiral metal center was low (from 1 : 1 for 15b to 1.8 : 1 for 14a). The diastereomeric mixtures were inseparable under all the conditions tested including chromatography and fractionated


Scheme 2

Synthesis of β-lactams having a metallic moiety at C3.

Org. Biomol. Chem., 2014, 12, 286–297 | 287

View Article Online


Paper

crystallization. Subsequently, enantiomerically pure 2-azetidinone 13 was reacted with (IrCp*Cl2)2 or (RhCp*Cl2)2 forming the β-lactams 16 as diastereomeric mixtures in the newly formed chiral metal center, again in an essentially quantitative yield. Notably, the stereoselection in the formation of the chiral metal center was considerably higher in the β-lactam 13 than in the racemic compounds 11 and 12.18 β-Lactams 17 and 18 were next prepared by the reaction of imine 8c with phenoxyacetyl chloride and Evans’ oxazolidinone derived acetyl chloride 10. Compounds 17 and 18 were obtained in acceptable yields (70% and 58% yields in pure isolated compounds) but as cis–trans mixtures. Thus 2-azetidinone 17 was a 4 : 1 cis–trans mixture and the pure isomers were separated by flash chromatography yielding the corresponding cis-17 and trans-17 in 60% and 10% yields, respectively. Similarly, the mixture of enantiomerically pure cis and trans 2-azetidinones 18 was separated by flash chromatography leading to enantiomerically pure cis-18 and trans-18 in 50% and 8% yields, respectively. Since it is well established that the stereochemical outcome of the Staudinger reaction is susceptible to factors like temperature, solvent, the order of addition of reagents, etc., several experiments were carried out to improve the cis–trans selectivity in the reaction of imine 8c. However, cis–trans mixtures were always obtained in variable ratios (Scheme 3). The cis and trans isomers of 2-azetidinone 17 were reacted with (IrCp*Cl2)2 and (RhCp*Cl2)2 in the presence of NaOAc in DCM at rt. Both isomers yielded uneventfully the corresponding metallacycles as diastereomeric mixtures: cis-19a (95%, 2.6 : 1), trans-19a (95%, 4 : 1), cis-19b (92%, 3.2 : 1) and trans-19b (94%, 4.7 : 1). Analogously, the isolated cis-18 and trans-18 were reacted with (IrCp*Cl2)2 or (RhCp*Cl2)2 yielding the desired enantiopure metalla-β-lactams 20a and 20b as diastereomeric mixtures on the newly created chiral metal center (Scheme 4). Imine 8a was unreactive towards both phenoxyacetyl chloride and Evans’ acid chloride at −78 °C, conditions that produced the above 2-azetidinones in good yields. The position of the bulky 2-pyridyl moiety in the o-position of the aryl group supporting imine nitrogen should be responsible for this

Scheme 3 Synthesis of 2-azetidinones having a 4-pyridylphenyl substituent at N1.

288 | Org. Biomol. Chem., 2014, 12, 286–297


Scheme 4

Synthesis of β-lactams having a metallic moiety at N1.

decreased reactivity. When the reaction was carried out in boiling toluene, the corresponding trans-β-lactams 21 and 22 were obtained in acceptable yields (41% and 46% isolated yields) as single diastereomers and, in the case of 2-azetidinone 22, as a single enantiomer. Reaction of compound 21 with (IrCp*Cl2)2 yielded the corresponding metallacycle 23a in nearly quantitative yield as a 4 : 1 diastereomeric mixture (Scheme 5).19 The analogous reaction of 21 with (RhCp*Cl2)2 and of compound 22 with both Ir and Rh precursors produced complex reaction mixtures in which the corresponding metallacycles could be detected by 1H NMR. However, pure compounds could not be isolated from these mixtures. The reasons for this anomalous behavior are unknown at the moment. β-Lactams 11–13, 17, 18 and 21–22 have either both ortho positions of the aromatic ring equivalent or have just one CH available for the directed C–H insertion. To address the regioselectivity of these processes with the aim of making this method general, 2-azetidinones 24–27 were prepared. cisβ-Lactams 24 and 25 will allow us to study the regio- and stereoselectivity of 2-azetidinones having a m-2-pyridyl substitution pattern in the aromatic ring attached to the C4 position of the four membered ring, while cis-2-azetidinones 26 and 27 will be used to learn the regioselectivity of 2-azetidinones having a m-2-pyridyl substitution pattern at the N1-position of the four membered ring.20 Compounds 24–27 were prepared from the corresponding imines 6a (compounds 24 and 25) and 8b (2-azetidinones 26 and 27), following the experimental methods for the synthesis of β-lactams described in the Experimental section, with the yields and selectivities depicted in Fig. 2. Both compounds 24 and 25 formed a mixture of metallacycles 28 and 29 by treatment with (IrCp*Cl2)2 or (RhCp*Cl2)2 as a 1 : 1 mixture of diastereomers and in nearly quantitative yields. Analogous results were obtained from 26 and 27, forming the metallacycles 30 and 31, respectively (Scheme 6).


View Article Online



Paper

Scheme 5 Synthesis of 2-azetidinones having a N-2-phenylpyridyl moiety and their C–H insertion reactions.

Scheme 6

Fig. 2 Synthesis of 2-azetidinones having a phenylpyridyl moiety at N1 or C4.

The nature of diastereomers and not regioisomers of compounds 28–31 was first established on spectroscopic grounds. As previously stated for compounds 14–16,18 the presence of two sets of β-lactam signals in the spectra of metallacycles 28 and 29 having characteristic cis coupling constants (3,4J =


Synthesis of β-lactams having a metallic moiety at N1.

4.5–5.2 Hz when M = Ir and 3,4J = 4.6–5.1 for M = Rh) justifies the absence of cis–trans β-lactam isomerization during the formation of the two metallacycles, revealing their nature as a pair of diastereomers arising from the newly created metal chiral centre. Nevertheless, it can be thought that the products may arise from the two possible regioisomeric CH insertions, and that the two observed products would be regioisomers instead of diastereomers. Analysis of the 1H NMR of these types of compounds shows, in most of them, an aromatic signal ranging from 7.52 to 7.98 ppm as a doublet with 4J = 1.9–2.2 Hz, which can only be explained by the exclusive metal insertion into the CH in the para position relative to the lactamic ring. The presence of all these signals indicates no isomerization of the β-lactam ring and the insertion in a single site, confirming both the formation of diastereomeric products at the newly formed Ir- or Rh-asymmetric center and a selective CH insertion directed to the less hindered CH bond of the phenyl ring.19 Additionally, we also prepared the β-lactam 32 from imine 6c and phenoxyacetyl chloride in 71% yield as a single cis-diastereomer. The reaction of 32 with (IrCp*Cl2)2 in the usual reaction conditions provided the metalla-β-lactam 33 in 90%

Org. Biomol. Chem., 2014, 12, 286–297 | 289

View Article Online


Paper


Scheme 7 Synthesis of 2-azetidinones having just one insertion position available.

yield as a 20 : 1 diastereomeric mixture (Scheme 7). Since 31 can only form a metallacycle, comparison of its spectroscopic data with those of compounds 27–30 corroborates the above assignation of these compounds. Finally, to stress the methodology to prepare 2-azetidinones containing pendant irida- or rhodametallacyclic moieties, β-lactam 34 was prepared from imine 9 and phenoxyacetyl chloride in 78% yield and as a single cis-diastereomer. Submission of 2-azetidinone 34 to reaction with (IrCp*Cl2)2 or (RhCp*Cl2)2 yielded bimetallic β-lactams 35 as a mixture of the four possible diastereomers. This mixture proved to be inseparable but it demonstrates that our approach is suitable for preparing β-lactams containing pendant polymetallic fragments (Scheme 8).

Scheme 8

Synthesis of bimetallic 2-azetidinones.

Given the complexity of the NMR spectra for the diastereomeric mixtures of complexes 35 and to fully ensure the structure of the bimetallic lactamic system an X-ray analysis of a single crystal of the diiridium complex 35a was performed. Fig. 3 shows an ORTEP diagram of this compound, thus unambiguously ascertaining its structure. The examples above demonstrate that it is possible to place at will a metal (Ir or Rh) at C3 or N1 or simultaneously at both positions of the four membered ring of a β-lactam, without affecting the labile 2-azetidinone moieties. This approach is an

290 | Org. Biomol. Chem., 2014, 12, 286–297

Fig. 3 ORTEP diagram of 35a. Representative distances (Å): Ir(1)–Cl(1) 2.406(3), Ir(2)–Cl(2) 2.401(2), Ir(1)–C(7) 2.047(7), Ir(2)–C(41) 2.028(8), Ir(1)–N(2) 2.093(5), Ir(2)–N(3) 2.087(6).

entry to a new class of β-lactams. Nevertheless, for subsequent studies on the mode of action of these new potential antibacterial and antitumor classes of compounds it would be of relevance to demonstrate that these compounds may be the object of further modifications without losing either the metal fragment or the integrity of the 2-azetidinone ring.21 In this regard this possibility was tested in compounds 16. Thus, diastereomeric mixtures of compounds 16a and 16b were first reacted with methyl acetylenedicarboxylate in MeOH at rt to yield a mixture of two compounds in 2 : 1 (36a, M = Ir) and 1.6 : 1 (36b, M = Rh) isomeric ratios. The two isomers of 36a were separated by column chromatography affording the insertion products, 36aa (major isomer, 57%) and 36ab (minor isomer, 29%). For 36b, the corresponding isomers 36ba (major isomer, 56%) and 36bb (minor isomer, 25%) were also separated. Nevertheless, the stereochemistry of the 2-azetidinone ring remains intact and the isolated isomers of 36a and 36b should be diastereomers at the metal center. Should any of the 2-azetidinone ring chiral centers be epimerized, a much more complicated stereoisomeric mixture would have been obtained (Scheme 9). The non-symmetric alkyne methyl 2-hexynoate was reacted next with 2-azetidinones 16a and 16b leading in both the cases to diastereoisomeric mixtures of metalla-β-lactams 37aa and 37ab (1 : 1) and 37ba and 37bb (1.5 : 1). Either diastereomer could


View Article Online



be separated by column chromatography yielding the isolated isomers of 37aa (minor 31%) and 37ab (major 39%), and 37ba (major isomer, 46%) and 37bb (minor isomer, 41%). Confirmation of the diastereomeric nature of these isomers instead of a possible lack of regioselectivity in the addition of the alkyne was achieved by nOe experiments in each of the four isolated products. In all cases, when irradiating the aromatic highlighted CH in Scheme 9 (37aa: 7.59 ppm, 37ab: 7.64 ppm, 37ba: 7.63 and 37bb: 7.71), a positive nOe was observed in the diastereotopic protons of the marked CH2 in the propyl group (2.94–2.32 ppm interval for the different products mentioned above). Unfortunately, compounds 36 and 37 were not crystalline and their stereochemistry remains unassigned.

Paper

of crude reaction mixtures. Two diastereomers are observed in the 1H NMR of the new structures 38a–b. No new protons are incorporated as the number of signals equals the one for the starting complexes 16. Displacement to lower field of some characteristic signals such as 4-MeOC6H4 groups, H2 of the pyridine ring or lactamic protons points to the expected reaction of CO insertion.

Conclusions New classes of metalla-β-lactams have been prepared from simple precursors in three steps. These unprecedented bioorganometallic compounds are synthetized from β-lactams having a phenylpyridyl moiety attached to the C4, N1 or C4 and N1 positions simultaneously, through a directed C–H metal-insertion, in the presence of (MCp*Cl2)2 (M = Ir, Rh). The reaction occurs under smooth conditions and in good to excellent yields. The starting 2-azetidinones are accessible by a conventional Staudinger reaction between an acid chloride and different phenylpyridine derived imines. The use of Evans’ oxazolidine derived acetic chloride led to enantiomerically pure 2-azetidinones, which in turn were transformed into diastereomeric (at the metal) mixtures of enantiopure metalla-2-azetidinones. Crystallographic data for selected metalladerivatives allow us to unambiguously characterize these compounds. Moreover, the insertion of alkynes into the M–C bond of the metalla-β-lactam occurs in excellent yields and as single regioisomers. The reaction of these metalla-β-lactams with CO is also feasible, leading to the corresponding benzoyl-metalladerivatives in excellent yields. These results constitute a versatile full methodology to prepare and functionalize novel β-lactam containing metal moieties. The use of these compounds as intermediates in synthesis, as well as the study of their potential biological activity, is actively pursued in our laboratories.

Experimental section General

Scheme 9 The insertion of electron-poor alkynes into the M–C bond of metalla-2-azetidinones.

Finally, metalla-β-lactams 16 were reacted with CO (bubbling) in a MeOH solution. The starting materials disappeared after 40 min, forming two new compounds 38a (1.6 : 1 diastereomeric ratio) and 38b (2 : 1 diastereomeric ratio). Compounds 38a and 38b were not stable to chromatographic or solvent partition separation, and therefore they could not be obtained in a pure form. Therefore, the structures 38a and 38b were tentatively assigned on the basis of the spectroscopic data


All the experiments involving the use of metallic complexes were carried out under an Ar atmosphere using standard Schlenk techniques and anhydrous solvents. Workups and purifications can be performed without special precautions. Et3N was distilled over CaH2 and stored under argon prior to use. Acid chlorides were distilled under Ar prior to use. RhCl3·3H2O and IrCl3·3H2O were kindly donated by Johnson Matthey Catalysts, and their dimers [RhCp*Cl2]2 and [IrCp*Cl2]2 were prepared following previously described methods.22 NMR spectra were registered at room temperature (rt) using benzene-d6 or CDCl3 as solvents. Chemical shifts are given in ppm relative to benzene (7.16 ppm) or to CHCl3 (7.27 ppm) for 1H NMR and benzene-d6 (128.06 ppm) or CDCl3 (77.00 ppm) for 13C NMR. IR spectra were registered in an apparatus with 1 cm−1 resolution. High-resolution mass spectra HRMS ESI or HRMS EI are provided. Specific rotation

Org. Biomol. Chem., 2014, 12, 286–297 | 291

View Article Online

Paper

[α]D is given in deg, and the concentration (c) is expressed in g per 100 mL. 4-(Pyridin-2-yl)benzaldehyde 5b was obtained from commercial sources and used without purification. ORTEP thermal ellipsoids are drawn at the 30% probability level.


General methods for the synthesis of imines 6, 8, and 9 Method A: A solution of amine (1.00 mmol) and the corresponding aldehyde (1.00 mmol) in 2 mL of CH2Cl2 was stirred at rt for 15 h in the presence of 1.00 g of anhydrous Na2SO4. The mixture was then filtered and evaporated to yield crude imine, which was used without further purification. Method B: A solution of amine (1.00 mmol) and the corresponding aldehyde (1.00 mmol) in 2 mL of MeOH was stirred at 50 °C for 3 h. The reaction was cooled to rt, and the solid was collected by filtration and washed with cold MeOH (2 × 2 mL) to obtain crude imine, which was used without further purification. Method C: A solution of amine (1.00 mmol) and the corresponding aldehyde (1.00 mmol) in 1.5 mL of anhydrous toluene was stirred at 110 °C for 15 h in a sealed tube and in the presence of 0.5 g of activated molecular sieves.17 The mixture was cooled to rt, and diluted with 3.0 mL of toluene, filtered and evaporated to yield crude imine, which was used without further purification. The following examples are representative of each method.23 4-Methoxy-N-(3-(pyridin-2-yl)benzylidene)aniline, 6a. Following Method A, from 4-methoxyaniline (0.09 g, 0.75 mmol) and 3-( pyridin-2-yl)benzaldehyde24 (0.14 g, 0.75 mmol) in 1.5 mL of anhydrous CH2Cl2, pure 6a (0.20 g, 0.70 mmol, 93%) was obtained as a brown oil. 1H NMR (300 MHz, CDCl3): δ = 8.73 (bd, 1H, J = 4.7 Hz), 8.59 (s, 1H), 8.51 (s, 1H), 8.13 (d, 1H, J = 7.8 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.85–7.75 (m, 2H), 7.58 (t, 1H, J = 7.7 Hz), 7.29–7.26 (m, 1H), 7.28 (d, 2H, J = 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 3.85 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 158.3, 158.1, 156.6, 149.7, 144.7, 139.9, 136.9, 136.8, 129.4, 129.2, 128.8, 127.2, 122.4, 122.2, 120.6, 114.3, 55.4. IR (CH2Cl2): ν = 1626 cm−1. HRMS EI: m/z [M]+ calcd for (C19H16N2O): 288.1257, found 288.1257. N-(4-Methoxybenzylidene)-2-(pyridin-2-yl)aniline, 8a. Following Method C, from 2-(pyridin-2-yl)aniline25 (0.30 g, 1.79 mmol) and 4-methoxy benzaldehyde (0.24 g, 1.79 mmol) in 1.5 mL of anhydrous toluene, pure 8a (0.49 g, 1.68 mmol, 94%) was obtained as a brown oil. 1H NMR (300 MHz, CDCl3): δ = 8.73–8.69 (m, 1H), 8.39 (s, 1H), 7.91 (dd, 1H, J = 7.7, 1.7 Hz), 7.84–7.69 (m, 3H), 7.65 (td, 1H, J = 7.7, 1.9 Hz), 7.44 (td, 1H, J = 7.5, 1.7 Hz), 7.35 (td, 1H, J = 7.5, 1.4 Hz), 7.23–7.17 (m, 1H), 7.08 (dd, 1H, J = 7.8, 1.4 Hz), 7.00–6.96 (m, 2H), 3.88 (s, 3H). 13C NMR (75.5 MHz, CHCl3): δ = 162.0, 159.5, 156.7, 150.0, 149.0, 134.9, 133.5, 130.4, 130.3, 129.4, 129.2, 125.9, 125.6, 121.3, 118.8, 114.0, 55.2. IR (CH2Cl2): ν = 1601 cm−1. HRMS EI: m/z [M]+ calcd for (C19H16ON2): 288.1257, found 288.1256. N-(4-Methoxybenzylidene)-4-(pyridin-2-yl)aniline, 8c. Following Method B, from 7c (0.20 g, 1.17 mmol) and 4-methoxybenzaldehyde (0.16 g, 1.17 mmol) in 2.0 mL of MeOH, pure 8c (0.30 g, 1.05 mmol, 90%) was obtained as a light yellow solid. mp 96–98 °C (EtOAc–Hex). 1H NMR (300 MHz, CDCl3): δ = 8.74 (bd, 1H, J = 4.7 Hz), 8.54 (s, 1H), 8.12 (d, 2H, J = 8.1 Hz), 8.00

292 | Org. Biomol. Chem., 2014, 12, 286–297


(d, 2H, J = 8.1 Hz), 7.79 (bs, 2H), 7.28 (d, 2H, J = 8.6 Hz), 7.27 (bs, 1H), 6.95 (d, 2H, J = 8.6 Hz), 3.84 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 162.3, 159.7, 156.9, 152.9, 149.5, 136.7, 136.5, 130.6, 129.1, 127.7, 121.8, 121.3, 120.1, 114.1, 55.4. IR (CH2Cl2): ν = 1581 cm−1. HRMS EI: m/z [M]+ calcd for (C19H16N2O): 288.1257, found 288.1256. General methods for the synthesis of β-lactams Method A. A solution of the acid chloride (1.50 mmol) in 5 mL of anhydrous toluene was dropwise added via a syringe to a solution of the corresponding imine (1.00 mmol) and Et3N (2.50 mmol) in 2.5 mL of refluxing toluene under argon. The resulting mixture was refluxed for 3 hours. The crude mixture was diluted with 15 mL of CH2Cl2 and washed with saturated NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anh. Na2SO4 and the solvent evaporated under vacuum. The crude mixture was purified by SiO2 chromatography (EtOAc–Hex mixtures) to yield analytically pure lactams. Method B. A solution of the corresponding acid chloride (1.50 mmol) in 5 mL of anhydrous CH2Cl2 was purged with argon and cooled to −78 °C. A solution of triethylamine (3.00 mmol) in 2.5 mL of CH2Cl2 was dropwise added. The mixture was stirred for 30 min at −78 °C, and a solution of the imine (1.00 mmol) in 2.5 mL of CH2Cl2 was slowly added dropwise. Upon completion of the addition, the cooling bath was removed, and the reaction was stirred at rt for 16 h and quenched with 2 mL of MeOH. The crude mixture was diluted with 15 mL of CH2Cl2 and washed with NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anh. Na2SO4 and the solvent was evaporated. SiO2 chromatography (Hex–EtOAc mixtures) yielded analytically pure β-lactams. The following examples are representative of each method.21 (±)-trans-4-(4-Methoxyphenyl)-3-phenoxy-1-(2-( pyridin-2-yl)phenyl)azetidin-2-one, 21. Following Method A, from imine 8a (0.10 g, 0.34 mmol), Et3N (0.10 g, 1.02 mmol) and phenoxyacetyl chloride (0.06 g, 0.52 mmol), pure 21 (0.06 g, 0.14 mmol, 41%) was obtained as a single trans isomer after purification by SiO2 chromatography (Hex–EtOAc 7 : 3) as a light brown solid. Mp 133–135 °C (EtOAc–Hex). 1H NMR (300 MHz, CDCl3): δ = 8.68 (d, 1H, J = 4.0 Hz), 7.75 (td, 1H, J = 7.8, 1.9 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.41–7.35 (m, 3H), 7.31–7.17 (m, 4H), 7.03–6.95 (m, 3H), 6.79 (d, 4H, J = 8.8 Hz), 5.00 (d, 1H, J = 1.8 Hz), 4.61 (d, 1H, J = 1.8 Hz), 3.78 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 163.6, 160.0, 157.4, 157.2, 149.1, 136.5, 133.9, 132.8, 131.3, 129.5, 129.2, 128.2, 127.2, 126.4, 124.3, 123.9, 122.2, 122.0, 115.5, 114.3, 87.0, 66.1, 55.2. IR (CHCl3): ν = 1763 cm−1. HRMS ESI: m/z [M + H]+ calcd for (C27H23N2O3): 423.1703, found 423.1687. (+)-trans-(S)-3-((2S,3S)-2-(4-Methoxyphenyl)-4-oxo-1-(2-(pyridin2-yl)phenyl)azetidin-3-yl)-4-phenyloxazolidin-2-one, 22. Following Method A, from imine 8a (0.10 g, 0.36 mmol), Et3N (0.12 g, 1.15 mmol) and (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetyl chloride (0.16 g, 0.65 mmol), pure 22 (0.08 g, 0.16 mmol, 45%) was obtained as a single trans isomer after purification by SiO2 chromatography (Hex–EtOAc 6 : 4) as a light brown solid.


View Article Online



Mp > 250 °C (CHCl3–Hex). [α]25 D = +43.1° (c = 1.2, CHCl3). 1 H NMR (300 MHz, CDCl3): δ = 8.51 (d, 1H, J = 4.7 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.54–7.32 (m, 7H), 7.31–7.16 (m, 3H), 7.04 (d, 1H, J = 7.6 Hz), 6.91 (d, 2H, J = 8.6 Hz), 6.69 (d, 2H, J = 8.6 Hz), 4.96 (dd, 1H, J = 9.0, 6.4 Hz), 4.75 (d, 1H, J = 2.7 Hz), 4.66 (t, 1H, J = 8.9 Hz), 4.30–4.13 (m, 2H), 3.70 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ = 162.5, 159.7, 157.4, 157.1, 148.9, 138.2, 136.4, 133.4, 132.4, 131.2, 129.5, 129.4, 128.8, 127.6, 127.4, 127.1, 125.9, 124.0, 122.0, 121.8, 114.1, 70.4, 67.4, 61.8, 58.6, 55.1. IR (CHCl3): ν = 1739 cm−1. HRMS ESI: m/z [M + H]+ calcd for (C30H26N3O4): 492.1918, found 492.1907. (±)-cis-3-Methoxy-1-(4-methoxyphenyl)-4-(4-(pyridin-2-yl)phenyl)azetidin-2-one, 12. Following Method B, from imine 6b (0.30 g, 1.04 mmol), Et3N (0.32 g, 3.12 mmol) and methoxyacetyl chloride (0.17 g, 1.56 mmol), pure 12 (0.23 g, 0.62 mmol, 60%) was obtained as a single cis isomer after purification by SiO2 chromatography (Hex–EtOAc 7 : 3) as a white solid. Mp 148–150 °C (EtOAc–Hex). 1H NMR (300 MHz, CDCl3): δ = 8.70 (d, 1H, J = 4.9 Hz), 8.02 (d, 2H, J = 8.4 Hz), 7.81–7.72 (m, 2H), 7.52 (d, 2H, J = 8.4 Hz), 7.32–7.25 (m, 3H), 6.79 (d, 2H, J = 9.0 Hz), 5.24 (d, 1H, J = 4.7 Hz), 4.87 (d, 1H, J = 4.7 Hz), 3.75 (s, 3H), 3.23 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 163.5, 156.3, 149.7, 139.7, 136.8, 134.2, 130.5, 128.4, 127.1, 122.3, 120.6, 118.8, 114.3, 114.2, 84.9, 61.6, 58.5, 55.4. IR (CHCl3): ν = 1740 cm−1. HRMS ESI: m/z: [M + H]+ calcd for C22H21N2O3: 361.1547, found 361.1546. (+)-(S)-3-((2R,3S)-2-(4-Methoxyphenyl)-4-oxo-1-(4-(pyridin-2-yl)phenyl-)azetidin-3-yl)-4-phenyloxazolidin-2-one, 18. Following Method B, from imine 8c (0.15 g, 0.52 mmol), Et3N (0.16 g, 1.56 mmol) and (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetyl chloride (0.13 g, 0.83 mmol), a crude 1 : 1.2 mixture of cis-18 and trans-18 was obtained. Purification by SiO2 chromatography (Hex–EtOAc 7 : 3) yielded pure cis-18 (0.08 g, 0.17 mmol, 33%) and trans-18 (0.10 g, 0.20 mmol, 38%) as white solids. 18 mg (0.04 mmol, 7%) of the cis–trans mixture were also recovered. cis-18: mp > 250 °C (CHCl3–Hex). [α]25 D = +67.2° (c = 1.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.64 (d, 1H, J = 4.8 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.72–7.62 (m, 2H), 7.43–7.35 (m, 3H), 7.41 (d, 2H, J = 8.5 Hz), 7.22–7.19 (m, 5H), 6.87 (d, 2H, J = 8.4 Hz), 5.23 (d, 1H, J = 5.2 Hz), 4.71 (d, 1H, J = 5.2 Hz), 4.58 (dd, 1H, J = 8.8, 7.2 Hz), 4.34 (t, 1H, J = 8.8 Hz), 4.02 (dd, 1H, J = 8.8, 7.2 Hz), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 160.7, 159.7, 157.0, 156.5, 149.6, 137.8, 136.7, 136.6, 135.4, 129.4, 129.3, 128.8, 127.6, 127.5, 124.0, 121.9, 120.1, 117.6, 114.2, 70.5, 62.9, 60.9, 59.7, 55.2. IR (CHCl3): ν = 1755 cm−1. HRMS ESI: m/z: [M + H]+ calcd for C30H26N3O4: 492.1918, found 492.1930. trans-18: mp > 250 °C (CHCl3–Hex). [α]25 D = +75.3° (c = 1.4 in CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.64 (d, 1H, J = 4.7 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.72 (td, 1H, J = 7.6, 1.7 Hz), 7.63 (d, 1H, J = 7.9 Hz), 7.46–7.39 (m, 2H), 7.38–7.30 (m, 3H), 7.24–7.16 (m, 1H), 7.12 (d, 2H, J = 8.4 Hz), 7.05 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz), 5.07 (dd, 1H, J = 9.0, 6.5 Hz), 4.88 (d, 1H, J = 2.4 Hz), 4.76 (t, 1H, J = 9.0 Hz), 4.38 (dd, 1H, J = 9.0, 6.5 Hz), 4.18 (d, 1H, J = 2.4 Hz), 3.76 (s, 3H). 13C NMR


Paper

(75 MHz, CDCl3): δ = 162.2, 159.9, 157.0, 156.4, 149.6, 137.8, 136.9, 136.8, 135.4, 129.7, 129.5, 127.6, 127.5, 127.3, 127.1, 121.9, 120.1, 117.8, 114.6, 70.2, 68.8, 60.6, 58.9, 55.3. IR (CHCl3): ν = 1753 cm−1. HRMS EI: m/z: [M]+ calcd for C30H25N3O4: 491.1840, found 491.1839. General procedure for the synthesis of cyclometallated complexes A mixture of [MCp*Cl2]2 (M = Ir, Rh) (10 μmol), NaOAc (47 μmol) and the corresponding β-lactam (20 μmol) was stirred at rt in 10 mL of CH2Cl2 overnight. The crude mixture was filtered through a short pad of celite and evaporated to dryness. The obtained solid was dissolved in the minimum amount of CH2Cl2, precipitated with hexane and filtered to obtain pure complexes as yellow or orange solids. The diastereomeric ratio was determined by integration of well-resolved signals in the 1H NMR and indicated as [M] for the major and [m] for the minor isomer in their corresponding spectra. For highly enriched isomeric mixtures, a list of the observed 13 C signals corresponding to the mixture is reported. In some cases, high temperature (50 °C) and benzene-d6 as a solvent were used to observe the coupling constants of the H of the 2-azetidinone ring. In all cases the separation of the diastereoisomers was not possible under any of the attempted conditions, including chromatography, crystallization and solvent partition.26 Iridium complex 14a. Following the general procedure, from β-lactam 11 (40.0 mg, 94 μmol), [IrCp*Cl2]2 (37.0 mg, 47 μmol) and NaOAc (18.3 mg, 222 μmol) in 5.0 mL of CH2Cl2 and after precipitation, a 1.8 : 1 diastereomeric mixture of 14a (69.0 mg, 88 μmol, 93%) was obtained as a yellow solid. 1 H NMR (300 MHz, CDCl3): δ = 8.72–8.59 (m, 2H, [M + m]), 7.88 (d, 1H, [m], J = 1.8 Hz), 7.81 (d, 1H, [M], J = 1.7 Hz), 7.79–7.69 (m, 2H, [M + m]), 7.66–7.52 (m, 4H, [M + m]), 7.42–7.32 (m, 4H, [M + m]), 7.24–7.12 (m, 4H, [M + m]), 7.10–7.02 (m, 4H, [M + m]), 6.98–6.85 (m, 6H, [M + m]), 6.82–6.73 (m, 4H, [M + m]), 5.66 (d, 1H, [M], J = 4.9 Hz), 5.55 (d, 1H, [m], J = 4.9 Hz), 5.44 (d, 1H, [M], J = 4.9 Hz), 5.41 (d, 1H, [m], J = 4.9 Hz), 3.72 (s, 3H, [m]), 3.71 (s, 3H, [M]), 1.63 (s, 15H, [m]), 1.55 (s, 15H, [M]). 13C NMR (75 MHz, CDCl3): δ = 167.0, 166.9, 163.8, 163.7, 163.3, 163.1, 157.9, 157.8, 156.8, 156.7, 151.7, 151.6, 145.0, 144.9, 137.4, 137.3, 135.9, 135.4, 135.0, 134.8, 130.9, 130.9, 129.7, 129.6, 124.1, 124.0, 122.9, 122.5, 122.3, 121.9, 119.6, 119.5, 119.4, 116.6, 116.0, 114.7, 88.9, 88.8, 82.6, 81.5, 63.2, 62.6, 55.8, 55.7, 9.2, 9.1. IR (CHCl3): ν = 1751 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C37H36IrN2O3: 749.2352, found 749.2369. Rhodium complex 16b. Following the general procedure, from β-lactam 13 (31.5 mg, 64 μmol), [RhCp*Cl2]2 (19.8 mg, 32 μmol) and NaOAc (12.4 mg, 151 μmol) in 3.5 mL of CH2Cl2 and after precipitation, a 3.6 : 1 diastereomeric mixture of 16b (45.0 mg, 59 μmol, 92%) was obtained as an orange solid. 1 H NMR (300 MHz, benzene-d6, 50 °C): δ = 8.52 (bd, 1H, [m], J = 5.2 Hz), 8.47 (bd, 1H, [M], J = 5.4 Hz), 8.19 (d, 1H, [m], J = 1.7 Hz), 7.77 (d, 1H, [M], J = 1.5 Hz), 7.70–7.65 (m, 2H, [M]), 7.50–7.24 (m, 9H, [M + m]), 7.24–6.78 (m, 10H, [M + m]),

Org. Biomol. Chem., 2014, 12, 286–297 | 293

View Article Online


Paper

6.77–6.66 (m, 3H, [M + m]), 6.63 (d, 2H, [m], J = 9.0 Hz), 6.58–6.51 (m, 1H, [m]), 6.50–6.45 (m, 1H, [M]), 4.82 (t, 1H, [M], J = 8.3 Hz), 4.70 (d, 1H, [m], J = 5.2 Hz), 4.66 (d, 1H, [M], J = 5.2 Hz), 4.60 (d, 1H, [m], J = 5.2 Hz), 4.42–4.26 (m, 1H, [m]), 4.34 (d, 1H, [M], J = 5.2 Hz), 4.20–4.04 (m, 2H, [M + m]), 3.56–3.42 (m, 1H, [m]), 3.43 (t, 1H, [M], J = 8.3 Hz), 3.31 (s, 3H, [M]), 3.27 (s, 3H, [m]), 1.47 (s, 15H, [M]), 1.46 (s, 15H, [m]). 13 C NMR (75 MHz, benzene-d6, 50 °C): δ = 178.8 (d, J (C, Rh) = 32.3 Hz), 165.3, 165.3, 165.2, 165.2, 160.6, 160.2, 158.0, 157.1, 156.8, 156.7, 151.7, 151.4, 144.8, 138.7, 138.3, 137.5, 137.3, 136.7, 136.4, 135.7, 135.0, 132.9, 132.3, 129.4, 128.7, 128.6, 124.1, 123.8, 123.3, 122.8, 122.2, 121.9, 119.6, 119.2, 119.0, 114.9, 114.8, 96.2 (d, J (C, Rh) = 6.1 Hz), 96.0 (d, J (C, Rh) = 6.1 Hz), 70.6, 70.4, 64.8, 63.8, 62.1, 61.9, 59.8, 55.2, 9.2, 9.1. IR (CHCl3): ν = 1753 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C40H39N3O4Rh: 728.1990, found 728.2022. Rhodium complex cis-19b. Following the general procedure, from β-lactam cis-17 (14.4 mg, 34 μmol), [RhCp*Cl2]2 (10.5 mg, 17 μmol) and NaOAc (6.6 mg, 80 μmol) in 2.0 mL of CH2Cl2 and after precipitation, a 3.2 : 1 diastereomeric mixture of cis19b (21.7 mg, 31 μmol, 92%) was obtained as an orange solid. 1 H NMR (300 MHz, benzene-d6, 50 °C): δ = 9.05 (d, 1H, [m], J = 1.8 Hz), 8.65 (d, 1H, [m], J = 5.6 Hz), 8.59 (d, 1H, [M], J = 5.5 Hz), 8.30 (dd, 1H, [M], J = 8.3, 1.9 Hz), 7.58 (d, 1H, [M], J = 8.4 Hz), 7.50–7.37 (m, 5H, [M + m]), 7.36–7.28 (m, 1H, [M]), 7.19–7.01 (m, 7H, [M + m]), 6.98 (d, 3H, [M + m], J = 8.0 Hz), 6.84 (t, 3H, [M + m], J = 7.2 Hz), 6.78–6.70 (m, 4H, [M + m]), 6.69–6.56 (m, 4H, [M + m]), 5.38 (d, 1H, [m], J = 4.9 Hz), 5.34 (d, 1H, [M], J = 4.9 Hz), 5.20 (d, 1H, [m], J = 4.9 Hz), 4.94 (d, 1H, [M], J = 4.9 Hz), 3.33 (s, 3H, [M]), 3.29 (s, 3H, [m]), 1.36 (s, 30H, [M + m]). 13C NMR (75 MHz, benzene-d6, 50 °C): δ = 181.2 (d, J (C, Rh) = 32.6 Hz), 165.5, 165.5, 164.1, 163.7, 160.7, 160.6, 158.4, 158.2, 151.8, 151.7, 141.0, 139.4, 138.9, 138.9, 137.2, 130.6, 130.3, 129.8, 129.8, 129.2, 126.9, 126.7, 125.2, 124.9, 124.3, 122.3, 121.6, 121.4, 119.3, 116.7, 116.5, 114.5, 114.5, 96.5 (d, J (C, Rh) = 6.2 Hz), 96.2 (d, J (C, Rh) = 6.2 Hz), 82.2, 82.1, 61.9, 55.1, 55.0, 9.5, 9.2. IR (CHCl3): ν = 1754 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C37H36N2O3Rh: 659.1775, found 659.1811. Rhodium complex trans-19b. Following the general procedure, from β-lactam trans-17 (14.3 mg, 34 μmol), [RhCp*Cl2]2 (10.4 mg, 17 μmol) and NaOAc (6.6 mg, 80 μmol) in 2.0 mL of CH2Cl2 and after precipitation, a 4.7 : 1 diastereomeric mixture of trans-19b (22.2 mg, 32 μmol, 94%) was obtained as an orange solid. 1H NMR (300 MHz, CDCl3): δ = 8.58 (d, 2H, [M + m], J = 5.6 Hz), 7.87 (d, 1H, [m], J = 2.1 Hz), 7.62–7.55 (m, 4H, [M + m]), 7.51 (d, 1H, [M], J = 2.0 Hz), 7.45 (d, 1H, [M], J = 8.4 Hz), 7.40–7.32 (m, 5H, [M + m]), 7.26–7.14 (m, 4H, [M + m]), 7.04–6.98 (m, 2H, [M + m]), 6.97–6.86 (m, 7H, [M + m]), 6.86–6.80 (m, 5H, [M + m]), 5.05 (d, 1H, [M], J = 1.7 Hz), 5.03 (d, 1H, [m], J = 1.7 Hz), 5.01 (d, 1H, [M], J = 1.7 Hz), 4.93 (d, 1H, [m], J = 1.7 Hz), 3.77 (s, 3H, [m]), 3.75 (s, 3H, [M]), 1.53 (s, 15H, [m]), 1.38 (s, 15H, [M]). 13C NMR (75 MHz, CDCl3, [M]): δ = 179.8 (d, J (C, Rh) = 32.8 Hz), 164.5, 162.9, 162.8, 160.2, 160.2, 157.1, 151.1, 151.0, 140.4, 140.3, 137.5, 137.0, 136.9, 129.6, 128.2, 128.1, 128.0, 127.7, 125.4,

294 | Org. Biomol. Chem., 2014, 12, 286–297


124.7, 123.9, 122.1, 122.1, 121.6, 118.9, 115.5, 115.4, 114.8, 113.2, 112.4, 96.1 (d, J (C, Rh) = 6.2 Hz), 95.9 (d, J (C, Rh) = 6.3 Hz), 87.7, 87.3, 64.4, 63.5, 55.4, 55.4, 9.1, 8.9. IR (CH2Cl2): ν = 1759 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C37H36N2O3Rh: 659.1775, found 659.1744. Iridium complex cis-20a. Following the general procedure, from β-lactam cis-18 (18.5 mg, 38 μmol), [IrCp*Cl2]2 (15.0 mg, 19 μmol) and NaOAc (7.4 mg, 90 μmol) in 2.0 mL of CH2Cl2 and after precipitation, a 4 : 1 diastereomeric mixture of cis20a (29.2 mg, 34 μmol, 90%) was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3): δ = 8.65 (d, 1H, [m], J = 5.6 Hz), 8.59 (d, 1H, [M], J = 5.8 Hz), 8.24 (d, 1H, [m], J = 2.1 Hz), 7.72 (d, 1H, [M], J = 8.0 Hz), 7.69–7.58 (m, 6H, [M + m]), 7.46–7.32 (m, 10H, [M + m]), 7.28–7.20 (m, 4H, [M + m]), 7.17 (bs, 1H, [M]), 7.02 (t, 2H, [M + m], J = 6.5 Hz), 6.93–6.82 (m, 4H, [M + m]), 6.55 (dd, 1H, [m], J = 8.3, 2.1 Hz), 5.28 (d, 1H, [M], J = 5.1 Hz), 5.16 (d, 1H, [m], J = 5.2 Hz), 4.67 (d, 1H, [m], J = 5.2 Hz), 4.65–4.56 (m, 1H, [m]), 4.60 (d, 1H, [M], J = 5.2 Hz), 4.50 (dd, 1H, [M], J = 8.8, 6.9 Hz), 4.35–4.25 (m, 2H, [M + m]), 4.00 (dd, 2H, [M + m], J = 8.8, 6.9 Hz), 3.83 (s, 3H, [m]), 3.82 (s, 3H, [M]), 1.67 (s, 15H, [m]), 1.42 (s, 15H, [M]). 13C NMR (75 MHz, CDCl3): δ = 166.9, 166.8, 165.0, 164.5, 161.2, 161.1, 160.2, 159.9, 157.6, 157.4, 151.5, 141.1, 141.0, 139.6, 139.1, 137.5, 137.4, 137.4, 137.2, 129.9, 129.7, 129.5, 129.3, 127.9, 127.8, 125.5, 125.3, 125.1, 125.0, 124.6, 124.5, 123.0, 122.2, 119.1, 114.6, 114.5, 113.3, 111.4, 89.2, 88.8, 86.7, 70.9, 70.8, 63.2, 63.0, 61.9, 61.4, 60.1, 59.9, 55.7, 55.6, 9.2, 9.0. IR (CHCl3): ν = 1758 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C40H39IrN3O4: 818.2567, found 818.2594. Iridium complex trans-20a. Following the general procedure, from β-lactam trans-18 (8.1 mg, 16 μmol), [IrCp*Cl2]2 (6.6 mg, 8 μmol) and NaOAc (3.2 mg, 39 μmol) in 1.0 mL of CH2Cl2 and after precipitation, a 3.2 : 1 diastereomeric mixture of trans-20a (13.2 mg, 15 μmol, 94%) was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3): δ = 8.67–8.60 (m, 2H, [M + m]), 7.93 (s, 1H, [m]), 7.73 (d, 1H, [M], J = 8.1 Hz), 7.67–7.62 (m, 2H, [M + m]), 7.60 (d, 2H, [M + m], J = 8.3 Hz), 7.49–7.26 (m, 12H, [M + m]), 7.09–7.00 (m, 6H, [M + m]), 6.87–6.80 (m, 5H, [M + m]), 6.40 (dd, 1H, [m], J = 8.3, 2.1 Hz), 5.12 (dd, 1H, [m], J = 9.0, 6.3 Hz), 5.07 (dd, 1H, [M], J = 9.0, 6.1 Hz), 4.97 (d, 1H, [m], J = 2.4 Hz), 4.93 (d, 1H, [M], J = 2.4 Hz), 4.77 (t, 2H, [M + m], J = 9.0 Hz), 4.44 (dd, 1H, [M], J = 9.0, 6.1 Hz), 4.38 (dd, 1H, [m], J = 9.0, 6.3 Hz), 4.06 (d, 1H, [m], J = 2.4 Hz), 3.96 (d, 1H, [M], J = 2.4 Hz), 3.77 (s, 3H, [m]), 3.75 (s, 3H, [M]), 1.64 (s, 15H, [m]), 1.42 (s, 15H, [M]). 13C NMR (75 MHz, CDCl3): δ = 166.4, 164.4, 164.2, 162.4, 162.3, 160.0, 159.9, 157.3, 157.1, 151.1, 140.8, 138.5, 138.0, 137.8, 137.3, 136.9, 136.9, 130.4, 129.9, 129.6, 129.5, 128.3, 127.6, 127.5, 127.3, 127.1, 124.5, 124.4, 124.0, 123.7, 121.9, 118.8, 118.7, 114.6, 112.8, 111.0, 88.7, 88.5, 70.2, 69.9, 69.1, 68.6, 61.1, 60.0, 58.7, 58.6, 55.4, 55.3, 8.8, 8.5. IR (CH2Cl2): ν = 1755 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C40H39IrN3O4: 818.2567, found 818.2558. Iridium complex 35a. Following the general procedure, from β-lactam 34 (20.0 mg, 42 μmol), [IrCp*Cl2]2 (33.9 mg, 42 μmol) and NaOAc (16.3 mg, 199 μmol) in 2.0 mL of CH2Cl2


View Article Online



and after precipitation, a mixture of four diastereomers of 35a (46.0 mg, 38 μmol, 91%) was obtained as a yellow solid. Suitable crystals for X-ray analysis were obtained by CH2Cl2–Hex crystallization. 1H NMR (300 MHz, CDCl3): δ = 8.76–8.56 (m, 8H), 8.02–7.50 (m, 30H), 7.46–7.34 (m, 2H), 7.30–6.84 (m, 34H), 6.46 (d, 1H, J = 8.2 Hz), 6.31 (d, 1H, J = 8.2 Hz), 7.73–5.50 (m, 6H), 5.46 (d, 1H, J = 5.0 Hz), 5.41 (d, 1H, J = 5.1 Hz), 1.75 (s, 15H), 1.72 (s, 15H), 1.63 (s, 15H), 1.62 (s, 15H), 1.57 (s, 15H), 1.56 (s, 15H), 1.45 (s, 15H), 1.38 (s, 15H). 13 C NMR (75 MHz, CDCl3): δ = 166.9, 166.8, 166.8, 166.7, 166.6, 165.2, 164.9, 164.6, 164.0, 163.9, 163.8, 163.7, 163.6, 163.3, 157.8, 157.7, 157.6, 151.5, 151.4, 151.2, 145.2, 145.1, 144.6, 141.1, 141.0, 139.0, 138.9, 138.4, 138.2, 137.2, 137.1, 137.1, 137.0, 135.9, 135.7, 135.6, 135.4, 135.2, 135.1, 134.7, 129.5, 129.4, 129.3, 125.8, 125.5, 124.8, 124.6, 124.5, 123.8, 123.7, 123.5, 123.2, 123.1, 122.7, 122.6, 122.5, 122.2, 122.1, 122.0, 121.9, 121.8, 121.7, 119.2, 119.1, 119.0, 118.8, 116.4, 115.9, 113.1, 112.8, 111.4, 88.9, 88.8, 88.7, 88.6, 88.5, 82.2, 81.3, 81.1, 63.0, 62.7, 62.5, 61.9, 9.0, 9.0, 8.9, 8.9. IR (CHCl3): ν = 1752 cm−1. HRMS EI: m/z [M]+ calcd for C51H51Cl2Ir2N3O2: 1194.2643, found 1194.3721. Rhodium complex 35b. Following the general procedure, from β-lactam 34 (15.7 mg, 33 μmol), [RhCp*Cl2]2 (20.6 mg, 33 μmol) and NaOAc (12.8 mg, 156 μmol) in 2.0 mL of CH2Cl2 and after precipitation, a mixture of four diastereomers of 35b (26.5 mg, 26 μmol, 80%) was obtained as an orange solid. 1 H NMR (300 MHz, CDCl3, [4 isomers]): δ = 8.78–8.54 (m, 8H), 8.05–7.45 (m, 32H), 7.34 (t, 2H, J = 7.8 Hz), 7.30–6.80 (m, 34H), 6.36 (d, 1H, J = 8.0 Hz), 6.33 (d, 1H, J = 7.9 Hz), 5.78–5.52 (m, 6H), 5.46 (d, 1H, J = 5.2 Hz), 5.40 (d, 1H, J = 5.1 Hz), 1.71 (s, 15H), 1.67 (s, 15H), 1.59 (s, 15H), 1.58 (s, 15H), 1.53 (s, 15H), 1.52 (s, 15H), 1.43 (s, 15H), 1.32 (s, 15H). 13C NMR (75 MHz, CDCl3): δ = 164.9, 164.8, 164.7, 164.5, 163.8, 163.6, 163.5, 157.6, 157.5, 151.3, 151.3, 151.0, 150.9, 144.4, 144.4, 140.5, 140.4, 138.0, 137.9, 137.4, 137.1, 137.0, 137.0, 136.9, 136.8, 135.6, 134.7, 129.4, 129.3, 129.3, 124.5, 124.1, 123.9, 123.3, 123.2, 123.1, 122.9, 122.4, 122.2, 122.1, 122.0, 121.5, 121.4, 119.1, 118.9, 118.8, 116.1, 115.7, 115.7, 96.2, 96.2, 96.1, 96.1, 96.1, 96.0, 96.0, 96.0, 95.9, 95.8, 95.8, 81.1, 9.2, 9.2, 9.1, 9.0, 8.8. IR (CHCl3): ν = 1754 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C51H51N3O2Rh2Cl: 978.1774, found 978.1822. General method for the synthesis of alkyne insertion products A mixture of 16a or 16b (50.0 μmol) and the corresponding alkyne (65.0 μmol) was stirred at room temperature in 11.0 mL of methanol for 10 h. The solvent was evaporated to obtain a crude mixture containing a mixture of diastereomers that was washed with hexane to eliminate excess alkyne. The crude mixture of diastereoisomers was purified by SiO2 chromatography (Hex–EtOAc mixtures). Iridium complex 36a. Following the general procedure, from 16a (48.0 mg, 56 μmol) and dimethyl acetylenedicarboxylate (10.4 mg, 73 μmol), a crude 2 : 1 mixture of diastereomers 36aa and 36ab was obtained. After washing with hexanes and purification by SiO2 chromatography (Hex–EtOAc 3 : 7),


Paper

pure 36aa (32 mg, 32 μmol, 57%) and 36ab (16 mg, 16 μmol, 29%) were obtained as yellow solids. 36aa. mp > 250 °C (CH2Cl2–Hex). [α]25 D = −22.8° (c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.36 (dd, 1H, J = 6.1, 1.7 Hz), 7.74 (td, 1H, J = 7.7, 1.7 Hz), 7.49 (dd, 1H, J = 7.9, 1.6 Hz), 7.42–7.30 (m, 6H), 7.29–7.15 (m, 4H), 7.10 (d, 1H, J = 8.1 Hz), 6.78–6.72 (m, 2H), 5.17 (d, 1H, J = 5.0 Hz), 4.60 (bt, 1H, J = 8.1 Hz), 4.51 (d, 1H, J = 5.0 Hz), 4.28 (t, 1H, J = 8.7 Hz), 3.90 (dd, 1H, J = 8.7, 7.4 Hz), 3.73 (s, 3H), 3.71 (s, 3H), 3.65 (s, 3H), 1.27 (s, 15H). 13C NMR (75 MHz, CDCl3): δ = 176.3, 168.9, 162.9, 159.9, 157.0, 156.4, 155.3, 141.4, 139.3, 138.4, 136.8, 133.9, 133.7, 133.4, 131.1, 130.8, 129.5, 129.3, 127.7, 127.4, 126.3, 124.4, 118.4, 114.3, 89.0, 70.5, 62.7, 60.8, 59.4, 55.5, 52.0, 49.9, 8.3. IR (CHCl3): ν = 1756, 1704 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C46H45N3O8Ir: 960.2834, found 960.2883. 36ab. mp > 250 °C (CH2Cl2–Hex). [α]25 D = +172.5° (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.41 (dd, 1H, J = 6.0, 1.6 Hz), 7.76 (td, 1H, J = 7.7, 1.7 Hz), 7.55–7.35 (m, 7H), 7.31 (d, 1H, J = 1.9 Hz), 7.26–7.19 (m, 3H), 7.16 (d, 1H, J = 8.1 Hz), 6.85–6.76 (m, 2H), 5.18 (d, 1H, J = 5.3 Hz), 4.68 (bt, 1H, J = 7.9 Hz), 4.59 (d, 1H, J = 5.3 Hz), 4.47 (t, 1H, J = 8.9 Hz), 4.12 (dd, 1H, J = 8.9, 7.0 Hz), 3.76 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 1.30 (s, 15H). 13C NMR (75 MHz, CDCl3): δ = 176.3, 169.0, 163.4, 163.0, 160.3, 156.4, 156.4, 155.6, 141.4, 138.6, 138.1, 136.5, 134.2, 134.1, 131.2, 130.4, 129.9, 129.8, 127.9, 127.5, 126.8, 124.5, 118.8, 114.4, 88.9, 70.4, 62.6, 61.7, 60.7, 55.5, 52.1, 50.2, 8.5. IR (CHCl3): ν = 1757, 1708 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C46H45N3O8Ir: 960.2834, found 960.2882. Rhodium complex 36b. Following the general procedure, from 16b (47.0 mg, 61 μmol) and dimethyl acetylenedicarboxylate (11.4 mg, 80 μmol), a crude 1.6 : 1 mixture of diastereomers 36ba and 36bb was obtained. After washing with hexanes and purification by SiO2 chromatography (Hex–EtOAc 2 : 3), pure 36ba (31 mg, 34 μmol, 56%) and 36bb (14 mg, 15 μmol, 25%) were obtained as orange solids. 36ba. mp > 250 °C (CH2Cl2–Hex). [α]25 D = −43.3° (c = 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.51 (bd, 1H, J = 5.9 Hz), 7.82 (td, 1H, J = 7.7, 1.8 Hz), 7.55 (d, 1H, J = 8.2 Hz), 7.48–7.35 (m, 7H), 7.34–7.25 (m, 3H), 7.22 (d, 1H, J = 8.1 Hz), 6.80 (d, 2H, J = 9.0 Hz), 5.24 (d, 1H, J = 5.0 Hz), 4.66 (t, 1H, J = 8.1 Hz), 4.59 (bd, 1H, J = 5.0 Hz), 4.35 (t, 1H, J = 8.8 Hz), 3.97 (t, 1H, J = 8.1 Hz), 3.78 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 1.32 (s, 15H). 13C NMR (75 MHz, CDCl3): δ = 174.6, 167.2, 162.4, 159.9, 157.0, 156.3, 155.0, 139.9, 138.8, 138.1, 136.7, 134.0, 133.7, 132.1, 131.2, 130.7, 129.4, 129.2, 127.5, 127.4, 126.4, 123.7, 118.3, 114.2, 96.6 (d, J (C, Rh) = 6.8 Hz), 70.4, 62.7, 60.8, 59.4, 55.5, 52.1, 50.1, 8.6. IR (CHCl3): δ = 1751, 1697 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C46H45N3O8Rh: 870.2256, found 870.2285. 36bb. Mp > 250 °C (CH2Cl2–Hex). [α]25 D = +115.0° (c = 0.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.53 (d, 1H, J = 5.4 Hz), 7.79 (td, 1H, J = 7.6, 1.6 Hz), 7.53–7.37 (m, 8H), 7.32–7.20 (m, 4H), 6.81 (d, 2H, J = 9.0 Hz), 5.20 (d, 1H, J = 5.4 Hz), 4.70 (t, 1H, J = 8.0 Hz), 4.62 (d, 1H, J = 5.4 Hz), 4.48 (t, 1H, J = 8.9 Hz), 4.13 (dd, 1H, J = 8.9, 7.0 Hz), 3.77 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 1.29 (s, 15H). 13C NMR (126 MHz, CDCl3): δ = 174.9, 167.8, 162.9, 160.7, 156.9, 155.6, 154.7, 140.5, 138.6,

Org. Biomol. Chem., 2014, 12, 286–297 | 295

View Article Online

Paper


138.3, 136.9, 134.5, 133.4, 131.8, 130.8, 130.2, 130.1, 128.1, 127.9, 127.4, 124.2, 119.2, 114.8, 97.0, 96.9, 70.8, 63.1, 62.0, 61.1, 55.9, 52.5, 50.7, 9.2. IR (CHCl3): ν = 1755, 1710 cm−1. HRMS ESI: m/z: [M − Cl]+ calcd for C46H45N3O8Rh: 870.2256, found 870.2257.


Acknowledgements Financial support from the Spanish MEC (CTQ2010-20714C02-01/BQU and Consolider-Ingenio 2010, CSD2007-00006) and CAM (S2009/PPQ-1634-AVANCAT) is acknowledged. A generous loan of IrCl3·3H2O and RhCl3·3H2O from Johnson Matthey Inc. is gratefully acknowledged.

Notes and references 1 Treatment of bacteria with low concentrations of bactericidal antibiotics generates multidrug resistance. See, among many others: (a) C. T. Walsh and G. Wright, Chem. Rev., 2005, 105, 391; (b) J. F. Fisher, S. O. Meroueh and S. Mobashery, Chem. Rev., 2005, 105, 395; (c) D. J. Payne, Science, 2008, 321, 1644. 2 See G. Schenk, N. Mitìc, L. R. Gahan, D. L. Ollis, R. P. McGeary and L. W. Ruddat, Acc. Chem. Res., 2012, 45, 2. 3 For a review on the emerging NDM carbapenemases, see: P. Nordmann, L. Poirel, T. R. Walsh and D. M. Livermore, Trends Microbiol., 2011, 19, 588. 4 Selected revisions on the synthesis and biology of β-lactams: (a) A. Brandi, S. Cicchi and F. M. Cordero, Chem. Rev., 2008, 108, 3988; (b) M. T. Aranda, P. Pérez-Faginas and R. González-Muniz, Curr. Org. Synth., 2009, 6, 325; (c) N. Fu and T. T. Tidwell, Tetrahedron, 2008, 64, 10465; (d) M. Gómez-Gallego, M. J. Mancheño and M. A. Sierra, Tetrahedron, 2000, 56, 5743. 5 The name bioorganometallic compounds is applied to entities having a M–C bond in a biologically active molecule. One of the main areas of application of bioorganometallic compounds is their potential use as therapeutic drugs. See: C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391. 6 Recent references: (a) O. A. Pierrat, K. Strisovsky, Y. Christova, J. Large, K. Ansell, N. Bouloc, E. Smiljanic and M. Freeman, Chem. Biol., 2011, 6, 325; (b) J. Mulchande, R. Oliveira, M. Carrasco, L. Gouveia, R. C. Guedes, J. Iley and R. Moreira, J. Med. Chem., 2010, 53, 241. 7 (a) C. M. L. Delpiccolo, S. A. Testero, F. N. Leyes, D. B. Boggian, C. M. Camacho and E. G. Mata, Tetrahedron, 2012, 68, 10780; (b) Y. Wang, H. Qian, J. Zhou, H. Zhang, J. Ji and W. Huang, Med. Chem., 2011, 7, 534 and the pertinent references therein. 8 (a) G. Gerona-Navarro, M. J. Pérez de Vega, M. T. GarcíaLópez, G. Andrei, R. Snoeck, E. De Clercq, J. Balzarini and R. González-Muniz, J. Med. Chem., 2005, 48, 2612;

296 | Org. Biomol. Chem., 2014, 12, 286–297

9

10 11

12

(b) P. R. Bonneau, F. Hasani, C. Plouffe, E. Malenfant, S. R. LaPlante, I. Guse, W. W. Ogilvie, R. Plante, W. C. Davidson, J. L. Hopkins, M. M. Morelock, M. G. Cordingley and R. Déziel, J. Am. Chem. Soc., 1999, 121, 2965 and references cited therein; (c) A. D. Borthwick, G. Weingarten, T. M. Haley, M. Tomaszewski, W. Wang, Z. Hu, J. Bedard, H. Jin, L. Yuen and T. S. Mansour, Bioorg. Med. Chem. Lett., 1998, 8, 365; (d) G. Gerona-Navarro, M. J. Pérez de Vega, M. T. García-López, G. Andrei, R. Snoeck, R. Snoeck, J. Balzarini, E. De Clercq and R. González-Muniz, Bioorg. Med. Chem. Lett., 2004, 14, 2253. J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli, Y. H. Huang, D. E. Bergles, L. Jin, M. D. Hoberg, S. Vidensky, D. S. Chung, S. V. Toan, L. I. Bruijn, Z.-z. Su, P. Gupta and P. B. Fisher, Nature, 2005, 433, 73. E. Turos, Top. Heterocycl. Chem., 2013, 30, 147 and references cited therein. (a) J. D. Buynak, L. Vogeti and H. Chen, Org. Lett., 2001, 3, 2953; (b) E. Hevia, J. Pérez, V. Riera, D. Miguel, P. Campomanes, M. I. Menéndez, T. L. Sordo and S. García-Granada, J. Am. Chem. Soc., 2003, 125, 3706; (c) T. R. Paul, N. G. Halligan, L. C. Blaszczak, T. R. Parr Jr. and T. J. Beveridge, J. Bacteriol., 1992, 174, 4689; (d) M. A. Sierra, M. J. Mancheño, R. Vicente and M. GómezGallego, J. Org. Chem., 2001, 66, 8920; (e) M. L. Lage, I. Fernández, M. J. Mancheño, M. Gómez-Gallego and M. A. Sierra, Chem.–Eur. J., 2009, 15, 593; (f) D. Pellico, M. Gómez-Gallego, P. Ramírez-López, M. J. Mancheño, M. A. Sierra and M. R. Torres, Chem.–Eur. J., 2009, 15, 6940; (g) M. A. Sierra, M. Rodríguez-Fernández, L. Casarrubios, M. Gómez-Gallego, C. P. Allen and M. J. Mancheño, Dalton Trans., 2009, 8399; (h) K. Kumar, P. Singh, L. Kremer, Y. Guerardel, C. Biot and V. Kumar, Dalton Trans., 2012, 41, 5778; (i) J. Balogh, R. Skoda-Foeldes, K. Vazdar and I. Habus, J. Organomet. Chem., 2012, 703, 51; ( j) J. Balogh, T. Kegl, L. Parkanyi, L. Kollar, F. Ungvary and R. SkodaFoeldes, J. Organomet. Chem., 2011, 696, 1394; (k) V. Kovac, K. Radolovic, I. Habus, D. Siebler, K. Heinze and V. Rapic, Eur. J. Inorg. Chem., 2009, 389; (l) T. Poljak, K. Molcanov, A. Visnjevac, I. Habus, V. Kovac and V. Rapic, J. Mol. Struct., 2005, 751, 60; (m) L. Bernardi, B. F. Bonini, M. ComesFranchini, G. Dessole, M. Fochi and A. Ricci, Eur. J. Org. Chem., 2005, 3326; (n) B. F. Bonini, C. Femoni, M. ComesFranchini, M. Foschi, G. Mazzanti, A. Ricci and G. Varchi, Synlett, 2001, 1092; (o) A. Ghatak, F. F. Becker and B. K. Banik, Heterocycles, 2000, 53, 2769; ( p) N.-Y. Fu and M.-S. Liu, Chin. J. Org. Chem., 2010, 30, 499. (a) S. Wöckel, J. Galezowska, S. Dechert and F. Meyer, Inorg. Chem., 2012, 51, 2486; (b) L. Dreesen, C. Silien, C. Volcke, Y. Sartenaer, P. A. Thiry, A. Peremans, J. Grugier, J. Marchand-Brynaert, A. Brans, S. Grubisic and B. Joris, ChemPhysChem, 2007, 8, 1071; (c) D. Kumar, A. Syamal, A. Kumar, D. Dass and A. Gupta, Asian J. Chem., 2009, 21, 7345; (d) M. J. Zaworotko, H. H. Hammud, I. Abbas, V. C. Kravtsov and M. S. Masoud, J. Coord. Chem., 2006, 59,


View Article Online



13

14 15

16

17 18

65; (e) J. R. Anacona and E. M. Figueroa, J. Coord. Chem., 1999, 48, 181; (f ) N. E. A. El-Gamel, J. Coord. Chem., 2010, 63, 534; (g) Z. H. Chohan, C. T. Supuran and A. Scozzafava, J. Enzyme Inhib. Med. Chem., 2004, 19, 79; (h) G. G. Mohamed, W. M. Hosny and M. A. Abd El-Rahim, Synth. React. Inorg. Met.-Org. Chem., 2002, 32, 1501; (i) T. Kupka, Spectrochim. Acta, Part A, 1997, 53, 2649. Recent reviews: (a) M. Albrecht, Chem. Rev., 2010, 110, 576; (b) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147. M. Martín-Ortiz, M. Gómez-Gallego, C. Ramírez de Arellano and M. A. Sierra, Chem.–Eur. J., 2012, 18, 12603. Ir-complexes are being evaluated as antitumor agents. See: Z. Liu, A. Habtemariam, A. M. Pizarro, G. J. Clarkson and P. J. Sadler, Organometallics, 2011, 30, 4702 and the pertinent references therein. For selected reviews on the synthesis of β-lactams and in the “lactam synthon method” see: (a) A. Brandi, S. Cicchi and F. M. Cordero, Chem. Rev., 2008, 108, 3988; (b) B. Alcaide, P. Almendros and C. Aragoncillo, Chem. Rev., 2007, 107, 4437. Commercial 3 Å MS were heated at 140 °C overnight in an oven, cooled to rt and stored under Ar. The relative stereochemistry of the 2-azetidinone ring for compounds 14–16 was ascertained by 1H NMR.


Paper

19 20 21 22

23 24

25

26

Characteristic 3,4J cis coupling constants between 4.5 and 5.2 Hz were observed for all the compounds. The structures of compounds 23a and 30b were ascertained by single crystal X-ray diffraction. See the ESI.† L. Li, W. W. Brennessel and W. D. Jones, Organometallics, 2009, 28, 3492. L. Li, Y. Jiao, W. W. Brennessel and W. D. Jones, Organometallics, 2010, 29, 4593. (a) J. W. Kang, K. Moseley and P. M. Maitlis, J. Am. Chem. Soc., 1969, 91, 5970; (b) C. White, A. Yates and P. M. Maitles, Inorg. Synth., 1992, 29, 228. Full experimental and spectroscopic data for the remaining compounds are included in the ESI.† M. A. Massa, D. P. Spangler, R. C. Durley, B. S. Hickory, D. T. Connolly, B. J. Witherbee, M. E. Smith and J. A. Sikorski, Bioorg. Med. Chem. Lett., 2001, 11, 1625. T. Furuya, D. Benítez, E. Tkatchouk, A. E. Strom, P. Tang, W. A. Goddard III and T. Ritter, J. Am. Chem. Soc., 2010, 132, 3793. The metal configurational stability of the Ir and Rhcomplexes prepared through this work was demonstrated by stirring in DCM at room temperature or by heating at 40 °C representative compounds for 48 hours. The initial diastereomer ratio remained unaltered (1H NMR).

Org. Biomol. Chem., 2014, 12, 286–297 | 297

Heterobimetallic complexes of polypyridyl ligands containing paramagnetic centers: synthesis and characterization by IR and EPR.

Letter: Synthesis of new beta-lactam antibiotics.

Electrochemical synthesis, characterization of Ir-Zn containing coordination polymer, and application in oxygen and glucose sensing.

Synthesis of tabtoxinine-delta-lactam.

Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands.

Synthesis and biological evaluation of new nitrogen-containing diselenides.

Synthesis and DFT investigation of new bismuth-containing MAX phases.

Synthesis and characterisation of magnesium complexes containing sterically demanding N,N'-bis(aryl)amidinate ligands.

Synthesis, spectral and catalytic dehydrogenation studies of ruthenium complexes containing NO bidentate ligands.

Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

Enantioselective synthesis of tunable chiral Clickphine P,N-ligands and their application in Ir-catalyzed asymmetric hydrogenation.

Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities.

Platinacycloalkane complexes containing [P,N] bidentate ligands: synthesis and decomposition studies.

Some dicopper complexes of benzimidazole-containing ligands.

Pyrimidine containing furanose derivative having antifungal, antioxidant, and anticancer activity.

Synthesis and characterization of new bivalent agents as melatonin- and histamine H3-ligands.

Synthesis, characterization, single crystal X-ray determination, fluorescence and electrochemical studies of new dinuclear nickel(II) and oxovanadium(IV) complexes containing double Schiff base ligands.

Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A.

New beta-lactam-antibiotics. Fluorinated cephalosporins.

Facile synthesis of dibenzopentalene dianions and their application as new π-extended ligands.

Ir genes New tests of familiar arguments.

Flux growth of Yb(6.6)Ir(6)Sn(16) having mixed-valent ytterbium.

Rational synthesis and characterization of dimolybdenum(II) compounds bearing ferrocenyl-containing ligands toward modulation of electronic coupling.

Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.