Article pubs.acs.org/Organometallics
Reactivity and Selectivity in Catalytic Reactions of Enoldiazoacetamides. Assessment of Metal Carbenes as Intermediates Yongming Deng,† Changcheng Jing,‡ Hadi Arman,† and Michael P. Doyle*,† †
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, 200062, People’s Repubic of China
‡
S Supporting Information *
ABSTRACT: Catalyst effectiveness for metal carbene formation and reactions has been surveyed using N-(tert-butyl)-3-[(tertbutyldimethylsilyl)oxy]-2-diazo-N-(4-chlorobenzyl)but-3-enamide in the formation of the products from both intramolecular C−H insertion and aromatic cycloaddition. Both products are indicators of metal carbene intermediates, and this system provides a means to assess catalysts for metal carbene formation. Donor−acceptor cyclopropene production from the reactant enoldiazoacetamide has been monitored to assess its formation, and the independently formed cyclopropene has also been used to assess metal carbene formation. Catalysts of rhodium(II), copper(I), silver(I), Pd(II), cationic Au(I), and Zn(II) convert the enoldiazoacetamide to the donor−acceptor cyclopropene which serves as the resting state for the intermediate metal carbene, and both the enoldiazoacetamide and its derivative cyclopropene give the same ratios of insertion to cycloaddition products. Catalysts of copper(II) and ruthenium(II) do not give the cyclopropene as an observable intermediate, and the product ratio from insertion/cycloaddition varies when the reactant is the enoldiazoacetate from that with its derivative cyclopropene. The variation of product ratio with the metal carbene precursor in copper(II)-catalyzed reactions is dependent on the catalyst ligand, the solvent, and substituents of the benzyl group of the reactant. [Ru(p-cymene)Cl2]2 formed the products from a metal carbene intermediate with the reactant enoldiazoacetamide catalytically but with an enoldiazoacetate formed a η3-allyl ruthenium complex stoichiometrically.
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INTRODUCTION We recently reported a highly enantioselective cis-β-lactam synthesis from enoldiazoacetamides that occurred by intramolecular C−H insertion using chiral dirhodium(II) carboxylate catalysts.1 In the course of this investigation we discovered that with N-benzylenoldiazoacetamides aromatic cycloaddition (the Büchner reaction) with the aromatic ring was competitive with C−H insertion into a benzyl C−H bond (Scheme 1), and this competition was dependent on the catalyst ligand. Furthermore, catalytic intramolecular cyclization of N-benzylenoldiazoacetamides occurred to form donor− acceptor cyclopropenes that were observable intermediates on the pathway to the aromatic cycloaddition and C−H-insertion products. These observations prompted us to further investigate details of these reactions to ascertain if the donor−acceptor © XXXX American Chemical Society
cyclopropene is always formed prior to the aromatic cycloaddition and C−H insertion products, to evaluate the competition between aromatic cycloaddition and C−H insertion, and to determine if this reaction system could be a viable test for metal carbene formation with a broad spectrum of catalysts. In recent years, catalysts suitable for carbene transformations2 have expanded from those of copper3 and rhodium4 to include those of ruthenium,5 silver,6 gold,7 palladium,8 cobalt,9 and even zinc,10 nickel,11 mercury,12 and iron.13 However, most reports have examined only diazo compounds, and they only rarely compared the activities of the reported catalyst with a broader set. Received: August 11, 2016
A
DOI: 10.1021/acs.organomet.6b00648 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics
Scheme 1. Dirhodium Catalyst Catalyzed C−H Insertion and Aromatic Cycloaddition Reactions of Enoldiazoacetamides through the Cyclopropene Intermediate
which has been well-established in dirhodium(II)-catalyzed reactions,18 is indicative of the kinetic pathway in which formation of the donor−acceptor cyclopropene from the intermediate metal carbene is faster than the intramolecular C−H insertion or aromatic cycloaddition of the same intermediate. To further assess the nature of processes that proceed through metal carbene intermediates, we performed catalytic reactions of both 1a and independently produced 2a. Both the 3a:4a product ratios and isolated yields of 3a and 4a were obtained over a specified reaction time at a specific reaction temperature, and these results are reported in Table 1. Product formation that occurred with traditional catalysts for metal carbene formation occurred rapidly, seemed to be related to their Lewis acidity, and often favored aromatic cycloaddition over C−H insertion. When the donor−acceptor cyclopropene was initially formed from 1a, the reactive metal carbene precursor for product formation is 2a in both processes. The 3a:4a product ratios from reactions of 1a and 2a with the same catalyst were the same within experimental error for all catalysts except those of copper(II), and with these catalysts enoldiazoacetamide 1a did not observably form donor− acceptor cyclopropene 2a prior to product formation. In addition, use of [Ru(p-cymene)Cl2]2, [Pd(C3H5)Cl]2, Rh(I), and Rh(III) (entries 8−11) did not reveal donor−acceptor cyclopropene 2a during the course of the reaction, but their 3a:4a product ratios for reactions with 1a and 2a were identical. Isolated yields for these reactions were not optimized, and those at or greater than 40% for 3a + 4a were considered to indicate viable catalytic systems. Potential catalysts (5 mol %) that did not undergo formation of either 3a or 4a in the temperature range of room temperature to 50 °C were considered to be inactive for the formation of metal carbene intermediates by N2 extrusion of enoldiazo compounds. The competitive formation of 3a and 4a results from stereoelectronic and steric competition between two conformational isomers for intramolecular reactions with an intermediate electrophilic metal carbene (Scheme 2).19 β-Lactam formation involves insertion of the metal carbene carbon into the benzylic C−H bond as the metal complex is dissociating from the carbene carbon,20 whereas aromatic cycloaddition involves addition of the metal carbene carbon into an electron-rich π bond of the aromatic ring to form a norcaradiene intermediate that undergoes electrocyclic ring opening. Strain energy inhibits the C−H insertion process, whereas dearomatization is a barrier for aromatic cycloaddition. The competition between C−H insertion and aromatic cycloaddition is common in reactions of diazoamides catalyzed by dirhodium(II) compounds21 and
Furthermore, different oxidation states of the same metal can exhibit significantly different activities.14 Catalytic C−H insertion reactions are universally recognized as metal carbene processes,15 and although they are less wellknown, so are aromatic cycloaddition reactions.16 Yet, in examining mercuric triflate as a catalyst for the process described in Scheme 1, a new product was uncovered (eq 1) that, although
resembling that from aromatic cycloaddition followed by a Cope rearrangement, could be interpreted as occurring through a pathway that did not involve a metal carbene intermediate; the same product was also formed with silver catalysis.17 This investigation of metal-catalyzed reactions of N-benzylenoldiazoacetamides was undertaken to reveal comparative information about the involvement or lack of involvement of metal carbene intermediates and to identify differences in their reactivities and selectivities.
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RESULTS AND DISCUSSION The initial evaluations of reactions of N-tert-butyl-N-benzylenoldiazoacetamides were performed with the p-chlorobenzyl derivative 1a. Reactions were monitored over time by NMR spectroscopy to determine if the donor−acceptor cyclopropene 2a was an observable intermediate in the processes that form C−H insertion and aromatic cycloaddition products 3a and 4a. A typical monitoring process is shown as Figure 1, which was obtained from the reaction of 1a with 5 mol % of silver(I) hexafluoroantimonate at room temperature in CDCl3. As is evident from the time course for this reaction, the donor− acceptor cyclopropene 2a is formed within 5 min and decreases slowly in concentration over time as the concentrations of 3a and 4a increase. This observation is consistent with the donor− acceptor cyclopropene/metal catalyst being the resting state for the metal carbene formed in reactions of these diazo compounds. Detection of 2a during the course of the reaction, B
DOI: 10.1021/acs.organomet.6b00648 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics
Figure 1. Intramolecular reaction of enoldiazoacetamide 1a catalyzed by AgSbF6 through its cyclopropene intermediate 2a to form 3a and 4a, as monitored by 1H NMR spectroscopy.
carbene precursors in reactions with 1a that are different from those formed from donor−acceptor cyclopropene 2a (entries 7−9). Copper(II) Catalysts. In view of the substantial disparity in product ratios for reactions of the enoldiazoacetamide precursor 1a and the donor−acceptor cyclopropene 2a (Table 1, entries 7−9) the copper(II) acetylacetonate and triflate catalysts were further investigated to ascertain the cause of the differences. Although they have been rarely investigated, solvent effects on metal carbene transformations have been reported to influence the reaction pathway.23 Treatment of both 1a and 2a with square-planar Cu(acac)224 and Cu(hfacac)2 in various solvents showed a significant solvent effect (Table 2), but extending this evaluation to reactions catalyzed by the more Lewis acidic Cu(OTf)2 produced substantially diminished differences. The largest differences in the 3a:4a ratios from 1a and 2a were found from reactions conducted in 1,2dichloroethane (DCE), and the smallest differences occurred in toluene. The polarity of the solvent does not appear to have a direct influence on the differences in the product ratio, but substantial differences in the 3a:4a ratio occur from reactions in the different solvents, with notable selectivity achieved for reactions of enoldiazoacetamide 1a in 2,3-dimethylbutane (Table 2, entry 4). In these investigations the percent yield reflects the reaction rate and/or solubility of the catalyst in the reaction medium; but the 3a:4a product ratio, which is reproducible, is not dependent on product yield. In addition to solvent influences, changing the substituent at the para position of enoldiazoacetamide 1 also affected the product distribution (Table 3), but neither a strongly electron donating substituent (OMe) nor a strongly electron withdrawing substituent (COOMe) had any detectable influence on product ratios for reactions of the enoldiazoacetamide precursor 1 and the donor−acceptor cyclopropene 2.
has also been described for those catalyzed by a ruthenium porphyrin catalyst,22 but reactions with other catalysts whose results are documented in Table 1 have not previously received attention. As has been previously reported,19 however, the 3:4 ratio is dependent on catalyst ligands. In the series of carboxylate-ligated dirhodium(II) catalysts, those that increase the Lewis acidity of the metal increase the relative amount of 4, but ligand Lewis acidity does not appear to have any significant influence on chemoselectivity with any other transition metal. This may be a function of the core structures of these transition-metal complexes, with rhodium(II) complexes having a structural paddlewheel framework that is uniquely able to reflect stereoelectronic influences.23 Product formation is independent of the source of the metal carbene for the majority of the entries in Table 1. In these cases, both enoldiazoacetate 1a and the donor−acceptor cyclopropene 2a formed products 3a and 4a with the same 3a:4a ratio and in comparable yields (entries 1−6, 11, and 19). This was due in most instances to the initial formation of 2a from 1a prior to the subsequent insertion or cycloaddition reactions. However, no cyclopropene intermediate was detected in the reactions with enoldiazoacetate 1a catalyzed by Cu(hfacac)2, Cu(acac)2, Cu(OTf)2, [Ru(p-cymene)Cl2]2, [Pd(C3H5)Cl]2, Rh(I), and Rh(III) (entries 7−9 and 12−15). With [Ru(p-cymene)Cl2]2, [Pd(C3H5)Cl]2, Rh(I), and Rh(III) as catalysts their reactions with donor−acceptor cyclopropene 2a proceeded much faster than those with 1a, giving 3a:4a product ratios identical with those from their reactions with 1a; these results indicate that the reactive metal carbene precursor for product formation is 2a, which is more rapidly converted to 3a than is its formation from enoldiazoacetamide 1a. The extrusion of dinitrogen from 1a is rate-limiting. In contrast, the substantial disparity in product ratios for reactions with Cu(II) catalysts of 1a and 2a reveals metal C
DOI: 10.1021/acs.organomet.6b00648 Organometallics XXXX, XXX, XXX−XXX
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Organometallics Table 1. Catalyst Survey of Intramolecular Reaction with Enoldiazoacetamide 1a and Cyclopropene Intermediate 2a
from 1aa entry
catalyst (x (mol %))
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Rh2(OAc)4 (2) Rh2(esp)4 (2) Rh2(pfb)4 (2) AgSbF6 (5) AgOTf (5) Cu(MeCN)4PF6 (5) Cu(hfacac)2 (5) Cu(acac)2 (5) Cu(OTf)2 (5) PtCl2(PhCN)2 (5) Pd(OAc)2 (2) [Pd(C3H5)Cl]2 (2) [Ru(p-cymene)Cl2]2 (2) [Rh(COD)Cl]2 (2) [Rh(C5Me5)Cl2]2 (2) Fe(TPP)Cl (2) Co-porphyrine (2) [Ir(COD)Cl]2 (2) ZnCl2f (5) Zn(OTf)2 (5) (CH3)2SAuCl (5) PyAuCl3 (5) Au[P(t-Bu)2(o-biphenyl)]Cl (2) JohnPhos-Au(MeCN)SbF6 (2)
T (°C) room room room room room room room room room room room room room room room room room room room room 50 50 room room
temp temp temp temp temp temp temp temp temp temp temp temp temp temp temp temp tempg tempg temp temp
temp tempg
from 2aa
time (h)
b
yield (%)
3a:4a
2a?
4 4 4 2 16 3.5 16 16 16 12 12 0.5 2 6 6 16 16 16 12 12 12 12 12 24
92 91 87 90 68 86 60 50 41 95:5 >95:5 12:88
64:36 47:53
a
Reactions were performed with 0.20 mmol of 1a or 2a in 4.0 mL of 1,2-dichloroethene (DCE) in N2-protected vials. bCombined yield of 3a and 4a. Determined by integration of characteristic 1H NMR absorptions from the spectrum of the reaction mixture. dWas 2a detected during the course of the reaction? Y = yes; NO = not observed. eCo-porphyrin = [Co(3,5-DitBu-IbuPhyrin)]. fZnCl2 solution (1.0 M in diethyl ether). gWhen the reaction temperature was raised to 50 °C, 1a was converted to the donor−acceptor cyclopropene 2a thermally.17 DCE = 1,2-dichloroethane. c
Scheme 2. Competing Formation of 3a and 4a through an Electrophilic Metal Carbene Intermediate
In fact, only the p-chloro substituent produced any substantial difference in product distribution (3:4) from reactions of 1 and 2. However, the 3:4 product ratio was greatly influenced by these para substituents, with C−H insertion substantially favored over aromatic cycloaddition with electron-donating substituents. Prior reports of the influence of substituents have also reported diverse outcomes.25
Why do the 3:4 product ratios change with the source of the reactant metal carbene source? The answer cannot be that 1a forms 2a, as in the case of dirhodium(II), silver(I), or Cu(MeCN)4PF6 catalysts, all of which are observed to produce 2a from 1a rapidly so that 3a and 4a are formed solely from 2a. One is tempted to propose that the acetylacetonate ligands or triflate play different roles in metal carbene formation from the D
DOI: 10.1021/acs.organomet.6b00648 Organometallics XXXX, XXX, XXX−XXX
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Organometallics
Table 2. Chemoselectivity for Insertion and Cycloaddition from Solvent Survey of Cu(II) Catalysts in Reactions with 1a and 2a
Cu(acac)2
Cu(hfacac)2
a
from 1a b
from 2a c
entry
solvent
yield (%)
3:4
1 2 3 4 5 6 7 8
DCE DCM CHCl3 DMB hexane toluene CH3CN Et2O
50 51 71 22 28 87 24 95:5 55:45 88:12 65:35
a
from 1a c
b
yield (%)
3:4
46 48 65 16 26 85 16 95:5 60:40 80:20 40:60
Cu(OTf)2
a
a
from 2a c
b
yield (%)
3:4
60 58 58 21 28 42 37 12
32:68 38:62 20:80 72:28 45:55 32:68 61:39 46:54
from 1a c
b
yield (%)
3:4
53 54 44 7 26 39
