Abstract
A highly diastereoselective formal [3+2+1]-cycloaddition reaction that produces multi-functionalized bicyclic pyrazolidinone derivatives is achieved in moderate to high yield by Rh2(4S-MPPIM)4-catalyzed reaction of azomethine imines with two molecules of a diazo ketone.
Cycloaddition reactions with azomethine imines,1-4 stable and easily prepared iminium ylides that were first reported by Dorn in 1968,1a have attracted considerable attention in dipolar [3+2]2 and [3+3]3 cycloaddition reactions that are effective methodologies to access a diverse array of heterocycles.4 Specifically, Fu,5 Kobayashi,6 Toste,7 Hayashi,8 and we9 have separately studied azomethine imines in cycloaddition reactions that furnish five- and six-membered ring heterocycles. Although there are numerous intermolecular dipolar cycloaddition reactions reported between a dipole and a dipolarophile (Scheme 1), cyclization between three molecules is very rare.10 Herein we report a formal highly diastereoselective [3+2+1]-cycloaddition of azomethine imines with two molecules of a diazo ketone, catalyzed by Rh2(4S-MPPIM)4, to give bicyclic pyrazolidinone derivatives in moderate to high yield.
Scheme 1.
[3+3]-Cycloaddition of azomethine imines with various dipolarophile precursors.
Diazocarbonyl compounds have been extensively studied during the last few decades, and their applications in organic syntheses are well known.11,12 In our research, we have been investigating formal [3+3]-cycloaddition reactions of enoldiazoacetates 6 with 1,3-dipolar substrates.13,14 In these reactions, metal enol carbene intermediates, generated by dinitrogen extrusion with dirhodium(II) catalysts, showed electrophilic character at both the carbene and vinylogous positions (reaction sites 1 and 2 of A in Scheme 2) and can be regarded as versatile synthetic equivalents of pyruvates 7. Based on this knowledge, we envisioned that dirhodium(II)-catalyzed decomposition of vinyl diazo ketone 4 would give metal carbene B, equivalent to diketone 8, with three electrophilic carbon centers (reaction sites 1, 2 and 3 of B); and with this added functionality in metal carbene B additional synthetic opportunities would be possible.
Scheme 2.
Analogies between vinyldiazoacetates and vinyldiazoketones.
With this in mind, the reaction of phenylazomethine imine 1a with 4-methyl-1-diazo-3-buten-2-one 4 was investigated using dirhodium acetate as the catalyst (Table 1). The reaction was performed by adding the diazo ketone to a dichloromethane solution of 1a and Rh2(OAc)4 at room temperature (Table 1, entry 1). Although a complex mixture of products was obtained, one compound was isolated in low yield whose surprising structure was determined to be 5 spectroscopically and by single-crystal X-ray diffraction analysis of its chloro derivative.15 This unexpected structure suggested that the azomethine imine 1a reacted with two diazo ketone 4 to give the bicyclic pyrazolidinone derivative (trans-5a) as single isomer via a formal three-component [3+2+1]-cycloaddition. Efforts to increase the yield of 5a by increasing the number of equivalents of diazo ketone 4 to 2.5 gave only a slightly higher conversion (entry 2). Scanning of dirhodium catalysts showed that the more Lewis acidic rhodium trifluoroacetate [Rh2(tfa)4] and rhodium perfluorobutyrate [Rh2(pfb)4] showed an expected higher reactivity in the decomposition of the diazoketone but exhibited no advantage over rhodium acetate in the formation of 5a (entries 6 and 7). Rh2(esp)4 and Rh2(cap)4 caused decomposition of the diazo compound, but the process did not incorporate azomethine ylide in product formation (entries 3 and 5). Compared to the other tested catalysts, the chiral dirhodium(II) carboxamidate Rh2(MPPIM)4 (entry 9) gave the highest conversion (45%) and yield (39%). The yield was increased to 89% by using 4.0 equivalents of diazo ketone 4 relative to 1 (entries 10~12). With this catalyst (entry 11) and several other chiral dirhodium catalysts (entries 13-15) product analyses showed no enantiocontrol in the formation of 5a. Copper and other Lewis acid catalysts did not form 5a.16
Table 1.
Optimization of conditions for the formal [3+2+1]-cycloadditiona
| entry | Cat. |
4 (eq) |
T (°C) |
t (h) |
conversion (%)b |
yield (%)c |
|---|---|---|---|---|---|---|
| 1 | Rh2(OAc)4 | 1.5 | 25 | 2 | ND | 23 |
| 2 | Rh2(OAc)4 | 2.5 | 25 | 2 | 35 | ND |
| 3 | Rh2(cap)4 | 2.5 | 40 | 12 | <5e | - |
| 4 | Rh2(oct)4 | 2.5 | 25 | 12 | 15 | ND |
| 5 | Rh2(esp)4 | 2.5 | 25 | 2 | <5e | - |
| 6 | Rh2(tfa)4 | 2.5 | 25 | 2 | 35 | 17 |
| 7 | Rh2(pfb)4 | 2.5 | 25 | 2 | 37 | 15 |
| 8 | Rh2(S-DOSP)4 | 2.5 | 25 | 2 | 34 | 23 |
| 9 | Rh2(4S-MPPIM)4 | 2.5 | 40 | 12 | 45 | 39 |
| 10 | Rh2(4S-MPPIM)4 | 5.0 | 40 | 12 | >99 | 89 |
| 11d | Rh2(4S-MPPIM)4 | 4.0 | 25 | 48 | >99 | 89 |
| 12 | Rh2(4S-MPPIM)4 | 3.0 | 25 | 48 | 87 | 81 |
| 13d | Rh2(5R-MEPY)4 | 4.0 | 40 | 12 | >99 | 73 |
| 14d | Rh2(S-DOSP)4 | 4.0 | 25 | 2 | 74 | 56 |
| 15d | Rh2(S-PTAP)4 | 4.0 | 25 | 2 | 82 | 63 |
Reactions were carried out on a 0.3 mmol scale with 4 (indicated equivalent), 1a (0.3 mmol), 4 Å MS (100 mg), in 2.0 mL DCM with 2.0 mol% of catalyst at the indicated temperature.
Percent conversion was determined from the proton NMR spectrum of the reaction mixture relative to limiting reagent 1a.
Isolated yield of 5a based on limiting reagent 1a.
Enantioselectivity was determined by HPLC analysis using chiral AD-H columns (hexanes:i-PrOH = 95:5, 254 nm, 1.0 mL/min, t1 = 7.8, t2 = 11.9) and only <2% of ee was detected in all cases.
Only decomposition of 4 was detected with unreacted 1a recovered in high yield. ND = not detected.
With the optimized conditions in hand, reactions with a variety of azomethine imines were then examined. As shown in Table 2, the electronic properties of para substituents on the phenyl group of azomethine imines had an obvious influence on the yield; azomethine imines with both electron-rich and electron-deficient aryl substituents gave lower yields of 5 (entries 5 and 6) than those with methyl and halide substituents (entries 2-4). Substrates with para, meta or ortho substituents showed similar high reactivity (entries 2, 7 and 8). Notably, 1-naphthyl- and 1-furylazomethine imines were tolerated under these conditions and generated 5i and 5j in 73% and 64% isolated yield, respectively (entries 9 and 10). In addition, an alkyl substituted azomethine imine also reacted well and gave the corresponding pyrazolidinone in 61% yield (entry 11). Reactions with other diazocarbonyl compounds, including ethyl diazoacetate and diazoacetophenone, gave only carbene dimers from dinitrogen extrusion of the diazo compound with all of the azomethine imine remaining untouched.
Table 2.
Azomethine imine substrate generalitya
| entry | Ar (1) | 5 | drb | yield (%)c |
|---|---|---|---|---|
| 1 | Ph (1a) | 5a | > 95:5 | 90 |
| 2 | 4-ClC6H4 (1b) | 5b | > 95:5 | 85 |
| 3 | 4-BrC6H4 (1c) | 5c | > 95:5 | 89 |
| 4 | 4-MeC6H4 (1d) | 5d | > 95:5 | 79 |
| 5 | 4-MeOC6H4 (1e) | 5e | > 95:5 | 61 |
| 6 | 4-NO2C6H4 (1f) | 5f | > 95:5 | 57 |
| 7 | 2-ClC6H4 (1g) | 5g | > 95:5 | 83 |
| 8 | 3-ClC6H4 (1h) | 5h | > 95:5 | 80 |
| 9 | 1-Naphthyl (1i) | 5i | > 95:5 | 73 |
| 10 | 1-Furyl (1j) | 5j | > 95:5 | 64 |
| 11 | Cyclohexyl (1k) | 5k | > 95:5 | 61 |
Reactions were carried out on a 0.3 mmol scale: 4 (4.0 eq), 1 (0.3 mmol), 4 Å MS (100 mg), in 3.0 mL DCM with Rh2(4S-MPPIM)4 (2.0 mol%) at room temperature.
Determined by the proton NMR spectrum of the reaction mixture.
Isolated yield of 5 based on limiting reagent 1.
The pathway to cycloaddition product 5 is perplexing, but there are a number of observations that lead to a proposed mechanism for the reaction: (1) adding diazo ketone 4 to the solution of 1 and rhodium catalyst at one time, or reversing the order of addition of reactants with diazo ketone added to the catalyst before azomethine imine 1, resulted in complex mixtures of products and low or no production of 5 depending on the time that 1 was added following 4; (2) dinitrogen extrusion from diazo ketones is slowed considerably in the presence of azomethine imine; and (3) effective enantiocontrol is absent with the use of chiral catalysts. These observations suggest that coordination of catalyst with azomethine imine precedes reaction with the diazo ketone and that a metal carbene generated from 4 is not involved in the formation of 5. Accordingly, the role of the dirhodium catalyst is that of a Lewis acid to activate the azomethine imine for electrophilic addition to the diazo ketone (Scheme 3). Association of 1a with dirhodium(II) compounds was verified by spectral shifts that occur in the visible region of the electromagnetic spectrum, as exemplified by the titration experiment with Rh2(5R-MEPY)4 (Figure 1) from which an association constant (Keq1) of 57±8 M−1 was determined.17 That Rh2(cap)4 does not undergo this formal [3 + 2 + 1]-cycloaddition is due to its inability to form a complex with 1, but the same is not true with Rh2(esp)4 (Keq1 of 489±9 M−1). Lower product yields with the more Lewis acidic dirhodium compounds, including Rh2(esp)4, may be due to their much greater reactivity towards the diazo ketone. Lewis acids including Cu(hfacac)2, Sc(OTf)3 and Zn(OTf)2 did not provide sufficient activation of 1 to cause reaction with diazoketone 4.16 There is in this transformation a delicate balance in the activation of 1 for electrophilic addition to the diazo ketone versus either no addition or reaction of the catalyst with the diazo ketone independent of reaction with 1.
Scheme 3.
Proposed mechanism for the formal [3+2+1]-cycloaddition.
Figure 1.
Sequential aliquots of azomethine imine 1a (2 × 10−3 mmol in 10 μL DCM) added to Rh2(5R-MEPY)4 (4 × 10−3 mmol in 2 mL DCM) gave a well-defined isosbestic point with an incremental shift of λmax from 650 nm to 620 nm. Keq1 was calculated at three different wavelengths and the average Keq1 was determined to 57±8.
In summary, we have discovered a diastereoselective formal [3+2+1]-cycloaddition that enables the efficient preparation of multi-functional bicyclic pyrazolidinone derivatives starting from azomethine imines and two molecules of a diazo ketone in moderate to high yield. This is a tactful annulation of three molecules catalyzed optimally by Rh2(4S-MPPIM)4. Additional studies with other diazoketones are underway to explore the scope of these reactions and to investigate alternative syntheses based on differential reactions with diazo ketones.
Supplementary Material
Acknowledgments
MPD is grateful to the National Institutes of Health (GM 465030) for support of this research.
Footnotes
Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/b000000x/
Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data.
Notes and references
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