Letter pubs.acs.org/OrgLett
Regioselective and Enantioselective Intermolecular Buchner Ring Expansions in Flow Gabrielle S. Fleming and Aaron B. Beeler* Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States S Supporting Information *
ABSTRACT: The first example of a regioselective and enantioselective intermolecular Buchner ring expansion is reported using continuous flow. The practicality and scope of the reaction are greatly improved under flow conditions. Reactions of ethyl diazoacetate with symmetric and nonsymmetric arenes afford cycloheptatrienes in good yield and excellent regioselectivity. The first example of an asymmetric intermolecular Buchner reaction is demonstrated with disubstituted diazo esters in good to excellent enantioselectivity. The asymmetric reactions proceed with absolute regioselectivity to afford cycloheptatrienes with an all-carbon quaternary center.
S
Scheme 1. Intermolecular Buchner Ring Expansion
even-membered rings are key elements of many bioactive natural product families such as guaianolide sesquiterpene lactones, guaiane sesquiterpenes, and diterpene tiglianes and daphnanes.1−3 Compared to five- and six-membered rings, there are substantially fewer methods for their synthesis.4,5 As such, efficient reactions to access these scaffolds are of continued interest. The Buchner ring expansion provides expedient access to seven-membered carbocycles in a single step from simple starting materials. Moreover, the products are highly oxidized, which is ideal for downstream functionalization and utilization in complex molecule synthesis and medicinal chemistry. Although first discovered in 1883,6 the photochemical and thermal Buchner ring expansions were of limited utility in synthesis7,8 due to facile isomerization of the cycloheptatriene (CHT) products to an inseparable mixture of seven thermodynamic conjugated esters. In 1980 Noels and coworkers reported that Rh2(OAc)4 catalyzed the intermolecular Buchner ring expansion9 to afford mixtures of only three kinetic cycloheptatrienes, but the reaction still suffered from issues of regioselectivity and limited scope. This initiated significant advances in the RhII-catalyzed intramolecular Buchner reaction, led by Maguire and co-workers, which has seen great success in a number of important synthesis efforts.10 However, as a general method to access seven membered rings, the intermolecular reaction remains largely unused due to continued challenges. These include requiring super-stoichiometric amounts of arene, limited scope, and most importantly, poor regioselectivity (Scheme 1).11 Nevertheless, a selective intermolecular Buchner reaction remains enticing and has potential to be one of the most efficient methods to rapidly access 7-membered rings. It is well established that flow conditions can have superior heat transfer and mixing compared to batch chemistry, which can significantly enhance the efficiency and selectivity of a reaction.12 Moreover, the scale and selectivity of exothermic reactions, including the Buchner ring expansion, can be limited © 2017 American Chemical Society
as a result of poor mixing and heat dissipation in batch. We were hopeful that the excellent heat transfer, mixing, and scalability of flow chemistry would enable the intermolecular Buchner reaction to be more selective, practical, and scalable. To examine our hypothesis, a flow set up was assembled (Figure 1) using two preloading loops which are charged with
Figure 1. Flow system piping and instrument diagram.
arene, diazoester, and catalyst. The reaction proceeds as pumped streams of solvent push the reaction forward after being combined with a static T-mixer. Flow rate and reactor volume can be tuned to optimize the reaction and a backpressure regulator applies a constant pressure to the system, Received: August 16, 2017 Published: September 11, 2017 5268
DOI: 10.1021/acs.orglett.7b02537 Org. Lett. 2017, 19, 5268−5271
Letter
Organic Letters controlling outgassing of nitrogen gas produced during the reaction. Initial reactions of EDA and anisole in flow with a common catalyst, Rh2(OAc)4, were unsuccessful (Table 1, entry 1).
Scheme 2. Optimized Conditions and Aromatic Substrate Scopea
Table 1. Optimization of the Intermolecular Buchner Reaction in Flow
entry
catalyst
solvent
flow ratea (mL/min)
tR (min)
yieldb (%)
1c,d 2c 3 4 5 6 7 8 9 10d 11d
Rh2(OAc)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(tfa)4 Rh2(esp)4
DCE DCE DCE DCE DCE DCE DCE DCM CHCl3 DCE DCE
0.25 0.25 0.25 0.25 1 1 2 1 1 1 1
2.5 2.5 2.5 5 20 39 19 20 20 20 20
0 17 35 50 81 50 36 24 37 71 43
a
Flow rate (mL/min) maintaining residence time by reactor volume. Quantitative NMR yield of major regioisomer 3c. cRun with 1 equiv of 2. dRun with 1 mol % of catalyst.
a
All reactions were run on a 1 mmol scale. Only the major 3-CHT regioisomeric product is shown. Yields determined by quantitative 1H NMR. Ratios determined by 1H NMR and reported as 1-CHT/2CHT/3-CHT.
b
However, we found that Rh2(oct)4 was modestly effective in catalyzing the reaction, cleanly providing a mixture of diethyl fumerate and a major regioisomer, 3-CHT 3c, in a 3:1 ratio and 17% isolated yield (Table 1, entry 2). We proceeded by trying to maximize the production of the major regioisomer 3c, first by increasing the arene substrate to 10 equiv which afforded an increased yield of 35% of 3c. After doubling the reaction time to 5 min, we observed 50% yield of 3c (Table 1, entries 3 and 4). The reaction proceeds best at high concentrations (1.6 M) and with an excess of arene. As a result of the high concentration, we observed significant outgassing of N2 which is produced in the reaction. Unregulated, this causes inconsistency in flow rate, residence time, and reaction yield. In order to regulate the outgassing to form controlled segments (“slugs”), we applied 150 psi of pressure to the reaction using a membrane back-pressure regulator. At higher pressures and lower concentrations, we were able to keep N2 in solution but observed a drop in yield. We continued to evaluate the effect of solvent, catalyst, loading, flow rate, and residence time (Table 1). Increasing both the residence time (20 min) and flow rate (1 mL/min) resulted in the best yield and selectivity of 3-CHT 3c (81%, 5:1) (Table 1, entry 5). Longer residence times and increasing the flow rate beyond 1 mL/min did not improve the reaction. With optimized conditions in hand, we set out to investigate a range of substrates (Scheme 2). Electron-rich aromatic substrates proceed in high yields with excellent regioselectivity (3c, 4). With neutral and electron poor arenes, we observed a significant influence of the catalyst selection (5−9). These substrates afford higher yields with Rh2(tfa)4 compared to Rh2(oct)4, albeit with some loss of selectivity. Moreover, yields increase with a higher catalyst loading of Rh2(tfa)4, whereas higher catalyst loading of Rh2(oct)4 leads to decreased yield of
CHT and increased dimerization. This can be attributed to a change in the nucleophilic/electrophilic nature of the metallocarbene as a result of the highly electron-poor trifluoroacetate ligand. We were pleased to observe that a number of disubstituted benzenes also proceeded in moderate to good yields and with excellent selectivity. Naphthalene proceeded in good yield with Rh2(oct)4 to afford a single regioisomer and, as has been previously reported, was isolated as the norcardiene 9.13 Notably, 1,4-dimethoxybenzene afforded a single regioisomer, 10, in good yield with both catalysts. Similarly, p-methylanisole and p-bromoanisole both afforded a single regioisomer (11, 12) with Rh2(oct)4, but p-methylanisole was less selective with Rh2(tfa)4. Reaction with nonsymmetric o-methylanisole could possibly afford up to six regioisomers, yet we observed only two, one as the norcaradiene (13, 14), which were separable by chromatography. We ran analogous batch reactions with our optimized conditions and found that the yields were generally comparable but selectivity decreased significantly (Scheme 3). Reaction with anisole showed comparable regioselectivity in batch when the reaction was run on 1 mmol scale. However, when the reaction was increased to a 10 mmol scale the selectivity decreased to 1:0:2. Most interestingly, reactions with pbromoanisole and p-methylanisole (11, 12) in batch resulted in inseparable mixtures of regiosisomers, in contrast to single regioisomers observed in flow. We hypothesized that the selectivity increase in flow could be due to differences in heat transfer since the reaction is exothermic. When carefully monitoring the temperature of the batch reaction, we observed an average of a 10 °C increase in reaction temperature upon addition of EDA, which took 20 min 5269
DOI: 10.1021/acs.orglett.7b02537 Org. Lett. 2017, 19, 5268−5271
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Organic Letters
time afford enantioselectivity (Scheme 4). We were pleased to find that reaction with phenyl diazoacetate 15 and anisole in
Scheme 3. Comparison of Regiochemical Outcome in Flow versus Batch Reaction Conditions
Scheme 4. Disubstituted Diazo Substrate Scope
a
Reactions run on a 1 mmol scale with 0.5 mol % catalyst, at 0.167 M for 20 min unless otherwise noted. bRatios were determined by 1H NMR and are reported as 1-CHT/2-CHT/3-CHT. cReaction run on a 10 mmol scale. dReaction heated to 35 °C in flow.
to cool to 25 °C. However, the in-line flow temperature only increases by 3 °C at the mixing T-junction, and after a 1 min residence time the temperature is restored to 25 °C (Scheme 3, inset). Moreover, we can induce a loss of regioselectivity in flow by heating the flow reactor, thereby demonstrating that highly efficient heat transfer in flow is likely the main factor improving regioselectivity (Scheme 3, substrate 12). We were hopeful that our flow reaction would be efficacious enough for nonterminal diazo reagents, for which there are currently very few examples, all of which suffer from poor selectivity.11c,12g,13 We found that reaction of anisole with phenyl diazoacetate 15 in the presence of several RhII catalysts produced only diazo dimerization products (Table 2). We then considered that commercially available chiral RhII catalysts,14 used for asymmetric cyclopropanations with disubstituted diazo substrates, might facilitate the desired reaction and at the same
the presence of the Davies’ Rh2(R-PTAD)4 17 (0.5 mol %) under standard reaction conditions afforded 3-CHT 20 as a single regioisomer with excellent enantioselectivity. Other known chiral Rh(II) catalysts15,16 were also successful, but Rh2(R-PTAD)4 (17) was the most effective (Table 2, entries 5−7). We proceeded to explore the scope of the disubstituted diazo esters in this reaction, beginning with the modification of the diazo substituent. Reaction of EDA with 1,4-dimethoxybenzene proceeded in good yield but low enantioselectivity (10). Reaction of diazopropionate with anisole to give 21 proceeded in moderate yield and enantioselectivity, which is to be expected given the nature of the paddlewheel D2-symmetric catalyst.15 However, upon investigating the effect of different aryl diazo esters, we observed moderate to high yields and consistently high levels of enantioselectivity (22−26). The effect of the ester substituent on the enantioselectivity was minor when changing to a methyl ester (27). We also found that the reaction’s enantioselectivity with diazo propionate can be improved to 89% by using the tert-butyl ester (28). Finally, we chose to investigate how the asymmetric reaction would perform with nonsymmetric arenes. When the reaction was carried out with o-methylanisole in the presence of phenyl diazoacetate ordiazo propionate we observed a single regioisomer (out of a possible six regioisomers). Phenyl diazoacetate proceeded in good yield (81%) and excellent ee (96%) to provide CHT 29. Reaction with diazopropionate afforded CHT 30 in good yield (60%), but with diminished enantioselectivity (21%). In conclusion, we have developed an efficient and selective intermolecular Buchner reaction using flow chemistry to overcome prevalent issues of regioselectivity. We have demonstrated a promising scope of both arene substrates and diazo reaction partners and a preliminary understanding of reagent and catalyst pairings that affect both conversion and selectivity of the reaction. We have also demonstrated, by utilizing the Davies’ PTAD RhII catalyst, that phenyl diazoacetate and diazopropionate are excellent substrates for the reaction and that moderate to high enantioselectivities are possible. Together, these results provide a promising foundation for developing the intermolecular Buchner as an effective tool in synthesis.
Table 2. Investigation of Reaction of Disubstituted Diazo Substrates
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(12) (a) Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. - Eur. J. 2015, 21, 2298−308. (b) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502−19. (c) Finelli, F.; Miranda, L. S. d. M. e.; de Souza, R. O. M. A. Chem. Commun. 2015, 51, 3708. (d) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675−680. (e) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17−57. (f) Yoshida, J.; Takahashi, Y.; Nagaki, A. Chem. Commun. 2013, 49, 9896−9904. (g) Zhang, Z.; Feng, J.; Xu, Y.; Zhang, S.; Ye, Y.; Li, T.; Chen, J.; Zhang, Y.; Wang, J. Synlett 2015, 26, 59−62. (13) Perez, P. J.; Diaz-Requejo, M. M.; Rivilla, I. Beilstein J. Org. Chem. 2011, 7, 653−657. (14) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437−3440. (15) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545− 555. (16) Deng, Y.; Qui, H.; Srinivas, H. D.; Doyle, M. P. Curr. Org. Chem. 2016, 20, 61−81.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02537. Experimental procedures, detailed flow chemistry setup, and characterization for all new compounds described herein (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
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Aaron B. Beeler: 0000-0002-2447-0651 Notes
NOTE ADDED AFTER ASAP PUBLICATION Scheme 4a and structure 19 in Table 2 were corrected on October 6, 2017.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from Boston University is gratefully acknowledged. We thank Dr. Norman Lee (Boston University) for high-resolution mass spectrometry data. NMR (CHE-0619339) and MS (CHE- 0443618) facilities at Boston University are supported by the NSF.
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REFERENCES
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