An Efficient and Waste-Minimized One-Pot Procedure for the

Institute of Chemistry, The Hebrew University, Edmond Safra Campus, Givat Ram, 91904 Jerusalem, Israel. Org. Process Res. Dev. , 2016, 20 (2), pp 474â...
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An Efficient and Waste-Minimized One-Pot Procedure for the Preparation of N-Boc-γ‑amino Alcohols Starting from α,βUnsaturated Ketones in Flow Eleonora Ballerini,† Raimondo Maggi,‡ Ferdinando Pizzo,† Oriana Piermatti,† Dmitri Gelman,*,§ and Luigi Vaccaro*,† †

Laboratory of Green Synthetic Organic Chemistry, CEMIN − Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia Via Elce di Sotto 8, 06123 Perugia, Italy ‡ “Clean Synthetic Methodology Group”, Dipartimento di Chimica, Università degli Studi di Parma, Parco Area delle Scienze 17A, 43124 Parma, Italy § Institute of Chemistry, The Hebrew University, Edmond Safra Campus, Givat Ram, 91904 Jerusalem, Israel S Supporting Information *

ABSTRACT: We report herein a clean multistep flow process that starting from α,β-unsaturated ketones 1 allows the preparation of N-Boc-γ-amino alcohols 3 in high yields. The final products have been isolated in pure form without any additional purification step. The cleanness and environmental efficiency achieved using our protocol are proven by the calculation of green metrics such as E-factors.



INTRODUCTION The term green/sustainable chemistry has been often used in several areas to introduce the efforts of academic and industrial scientists toward the development of new tools to access cleaner and more efficient chemical production by also considering the corresponding environmental impact.1,2 In this scenario, the strategic role of scientists from both industry and research institutions is evident, as they should be able not only to develop new safer chemical tools but also to reach common economic interests in keeping the production highly efficient and environmentally sustainable. Great attention must be paid to waste production and, accordingly, to the use of green metrics that allow a better evaluation of all of the features of a synthetic procedure.3 Among these, one of the simplest and most effective metrics is the environmental factor (E-factor) introduced by Sheldon.4 This simple value is the ratio of the number of kilograms of waste produced to the number of kilograms of desired product, and it gives an immediate idea of how elegant and complex chemistry may result in a highly environmentally costly process. According to the work of Andraos, this factor can be further divided into its components for a better evaluation of the results.3a,d In modern chemical production of fine chemicals, technological advances may be truly helpful to define a more productive synthetic route and to enhance both the chemical and economic efficiency. In this context, the definition of chemical processes in flow represents an important tool for the replacement of classic reactor schemes based on stirring that may open novel routes toward the identification of modern protocols to develop highly efficient chemistry.5 Besides the undoubted innovative contribution of flow chemistry for the definition of novel reaction windows, the adoption of flow may also be of great advantage for designing novel approaches to © 2015 American Chemical Society

batchlike reactors that allow different and unique chemical outcomes to be reached.5f Flow conditions may also offer a safe alternative to batch processes whenever dangerous/unstable intermediates/reagents are involved in a chemical process. In this contribution, we report the results obtained by exploiting flow mixing for the definition of a clean and sustainable protocol for the preparation of N-Boc-γ-amino alcohols, known as valuable fine chemicals. γ-Amino alcohols are interesting compounds because they are common motifs in many natural products and biologically active molecules and are precursors of β-amino acids, β-lactams, and pyrrolidines.6 They also are useful as chiral ligands and auxiliaries.7 Racemic γamino alcohols have been synthesized by reductions of β-amino ketones8 or β-hydroxy imines and oximes,9 by the addition of organometallic reagents to β-amino aldehydes and ketones,10 and by borylation−reduction−oxidation of unsaturated imines.11 A large number of target molecules, including βamino acids, γ-amino alcohols, pharmaceuticals, and natural products,12 have been synthesized starting from β-amino carbonyl compounds.13 These versatile intermediates can be prepared by conjugate addition of a nitrogen nucleophile (e.g., N3−) to α,β-unsaturated ketones, and an useful method for the selective introduction of a primary amino group is represented by the addition of the azido ion and its subsequent reduction.14 Within the context of our research devoted to the development of eco-friendly protocols based on the use of supported organocatalysts15 and the use of safer reaction media such as water16 and solvent-free conditions (SolFC),17,18 we Special Issue: Continuous Processing, Microreactors and Flow Chemistry Received: May 26, 2015 Published: July 15, 2015 474

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have previously reported two alternative protocols for the βazidation of α,β-unsaturated ketones 1 based on the use of recoverable Amberlite IRA900F (Amb-F) as the catalyst under SolFC18 and of recoverable PS-DABCOF2 as the catalyst in water.15h The proposed protocols allowed the preparation of βazido ketones 2 with minimal production of waste (low Efactors). In addition, to further manipulate the intermediate β-azido ketones 2, we have defined a procedure for the one-pot reduction of the azido group that allows the multistep one-pot preparation of β-amino ketones. Exploiting the use of batchlike flow mixing reactors enabled the optimization of the azido group reduction of 2 and concomitant amino group protection with the use of Pd/Al2O3 (5 mol %) and an equimolar amount of HCOOH as the reducing system in the presence of 1 equiv of Boc2O as the protective agent. In this manner, a multistep flow mixed reactor system has been set to combine the βazidation and azido group reduction steps in aqueous media to prepare N-Boc-β-amino ketones.15h,19 While this approach is useful for reducing the azido group of the β-azido ketones, it does not provide a suitable method for accessing γ-amino alcohols 3 starting from unsaturated ketones 1 by the concomitant reduction of both the azido and keto groups. For this reason, we directed our attention to other reductive systems that can reduce both functionalities of βazido ketones 2. As the reductive system we selected CoCl2· 6H2O/NaBH4, which previously was successfully used for the first time by our research group for the chemoselective reduction of azides in water.20,21 Critical issues regarding its use on larger scales are related to the very fast reaction of borohydrides, which decompose to form hydrogen when in contact with a metal salt or its corresponding metal boride, producing high volumes of gas in a very short time.21 This makes its use in flow very challenging although interesting. As a continuation of our interest in the use of flow approaches to reduce waste, in this contribution we report our results on the use of CoCl2·6H2O/borohydride as an efficient reductive system that can be used in flow to promote the reduction of both the azido and keto groups of β-azido ketones 2. Toward this aim, we have investigated the definition of a waste-minimized multistep flow procedure for the preparation of N-Boc-γ-amino alcohols 3 based on β-azidation of α,βunsaturated ketones 1 and subsequent reduction/protection of β-azido ketones 2 (Scheme 1).

Scheme 2. β-Azidation of α,β-unsaturated ketones 1

Table 1. Screening of the catalyst and medium in the reduction reaction of 2a

entry

catalyst (10 mol %)

mediuma

yield (%)

1 2 3 4 5 6 7d 8d

CuCl2·2H2O NiCl2·6H2O CoCl2·6H2O CoCl2·6H2O CoCl2·6H2O CoCl2·6H2O CoCl2·6H2O CoCl2·6H2O

H2O H2O H2O H2O/MeOHc EtOH MeOH EtOH MeOH

mixb mixb 90 89 92 91 90 90

a

1 M. bComplex mixture of products. cH2O:MeOH = 2:1. d2.5 equiv of NaBH4 was used.

one (2a) and concomitant in situ selective N-Boc protection of the resulting amino group. Table 1 presents the results. Some metal salts such as CuCl2 and NiCl2 were not effective in achieving the conversion of β-azido ketone 2a into the corresponding N-Boc-γ-amino alcohol 3a (entries 1 and 2). However, CoCl2·6H2O/NaBH4 effectively promoted the reduction in different reaction media, such as water, ethanol, water/methanol, and methanol, at room temperature with short reaction times (entries 3−6). In the presence of this catalytic system, the reduction proceeded well with 3 and also with 2.5 equiv of NaBH4 (entries 7 and 8). It should be noticed that when treated with NaBH4 in protic solvents, cobalt(II) salts uniformly produce the corresponding borides, which are the actual catalytic active species. Different cobalt(II) salts lead to different types of borides, and generally, chloride afford the most effective boride for hydrogen production.20,21 When CoCl2 is treated with NaBH4 in EtOH or MeOH for 10 min, a finely dispersed Co(B) compound is formed. This compound is an air-stable black solid that can be easily isolated by filtration. The formula of Co(B) is not precisely defined, and it is known that boron is present at different oxidation states. 21 (Caution! Co(B) becomes pyrophoric when dried under vacuum.21) From these data, we then investigated the possibility of a multistep protocol for the synthesis of N-Boc-γ-amino alcohols 3a−g starting from α,β-unsaturated ketones 1a−g, focusing on the amount of organic solvent needed to isolate the final products in order to minimize waste. We directed our attention to the use of flow mixing as an alternative to classic mechanical stirring and as an effective approach for the optimal recovery and reuse of heterogeneous catalysts while preserving their chemical and physical stability and also their chemical efficiency. In our process, a major issue that made the definition of a flow procedure difficult is the very fast production of H2 gas when a NaBH4 solution comes into contact with Co(B). In addition, clogging of the system occurred because of the

Scheme 1. Multistep procedure for the synthesis of N-Boc-γamino alcohols



RESULTS AND DISCUSSION β-Azido ketones 2 were synthesized starting from α,βunsaturated ketones 1 by means of our previously reported procedure18 using trimethylsilyl azide (TMSN3) as the source of azido ions and Amb-F as the catalyst under SolFC (Scheme 2). Preliminary studies (Table 1) were directed to the selection of the best catalyst as well as reaction conditions for the reduction of the representative β-azido ketone 4-azidoheptan-2475

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inevitable precipitation of inorganic salts during the decomposition of NaBH4 to give hydrogen. Direct translation of the results obtained in Table 1 into flow conditions was unsuccessful. Therefore, we extended the study to different reducing agents that could allow the reaction to be performed in flow and avoid clogging of the reactor. We performed the flow reduction of 2a in the presence of reducing agents such as sodium cyanoborohydride (NaBH3CN), tetrabutylammonium borohydride ([CH3(CH2)3]4NBH4), and tetramethylammonium borohydride ((CH3)4NBH4). The results are reported in Table 2. Table 2. Reduction in flow of 2a with different hydrides Figure 1. Schematic of the reactor for the synthesis of N-Boc-γ-amino alcohols 3. entrya

borohydride (equiv)

yield (%)

1 2 3 4 5 6

NaBH3CN (2.5) [(CH3(CH2)3]4NBH4 (2.5) (CH3)4NBH4 (2.5) (CH3)4NBH4 (2.4) (CH3)4NBH4 (2.2) (CH3)4NBH4 (2.1)

85 85 85 83 84b mixb

to transfer the product 2 into the reservoir and empty the AmbF column. To completely wash the Amb-F column, some ethanol (0.1 mL/mmol) was pumped from the air/solvent valve and collected in the reservoir as well. Melted Boc2O (1 equiv) was added into the reservoir containing intermediate azido ketone 2. At this point, (CH3)4NBH4 was charged as a solution of tetramethylammonium borohydride in ethanol. Two pumps were run in order to simultaneously direct the two ethanol solutions (one of the β-azido ketone 2 and Boc2O and the other of (CH3)4NBH4) through the Co(B) column at a flow rate of 0.5 mL min−1 for the time necessary to reach complete formation of 3. The pump connected to the reservoir was then left to run in order to recover again the overall reaction mixture. Then additional EtOH was added from the air/solvent valve to wash the catalyst and then collected into the reservoir; the solution of the product in ethanol was transferred into a continuous liquid/liquid extraction apparatus, and product 3 was continuously extracted with immiscible heptane (10 mL) and, after phase separation, was isolated in pure form in high yield. EtOH and heptane were recovered by simple distillation. A variety of α,β-unsaturated ketones 1a−g were successfully screened to afford the corresponding N-Boc-γ-amino alcohols 3a−g in good to excellent yields. Table 3 shows the results obtained. As expected, 3a and 3b were obtained in an almost 1:1 syn/anti diastereomeric ratio (entries 1 and 2), while in the case of 3g prevalent formation of the syn product was observed (entry 7). In the case of 1d−f, the cis diastereomers of the corresponding γ-amino alcohols 3d−f were preferentially formed (entries 4−6), and in the case of 3f, the trans isomer could not actually be detected. In the case of 1e, β-azidation proceeded with the formation of a 60:40 trans/cis mixture of βazidoketone 2e, and subsequent reduction produced the corresponding isomers (1S,2R,4R)/(1S,2S,4R) in a 78:22 ratio and (1R,2S,4R)/(1R,2R,4R) in a 98:2 ratio, respectively (entry 5). After the reduction step, Co(B) was washed with a small amount of ethanol. Both catalysts, safely conserved in their glass columns could be was successfully reused in flow for additional four consecutive runs without observing any decrease in their efficiency. It should be noticed that a comparison with a larger-scale protocol in batch using classic mechanical stirring cannot be properly conducted because on a 10−50 mmol scale mechanical stirring causes the crunching of both catalytic

a

Reaction conditions: EtOH, r.t., 30′. bIn the absence of Co(B), 20% unreacted starting material 2a was recovered. In all the cases 3a was isolated with a syn/anti ratio of 53:47.

With all of the hydrides used, the process proceeded with total conversion to the desired product, and no precipitate was formed during the reaction. At the end of the reduction step, only when (CH3)4NBH4 was used as the hydride source (entry 3) could the product be efficiently isolated from the ethanolic reaction mixture by heptane extraction. In addition, we attempted to reduce the amount of hydride used (entries 3− 6). We found that the reduction of 2a in EtOH using 10 mol % CoCl2·6H2O in the presence of 2.2 equiv of (CH3)4NBH4 and 1.0 equiv of Boc2O afforded the desired N-Boc-γ-amino alcohol 3a in 84% yield (entry 5). To deal with gas evolution, optimal results were obtained by setting a purge valve at 2.5 atm to regulate the reactor pressure. Starting from these optimized conditions, we defined the one-pot multistep flow protocol for the β-azidation/hydride reduction of α,β-unsaturated ketones 1. A schematic of the reactor for the preparation of pure N-Bocγ-amino alcohols 3 in high yield is depicted in Figure 1. It is worth highlighting again that the reactor operating with flow mixing also allows the preservation of the integrity (chemical and physical) of the solid catalysts (Amb-F and Co(B)), making their recovery and reuse straightforward and efficient. The flow reactor was assembled by setting up two different lowpressure glass columns, labeled as “Amb-F” and “Co(B)” in Figure 1. On a representative scale of 50 mmol, reactant 1 and TMSN3 (1.1−3.0 equiv) were charged into a third column used as a reservoir. The equipment was connected to a pump using the appropriate valves and installed in a thermostated box (not shown in Figure 1 for clarity). After the temperature was set (30−60 ◦C, according to the βazidation step requirements for substrates 1a−g), the reactants were pumped continuously through the Amb-F catalyst at a flow rate of 1 mL min−1 for the time necessary to complete the β-azidation step. After this time, the air/solvent valve was opened, and the pump was set to work at 5 mL min−1 in order 476

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Table 3. Multistep synthesis in flow of N-Boc-γ-amino alcohols 3a−g

of all of the reagents used (including solvents at all stages). We calculated several representative parameters of green metrics, including overall percent yield, overall atom economy (AE),24 overall E-factor4 and its components, and process mass intensity (PMI).3d The data are reported in the Supporting Information. The quantitative influence of the recovery of the solvents used for the reaction and the workup (ethanol and heptane) on the E-factor values is clearly visible. The overall Efactor values for the different substrates ranged from 2.02 to 6.58 (see the Supporting Information for details). The flow approach allowed the use of the minimal amount of organic solvent to recover the pure final products and consequently reduced the reaction waste, resulting in low values of E-aux and E-total. A tentative comparison of our synthetic strategy with already published protocols for the synthesis of racemic N-Boc-γ-amino alcohols 3 is reported in the Supporting Information.



CONCLUSIONS

We have reported an efficient and clean multistep process performed using a flow reactor that, starting from α,βunsaturated ketones 1, allows N-Boc-γ-amino alcohols 3 to be produced in high yields. The final products have been isolated in pure form without any additional purification step. The easy availability of the reducing system and the possibility to recycle the catalysts make this procedure attractive and advantageous. Furthermore, this is the first time that the CoCl2·6H2O/ Me4NBH4 system has been used to catalyze a reaction under flow conditions. The combination of SolFC for the first reaction step (β-azidation), highly concentrated conditions for the second reaction step (azido group reduction), and recoverable solid catalysts, together with the flow mixing technology, represents an interesting practical example of how promising the flow approach is for minimizing the environmental cost of organic syntheses.

a

Unless otherwise indicated, syn/anti or cis/trans ratios were determined by GC−MS analyses. bIsolated yields of the pure products. cCis/trans ratio as determined by 1H NMR analysis. d From the reduction of the 60:40 trans/cis mixture of β-azido ketone 2e, the corresponding isomers (1S,2R,4R)/(1S,2S,4R) and (1R,2S,4R)/(1R,2R,4R) were obtained in ratios of 78:22 and 98:2 ratio, respectively. eSee ref 22.



EXPERIMENTAL SECTION Unless otherwise stated, all of the chemicals were purchased and used without any further purification. GC analyses were performed using a Hewlett-Packard HP 5890A gas chromatograph equipped with a DB-35MS capillary column (30 m, 0.53 mm), a flame ionization detector, and hydrogen as the carrier gas. GC−EI-MS analyses were carried out using a HewlettPackard HP 6890N Network GC system/5975 mass selective detector equipped with an electron impact ionizer at 70 eV. N-Boc-γ-amino alcohols 3a, 3b, 3c, 3d, 3e, and 3g are new compounds, while 3f is a known compound.23 Characterization data are reported in the Supporting Information. Representative Batch Procedure for β-Azidation and Subsequent Reduction of α,β-Unsaturated Ketones 1a− g. In a screw-capped vial equipped with a magnetic stirrer, Amberlyst-F (10 mol %, 0.026 g), (E)-hept-3-en-2-one (1a) (1 mmol, 0.112 g) and TMSN3 (1.1 mmol, 0.146 mL) were consecutively added. The resulting mixture was left under stirring at 60 °C for 2.5 h to reach the complete conversion to 4-azidoheptan-2-one (2a). Then ethyl acetate was added, and the catalyst was recovered by filtration and washed with ethyl acetate. The solvent was removed under vacuum to furnish 2a. Next, in a screw-capped vial equipped with a magnetic stirrer, CoCl2·6H2O/NaBH4 (CoCl2·6H2O, 0.049 g, 0.09 mmol; NaBH4, 0.0068 g, 0.18 mmol), ethanol (0.9 mL), 2a, and Boc2O (0.196 g, 0.9 mmol) were consecutively added; then

systems (the organic polymer Amb-F and the inorganic compound Co(B)). The finely dispersed catalysts cannot be easily filtered and then completely recovered even after the first reuse. The reactions in flow were performed on 50 mmol scale, and it is noteworthy that this is only a minimal representative scale. In fact, on a larger scale the flow protocol can be intensified and is even more efficient in terms of waste because the organic solvent needed for cleaning the reactor system (columns, pumps, connectors, and tubes) and recovering the product can be proportionally reduced. The procedure can easily be scaledup without significant changes in the equipment except the sizes of the columns containing the reactants and catalysts. Reproducibility of the results on different scales is closely dependent on gas evolution and exothermic phenomena. Our results were obtained at a hydrogen pressure of 2.5 atm with measurements of the actual temperature of the catalyst columns to regulate the heating of the thermostated box. Finally, after the completion of an optimization, the cleanness and efficiency of the process must be carefully evaluated by using appropriate metrics to measure the masses 477

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Notes

NaBH4 (0.085 g, 2.25 mmol) was slowly added, and the resulting mixture was left under stirring at room temperature. After 30 min, the catalyst was recovered by filtration and washed with ethanol (0.5 mL). Water (1 mL) was added to the reaction mixture, and then AcOEt (7 mL) was added to extract the pure product. The organic phase was dried with Na2SO4 (2.5 g), and the solvent was removed under vacuum to furnish tert-butyl 2-hydroxyheptan-4-ylcarbamate (3a) in 84% yield (0.194 g, 0.84 mmol). Representative Flow Procedure for Multistep βAzidation/Reduction of α,β-Unsaturated Ketones 1a−g. (E)-Hept-3-en-2-one (1a) (50 mmol, 5.608 g) and TMSN3 (55 mmol, 7.3 mL) were charged into a glass column functioning as a reservoir. Amberlyst-F (10 mol %, 1.316 g), suitably dispersed in 1 mm diameter solid glass beads, was charged into a glass column; the equipment was installed in a thermostated box and connected to a pump using appropriate valves. The reaction mixture was continuously pumped (flow rate 1.0 mL min−1) through the catalyst column at 60 °C for 2.5 h to reach the complete conversion to 4-azidoheptan-2-one (2a). At this stage, the pump was left to run in order to recover the reaction mixture into the reservoir. To completely recover the product and clean the reactor, ethanol (2 × 2.5 mL at 1.5 mL min−1) was cyclically pumped through the catalyst column for 10 min (each fraction) and then collected in the reservoir. Two columns labeled as Co(B) and (CH3)4NBH4 were prepared. The first column was charged with cobalt boride previously prepared from CoCl2·6H2O (10 mol %, 1.19 g) and NaBH4 (2 equiv with respect to CoCl2·6H2O, 0.378 g), suitably dispersed in 1 mm diameter solid glass beads; the second one was charged with (CH3)4NBH4 (110 mmol, 9.79 g) dissolved in EtOH (10 mL) and connected to a syringe pump using appropriate valves. Melted Boc2O (50 mmol, 10.91 g) was pumped into the reservoir. The two pumps were run in order to continuously push the solution of β-azido ketone and Boc2O and the solution of borohydride through the catalyst column at a flow rate of 0.5 mL min−1 for the time necessary (20 min) for the complete conversion to tert-butyl 2-hydroxyheptan-4ylcarbamate (3a). At this stage, the pump was left to run in order to recover the reaction mixture into the reservoir. Then EtOH (2 × 2.5 mL at 1.5 mL min−1) was added from the air/ solvent valve to wash the catalyst and then was collected into the reservoir. The solution of product in ethanol was transferred into a continuous liquid/liquid extraction apparatus, and the product was continuously extracted with heptane (10 mL) to afford pure 3a in 84% yield (42 mmol, 9.702 g). With this procedure the catalysts were left inside the reactor and were successfully reused for five consecutive runs, achieving identical results.



The authors declare no competing financial interest.



ACKNOWLEDGMENTS We gratefully acknowledge the Università degli Studi di Perugia, and the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) for financial support.



(1) Linthorst, J. A. Found. Chem. 2010, 12, 55. (2) Pollution Prevention Act of 1990; U.S. Government Printing Office: Washington, DC, 1995; p 617. (3) (a) Andraos, J. Org. Process Res. Dev. 2009, 13, 161. (b) Ravelli, D.; Protti, S.; Neri, P.; Fagnoni, M.; Albini, A. Green Chem. 2011, 13, 1876. (c) Jimenez−Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912. (d) Andraos, J. Org. Process Res. Dev. 2012, 16, 1482. (4) (a) Sheldon, R. A. Chemtech 1994, 24, 38. (b) Sheldon, R. A. Chem. Ind. 1997, 12. (c) Sheldon, R. A. Chem. Commun. 2008, 3352. (d) Augè, J. Green Chem. 2008, 10, 225. (5) (a) Anderson, N. G. Org. Process Res. Dev. 2012, 16, 852. (b) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. ChemSusChem 2013, 6, 746. (c) Yoshida, J.; Takahashi, Y.; Nagaki, A. Chem. Commun. 2013, 49, 9896. (d) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849. (e) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384. (f) Vaccaro, L.; Lanari, D.; Marrocchi, A.; Strappaveccia, G. Green Chem. 2014, 16, 3680 and references cited therein. (6) (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353. (b) Kozikowski, A. P.; Chen, Y.-Y. J. Org. Chem. 1981, 46, 5248. (c) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465. (d) Knapp, S. Chem. Rev. 1995, 95, 1859. (e) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc. 1997, 119, 4112. (f) Carlier, P. R.; Lo, M. M.-C.; Lo, P. C.-K.; Richelson, E.; Tatsumi, M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med. Chem. Lett. 1998, 8, 487. (g) Benedetti, F.; Norbedo, S. Chem. Commun. 2001, 203. (7) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767. (8) (a) Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985, 50, 4052. (b) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1 1990, 1213. (c) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. J. Org. Chem. 1992, 57, 1219 and references cited therein.. (d) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131. (9) (a) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn. 1986, 59, 525. (b) Veenstra, S. J.; Kinderman, S. S. Synlett 2001, 2001, 1109. (c) Williams, D. R.; Osterhout, M. H. J. Am. Chem. Soc. 1992, 114, 8750. (10) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665. (11) Calow, A. D. J.; Whiting, A. Org. Biomol. Chem. 2012, 10, 5485− 5497. (12) (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (c) Bandala, Y.; Juaristi, E. Amino Acids, Peptides and Proteins in Organic Chemistry; Wiley-VCH: Weinheim, Germany, 2009. (13) (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Torregiani, E. J. Org. Chem. 2005, 70, 169. (b) Enders, D.; Wang, C.; Liebich, J. X. Chem. - Eur. J. 2009, 15, 11058. (c) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319. (d) Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2004, 45, 4507. (14) (a) Organic Azides: Syntheses and Applications; Bräse, S., Banert, K., Eds.; John Wiley & Sons: Chichester, U.K., 2010. (b) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem. 2005, 117, 5320;(c) Angew. Chem., Int. Ed. 2005, 44, 5188. (d) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297. (15) (a) Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Green Chem. 2010, 12, 1301. (b) Zvagulis, A.; Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Adv. Synth. Catal. 2010, 352, 2489. (c) Lanari, D.; Ballini,

ASSOCIATED CONTENT

S Supporting Information *

Full characterization of compounds 3a−g and copies of the 1H and 13C NMR spectra. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00163.



REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*Fax: +39 075 5855560. Tel: +39 075 5855541. E-mail: luigi. [email protected]. *E-mail: [email protected]. 478

DOI: 10.1021/acs.oprd.5b00163 Org. Process Res. Dev. 2016, 20, 474−479

Organic Process Research & Development

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DOI: 10.1021/acs.oprd.5b00163 Org. Process Res. Dev. 2016, 20, 474−479