DOI: 10.1002/chem.201402092
Communication
& Organic Synthesis
Multicomponent, Flow Diazotization/Mizoroki–Heck Coupling Protocol: Dispelling Myths about Working with Diazonium Salts Kumara S. Nalivela,[a] Michael Tilley,[a] Michael A. McGuire,*[b] and Michael G. Organ*[a] and quench diazonium salts long before it became fashionable to use such technology.[3] The idea here is to make tiny quantities of the salt at any one point in time and react them immediately; continuous operation of the microreactor allows the product to accrue over time. One interesting application of diazonium salts pioneered by Matsuda[4] was as the oxidative addition partner in Mizoroki– Heck coupling.[5] Recently, flow technology has been used to address the issue of diazonium salt safety while taking advantage of the reactivity of these high-energy intermediates in this application.[6] Wirth and co-workers have developed a segmented flow strategy to produce styrene products in yields that ranged from 18 to 90 %, although the average yield was ~ 50 %.[7] Like other flow protocols in the literature involving diazonium salts,[6] oxidation was conducted separately at 0 8C and then the subsequent reaction components, Pd and the alkene in this case, were teed into this stream and reacted at room temperature. The authors hypothesized that higher yields might be obtained with pre-formed, pure diazonium salts and by using them directly in the flowed cross-coupling, but the average yield only improved marginally to 55 %. We have no doubts that the diazotization in the Wirth study was very efficient and complete by the time the salt entered the cross-coupling reactor zone, which is what the authors concluded. While no description of the mass balance of these reactions was provided in their report, we suspect that hydrodediazotization was taking place, which could be overlooked due to reduced polarity or volaltility of the aromatic by-products. Further, we believe that the rate of this process, relative to the desired cross-coupling, may in fact be concentration dependent. In the Wirth study, whether the diazotization was done in-line, or the pure diazonium salt was used directly from the outset, the same concentration of salt would be entering the cross-coupling reactor zone of their flow set up. Given the attractiveness of this diazatization/cross-coupling sequence, we felt that we could make this sequence more practical to implement if the process was better understood. Consequently we undertook an investigation of the diazotization process itself, diazonium salt stability, the salt decomposition products, their formation, and how these factors impact on the Pd-catalysed Mizoroki–Heck reaction. The first thing that we envisioned would aid in the creation of a streamlined flow diazotization/cross-coupling sequence is to see if cooling could be avoided during diazotization as it is detrimental to the cross-coupling. Consequently, we prepared 2 both at 0 and 23 8C (room temperature) and followed its formation by 1H NMR spectroscopy (Figure 1). The reaction in the
Abstract: A single pass flow diazotization/Mizoroki–Heck protocol has been developed for the production of cinnimoyl and styryl products. The factors that govern aryl diazonium salt stability have been examined in detail leading to the development of a MeOH/DMF co-solvent system in which the diazonium salts can be generated in the presence of all other reaction components and then coupled selectively to give the desired products. Finally the key role of the reaction quench for flow reactions has been demonstrated.
High-energy intermediates possess sufficient potential energy to react spontaneously with generally low transition state barriers. This makes their use in chemical synthesis, at least from a conceptual point of view, attractive because reactions involving them are likely to be fast and not require heat. However, this energetic behaviour also has a serious drawback in that such compounds are typically unstable and have the potential to react uncontrollably or even explosively. Diazonium salts and azides are two such compounds the use of which in synthesis is attractive on paper, but are rarely used on a synthetically useful scale.[1] Diazonium salts are derived from the corresponding anilines that are widely available commercially or generated by reduction of the corresponding nitroarene, which may serve as a protected amine in a synthetic route.[2] The oxidation process to make the diazonium salt, known as diazotization, is very facile and generally only requires a few minutes at 0 8C. Once in hand, the diazonium salt can be readily converted into a plethora of diverse functionalities including diazos, phenols and halides.[3] Given the rich chemistry that can be accessed by using these versatile compounds, it is not surprising that many people have investigated how to use them in safer and more sustainable ways. Microscale flow chemistry was used to make
[a] Dr. K. S. Nalivela, M. Tilley, Prof. M. G. Organ Department of Chemistry, York University 4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada) E-mail: [email protected] [b] Dr. M. A. McGuire GlaxoSmithKline Pharmaceuticals Inc. 709 Swedeland Road PO Box 1539, UMW 2810, King of Prussia PA 19406, (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402092. Chem. Eur. J. 2014, 20, 1 – 6
These are not the final page numbers! ÞÞ
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication
Scheme 1. Batch diazotization/Mizoroki–Heck sequence in either straight DMF or MeOH/DMF at 0 8C and at RT.
in DMF after 30 min and warmed to RT (Scheme 1). In DMF (Scheme 1a), no coupled product was observed, only dediazotization (3). However, when diazotization was carried out in MeOH (Scheme 1b) no reduction occurred and full conversion to 6 took place. When the same reaction was repeated but now the diazotization was performed at RT (Scheme 1c), half of the salt was reduced and the other half coupled. Of course, this could mean a number of things. Solubility could be important or the cooler initial temperature when the two solutions are first mixed suppresses reduction in favour of coupling and that the Mizoroki–Heck reaction finishes fast enough to avoid reduction of 2 as the mixture reaches room temperature. With a better understanding of the role and inter-relationship of solvent and temperature, we set out initially to develop a high-yielding two-step flow sequence. The flow diagram of the device assembled for this task is shown in Scheme 2.[10]
Figure 1. Temperature study for diazotization in methanol and DMF. a) Nitrodiazonium salt (2) in CD3OD at 0 8C after 30 min. b) Salt 2 in CD3OD at RT after 60 min. c) Sample in (b) after an additional 48 h at RT. Reduction of 2 produces 2-deuteronitrobenzene ([D1]3) in which the deuterium comes from the CD3OD. d) Salt 2 in [D7]DMF at 0 8C after 30 min. e) Sample in (d) after 2.5 h at RT, showing complete reduction of 2 to [D1]3. f) Salt 5 in DMF after 48 h at RT.
ice bath worked nicely in CD3OD as expected (Figure 1a), but it also proceeded cleanly at room temperature (Figure 1b). Further, stirring the mixture at room temperature for 48 h resulted in no visible salt decomposition (Figure 1c). In a separate operation the diazotization was carried out in [D7]DMF, the solvent used in the Wirth study.[7] Again diazotization occurred smoothly at 0 8C; however, after 30 min 50 % deutero-dediazotization (to [D1]3) had occurred (Figure 1d). At this time, a small amount of [Pd(OAc)2] was added to see if this process could be catalysed by Pd, but no significant increase in the rate of dediazotization was observed. After stirring (with or without Pd) for an additional 2.5 h complete reduction to [D1]3 occurred, thus confirming DMF as the hydride source (Figure 1e). The reduction of aryldiazonium salts in DMF has been investigated previously. It was reported that in the presence of promoters, such as Fe[8] or Rh,[9] reduction occurs smoothly, but either nothing occurs without Rh or the transformation takes days.[9] This statement may not be globally true. Rather reduction is substrate dependent and electron-poor examples are more active partners. Indeed, when we formed the 2-methoxy salt 5 in DMF it was stable for at least 48 h (Figure 1f). That reduction occurred extensively with 1, which suggests that the moderate yields (ca. 50 %) of Mizoroki–Heck products in Wirth’s case[7] were the result of salt loss, while sitting in DMF before the Pd and alkene were teed into the flow stream. To further examine the impact of solvent and temperature on the process, we prepared the diazonium salt in methanol or DMF at 0 8C in batch, added the Mizoroki–Heck components &
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
Scheme 2. Optimized two-step flow diazotization/Mizoroki–Heck sequence.
The flow rate into diazotization was kept fixed (6 mL min 1 from each pump) and the residence time was optimized by adjusting the length of the reactor tubing leading the to the residence times indicated. Felpin had demonstrated a necessity for anisole as an additive to stabilize the Pd catalyst in their diazotization/Mizoroki–Heck studies;[11] we used it in earlier runs (e.g., Scheme 1) but observed no deleterious effect of removing it. By conducting the diazotization in MeOH, which appears to stabilize aryldiazonium salts (vide supra), we could enhance the lifetime of 2 when it teed into the DMF cross-coupling solution sufficiently to allow a high yield of coupled product to be obtained (DMF was essential to see any coupling). 2
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Communication With the knowledge that we could now obtain an excellent yield of the desired styryl product using flow, while mitigating salt loss through dediazotization, we refocused our efforts on the establishment of the most streamlined and simple process. If the diazonium salt could be consumed directly as it was produced, we could perform the entire sequence at RT, which was an original key goal of this study. Putting the pieces together, it made sense that we should be able to create what amounts to a ‘one-pot’, multicomponent reaction (MCR) flow process whereby diazotization and cross-coupling occur in an ordered sequence in just one single reactor. To this end we set out to design the reactor and to develop optimal conditions for a generally applicable, high-yielding protocol. Intrigued by the catalytic diazotization/Mizoroki–Heck batch process developed by Felpin and co-workers who used less than one equivalent of acid,[11] we felt that we could reduce the amount of CH3SO3H used to at least 1.0 equivalent. Drawing from our earlier optimization studies for the two-step protocol, we opted to begin with just over two equivalents of nitrite and 2 mol % of [Pd(OAc)2]. The co-solvent system of MeOH/DMF (1:1) would ensure suitable stability of the diazonium salts as they are formed by MeOH, while the DMF solubilized the Pd and facilitated the coupling step. With these reaction parameters confirmed, we set out to optimize flow rate, hence the residence time for the single operation protocol using the reactor design illustrated in Table 1.[12] At 50 mL min 1 good conversion was obtained (Table 1, entry 4), but by 12 mL min 1.conversion was complete, no by-products were observed, and product yield was excellent. With these highly streamlined, one-reactor, MCR flow conditions thus developed, we then set out to see if this protocol was suitable for wider application (Table 2). The impression
Table 2. Scope study for streamlined diazotization Mizoroki–Heck flow reaction.[a]
Entry Aniline
Table 1. Optimization of flow rate and residence time for the diazotization/cross-coupling sequence based on 1H NMR spectroscopic analysis.[a]
Entry
Flow rate[a]
Residence t [min][b]
6 [%]
3 [%]
1 [%]
1 2 3 4 5 6
400 200 100 50 24 12
2.8 5.7 11.5 23.0 48.0 96.0
13 29 61 80 96 100
19 19 16 12 0 0
68 52 23 8 4 0
[a] Syringe 1 was loaded with a methanol solution containing 1 and methyl acrylate while syringe 2 contained MeSO3H, tert-butylnitrite, and [Pd(OAc)2] in DMF. The two solutions were flowed together into one DuPont FEP tube 1152 mL (1/8“ OD 0.06” ID) at RT at the specified flow rate. After traversing the reaction tube, the reaction mixture emptied into a quenching flask containing triethylamine in ethyl acetate (see below). [b] The experiment was started at a flow rate of 400 mL min 1 and decreased until 1H NMR spectral analysis indicated complete consumption of 1.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
These are not the final page numbers! ÞÞ
3
Product (8)
Flow[b] 8/9/7 Yield [%][c]
1
12
1:0:0 90
2
6
1:0:0 87
3
12
1:0:0 92
4
12
1:0:0 95
5
12
1:0:0 93
6
12
1:0:0 80
7
12
1:0:0 98
8
12
1:0:0 92
9
12
1:0:0 91
10
12
1:0:0 96
11
12
1:0:0 93
12
12
1:0:0 95
13
6
1:0:0 90
14
6
5:1:2 51
15
3
1:0:0 79
16
3
1:0:0 81
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication Table 2. (Continued)
Entry Aniline
17
Product (8)
Flow[b] 8/9/7 Yield [%][c]
3
1:0:0 83[d]
[a] Syringe 1 was loaded with a methanol solution containing 1 and methyl acrylate while syringe 2 contained MeSO3H, tert-butylnitrite, and [Pd(OAc)2] in DMF. The two syringes were flowed together into one DuPont FEP tube 1152 mL (1/8 OD 0.06 ID) at RT at the specified flow rate. After traversing the reaction tube, the reaction mixture emptied into a quenching flask containing triethylamine in ethyl acetate. [b] The flow rate reported is in mL min 1. [c] After collecting the effluent from the reactor in the Et3N quenching solution, product was extracted into ether, concentrated, and purified by column chromatography. Yield is based on the volume of the starting material solutions infused after reaching steady state. [d] 5 mol % of [Pd(OAc)2] used.
Scheme 3. Diazotization/Mizoroki–Heck reaction quenching study. [a] CD3OD was used in place of CH3OH/DMF.
ing. While the conditions that are used with tBuONO are anhydrous, one must also remember that diazonium salts are also made using NaNO2 in water,[1] thus they are quite stable in water. To examine the above concerns, a series of control experiments were conducted (see Scheme 3). First, a diazotization solution of 2 in MeOH/DMF (1:1) was added to a flask containing the remaining reactants necessary for the Mizoroki–Heck reaction in an ether/water mixture at RT (Scheme 3a). To mimic the reactions in this report, the mixture was stirred for 4 h and the layers were separated and worked up as usual (e.g., see Table 2). The cross-coupling proceeded to give an 8 % yield of 6 and 54 % when the quenching solution was stirred for 24 h. When the quenching solution contained only water (Scheme 3b), 5 % conversion was attained after 4 h, and 18 % after 24 h. It would appear that reports in the literature using any of these methods to quench the reactor effluent need to be revisited. To ensure that the results derived from the new protocols developed in this manuscript were meaningful, a quenching strategy was developed.[10] It is known that Et3N effectively causes dediazotization,[13, 14] so a quenching solution of Et3N (one equiv relative to 1) in ethyl acetate was created. Diazonium salt 2 was created in batch and added in one shot to the quenching solution and after 60 s a 1H NMR spectrum of the resultant solution was recorded (Scheme 3c).[10] Dediazotization proceeded to approximately 67 %, while addition to a solution containing 2 equiv of Et3N (Scheme 3d) led to complete formation of 3. To confirm that dediazotization in the quenching flask is fast enough to preclude any Mizoroki–Heck coupling from occurring, that is, all diazonium salt is destroyed rapidly, the cross-coupling components were added to the quenching solution (Scheme 3e). This time when 2 was added, zero coupled product was observed confirming that this new quenching strategy is efficient. When the reactions are performed in flow, even with only 1.0 equiv of Et3N present, the flow of effluent is slow enough to ensure that the base is always in vast excess of the diazonium salt to ensure thorough quenching. Thus, the results presented in this manuscript originate solely from what happens in the reactor and the conclusions can be viewed with confidence from that perspective.
that one gets from reading the literature on this protocol is that diazotization is generally favoured by electron-withdrawing groups on the ring and an ortho substituent appears to enhance salt lifetime, presumably due to steric effects.[8, 9] Moving the nitro group to the 4-position and leaving the ortho site empty (8 b) did not adversely impact the process (Table 2, entry 2), although completely removing it did reduce conversion through to coupling (entries 14 and 15). Further, the presence of electron-donating groups were very nicely tolerated (entries 3, 4, 7, 9, 11, and 13). The process also works on styrylbased coupling partners (entry 17). Careful study of the literature involving not only diazonium salt use in flow, but flow chemistry in general indicates that proper control and quenching experiments are not always conducted to support the claims made in the manuscripts. Many authors report flow rates, residence times, and yields that relate to a specific reaction’s performance in the reactor, yet they merely flow the effluent from the reactor into a flask to collect it over the course of hours, or in some cases even days. Unless the reaction requires something affixed to the reactor lumen, for example, a catalyst flow bed, most reactions could simply continue to proceed in the collection vessel. Ironically the controlled contact time of reactants is one of the key features that enables flow chemistry to produce such clean, highyielding and reproducible transformations. Not properly quenching reactor effluent may undo much of what is gained by working in flow in the first place. Consequently, the claims made in a number of flow chemistry reports have yet to be validated. Even flowing effluent into a cooled flask is no guarantee that the reaction has terminated; it must be chemically quenched and validated to be so. In the flow diazonium salt literature, reported ‘quenches’ include flowing reactor effluent into empty chilled flasks, into water, and into a water/ether mixture. As many diazonium salt reactions are actually conducted at 0 8C,[1, 2] it is safe to reject the first quench method straight off. The quenches involving water are equally perplex&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
4
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Communication In this manuscript, we have demonstrated that diazonium salts prepared in MeOH have a considerable lifetime (days), whereas those in DMF undergo significant dediazotization in just 30 min. The multicomponent flowed diazotization/Mizoroki–Heck protocol developed herein uses both of these solvents together to ensure solubility while giving the salt sufficient lifetime to undergo the cross-coupling in high yield. Finally, it is essential to assure effective quenching of the effluent from a flow reactor because the reaction may continue in the collection flask giving rise to potentially erroneous results and conclusions.
[5] a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jap. 1971, 44, 581 – 581; b) R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320 – 2322. [6] a) Z. Yu, Y. Lv, C. Yu, Org. Process Res. Dev. 2012, 16, 1669 – 1672; b) N. Chernyak, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12466 – 12469; c) P. Salice, D. Fenarolie, C. C. De Filippo, E. Menna, G. Gasarini, M. Maggini, chimica oggi/Chemistry Today, 2012, Vol. 30 no. 6 Nov/Dec; d) B. Li, D. Widlicka, S. Boucher, C. Hayward, J. Lucas, J. C. Murray, B. T. O’Neil, D. Pfisterer, L. Samp, J. VanAlsten, Y. Xiang, J. Young, Org. Process Res. Dev. 2012, 16, 2031 – 2035; e) L. Malet-Sanz, J. Madrzak, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 5324 – 5332; f) L. Malet-Sanz, J. Madrzak, R. S. Holvey, T. Underwood, Tetrahedron Lett. 2009, 50, 7263 – 7267; g) R. C. R. Wootton, R. Fortt, A. J. de Mello, Lab Chip 2002, 2, 5 – 7. [7] B. Ahmed-Omer, D. A. Barrow, T. Wirth, Tetrahedron Lett. 2009, 50, 3352 – 3355. [8] F. W. Wassmundt, W. F. Kiesman, J. Org. Chem. 1995, 60, 1713 – 1719. [9] G. S. Marx, J. Org. Chem. 1971, 36, 1725 – 1726. [10] For complete details of this transformation, see the Supporting Information. [11] N. Susperregui, K. Miqueu, J.-M. Sotiropoulos, F. Le Callonnec, E. Fouquet, F.-X. Felpin, Chem. Eur. J. 2012, 18, 7210 – 7218. [12] For complete details and NMR spectra, see the Supporting Information. [13] a) K. V. Kutonova, M. E. Trusova, P. S. Postnikov, V. D. Filimonov, Russian Chem. Bull. Int. Ed. 2012, 61, 206 – 208; b) K. H. Park, Y. H. Cho, Synth. Commun. 1996, 26, 1569 – 1574. [14] For dediazotization studies involving polar additives/solvents, see: a) H. Zollinger, Angew. Chem. 1978, 90, 151 – 160; Angew. Chem. Int. Ed. Engl. 1978, 17, 141 – 150; b) I. Szele, H. Zollinger, Helv. Chim. Acta 1978, 61, 1721 – 1729.
Acknowledgements The authors thank NSERC Canada for support of this research. Keywords: cross-coupling · diazonium salts · flow · Heck reaction · microreactors [1] H. Zollinger, Diazo Chemistry I.; VCH: Weinheim, 1994. [2] a) P. Griess, Liebigs Ann. Chem. 1858, 106, 123 – 125; b) D. T. Flood, Org. Synth. 1943, 2, 295 – 298; c) M. Barbero, M. Crisma, I. Degani, R. Fochi, P. Perracino, Synthesis 1998, 1171 – 1175. [3] R. Fortt, R. C. R. Wootton, A. J. de Mello, Org. Process Res. Dev. 2003, 7, 762 – 768. [4] K. Kikukawa, T. Matsuda, Chem. Lett. 1977, 159 – 162.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
These are not the final page numbers! ÞÞ
Received: February 9, 2014 Published online on && &&, 0000
5
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication
COMMUNICATION & Organic Synthesis K. S. Nalivela, M. Tilley, M. A. McGuire,* M. G. Organ* && – && Multicomponent, Flow Diazotization/ Mizoroki–Heck Coupling Protocol: Dispelling Myths about Working with Diazonium Salts
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
Diazonium salts in flow: A single pass flow diazotization/Mizoroki–Heck protocol has been developed for the production of cinnimoyl and styryl products. The factors that govern aryl diazonium salt stability have been examined in
detail leading to the development of a MeOH/DMF co-solvent system in which the diazonium salts can be generated in the presence of all other reaction components and then coupled selectively (see scheme).
6
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Communication
& Organic Synthesis
Multicomponent, Flow Diazotization/Mizoroki–Heck Coupling Protocol: Dispelling Myths about Working with Diazonium Salts Kumara S. Nalivela,[a] Michael Tilley,[a] Michael A. McGuire,*[b] and Michael G. Organ*[a] and quench diazonium salts long before it became fashionable to use such technology.[3] The idea here is to make tiny quantities of the salt at any one point in time and react them immediately; continuous operation of the microreactor allows the product to accrue over time. One interesting application of diazonium salts pioneered by Matsuda[4] was as the oxidative addition partner in Mizoroki– Heck coupling.[5] Recently, flow technology has been used to address the issue of diazonium salt safety while taking advantage of the reactivity of these high-energy intermediates in this application.[6] Wirth and co-workers have developed a segmented flow strategy to produce styrene products in yields that ranged from 18 to 90 %, although the average yield was ~ 50 %.[7] Like other flow protocols in the literature involving diazonium salts,[6] oxidation was conducted separately at 0 8C and then the subsequent reaction components, Pd and the alkene in this case, were teed into this stream and reacted at room temperature. The authors hypothesized that higher yields might be obtained with pre-formed, pure diazonium salts and by using them directly in the flowed cross-coupling, but the average yield only improved marginally to 55 %. We have no doubts that the diazotization in the Wirth study was very efficient and complete by the time the salt entered the cross-coupling reactor zone, which is what the authors concluded. While no description of the mass balance of these reactions was provided in their report, we suspect that hydrodediazotization was taking place, which could be overlooked due to reduced polarity or volaltility of the aromatic by-products. Further, we believe that the rate of this process, relative to the desired cross-coupling, may in fact be concentration dependent. In the Wirth study, whether the diazotization was done in-line, or the pure diazonium salt was used directly from the outset, the same concentration of salt would be entering the cross-coupling reactor zone of their flow set up. Given the attractiveness of this diazatization/cross-coupling sequence, we felt that we could make this sequence more practical to implement if the process was better understood. Consequently we undertook an investigation of the diazotization process itself, diazonium salt stability, the salt decomposition products, their formation, and how these factors impact on the Pd-catalysed Mizoroki–Heck reaction. The first thing that we envisioned would aid in the creation of a streamlined flow diazotization/cross-coupling sequence is to see if cooling could be avoided during diazotization as it is detrimental to the cross-coupling. Consequently, we prepared 2 both at 0 and 23 8C (room temperature) and followed its formation by 1H NMR spectroscopy (Figure 1). The reaction in the
Abstract: A single pass flow diazotization/Mizoroki–Heck protocol has been developed for the production of cinnimoyl and styryl products. The factors that govern aryl diazonium salt stability have been examined in detail leading to the development of a MeOH/DMF co-solvent system in which the diazonium salts can be generated in the presence of all other reaction components and then coupled selectively to give the desired products. Finally the key role of the reaction quench for flow reactions has been demonstrated.
High-energy intermediates possess sufficient potential energy to react spontaneously with generally low transition state barriers. This makes their use in chemical synthesis, at least from a conceptual point of view, attractive because reactions involving them are likely to be fast and not require heat. However, this energetic behaviour also has a serious drawback in that such compounds are typically unstable and have the potential to react uncontrollably or even explosively. Diazonium salts and azides are two such compounds the use of which in synthesis is attractive on paper, but are rarely used on a synthetically useful scale.[1] Diazonium salts are derived from the corresponding anilines that are widely available commercially or generated by reduction of the corresponding nitroarene, which may serve as a protected amine in a synthetic route.[2] The oxidation process to make the diazonium salt, known as diazotization, is very facile and generally only requires a few minutes at 0 8C. Once in hand, the diazonium salt can be readily converted into a plethora of diverse functionalities including diazos, phenols and halides.[3] Given the rich chemistry that can be accessed by using these versatile compounds, it is not surprising that many people have investigated how to use them in safer and more sustainable ways. Microscale flow chemistry was used to make
[a] Dr. K. S. Nalivela, M. Tilley, Prof. M. G. Organ Department of Chemistry, York University 4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada) E-mail: [email protected] [b] Dr. M. A. McGuire GlaxoSmithKline Pharmaceuticals Inc. 709 Swedeland Road PO Box 1539, UMW 2810, King of Prussia PA 19406, (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402092. Chem. Eur. J. 2014, 20, 1 – 6
These are not the final page numbers! ÞÞ
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication
Scheme 1. Batch diazotization/Mizoroki–Heck sequence in either straight DMF or MeOH/DMF at 0 8C and at RT.
in DMF after 30 min and warmed to RT (Scheme 1). In DMF (Scheme 1a), no coupled product was observed, only dediazotization (3). However, when diazotization was carried out in MeOH (Scheme 1b) no reduction occurred and full conversion to 6 took place. When the same reaction was repeated but now the diazotization was performed at RT (Scheme 1c), half of the salt was reduced and the other half coupled. Of course, this could mean a number of things. Solubility could be important or the cooler initial temperature when the two solutions are first mixed suppresses reduction in favour of coupling and that the Mizoroki–Heck reaction finishes fast enough to avoid reduction of 2 as the mixture reaches room temperature. With a better understanding of the role and inter-relationship of solvent and temperature, we set out initially to develop a high-yielding two-step flow sequence. The flow diagram of the device assembled for this task is shown in Scheme 2.[10]
Figure 1. Temperature study for diazotization in methanol and DMF. a) Nitrodiazonium salt (2) in CD3OD at 0 8C after 30 min. b) Salt 2 in CD3OD at RT after 60 min. c) Sample in (b) after an additional 48 h at RT. Reduction of 2 produces 2-deuteronitrobenzene ([D1]3) in which the deuterium comes from the CD3OD. d) Salt 2 in [D7]DMF at 0 8C after 30 min. e) Sample in (d) after 2.5 h at RT, showing complete reduction of 2 to [D1]3. f) Salt 5 in DMF after 48 h at RT.
ice bath worked nicely in CD3OD as expected (Figure 1a), but it also proceeded cleanly at room temperature (Figure 1b). Further, stirring the mixture at room temperature for 48 h resulted in no visible salt decomposition (Figure 1c). In a separate operation the diazotization was carried out in [D7]DMF, the solvent used in the Wirth study.[7] Again diazotization occurred smoothly at 0 8C; however, after 30 min 50 % deutero-dediazotization (to [D1]3) had occurred (Figure 1d). At this time, a small amount of [Pd(OAc)2] was added to see if this process could be catalysed by Pd, but no significant increase in the rate of dediazotization was observed. After stirring (with or without Pd) for an additional 2.5 h complete reduction to [D1]3 occurred, thus confirming DMF as the hydride source (Figure 1e). The reduction of aryldiazonium salts in DMF has been investigated previously. It was reported that in the presence of promoters, such as Fe[8] or Rh,[9] reduction occurs smoothly, but either nothing occurs without Rh or the transformation takes days.[9] This statement may not be globally true. Rather reduction is substrate dependent and electron-poor examples are more active partners. Indeed, when we formed the 2-methoxy salt 5 in DMF it was stable for at least 48 h (Figure 1f). That reduction occurred extensively with 1, which suggests that the moderate yields (ca. 50 %) of Mizoroki–Heck products in Wirth’s case[7] were the result of salt loss, while sitting in DMF before the Pd and alkene were teed into the flow stream. To further examine the impact of solvent and temperature on the process, we prepared the diazonium salt in methanol or DMF at 0 8C in batch, added the Mizoroki–Heck components &
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
Scheme 2. Optimized two-step flow diazotization/Mizoroki–Heck sequence.
The flow rate into diazotization was kept fixed (6 mL min 1 from each pump) and the residence time was optimized by adjusting the length of the reactor tubing leading the to the residence times indicated. Felpin had demonstrated a necessity for anisole as an additive to stabilize the Pd catalyst in their diazotization/Mizoroki–Heck studies;[11] we used it in earlier runs (e.g., Scheme 1) but observed no deleterious effect of removing it. By conducting the diazotization in MeOH, which appears to stabilize aryldiazonium salts (vide supra), we could enhance the lifetime of 2 when it teed into the DMF cross-coupling solution sufficiently to allow a high yield of coupled product to be obtained (DMF was essential to see any coupling). 2
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Communication With the knowledge that we could now obtain an excellent yield of the desired styryl product using flow, while mitigating salt loss through dediazotization, we refocused our efforts on the establishment of the most streamlined and simple process. If the diazonium salt could be consumed directly as it was produced, we could perform the entire sequence at RT, which was an original key goal of this study. Putting the pieces together, it made sense that we should be able to create what amounts to a ‘one-pot’, multicomponent reaction (MCR) flow process whereby diazotization and cross-coupling occur in an ordered sequence in just one single reactor. To this end we set out to design the reactor and to develop optimal conditions for a generally applicable, high-yielding protocol. Intrigued by the catalytic diazotization/Mizoroki–Heck batch process developed by Felpin and co-workers who used less than one equivalent of acid,[11] we felt that we could reduce the amount of CH3SO3H used to at least 1.0 equivalent. Drawing from our earlier optimization studies for the two-step protocol, we opted to begin with just over two equivalents of nitrite and 2 mol % of [Pd(OAc)2]. The co-solvent system of MeOH/DMF (1:1) would ensure suitable stability of the diazonium salts as they are formed by MeOH, while the DMF solubilized the Pd and facilitated the coupling step. With these reaction parameters confirmed, we set out to optimize flow rate, hence the residence time for the single operation protocol using the reactor design illustrated in Table 1.[12] At 50 mL min 1 good conversion was obtained (Table 1, entry 4), but by 12 mL min 1.conversion was complete, no by-products were observed, and product yield was excellent. With these highly streamlined, one-reactor, MCR flow conditions thus developed, we then set out to see if this protocol was suitable for wider application (Table 2). The impression
Table 2. Scope study for streamlined diazotization Mizoroki–Heck flow reaction.[a]
Entry Aniline
Table 1. Optimization of flow rate and residence time for the diazotization/cross-coupling sequence based on 1H NMR spectroscopic analysis.[a]
Entry
Flow rate[a]
Residence t [min][b]
6 [%]
3 [%]
1 [%]
1 2 3 4 5 6
400 200 100 50 24 12
2.8 5.7 11.5 23.0 48.0 96.0
13 29 61 80 96 100
19 19 16 12 0 0
68 52 23 8 4 0
[a] Syringe 1 was loaded with a methanol solution containing 1 and methyl acrylate while syringe 2 contained MeSO3H, tert-butylnitrite, and [Pd(OAc)2] in DMF. The two solutions were flowed together into one DuPont FEP tube 1152 mL (1/8“ OD 0.06” ID) at RT at the specified flow rate. After traversing the reaction tube, the reaction mixture emptied into a quenching flask containing triethylamine in ethyl acetate (see below). [b] The experiment was started at a flow rate of 400 mL min 1 and decreased until 1H NMR spectral analysis indicated complete consumption of 1.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
These are not the final page numbers! ÞÞ
3
Product (8)
Flow[b] 8/9/7 Yield [%][c]
1
12
1:0:0 90
2
6
1:0:0 87
3
12
1:0:0 92
4
12
1:0:0 95
5
12
1:0:0 93
6
12
1:0:0 80
7
12
1:0:0 98
8
12
1:0:0 92
9
12
1:0:0 91
10
12
1:0:0 96
11
12
1:0:0 93
12
12
1:0:0 95
13
6
1:0:0 90
14
6
5:1:2 51
15
3
1:0:0 79
16
3
1:0:0 81
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication Table 2. (Continued)
Entry Aniline
17
Product (8)
Flow[b] 8/9/7 Yield [%][c]
3
1:0:0 83[d]
[a] Syringe 1 was loaded with a methanol solution containing 1 and methyl acrylate while syringe 2 contained MeSO3H, tert-butylnitrite, and [Pd(OAc)2] in DMF. The two syringes were flowed together into one DuPont FEP tube 1152 mL (1/8 OD 0.06 ID) at RT at the specified flow rate. After traversing the reaction tube, the reaction mixture emptied into a quenching flask containing triethylamine in ethyl acetate. [b] The flow rate reported is in mL min 1. [c] After collecting the effluent from the reactor in the Et3N quenching solution, product was extracted into ether, concentrated, and purified by column chromatography. Yield is based on the volume of the starting material solutions infused after reaching steady state. [d] 5 mol % of [Pd(OAc)2] used.
Scheme 3. Diazotization/Mizoroki–Heck reaction quenching study. [a] CD3OD was used in place of CH3OH/DMF.
ing. While the conditions that are used with tBuONO are anhydrous, one must also remember that diazonium salts are also made using NaNO2 in water,[1] thus they are quite stable in water. To examine the above concerns, a series of control experiments were conducted (see Scheme 3). First, a diazotization solution of 2 in MeOH/DMF (1:1) was added to a flask containing the remaining reactants necessary for the Mizoroki–Heck reaction in an ether/water mixture at RT (Scheme 3a). To mimic the reactions in this report, the mixture was stirred for 4 h and the layers were separated and worked up as usual (e.g., see Table 2). The cross-coupling proceeded to give an 8 % yield of 6 and 54 % when the quenching solution was stirred for 24 h. When the quenching solution contained only water (Scheme 3b), 5 % conversion was attained after 4 h, and 18 % after 24 h. It would appear that reports in the literature using any of these methods to quench the reactor effluent need to be revisited. To ensure that the results derived from the new protocols developed in this manuscript were meaningful, a quenching strategy was developed.[10] It is known that Et3N effectively causes dediazotization,[13, 14] so a quenching solution of Et3N (one equiv relative to 1) in ethyl acetate was created. Diazonium salt 2 was created in batch and added in one shot to the quenching solution and after 60 s a 1H NMR spectrum of the resultant solution was recorded (Scheme 3c).[10] Dediazotization proceeded to approximately 67 %, while addition to a solution containing 2 equiv of Et3N (Scheme 3d) led to complete formation of 3. To confirm that dediazotization in the quenching flask is fast enough to preclude any Mizoroki–Heck coupling from occurring, that is, all diazonium salt is destroyed rapidly, the cross-coupling components were added to the quenching solution (Scheme 3e). This time when 2 was added, zero coupled product was observed confirming that this new quenching strategy is efficient. When the reactions are performed in flow, even with only 1.0 equiv of Et3N present, the flow of effluent is slow enough to ensure that the base is always in vast excess of the diazonium salt to ensure thorough quenching. Thus, the results presented in this manuscript originate solely from what happens in the reactor and the conclusions can be viewed with confidence from that perspective.
that one gets from reading the literature on this protocol is that diazotization is generally favoured by electron-withdrawing groups on the ring and an ortho substituent appears to enhance salt lifetime, presumably due to steric effects.[8, 9] Moving the nitro group to the 4-position and leaving the ortho site empty (8 b) did not adversely impact the process (Table 2, entry 2), although completely removing it did reduce conversion through to coupling (entries 14 and 15). Further, the presence of electron-donating groups were very nicely tolerated (entries 3, 4, 7, 9, 11, and 13). The process also works on styrylbased coupling partners (entry 17). Careful study of the literature involving not only diazonium salt use in flow, but flow chemistry in general indicates that proper control and quenching experiments are not always conducted to support the claims made in the manuscripts. Many authors report flow rates, residence times, and yields that relate to a specific reaction’s performance in the reactor, yet they merely flow the effluent from the reactor into a flask to collect it over the course of hours, or in some cases even days. Unless the reaction requires something affixed to the reactor lumen, for example, a catalyst flow bed, most reactions could simply continue to proceed in the collection vessel. Ironically the controlled contact time of reactants is one of the key features that enables flow chemistry to produce such clean, highyielding and reproducible transformations. Not properly quenching reactor effluent may undo much of what is gained by working in flow in the first place. Consequently, the claims made in a number of flow chemistry reports have yet to be validated. Even flowing effluent into a cooled flask is no guarantee that the reaction has terminated; it must be chemically quenched and validated to be so. In the flow diazonium salt literature, reported ‘quenches’ include flowing reactor effluent into empty chilled flasks, into water, and into a water/ether mixture. As many diazonium salt reactions are actually conducted at 0 8C,[1, 2] it is safe to reject the first quench method straight off. The quenches involving water are equally perplex&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
4
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Communication In this manuscript, we have demonstrated that diazonium salts prepared in MeOH have a considerable lifetime (days), whereas those in DMF undergo significant dediazotization in just 30 min. The multicomponent flowed diazotization/Mizoroki–Heck protocol developed herein uses both of these solvents together to ensure solubility while giving the salt sufficient lifetime to undergo the cross-coupling in high yield. Finally, it is essential to assure effective quenching of the effluent from a flow reactor because the reaction may continue in the collection flask giving rise to potentially erroneous results and conclusions.
[5] a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jap. 1971, 44, 581 – 581; b) R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320 – 2322. [6] a) Z. Yu, Y. Lv, C. Yu, Org. Process Res. Dev. 2012, 16, 1669 – 1672; b) N. Chernyak, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12466 – 12469; c) P. Salice, D. Fenarolie, C. C. De Filippo, E. Menna, G. Gasarini, M. Maggini, chimica oggi/Chemistry Today, 2012, Vol. 30 no. 6 Nov/Dec; d) B. Li, D. Widlicka, S. Boucher, C. Hayward, J. Lucas, J. C. Murray, B. T. O’Neil, D. Pfisterer, L. Samp, J. VanAlsten, Y. Xiang, J. Young, Org. Process Res. Dev. 2012, 16, 2031 – 2035; e) L. Malet-Sanz, J. Madrzak, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 5324 – 5332; f) L. Malet-Sanz, J. Madrzak, R. S. Holvey, T. Underwood, Tetrahedron Lett. 2009, 50, 7263 – 7267; g) R. C. R. Wootton, R. Fortt, A. J. de Mello, Lab Chip 2002, 2, 5 – 7. [7] B. Ahmed-Omer, D. A. Barrow, T. Wirth, Tetrahedron Lett. 2009, 50, 3352 – 3355. [8] F. W. Wassmundt, W. F. Kiesman, J. Org. Chem. 1995, 60, 1713 – 1719. [9] G. S. Marx, J. Org. Chem. 1971, 36, 1725 – 1726. [10] For complete details of this transformation, see the Supporting Information. [11] N. Susperregui, K. Miqueu, J.-M. Sotiropoulos, F. Le Callonnec, E. Fouquet, F.-X. Felpin, Chem. Eur. J. 2012, 18, 7210 – 7218. [12] For complete details and NMR spectra, see the Supporting Information. [13] a) K. V. Kutonova, M. E. Trusova, P. S. Postnikov, V. D. Filimonov, Russian Chem. Bull. Int. Ed. 2012, 61, 206 – 208; b) K. H. Park, Y. H. Cho, Synth. Commun. 1996, 26, 1569 – 1574. [14] For dediazotization studies involving polar additives/solvents, see: a) H. Zollinger, Angew. Chem. 1978, 90, 151 – 160; Angew. Chem. Int. Ed. Engl. 1978, 17, 141 – 150; b) I. Szele, H. Zollinger, Helv. Chim. Acta 1978, 61, 1721 – 1729.
Acknowledgements The authors thank NSERC Canada for support of this research. Keywords: cross-coupling · diazonium salts · flow · Heck reaction · microreactors [1] H. Zollinger, Diazo Chemistry I.; VCH: Weinheim, 1994. [2] a) P. Griess, Liebigs Ann. Chem. 1858, 106, 123 – 125; b) D. T. Flood, Org. Synth. 1943, 2, 295 – 298; c) M. Barbero, M. Crisma, I. Degani, R. Fochi, P. Perracino, Synthesis 1998, 1171 – 1175. [3] R. Fortt, R. C. R. Wootton, A. J. de Mello, Org. Process Res. Dev. 2003, 7, 762 – 768. [4] K. Kikukawa, T. Matsuda, Chem. Lett. 1977, 159 – 162.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
These are not the final page numbers! ÞÞ
Received: February 9, 2014 Published online on && &&, 0000
5
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication
COMMUNICATION & Organic Synthesis K. S. Nalivela, M. Tilley, M. A. McGuire,* M. G. Organ* && – && Multicomponent, Flow Diazotization/ Mizoroki–Heck Coupling Protocol: Dispelling Myths about Working with Diazonium Salts
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
Diazonium salts in flow: A single pass flow diazotization/Mizoroki–Heck protocol has been developed for the production of cinnimoyl and styryl products. The factors that govern aryl diazonium salt stability have been examined in
detail leading to the development of a MeOH/DMF co-solvent system in which the diazonium salts can be generated in the presence of all other reaction components and then coupled selectively (see scheme).
6
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
