Letter pubs.acs.org/OrgLett
Selective Lithiation, Magnesiation, and Zincation of Unsymmetrical Azobenzenes Using Continuous Flow Marthe Ketels, David B. Konrad, Konstantin Karaghiosoff, Dirk Trauner, and Paul Knochel* Department Chemie, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 München, Germany S Supporting Information *
ABSTRACT: A mild and general set of metalation procedures for the functionalization of unsymmetrical azobenzenes using a commercially available continuous-flow setup is reported. The metalations proceed with TMPLi under convenient conditions (0 °C, 20 s), and various classes of electrophiles can be used. With sensitive substrates, an in situ trapping metalation in which TMPLi is added to a mixture of the azobenzene and ZnCl2 or MgCl2·LiCl was very effective for achieving high yields.
A
Scheme 1. In Situ Trapping Metalation of Aromatic Substrates
zobenzenes function as versatile photoswitches that can be cycled between their cis- and trans-configuration with light.1 Their synthetic accessibility,2 small size, and robust switching, paired with a low rate of photobleaching, makes them excellent building blocks for the incorporation into more complex optical devices.3 Photopharmaceuticals, for instance, contain azobenzene units as on and off switches, which allows for the control of biological functions with a high spatiotemporal resolution of light.4 It is noteworthy that the switching wavelengths, the stability of the cis- and trans-isomers, and the switching kinetics are strongly influenced by the substitution pattern of the azobenzene core.1,5 Therefore, the syntheses of elaborate photopharmaceuticals and the fine-tuning of the desired photoswitching properties rely on the availability of efficient synthetic methods for the direct functionalization of azobenzenes.2,6 One approach for preparing functionalized azobenzenes is their metalation with strong bases. Thus, lithiation under standard conditions with TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) is reported for cryogenic temperatures of −78 °C and a large excess of the base quenching with CO2 or TMSCl.7 Alternatively, the selective lithiation of unsymmetrical azobenzenes was only realized using a halogen−lithium or a tin−lithium exchange.8 The generation of reactive organometallic intermediates can be greatly improved using continuous flow.9 Recently, we have shown that the metalation of polyfunctional aromatics can be advantageously realized using a continuous-flow setup. Especially practical was the use of in situ trapping metalation procedures, where a mixture of the aromatic substrate and ZnCl2 or MgCl2 was treated in a commercial flow reactor with TMPLi at 0 °C.10 The success of this procedure relies on the fact that the lithiation of the aromatic substrate with TMPLi is faster than the transmetalation of TMPLi with MgCl2 or ZnCl2 (Scheme 1).11 © XXXX American Chemical Society
Scheme 2. Lithiation of Methoxy-Substituted Azobenzenes in Continuous Flow
Herein, we report a practical lithiation, magnesiation, or zincation of azobenzenes using various flow techniques including in situ trapping metalation procedures. Thus, we first turned our attention to the less sensitive 4-methoxyphenyl-2-phenyldiazene (1a). Its reaction with TMPLi, completed within 20 s at 0 °C in THF using a flow rate of 3 mL/min, produces the aryllithium 2a and affords after an iodine quench 1-(3-iodo-4-methoxyphenyl)2-phenyldiazene (3a) in 55% yield (Scheme 2).12,13 Received: February 15, 2017
A
DOI: 10.1021/acs.orglett.7b00460 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Functionalized Methoxy-Substituted Azobenzenes of Type 4 Obtained via Lithiation in Continuous Flow and Subsequent Trapping with an Electrophile (E-X) in Batch
Scheme 3. In Situ Trapping Procedure Allowing the Zincation and Iodolysis of Various Unsymmetrical Azobenzenes in Continuous Flow
products (3c′ and 3c″) in a 3:1 ratio and 59% yield. In addition to iodine, various other electrophiles were used successfully, such as Bu2S2 leading to azobenzene 4a (Table 1, entry 1), aryl bromides in the presence of a palladium catalyst14 (4 mol % of Pd(dba)2, 8 mol % of DavePhos, after transmetalation to the corresponding zinc reagent with ZnCl2), affording diazenes 4b−d14 and 4h (entries 2−4 and 8), benzaldehyde leading to diazene 4e (entry 5), allyl bromide in the presence of 10% CuCN·2LiCl leading to azobenzene 4f (entry 6), as well as propylene oxide affording diazene 4g (after transmetalation to the corresponding Grignard reagent using MgCl2·LiCl and 10% CuI as catalyst, entry 7). Although the lithiation with TMPLi under flow conditions was satisfactory with the relatively low functionalized diaryl diazenes 1a−c, the use of more sensitive azobenzenes bearing a fluoro-, bromo-, or cyano-substituent required an in situ trapping metalation procedure using ZnCl2. Thus, the treatment of a mixture of 4-fluorophenyl-2-phenyldiazene (1d) (1.0 equiv) and ZnCl2 (0.5 equiv) with TMPLi (1.5 equiv) under flow conditions (3.0 mL/min, 0 °C, 20 s) led to a highly regioselective lithiation of 1d in the ortho-position of the fluoro-substituent, giving after transmetalation with ZnCl2 the corresponding arylzinc reagent 2d, which was quenched with iodine, providing the desired azobenzene 3d in 85% yield.14 Similarly, the fluoro-, bromo-, and cyano-substituted diazenes 1e−g were regioselectively lithiated, transmetalated to the zinc species, and iodinated, affording the unsymmetrical azobenzenes 3e−g16 in 66−83% yield (Scheme 3). This procedure was extended to a range of other electrophiles besides iodine. Thus, a bromination of 2d directly performed with Br2 on a gram scale provided the bromo derivative 5a in 74% isolated yield without further optimization (Table 2, entry 1). A copper-catalyzed allylation with allyl bromide provided the 3allylated azobenzene 5b in 85% yield (entry 2). The zinc intermediate 2d underwent various Negishi cross-couplings17 with aryl iodides using 2 mol % of Pd(OAc)2 and 4 mol % of SPhos,15 leading to the unsymmetrical azobenzenes 5c−f in 69− 83% yield (entries 3−6). Similarly, the cyano-substituted azobenzene 1g was zincated under the same conditions at the ortho-position to the cyano-substituent and arylated via a Negishi cross-coupling, providing the azobenzene 5g in 67% yield (entry 7). This in situ trapping metalation procedure was extended for preparing Grignard reagents that are more reactive than organozinc species and are much better suited for reactions with aldehydes or acyl chlorides. Thus, the azobenzene 5a was mixed with MgCl2·LiCl (0.5 equiv) and reacted with TMPLi (1.5
0.8 equiv of E+. b0 °C, 10 min. cYield based on electrophile used as limiting reagent. d0.7 equiv of E+. e1.1 equiv of ZnCl2, 4 mol % of Pd(dba)2, 8 mol % of DavePhos, rt, 12 h. f1.1 equiv of ZnCl2, 0 °C, 15 min; then 0.8 equiv of E+, 4 mol % of Pd(dba)2, 8 mol % of DavePhos, rt, 12 h. g1.1 equiv of MgCl2·LiCl. h0 °C, 5 h. i0.1 equiv of CuCN· 2LiCl, rt, 1 h. j10 mol % of CuI, rt, 12 h. a
Similarly, 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)diazene (1b) is lithiated under the same conditions, providing after iodolysis the corresponding iodo-substituted azobenzene 3b in 73% yield. In the case of 3-methoxyphenyl-2-phenyldiazene (1c), the lithiation with TMPLi is only moderately selective, furnishing after iodolysis two easily separable ortho-substituted B
DOI: 10.1021/acs.orglett.7b00460 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Functionalized Fluoro- and Cyano-Substituted Azobenzenes of Type 5 Obtained via an In Situ Trapping Procedure in Continuous Flow Using ZnCl2 and Subsequent Trapping with an Electrophile (E-X) in Batch
Table 3. Functionalized Fluoro- and Bromo-Substituted Azobenzenes Obtained via an In Situ Trapping Procedure in Continuous Flow Using MgCl2·LiCl and Subsequent Trapping with an Electrophile (E-X) in Batch
a 0.8 equiv of E+, 0 °C, 3−5 h. bYield based on electrophile used as limiting reagent. c0.8 equiv of E+, 1.1 equiv of CuCN·2LiCl, 0 °C, 2 h.
Scheme 4. In Situ Trapping Metalation Procedure Allowing the Zincation and Iodolysis of the Tetra-ortho-chloroSubstituted Azobenzene 8 in Continuous Flow
a 3.0 equiv of E+, on a gram scale, 0 °C, 1 h. b1.1 equiv of E+. c0.1 equiv of CuCN·2LiCl, 0 °C, 1 h. d2.0 equiv of E+, on a gram scale, 0 °C, 1 h. e 2 mol % of Pd(OAc)2, 4 mol % of SPhos, rt, 3 h. f0.8 equiv of E+; yield based on electrophile used as limiting reagent.
respectively (Table 3, entries 1 and 2). Similarly, quenching reactions with acid chlorides in the presence of CuCN·2LiCl (1.1 equiv) furnished the corresponding keto-substituted azobenzenes 7d and 7e in 81 and 78% yield (entries 3 and 4). We have further applied this methodology to the highly functionalized azobenzene 8. Its tetra-ortho-chloro substitution pattern enables visible-light photoswitching, which makes it a valuable synthetic intermediate for photopharmaceuticals that target complex animal tissues.5 This additional functionalization proceeded smoothly through an in situ trapping zincation using TMPLi followed by a batch iodination and afforded the selectively iodinated azobenzene 914 in 65% yield (Scheme 4). In summary, we have developed a general methodology for the functionalization of unsymmetrical azobenzenes using a
equiv) in a continuous-flow setup (3 mL/min, 0 °C, 20 s), providing the magnesium intermediate 6a. After being quenched in batch with TMSCl, the silylated azobenzene 7a was obtained in 92% yield (Table 3). We have extended this procedure for performing quenching reactions with benzaldehyde or acid chlorides using the azobenzene 1d as starting material. Thus, the quenching of the corresponding magnesiated azobenzene with benzaldehyde or 4-fluorobenzaldehyde provided the hydroxyazobenzene derivatives 7b and 7c in 77 and 74% yield, C
DOI: 10.1021/acs.orglett.7b00460 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
1261−1274. (g) Trads, J. B.; Burgstaller, J.; Laprell, L.; Konrad, D. B.; de la Osa de la Rosa, L.; Weaver, C. D.; Baier, H.; Trauner, D.; Barber, D. M. Org. Biomol. Chem. 2017, 15, 76−81. (6) Leonard, E.; Mangin, F.; Villette, C.; Billamboz, M.; Len, C. Catal. Sci. Technol. 2016, 6, 379−398. (7) Nguyen, T. T. T.; Boussonniere, A.; Banaszak, E.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. J. Org. Chem. 2014, 79, 2775−2780. (8) (a) Soga, T.; Jimbo, Y.; Suzuki, K.; Citterio, D. Anal. Chem. (Washington, DC, U. S.) 2013, 85, 8973−8978. (b) Segarra-Maset, M. D.; van Leeuwen, P. W. N. M.; Freixa, Z. Eur. J. Inorg. Chem. 2010, 2010, 2075−2078. (c) Unno, M.; Kakiage, K.; Yamamura, M.; Kogure, T.; Kyomen, T.; Hanaya, M. Appl. Organomet. Chem. 2010, 24, 247−250. (d) Garlichs-Zschoche, F. A.; Doetz, K. H. Organometallics 2007, 26, 4535−4540. (e) Kozlecki, T.; Syper, L.; Wilk, K. A. Synthesis 1997, 1997, 681−684. (f) Strueben, J.; Lipfert, M.; Springer, J.-O.; Gould, C. A.; Gates, P. J.; Soennichsen, F. D.; Staubitz, A. Chem. - Eur. J. 2015, 21, 11165−11173. (9) For recent advances in flow chemistry and reviews, see: (a) Becker, M. R.; Knochel, P. Org. Lett. 2016, 18, 1462−1465. (b) Ganiek, M. A.; Becker, M. R.; Ketels, M.; Knochel, P. Org. Lett. 2016, 18, 828−831. (c) Petersen, T. P.; Becker, M. R.; Knochel, P. Angew. Chem., Int. Ed. 2014, 53, 7933−7937. (d) Hartwig, J.; Metternich, J. B.; Nikbin, N.; Kirschning, A.; Ley, S. V. Org. Biomol. Chem. 2014, 12, 3611−3615. (e) Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016, 45, 4892−928. (f) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675−680. (g) Morse, P. D.; Beingessner, R. L.; Jamison, T. F. Isr. J. Chem. 2016, DOI: 10.1002/ ijch.201600095. (h) Noel, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010−5029. (i) Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos, A. Acc. Chem. Res. 2015, 48, 349−362. (j) Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Org. Process Res. Dev. 2012, 16, 1102−1113. (k) Somerville, K.; Tilley, M.; Li, G.; Mallik, D.; Organ, M. G. Org. Process Res. Dev. 2014, 18, 1315−1320. (l) Kim, H.; Nagaki, A.; Yoshida, J.-i. Nat. Commun. 2011, 2, 264. (m) Nagaki, A.; Imai, K.; Ishiuchi, S.; Yoshida, J.-I. Angew. Chem., Int. Ed. 2015, 54, 1914−1918. (n) He, Z.; Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 3353−3357. (o) Becker, M. R.; Ganiek, M. A.; Knochel, P. Chem. Sci. 2015, 6, 6649−6653. (p) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Angew. Chem., Int. Ed. 2014, 53, 557−561. (q) Hafner, A.; Mancino, V.; Meisenbach, M.; Schenkel, N.; Sedelmeier, J. Org. Lett. 2017, 19 (4), 786−789. (10) Becker, M. R.; Knochel, P. Angew. Chem., Int. Ed. 2015, 54, 12501−12505. (11) Experimental evidence suggests that the metalation of the aromatic substrate by TMPLi at −78 °C proceeds at least 6 times faster than the transmetalation of TMPLi with a metal salt additive. See: Frischmuth, A.; Fernández, M.; Barl, N. M.; Achrainer, F.; Zipse, H.; Berionni, G.; Mayr, H.; Karaghiosoff, K.; Knochel, P. Angew. Chem., Int. Ed. 2014, 53, 7928−7932. (12) Flow reactions were performed with commercially available equipment from Uiniqsis Ltd (FlowSyn; http://www.uniqsis.com). (13) Adding TMPLi at 0 °C under batch conditions to azobenzene 1a leads mostly to decomposition and a mixture of products as indicated by GC analysis. (14) Instead of TMPLi, the cheaper base Cy2NLi can be employed under similar conditions, leading to ∼10% lower GC yields of the iodolysis product. (15) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461−1473. (16) X-ray analysis of compounds 3g, 4d, and 9 confirms the metalation regioselectivity. (17) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298−3299. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340− 348.
commercially available continuous-flow setup. With sensitive substrates, an in situ trapping metalation using ZnCl2 or MgCl2· LiCl was very effective to achieve high yields. The metalations proceeded with TMPLi under very convenient conditions (0 °C, 20 s), and various classes of electrophiles gave satisfactory results. Also a simple scale-up without further optimization of the reaction conditions was possible. We demonstrated that even highly functionalized azobenzenes that are of interest for the preparation of elaborated photopharmaceuticals could be further functionalized by this in situ trapping procedure. This procedure is currently being extended to more complex systems.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00460. Full experimental details and NMR data (PDF) Crystallographic data for 3g (CIF) Crystallographic data for 9 (CIF) Crystallographic data for 4d (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Dirk Trauner: 0000-0002-6782-6056 Paul Knochel: 0000-0001-7913-4332 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS M.K. thanks the Foundation of German Business, and D.K. thanks the Friedrich-Ebert Foundation for financial support. Dr. Oliver Thorn-Seshold (Ludwig-Maximilians-Unversität) and Rebecca Bechtel (Ludwig-Maximilians-Unversität) are acknowledged for providing starting materials. We thank Albermarle (Frankfurt am Main) and BASF AG (Ludwigshafen) for the generous gift of chemicals.
■
REFERENCES
(1) Bandara, H. M. D.; Burdette, S. C. Chem. Soc. Rev. 2012, 41, 1809− 1825. (2) Merino, E. Chem. Soc. Rev. 2011, 40, 3835−3853. (3) Russew, M.-M.; Hecht, S. Adv. Mater. 2010, 22, 3348−3360. (4) (a) Beharry, A. A.; Woolley, G. A. Chem. Soc. Rev. 2011, 40, 4422− 4437. (b) Brieke, C.; Rohrbach, F.; Gottschalk, A.; Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2012, 51, 8446−8476. (c) Broichhagen, J.; Frank, J. A.; Trauner, D. Acc. Chem. Res. 2015, 48, 1947−1960. (d) Fehrentz, T.; Schönberger, M.; Trauner, D. Angew. Chem., Int. Ed. 2011, 50, 12156−12182. (e) Szymański, W.; Beierle, J. M.; Kistemaker, H. A. V.; Velema, W. A.; Feringa, B. L. Chem. Rev. 2013, 113, 6114−6178. (f) Velema, W. A.; Szymanski, W.; Feringa, B. L. J. Am. Chem. Soc. 2014, 136, 2178−2191. (5) (a) Bléger, D.; Hecht, S. Angew. Chem., Int. Ed. 2015, 54, 11338− 11349. (b) Dong, M.; Babalhavaeji, A.; Samanta, S.; Beharry, A. A.; Woolley, G. A. Acc. Chem. Res. 2015, 48, 2662−2670. (c) Hammerich, M.; Schütt, C.; Stähler, C.; Lentes, P.; Röhricht, F.; Höppner, R.; Herges, R. J. Am. Chem. Soc. 2016, 138, 13111−13114. (d) Hansen, M. J.; Lerch, M. M.; Szymanski, W.; Feringa, B. L. Angew. Chem., Int. Ed. 2016, 55, 13514−13518. (e) Konrad, D. B.; Frank, J. A.; Trauner, D. Chem. - Eur. J. 2016, 22, 4364−4368. (f) Calbo, J.; Weston, C. E.; White, A. J. P.; Rzepa, H. S.; Contreras-García, J.; Fuchter, M. J. J. Am. Chem. Soc. 2017, 139, D
DOI: 10.1021/acs.orglett.7b00460 Org. Lett. XXXX, XXX, XXX−XXX
