Palladium-Catalyzed Coupling of Sulfonylhydrazones with

Communication pubs.acs.org/OPRD

Palladium-Catalyzed Coupling of Sulfonylhydrazones with Heteroaromatic 2‑Amino-Halides (Barluenga Reaction): Exploring the Electronics of the Sulfonylhydrazone Hongyu Tan,†,§ Ioannis Houpis,*,‡ Renmao Liu,§ Youchu Wang,§ Zhilong Chen,*,† and Matthew J. Fleming∥ †

Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, P. R. China ‡ Janssen Pharmaceutica, API Development, Turnhoutseweg 30, 2340 Beerse, Belgium § STA Pharmaceuticals, 288 Fute Zhong Rd, Shanghai 200131, P. R. China ∥ Solvias AG, Romerpark 2, 4303 Kaiseraugst, Switzerland S Supporting Information *

■

RESULTS AND DISCUSSION In our work toward the synthesis of 1, we had the need for a new approach, as the existing synthesis (Scheme 1) was rather lengthy and certainly “violated” both atom and step-economy principles. In particular, the rather expensive and difficult to purify ketone 3c had to be converted to the nonaflate 3b,14 which was converted to the vinyl boronate 3a, which could then be coupled with 2 to form the desired product. So, we considered the much more attractive option of reacting a derivative of 2 (i.e., 2a or 2b) with the tosylhydrazone 4 under the Barluenga conditions. From the beginning, we were aware of the challenges in achieving the desired transformation as there are few examples in the literature describing successful cross coupling of heteroaromatic halides with hydrazones.15 Even more challenging seemed the presence of the N-heteroatom adjacent to the reaction center.16 One could foresee that significant interference could be caused by an unprotected nitrogen atom via coordination to the Pd. Indeed when the unprotected 2 was reacted with 4 (Table 1 entry 1), under typical Barluenga conditions (LiOBu-t, XPhos, in dioxane), the desired product (1, P = H) was observed as the minor component of the reaction mixture (2%), while the dimeric and reduced compounds 5 and 6 were the main reaction products. In addition, 44% of the starting material 2 remained, while less than 6% of the tosylhydrazone 4 could be detected in the crude reaction mixture, indicating that decomposition of 4 via unproductive pathways was faster than the desired crosscoupling path. Also significant was the observation that impurities 7 and 9 were formed (Scheme 2). The former might explain the unproductive decomposition path of hydrazone, while the latter may explain the eventual formation of 8, as we will discuss below. Changing the Pd source, solvent, temperature, and addition sequence did not improve the reaction further although slow addition of 4 afforded slightly higher yield of 1 (ca. 15%). Therefore, a systematic examination was undertaken to study the effect of the substrate structure, ligand, metal precursor, base,

ABSTRACT: This paper describes a new reactivity of the Pd-catalyzed coupling of 2-amino-3-bromo-aromatic and heteroaromatic compounds with sulfonylhydrazones (Barluenga reaction).The new catalyst system and modulation of the electronic nature of hydrazone that were needed for successful reaction are described herein.

■

INTRODUCTION Hydrazones have been valuable synthetic intermediates and have been used for such diverse purposes as identification and purification of ketones1,2 and in enantioselective carbon−carbon bond-forming reactions.3 In 1952 Bamford and Stevens4 discovered that sulfonylhydrazones decompose in a controlled fashion under basic conditions to form carbon−carbon double bonds via the diazo derivative. Shapiro et al.5 later discovered that tosylhydrazones could be converted to a vinyl lithium species, allowing for further functionalization. Several innovative uses of sulfonylhydrazones as diazo precursors have been reported as well.6 However, a more general synthetic utility of hydrazones was not developed until 2007 when Barluenga7 discovered that the diazo derivative resulting from the tosylhydrazone decomposition could be converted to a Pd (II) carbene, which in the presence of an aryl halide can lead to alkenes (eq 1). This

initial discovery led to a number of useful applications: from the synthesis of structurally diverse olefins,8 to dienes,9 enol ethers,10 and sulphones11 to cross coupling of the resulting reactive intermediate with boronic acid derivatives12 and, recently, nitrogen nucleophiles to prepare enamines.13 © XXXX American Chemical Society

Received: June 4, 2015

A

DOI: 10.1021/acs.oprd.5b00211 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Scheme 1. Original Approach to Key Intermediate 1

Table 1. Evaluation of the Ligand and Base in the Coupling of 2, 2a, or 2b with Hydrazone 4a,b entry

metal prec.

L

base

starting material

solvent

residual 2/4 %

product (yield %)c

5 yield %

6 yield %

8 yield %

1 2 3 4 5 6 7 8 9b 10 11 12 13 14b) 15 b) 16 b) 17 18 19 20 21 22 23 24b 25 26

Pd2(dba)3 Pd(OAc)2 Pd2(dba)3 Pd(OAc)2 Pd2(dba)3 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2-(MeCN)2 Pd(OAc)2 18 18 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2

10 11 10 11 10 11 11 17 11 11 11 18 18 14 14 12 13 13 13 20 20 20 20 20 16 17

LiOBu-t Cs2CO3 LiOBu-t Cs2CO3 LiOBu-t Cs2CO3 Cs2CO3 LiOBu-t Cs2CO3 Cs2CO3 LiOBu-t Cs2CO3 K3PO4 K3PO4 K2CO3 Cs2CO3 K2CO3 K3PO4 K2CO3 K3PO4 K2CO3 K3PO4 K2CO3 K2CO3 K2CO3 K2CO3

2 2 2a 2a 2b 2b 2a 2a 2a 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2a

dioxane dioxane dioxane dioxane dioxane dioxane dioxane DME dioxane dioxane dioxane dioxane DMA dioxane diglyme dioxane diglyme dioxane Me-THF dioxane Me-THF Me-THF DMA DMA dioxane DMA

44/6 21/0 24/0 8/4 30/2 18/22 43/0 16/7 43/0 20/2 16/6 12/0 40/8 31/15 0/0 0/0 5/0 18/0 13/2 0/13 0/3 15/7 0/0 0/0 51/2 3/1

1 (2) 1 (40) 1a (47) 1a (67) 1 (19) 1 (26) 1a (43) 1a (43) 1a (80) 1 (34) 1 (34) 1 (3) 1 (20) 1 (19) 1 (26) 1a (40) 1 (55) 1 (58) 1 (59) 1 (60) 1 (67) 1 (0) 1 (82) 1 (85) 1 (31) 1a (34)

30 22 13 10 25 20 7 16 1 18 27 30 10 13 17 0 19 10 10 10 5 5

19 20 12 10 24 20 7 16 1 20 20 50 19 20 50 25 25 19 20 13 29 42

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 15 12

5 30

7 31

All screening reactions were conducted at 110 °C with S/C ratio = 50. Pd−L ratio = 1:2. The solids were added first under an Ar blancket followed by the solvents. All ligands and Pd precursors were handled in a glovebox as was LiOBu-t. bS/C ratio = 100. cQuantitative HPLC yields based on analytically qualified standards. a

Scheme 2. Barluenga Approach to 1

B



Communication

In order to be able to use the effectiveness of the Barluenga reaction for our synthesis, we had to understand the reaction conditions that induced the formation of 8 in the hopes of suppressing it. First we investigated whether the formation of 8 was due to the structures of our particular substrate or a general phenomenon of α-amino substrates (Scheme 3). Reaction of 2-Br aniline 21 with

solvent, and order of addition to the outcome of the reaction. Some representative results are shown in Table 1. From these experiments the following conclusions can be derived. (a) Protecting the nitrogen makes little difference in the product distribution under the original reaction conditions (Table 1, entries 1, 3, 5). (b) CataXium A (11) was at first thought to be a better ligand when combined with carbonate bases (Table 1, entries 2, 4, 5, 7) and Boc protection on the nitrogen. However, (c) in order to achieve useful yields and reduce byproducts, two equivalents of the expensive sulfonylhydrazone were required (Table 1, entry 9). Moreover, addition of the latter had to be carried out over 8 h at the reaction temperature, a tedious and hazardous process on medium- and large-scale production.

Scheme 3. Coupling of 21 with 24aa

Conditions A: [Pd2(dba)3] 1%, XPhos 4%, LiOBu-t, dioxane 110 °C. Conditions B: Pd(OAc)2 3%, t-Bu2MeP-HBF4, (6.5%), K2CO3, DMA, 110 °C.

a

hydrazone 24a under the normal Barluenga conditions (conditions A, Scheme 3) showed the same behavior as the reaction of 2 with 4, with low yields of the desired 25a, decomposition of 24a, and formation of 5,10-dihydrophenazine (21c) as the byproduct. On the other hand, using the best conditions for the preparation of 1 (conditions B, Scheme 3) afforded 25a in good yield along with 28a, analogously to what previously observed with 2 and 4. Clearly the formation of the tolyl adducts (8 and 28a) is a general feature of the reaction in the presence of the nitrogen heteroatom. In order to understand and then prevent its formation, we decided to investigate the reaction of the various aniline isomers, the substitution on the nitrogen heteroatom and the electronic properties of the sulfonylhydrazone (Figure 2 and Table 2) under different reaction conditions (A or B in Scheme 3). For the coupling of ortho substituted anilines with sulfonylhydrazones, the electronics of the aryl group of the sulfonylhydrazone seem to be the most important factor under our reaction conditions (condition B, Table 2, entries 1−3). The election-rich sulfonylhydrazone 24b afforded only 65% yield of the desired compound 25a with a significant 30% yield of the anisole coupling product 28b. On the other hand the nitro sulfonylhydrazone 24d gave the highest yield of 25a (95%) and none of 28d. Interestingly, with the electron-rich sulfonylhydrazone 24b, even the para substituted and protected aniline 23b, normally the” best behaved” of the substrates, formed 7% of the undesired coupling product 30a. This interesting behavior implies that, under appropriate conditions and in the absence of external coupling partners, electron-rich sulfonylhydrazones can provide products resulting from an internal collapse of the hydrazone (extruding SO2 and N2) to afford products of an

Figure 1. Ligands used in this study.

Given the observations above, we decided to focus our attention on the free amino derivative 2, which would allow us to avoid the two additional steps of protection and deprotection. Our efforts were rewarded (Table 1, entries 11−24) when we were able to achieve good yields and suppress the formation the byproducts 5 and 6, by using di-tert-butyl methyl phosphine as the ligand and milled K2CO3 as the base and by using 1.1−1.2 equiv of the sulfonylhydrazone. Surprisingly the reaction works best in dimethylacetamide which is not the preferred solvent for Barluenga reactions (Table 1, compare entries 20−23). The S/C ratio can be improved to 100−150 without significant loss in reaction efficiency (Table 1, entries 23, 24). It is worth noting that the related ligand 13 gave satisfactory results, while hindered but very electron-rich ligands (12, 14, 15, 18 or 19) gave lower yields and poor chemoselectivity. Bidente ligands 16 and 17 with different bite angles were also not very effective (Table 1, entries 25, 26). When the reaction mixture from entries 23 and 24 was examined further, we were surprised to find that, although 5 and 6 could not be detected, a new impurity (8) was formed in substantial amounts (ca. 15%). C



Communication

Table 2. Evaluation of the Substitution of the Aniline and Electronics of the Hydrazone entry

react.a cond.

aniline

hydrazone

product % yield

by-pdt % yield

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

B B B B A A A A A B A B A B A B A B

21a 21a 21a 23b 21a 21a 21a 21b 23a 23a 23b 23b 23b 23b 23b 23b 22 22

24b 24c 24d 24b 24b 24c 24d 24d 24d 24d 24b 24b 24d 24d 24c 24c 24d 24d

25a (65%) 25a (85%) 25a (95%) 27a (83%) 25a (35%) 25a (30%) 25a (15%) 25b (30%) 27a (92%) 27a (40%) 27b (88%) 27b (83%) 27b (71%) 27b (95%) 27b (87%) 27b (84%) 26 (95%) 26 (38%)

28b (30%) 28c (11%) 28d (0%) 30a (7%) 21c (30%) 21c (11%) 21c (35%) 21c (0%) 30c (0%) 30c (0%) 30b (0%) 30b (0%) 30b (0%) 30b (0%) 30b (0%) 30b (0%) 29c (0%) 29c (0%)

Conditions A: [Pd2(dba)3] 1%, XPhos 4%, LiOBu-t, dioxane 110 °C. Conditions B: Pd(OAc)2 3%, t-Bu2MeP-HBF4, (6.5%), K2CO3, DMA, 110 °C.

a

Scheme 4. Intermolecular vs Intramolecular Coupling of Sulfonylhydrazones

Figure 2. Starting materials, products, and byproducts of the Barluenga reaction of substituted anilines with hydrazone derivatives.

apparent intramolecular coupling reaction. On the other hand, the electron poor analogues do not participate in this reaction and so constitute the preferred starting material when the intermolecular coupling reaction is desired with external reagents. We have been able to demonstrate that this is a general reaction (Scheme 4), although it appears that the intermolecular variant requires air to achieve synthetically useful results, and will present our results in due course. The original conditions (condition A, Table 2, entries 5−8) for this coupling reaction seem to be unsuccessful with the ortho substituted substrate even when the nitrogen is protected. Surprisingly, for the meta and para substituted 23a, 23b, and 22, conditions B, which were so successful with the ortho substituted anilines, perform poorly compared to the typical Barluenga conditions A (compare entries 9−10 and 17−18, Table 2). Finally, the protected para substituted 23b coupled well irrespective of the procedure used or the electronic nature of the hydrazone coupling partner (Table 2, entries 11−16). Having established the reactivity patterns of the aniline regioisomeric halides and the electronic properties of the hydrazone and derivatives, we examined the electronic properties of various o-bromoaniline substrates in their coupling with our best hydrazone 24d under reaction condition B (Figure 3). The results show that there is no significant electronic effect of the

aniline substitution patterns and that most functionality is welltolerated.

Figure 3. Scope of the coupling of o-bromoanilines with hydrazone 24d. D



Communication

*E-mail: [email protected].

Finally, we were able to complete the synthesis of our key intermediate 1 in 85% isolated yield free from contamination by 38 as shown in eq 2:

Notes

The authors declare no competing financial interest.

■

■

CONCLUSION In conclusion, we have discovered an interesting variation of the Barluenga reaction that is useful in the coupling of both heterocyclic and carbocyclic ortho-halo-amino aromatics with sulfonylhydrazones. In addition, the possibility of a very exciting new reactivity of hydrazones has been discovered, namely, the extrusion of N2 and SO2 from a hydrazone and the formally intramolecular cross coupling of the two organic components. More on this reactivity and its synthetic utility will be reported soon.

■

EXPERIMENTAL SECTION A mixture of compound 2 (52.6 g, 95.2 wt %, 159.6 mmol, 1.0 equiv), t-Bu2PMeHBF4 (2.57 g, 10.37 mmol, 6.5 mol %), Pd(OAc)2 (1.08g, 4.79 mmol, 3 mol %), K2CO3 (66.2 g, 478.9 mmol, 3.0 equiv) (Aldrich, powder), and DMA (900 mL) was heated to 110 °C under a nitrogen atmosphere. A solution of compound 37 (75.2 g, 231.4 mmol, 1.45 equiv) in DMA (80 mL) was added to the mixture dropwise over 3.0 h at 110 °C. After addition, the mixture was stirred for 3.0 h. The mixture was cooled to 25 °C. Water (2 L) was added and the mixture was stirred for 1.0 h. The mixture was filtered, and the cake was washed with water (100 mL). The cake was dissolved in MTBE (700 mL). 0.5 N HCl solution (200 mL) was added. The phase was separated. 0.5 N HCl solution (100 mL) was added, and the phase was separated. The combined aqueous layer was washed with MTBE (400 mL). 5% of NaOH solution (350 mL) was added to the aqueous layer after phase separation. The suspension was filtered. The cake was washed with water (100 mL) and dried at 50 °C to afford compound 1 (46.3 g, 84.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 6H), 1.13 (s, 6H), 1.27 (s, 6H), 1.38 (t, J = 12.74 Hz, 2H), 1.47 (s, 2H), 1.62− 1.71 (m, 2H), 1.94−2.01 (m, 2H), 2.31−2.39 (m, 2H), 4.70 (s, 2H), 5.83−5.89 (m, 1H), 6.83 (d, J = 8.16 Hz, 1H), 6.97 (d, J = 8.16 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 25.6, 28.1, 28.5, 28.7, 34.2, 35.4, 35.8, 43.3, 71.9, 119.6, 123.0, 125.5, 135.2, 139.3, 144.6, 151.7.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00211. Spectral data for all new compounds listed in the paper (PDF)

■

REFERENCES

(1) (a) Harrison, H. R.; Eisenbraun, E. J. J. Org. Chem. 1966, 31, 1294. (b) McMurry, J. E. J. Am. Chem. Soc. 1968, 90, 6821. (c) Allen, H. Can. J. Chem. 1975, 53, 865. (2) (a) Newkome, G. R.; Fishel, D. L. Org. Synth., Collect. 1988, VI, 12. (b) Bildstein, B.; Denifl, P. Synthesis 1994, 1994, 158. (c) Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613. (3) (a) Enders, D. Asymmetric Synth. 1984, 3, 275. (b) Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer, K. A. M. Tetrahedron 1984, 40, 1345. (c) Enders, D.; Plant, A. Liebigs Annalen der Chemie 1991, 1991, 1241. (d) Enders, D.; Nolte, B.; Runsink, J. Tetrahedron: Asymmetry 2002, 13, 587. (4) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735. (5) (a) Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734. (b) Shapiro, R. H. Org. React. 1976, 23, 405. (6) Fulton, J. R.; Aggarwal, V. K.; De Vicente, J. Eur. J. Org. Chem. 2005, 2005, 1479. (7) (a) Barluenga, J.; Moriel, P.; Valdé s, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50, 7486. (c) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50, 7486. (8) (a) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem. - Eur. J. 2008, 14, 4792. (b) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009, 11, 4732. (c) Barluenga, J.; Escribano, M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed. 2010, 49, 6856. (d) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Adv. Synth. Catal. 2010, 352, 3235. (e) Brachet, E.; Hamze, A.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12, 4042. (f) Roche, M.; Hamze, A.; Brion, J.-D.; Alami, M. Org. Lett. 2013, 15, 148. (g) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org. Lett. 2015, 17, 2474. (9) Barluenga, J.; Tomas-Gasama, M.; Aznar, F.; Valdes, C. Adv. Synth. Catal. 2010, 352, 3235. (10) (a) Barluenga, J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem. - Eur. J. 2009, 12, 13291. (b) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2010, 49, 4993. (11) (a) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Chem. - Eur. J. 2010, 16, 12801. (b) Ojha, D. P.; Prahbu, K. R. Org. Lett. 2015, 17, 18. (12) (a) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat. Chem. 2009, 1, 494. (b) Tsoi, Y. K.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 4506. (c) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 46, 1724. (13) (a) Roche, M.; Bignon, J.; Brion, J.-D.; Hamze, A.; Alami, M. J. Org. Chem. 2014, 79, 7583. (b) Zeng, X.; Cheng, G.; Shen, J.; Cui, X. Org. Lett. 2013, 15, 3022. (14) For the use of enol nonaflates, instead of the more difficult to handle triflates, in cross coupling reactions see: (a) Rottlaender, M.; Knochel, P. J. Org. Chem. 1998, 63, 203. (b) Bellina, F.; Ciucci, D.; Rossi, R.; Vergamini, P. Tetrahedron 1999, 55, 2103. (15) Ojha, D. P.; Prabhu, K. R. J. Org. Chem. 2012, 77, 11027. (16) Recently, an elegant transformation combining the principles of the Barluenga reaction with the Cattellani reaction has been published: Zhou, P.-X.; Ye, Y.-Y.; Ma, J.-W.; Zheng, L.; Tang, Q.; Qiu, Y.-F.; Song, B.; Qiu, Z.-H.; Xu, P.-F.; Liang, Y.-M. J. Org. Chem. 2014, 79, 6627. Other examples of the Barluenga reaction in the presence of proximal heteroatoms: Barluenga, J.; Quinones, N.; Cabal, M.-P.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50, 2350.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. E


Palladium-Catalyzed Coupling of Sulfonylhydrazones with

Recommend Documents