Modular Access to Triarylethylene Units from Arylvinyl MIDA

Letter pubs.acs.org/OrgLett

Modular Access to Triarylethylene Units from Arylvinyl MIDA Boronates Using a Regioselective Heck Coupling R. N. Khanizeman,†,‡ E. Barde,† R. W. Bates,‡ A. Guérinot,*,† and J. Cossy*,† †

Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation, (CBI)-UMR 8231 ESPCI Paris/CNRS/PSL* Research University, 10 rue Vauquelin, Paris 75231 Cedex 05, France ‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 S Supporting Information *

ABSTRACT: A palladium-catalyzed, silver-mediated Heck coupling between arylvinyl MIDA boronate esters and aryl iodides is disclosed. The reaction provides an efficient and modular access to a range of 1,1-diaryl alkenyl MIDA boronates that can be easily transformed into triarylethylene compounds through a Suzuki coupling.

T

and an aryl halide would appear to be an attractive strategy to access these triarylethylene units.9 Nevertheless, the Heck reaction is usually performed on terminal olefins, and 1,2disubstituted alkenes were shown to be challenging substrates. As a consequence, only a few examples of Heck coupling applied to 1,2-diarylalkenes have been described to access triarylethylene products, and most of them are restricted to (E)-stilbene (Scheme 1, eq 1).10−13 In a recent work, we showed that N-

he triarylethylene motif is present in a myriad of molecules that find application in various areas ranging from the pharmaceutical industry to optics. Numerous triarylethylene derivatives possess interesting biological activities, the most famous being the estrogen receptor antagonist (Z)-tamoxifen, which is used in the treatment of breast cancer.1 The COX-2 inhibitor 1 is another example of a bioactive triarylethylene compound (Figure 1).2 In addition, the highly conjugated π-

Scheme 1. Access to Triarylethylene Derivatives Using Heck Coupling

Figure 1. Bioactive triarylethylene compounds.

system provides attractive optical properties to the molecule. Thus, some strong blue-light emitting products incorporating a triarylethylene subunit have been identified and could be used as dyes in OLED devices.3 Some organic dyes based on a triarylethylene motif could also be used as organic sensitizers in solar cells.4 Due to the application of triarylethylene derivatives in such expanding and dynamic fields, various methods have been developed for their synthesis.5 Carbometalation6 and hydroarylation7 of 1,2-diaryl alkynes have been developed, but due to regioselectivity issues, they are generally restricted to symmetrical internal alkynes. Metal-catalyzed Csp2−Csp2 crosscouplings between an alkenyl halide and an aryl organometallic constitute one of the most powerful reactions to access triarylethylene derivatives in a stereospecific fashion.8 However these reactions required the synthesis of a functionalized trisubstituted alkene (halide or organometallic partner). A Heck coupling between a functionalized 1,2-disubstituted alkene © 2017 American Chemical Society

methyliminoacetic acid (MIDA) boronates14 were compatible with Heck reaction conditions.15 In the course of our studies toward the preparation of polyunsaturated building blocks, we decided to investigate the Heck coupling between 1,2disubstituted alkenes 1 and aryl halides (Scheme 1, eq 2). We envisioned taking advantage of the presence of the MIDA boronate on the Heck product to access triarylethylene products using a subsequent Suzuki cross-coupling. The reaction between phenylvinyl MIDA boronate 1a and 1‑iodo-4-methylbenzene was first investigated, and pleasingly, the conditions that we recently reported for the Heck coupling between alkenes and vinyl iodo MIDA boronate appeared promising [Pd(OAc)2, AgOAc, CH3CN]. Indeed, when 1a was treated with 1 equiv of 1-iodo-4-methylbenzene in the presence Received: July 20, 2017 Published: September 22, 2017 5046

DOI: 10.1021/acs.orglett.7b02218 Org. Lett. 2017, 19, 5046−5049

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Organic Letters

Table 2. Para-Substituted Aryl Iodides in Heck Reaction with 1a

of Pd(OAc)2 (10 mol %) and AgOAc (1.5 equiv) in CH3CN, after 18 h at 100 °C, an encouraging 86% conversion of 1a into the Heck products 3a and 4a was reached. The two regioisomers were formed in a 5:1 ratio, and the major product was obtained as a 14:1 mixture of E/Z-isomers (Table 1, entry 1).16 However, the Table 1. Optimization of the Conditions

entry

2a (equiv)

time (h), temp (°C)

conv of 1aa (%)

3a/4ab (yield, %)

1 2 3

1 3 1.5

18, 80 18, 80 5, 130

86 100 87

5:1 (nd)c 5:1(85, 14)c 4:1 (nd)

a

Estimated using 1H NMR of the crude. bRatio estimated using 1H NMR of the crude reaction mixture, isolated yields. c3a obtained as a 14:1 E/Z mixture.

entry

2

R

3 (yield, %, E/Z)a

4 (yield, %)b,c

1 2 3 4 5 6 7 8 9 10 11 12

2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m

OMe NH2 NHBoc CF3 F Br C(O)Me CO2Et CONHBn CONBn2 CN NO2

3b (93, 12:1) 3c (0) 3d (73, >20:1) 3e (78, 20:1) 3f (73, 8:1) 3g (70, 12:1) 3h (72, 12:1) 3i (73, 40:1) 3j (0) 3k (86, >20:1) 3l (0) 3m (0)

4b (7) 4c (0) 4d (8) 4e (21) 4f (8) 4g (17) 4h (26) 4i (16) 4j (0) 4k (7) 4l (0) 4m (0)

a

Heck products could not be separated from the remaining starting material, and consequently, some efforts were dedicated to finding conditions allowing the completion of the reaction. Fortunately, an increase of the amount of the aryl iodide partner (3 equiv) proved beneficial, and the Heck products 3a and 4a were isolated in 85% and 14% yield, respectively (Table 1, entry 2).17−19 Increasing the temperature to 130 °C in the presence of 1.5 equiv of the aryl iodide led to an incomplete conversion of 1a (87%), and no improvement was observed even after 13 h (Table 1, entry 3).20 Finally, to investigate the scope of the reaction, we decided to use 3 equiv of the aryl iodide and to heat the reaction at 80 °C for 18 h (Table 1, entry 2) to ensure total consumption of the starting material and avoid purification issues.21 A panel of para-substituted aryl iodides was first evaluated in the Heck reaction with 1a under the previously optimized conditions. Electron-rich aryl iodides such as 4-iodoanisole proved particularly reactive, and the Heck reaction proceeded in a quantitative yield. Fortunately, the two regioisomeric products could be separated by flash chromatography and isolated (Table 2, entry 1). In contrast, when 1a was reacted with 4-iodoaniline, no conversion of the starting material was observed, probably due to catalyst poisoning upon coordination by the free amine (Table 2, entry 2). Protection of the aniline function as a carbamate restored the reactivity, allowing the isolation of the coupling product with a good yield of 73% (Table 2, entry 3). The influence of other electron-withdrawing substituents on the iodide partner was then examined. When a trifluoromethyl group was present, a global quantitative yield was obtained, and the major regioisomer 3e could be isolated in good yield (78%) (Table 2, entry 4). The reaction conditions tolerate the presence of halogen atoms (F, Br) on the aromatic ring of the aryl iodide partner (Table 2, entries 5 and 6). Interestingly, when 1-iodo-4bromobenzene was involved in the reaction, a chemoselective coupling of the iodide occurred, delivering the Heck products 3g and 4g in 70% and 17% yield, respectively.22 The presence of a bromine atom on these latter compounds could offer opportunities for further functionalizations. The influence of a carbonyl para-substituent was then evaluated, and the reaction between 1a and 4-iodoacetophenone delivered the expected product in 72% yield (Table 2, entry 7). An ester group was well tolerated as 2i provided the pure major regioisomer 3i with a good yield of 73% (Table 2, entry 8).23 In contrast, when the

c

Isolated yields; E/Z ratio determined by 1H NMR. bIsolated yields. Mixture of E/Z-isomers.

reaction was attempted with iodide 2j, possessing a secondary amide, no conversion of the phenyl vinyl boronate 1a was observed (Table 2, entry 9). Gratifyingly, with a tertiary amide on the aryl iodide, the reaction proceeded well, providing the major Heck product in good yield (86%) (Table 2, entry 10). Some limitations to the coupling were identified such as the presence of a cyano or a nitro group, which were not compatible with the reaction conditions (Table 2, entries 11 and 12). In both cases, very low conversion of the starting material was observed and a deactivation of the catalyst was hypothesized. Despite these negative results, the reaction remains quite general, tolerating a broad range of electron-donating and electron-withdrawing groups in the para position of the aryl iodide partner. The coupling proceeded with a good regioselectivity and the major regioisomers were always obtained with good to excellent selectivity in favor of the E-isomer. The influence of the position of the substituent on the aryl iodide was then studied, and several meta-substituted aryl iodides were involved in the Pd-catalyzed Heck coupling with 1a. When 1-iodo-3-methylbenzene or 1-iodo-3-methoxybenzene were involved in the reaction, the major regioisomers 6a and 6b were formed with excellent yields as major E-isomers (Table 3, entries 1−2). As previously, the minor regioisomers 7a and 7b Table 3. meta-Substituted Aryl Iodides in Heck Reaction with 1a

a

entry

5

R

6 (yield, %, E/Z)a

7 (yield, %)a,b

1 2 3 4

5a 5b 5c 5d

Me OMe Br CO2Me

6a (85, >20:1) 6b (90, nd)c 6c (73, 13:1) 6d (72, 7:1)

7a (15) 7b (9) 7c (26) 7d (25)

Isolated yields. determined. 5047

b

Mixture of E/Z-isomers.

c

E/Z could not be

DOI: 10.1021/acs.orglett.7b02218 Org. Lett. 2017, 19, 5046−5049

Letter

Organic Letters could also be isolated resulting in a global quantitative yield for the Heck coupling. The presence of a bromine atom on the aryl iodide was still tolerated even if, in this case, a slight drop in the stereo- and regioselectivity was observed (Table 3, entry 3). A similar result was obtained with an ester substituent at the meta position of the aryl iodide (Table 3, entry 4). Disappointingly, the reaction was sensitive to steric hindrance as only partial conversion of the phenyl vinyl boronate 1a was obtained using ortho-substituted aryl iodides as partners (Table 4, entries 1 and 2).24

Table 5. Heck Reaction between PhI and Various Boronates

entry 1 2 3

1 1b 1c 1d

R p-CO2Me m-Me m-CO2Me

3−6 (yield %, Z/E)a b

3n (79, >20:1) 6a (87, >20:1)b 6d (85, >20:1)b

13 (yield, %)a 13d (11)b 13e (4) 13f (0)c

a

Isolated yields. bContaminated with traces of 3n. c13f was not observed in the crude 1H NMR.

Table 4. Ortho-Substituted Aryl Iodides in Heck Reaction with 1a

tolerated and the Z-Heck products were obtained with excellent yield and regioselectivity (Table 5, entries 2 and 3). Finally, a palladium-catalyzed Suzuki coupling was performed between various vinyl boronates resulting from a Heck coupling and a diversity of (hetero)aryl halides (Table 6).26 Thus, a panel

a

entry

8

R

conv of 1aa (%)

1 2

8a 8b

OMe CO2Me

39 53

Table 6. Suzuki Coupling toward Triaryethylene Frameworks*

Estimated on the 1H NMR of the crude mixture.

Heteroaromatic iodides were then evaluated in the Heck coupling with vinyl MIDA boronate 1a (Scheme 2). UnfortuScheme 2. Heteroaryl Iodides in Heck Reaction with 1a

nately, 2-iodopyridine 11a was totally unreactive under the optimized conditions, and the phenyl vinyl boronate 1a was recovered. A deactivation of the palladium catalyst upon coordination of the nitrogen atom was suspected. To decrease the Lewis basicity of the nitrogen in the pyridine moiety, a chlorine atom was introduced at C2 and the reaction between 2‑chloro-5-iodopyridine and 1a was investigated. Under the previous conditions, a low conversion of 1a into 12b (15%) was estimated by 1H NMR analysis. Interestingly, adding a catalytic amount of triphenylphosphine as a ligand (12 mol %) improved the conversion of 1a to 54%, and only one regioisomer was formed. The Heck product could be separated from the starting material and was isolated with a yield of 53% as a 3:1 mixture of E/Z-isomers. Three alkenyl boronates, differing in the substituents of the aryl group, were then reacted with iodobenzene under the optimized conditions. Interestingly, the major Heck products were obtained as the Z-isomers.25 Boronate 1b, which possesses an ester group at the para position, reacted smoothly with iodobenzene affording Z-3n (Table 5, entry 3). However, the formation of the regioisomer 13d was also observed. Substituents at the meta position such as a methyl or an ester group were well

*

Conditions A: Pd(OAc)2 (8 mol %), SPhos (17 mol %), NaOH 1 M (2.5 equiv), rt, THF. Conditions B: Pd(OAc)2 (5 mol %), SPhos (10 mol %), K3PO4 3 M (7.5 equiv), 60 °C, dioxane. aTraces of the Zisomer were observed on the 1H NMR after purification.27

of triarylethylene compounds were prepared with good to excellent yields. Worthy of note, heteroaryl moieties could be introduced efficiently using the Suzuki coupling, compensating for the lower functional tolerance of the Heck reaction (Table 6, entries 4 and 5). In summary, an efficient Heck coupling between phenyl vinyl MIDA boronate and aryl iodides has been developed. The reaction generally proceeded with high yields, good regio-, chemo-, and stereoselectivity. A range of substituents is tolerated on both partners including a bromine atom. The MIDA boronate could be involved in a subsequent Suzuki cross-coupling with aryl (hetero)halides, affording an easy and modular access to triaryl substituted alkenes. Thus, this combination of two efficient and flexible palladium-catalyzed reactions could appear as a 5048

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Tetrahedron 2011, 67, 2815. (e) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (f) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122. (10) Selected examples of Heck reaction on (E)-stillbene and derivatives: (a) Limberger, J.; Poersch, S.; Monteiro, A. L. J. Braz. Chem. Soc. 2011, 22, 1389. (b) Nunes, C. M.; Limberger, J.; Poersch, S.; Seferin, M.; Monteiro, A. L. Synthesis 2009, 2009, 2761. (c) Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2003, 2003, 1091. (d) Calò, V.; Nacci, A.; Monopoli, A.; Cotugno, P. Angew. Chem., Int. Ed. 2009, 48, 6101. (e) Bolliger, J. L.; Blacque, O.; Frech, C. M. Chem. - Eur. J. 2008, 14, 7969. (f) Lee, D.-H.; Taher, A.; Hossain, S.; Jin, M.-J. Org. Lett. 2011, 13, 5540. (g) Sharma, D.; Kumar, S.; Shil, A. K.; Guha, N. R.; Bandna; Das, P. Tetrahedron Lett. 2012, 53, 7044. (h) Yu, L.; Huang, Y.; Wei, Z.; Ding, Y.; Su, C.; Xu, Q. J. Org. Chem. 2015, 80, 8677. (11) Double-Heck reactions on styrenic compounds have also been reported to access triarylethylene derivatives; see, for example: (a) Xu, D.; Lu, C.; Chen, W. Tetrahedron 2012, 68, 1466. (b) Sharma, D.; Kumar, S.; Shil, A. K.; Guha, N. R.; Bandna; Das, P. Tetrahedron Lett. 2012, 53, 7044. (c) Li, Y.; Liu, G.; Cao, C.; Wang, S.; Li, Y.; Pang, G.; Shi, Y. Tetrahedron 2013, 69, 6241. (12) Heck reactions on 1,1-diarylalkenes have also been reported to access triarylethylene derivatives; see, for example: (a) Yi, C.; Hua, R. Tetrahedron Lett. 2006, 47, 2573. (b) Wu, S.; Ma, H.; Jia, X.; Zhong, Y.; Lei, Z. Tetrahedron 2011, 67, 250. (c) Liu, P.; Pan, Y.-M.; Hu, K.; Huang, X.-C.; Liang, Y.; Wang, H.-S. Tetrahedron 2013, 69, 7925. (d) Guastavino, J. F.; Budén, M. E.; Rossi, R. A. J. Org. Chem. 2014, 79, 9104. (13) For double-Heck reactions on vinyl pinacol borane or vinyl silane, see: (a) Itami, K.; Tonogaki, K.; Ohashi, Y.; Yoshida, J.-I. Org. Lett. 2004, 6, 4093. (b) Tonogaki, K.; Soga, K.; Itami, K.; Yoshida, J.-I. Synlett 2005, 11, 1802. (c) Itami, K.; Ohashi, Y.; Yoshida, J.-I. J. Org. Chem. 2005, 70, 2778. (14) (a) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084. (c) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961. (d) Close, A. J.; Kemmitt, P.; Emmerson, M. K.; Spencer, J. Tetrahedron 2014, 70, 9125. (15) Cornil, J.; Echeverria, P.-G.; Phansavath, P.; RatovelomananaVidal, V.; Guérinot, A.; Cossy, J. Org. Lett. 2015, 17, 948. (16) To explain the major formation of 3a over 4a, we hypothesized that during the carbometalation step the Pd may insert at the most hindered position α to the BMIDA while the aryl group may move to the β position. Indeed, the Pd−C bond is longer than the C−C bond and consequently less sensitive to steric hindrance; see: Heck, R. F. In Organotransition Metal Chemistry: a Mechanistic Approach; Academic Press: New York, 1974; p 100. (17) X-ray diffraction performed on 3a confirmed the geometry of the double bond; see the Supporting Information. (18) No reaction occurred when 1-bromo-4-methylbenzene was used. (19) When the phenyl vinyl pinacol boronate was used instead of 1a, 3a was obtained with a low yield of 16%. (20) Several tests were performed under microwave irradiations, but incomplete conversions of 1a were obtained with 1.5 equiv of 3a; see the Supporting Information for details. (21) The Heck reaction between 1a and 2a could be performed on 1 mmol of 1a to afford the coupling product in 66% yield. (22) For other examples of chemoselective Heck (Br over I), see: Tao, W.; Nesbitt, S.; Heck, R. F. J. Org. Chem. 1990, 55, 63. (23) The presence of a carboxylic acid on the aryl iodide was not detrimental to the reaction but made the purification difficult as the two regioisomers could not be separated. (24) In both cases, a mixture of the two regioisomers was formed. (25) The major isomers obtained are in accordance with the classical Heck mechanism. (26) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961. (27) The Z-isomer present in the starting material was converted to the corresponding Z-coupling product, which was partially removed through purification.

straightforward method for the construction of a library of triarylethylene derivatives.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02218. Experimental procedures and spectral data for all new compounds (PDF) X-ray data for (E)-3a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

A. Guérinot: 0000-0002-7002-8215 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS R.N.K. and R.W.B. thank NTU for financial support. REFERENCES

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