Letter Cite This: Org. Lett. 2018, 20, 3745−3748
pubs.acs.org/OrgLett
Pyrimidine as an Aryl C−H Activating Group Sahaj Gupta,† Jennifer A. Melanson,† Louis Vaillancourt,‡,§ William A. Nugent,‡,# Gerald J. Tanoury,*,‡ Gabriele Schatte,† and Victor Snieckus*,† †
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States
‡
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S Supporting Information *
ABSTRACT: The Pd-catalyzed regioselective C−H activation/arylation, /iodination, and/acetoxylation reactions of 4arylpyrimidines using aryl iodides, N-iodosuccinimide, and (diacetoxyiodo)benzene respectively as coupling partners are described. Suzuki−Miyaura coupling and Sonogashira reactions of the resulting aryl iodides are demonstrated. The scalability of the C−H activation/functionalization starting with readily accessible 4-aryl pyrimidines is also reported.
I
Scheme 1. Aromatic C−H Activation Reaction
n the past two decades, transition metal catalyzed reactions have become a dominant theme in organic synthesis.1 As part of the cross-coupling reaction landscape, which was initially established for C−C bond formation using C−halogen2 and C− M partners (M = B,3 Zn,4 Mg,5 Sn,6 Si7) under transition metal catalysis, there has been an expansion to include a large number of C−H partners.1c The seminal results of Murai paved the way for the C−H activation reactions that lead to C−C bond formation, many of which we now rely on as routine chemical transformations.8 More recently, this area has evolved into a robust and active area for synthetic chemists9 and expanded into C−O,10 C−N,11 and C−S12 bond activation processes. Among the multitude of opportunities presented by the C−H activation concept, the use of the directing group (DG) effect of a pyridine moiety for diverse functionalization has received voluminous attention (Scheme 1b).1c However, few reports are available for other heterocycles such as pyrazoles,1c,13 pyrrolidin-2-ones,14 quinolines,15 and isoquinolines.16 To the best of our knowledge, pyrimidine-directed C−H activation reactions have been mainly limited to C−H bonds of 2-aryl pyrimidines (Scheme 1c).17 In 1997, Murai and co-workers demonstrated one example of the Ru(III)-catalyzed C−H propynylation of 4-phenylpyrimidine using CO and ethylene gases under high pressure and temperature (20 atm at 160 °C).18c Subsequently, Nakamura also employed 4-phenylpyrimidine in the Fe(III)-catalyzed arylation reaction with excess PhMgBr furnishing a monophenyl product in 18% yield.18b Požgan et al. used a highly reactive Ru(II) carboxylate catalyst system generated in situ from [RuCl2(p-cymene)]2 and 1-phenyl-1-cyclopentanecarboxylic acid to achieve predominantly diarylation of 4-phenylpyrimidine by employing various bromo- and chloro-arenes as coupling partners.18a Herein we report the first Pd-catalyzed C−H activation/ arylation reactions illustrating the 4-pyrimidinyl N-DG effect, which afford predominantly monoarylated products (Scheme 1d). Furthermore, we demonstrate the first corresponding iodination and acetoxylation reactions. After pyridines, pyr© 2018 American Chemical Society
imidines are the next most commonly reported heterocycles in medicinal chemistry.19 Additionally, biaryl and aryl-heteroaryl skeletons are found in many key compounds in material and life sciences.20 As a whole, the results presented herein provide new methodology for the functionalization of an important class of bioactive and medicinally vital heterocycles.19,20 To initiate the study, we set forth to optimize our initial observation of the reaction of pyrimidine 1a, prepared by a Suzuki−Miyaura cross-coupling tactic (see Supporting Information (SI)), with 4-iodoanisole 2a following selected conditions that are commonly used in the C−H activation of heteroaromatic Received: April 24, 2018 Published: June 13, 2018 3745
DOI: 10.1021/acs.orglett.8b01300 Org. Lett. 2018, 20, 3745−3748
Letter
Organic Letters systems21 (Table 1; for the complete study, see SI). The use of catalytic Pd(OAc)2 in acetic acid, either in combination with or in
Scheme 2. Substrate Scope for C−H Activation/Arylation Reaction of Pyrimidines 1a−s
Table 1. Pyrimidine 1a C−H Activation/Arylation Reaction: Optimization of Conditions
entry
catalyst
oxidant
time
3a, % yielda,b
d
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(MeCN)2(BF4)2 Pd(TFA)2 Pd(OAc)2
− K2S2O8 Oxone Cu(OAc)2 AgOAc AgOCOCF3 AgOCOCF3 AgOCOCF3 AgOCOCF3
5d 5d 5d 5d 5d 2h 2h 2h 15 h
−c − −c 25 46 52 44 43 46
1 2d 3d 4d 5d 6e 7e 8e 9f,g a
Yields of isolated compounds. b1a was recovered (15−40% yield) in a number of cases (see SI). c10−18% conversion of 1a to 3a by GCMS analysis. dHeated at 130 °C in AcOH. eMicrowave irradiation at 170 °C in EtCOOH. fHeated at 170 °C in EtCOOH. g2.5 equiv of 2a were used.
the absence of oxidant, led to decomposition or low conversion (entries 1−3). Employing Cu(OAc)2 as an oxidant22 led to the isolation of the diazatetraaryl derivative 3a in low yield (entry 4). Adapting Daugulis’ conditions,21a which use AgOAc, to the aforementioned reaction afforded reasonable conversion and modest yield of the expected product (entry 5). Further modification of the palladium catalyst employed (entries 7 and 8), the silver salt additive (see SI), the equivalents of 2a (entry 9), and a change in solvent to propionic acid provided our optimized reaction conditions (entries 6 and 9). Based on the optimization results, the substrate scope for the C−H activation reaction was investigated (Scheme 2). Treating 6-unsubstituted systems 1b, 1d, and 1e with electron-rich 4iodoanisole 2a afforded products 3f, 3h, and 3g, respectively, in modest yields. Likewise, substrates bearing electron-withdrawing character (i.e., 4-iodoacetophenone 2b) gave a similar result forming 3b in 38% yield. The use of excess 2a (2.5−5.0 equiv) with 1f under the prescribed reaction conditions led to the formation of diarylated product 3i′ (see SI). To minimize formation of product 3i′, decreased amounts of reagent 2 (1.5 equiv) were used when employing substrates 1f−k under the reaction conditions. With the focus turned toward 6-substituted pyrimidines, the 6-phenyl 1a and 6-t-Bu (1f−j) derivatives were then investigated. There was no discernible trend observed when considering electron-withdrawing group (EWG) or electrondonating group (EDG) effects on the iodoaryl partner 2a−c in the formation of product 3i, 3m, and 3n. Thus, the 4-OMe, 4COMe, and 4-CF3 iodo benzenes 2a, 2b, and 2c in C−H activation/coupling reactions with the 6-phenyl 1a and 6-t-Bu 1f−j pyrimidines afforded a yield range (37−58%) similar to that of corresponding products 3a and 3i−o. Thus, the 6-substituted pyrimidines undergo more efficient coupling compared to 6unsubstituted substrates 1b−e, which afforded 3b−h in lower yields (25−39%, Scheme 2). This may be attributed to the interference of the remote nitrogen group by causing nonproductive coordination to the metal atom.18b The failure of 1m
a
Yield of isolated product. bCorresponding pyrimidine 1 was recovered in 10−38% yields. c2.5 equiv of 2a−c were used. d1.5 equiv of 2a−c were used. e5.0 equiv of 2a were used. fDiarylated product 3i′ was also isolated in 22−39% yield (see SI). gNo reaction.
to provide the desired product (3r) under the prescribed reaction conditions indicates that these conditions are not favorable for use with substrates bearing substituents at the ortho position due to steric hindrance. Heteroatom containing substituents (SMe, NHBn, pyridinyl, thienyl, and indolyl) are not tolerated under the reaction conditions, presumably due to potential nonproductive coordination to the Pd-catalyst which prevents the delivery of the arylated products 3s−w. The C−H activation−arylation results (vide supra) prompted investigation of other forms of C−H activation/functionalization of the aryl pyrimidines. Iodination23 and acetoxylation24 reactions were chosen on the basis of the further functionalization potential of derived products. After considerable trials on pyrimidine 1f under various iodination conditions (see Table, S2), use of NIS and catalytic Pd(OAc)2 in 1,4-dioxane at 100 °C proved optimal. Under these conditions, the scope of the reaction was further probed (Scheme 3). The t-Bu pyrimidines 1f−j, designed to hinder catalyst complexation at the alternate N1 site, afforded the corresponding products 4a−e and 4g,h in reasonable synthetic yields. No significant variation in yields was observed as a function of electron-donating 1o (R = 4-OMe) or -withdrawing 1h (R = 4-F) groups. Although no reaction was observed for 1m (R = 2-Me), presumably due to steric effects, the 2-thiomethyl derivative 4g was obtained without incident, and the 6-CF3 (4i) and 6-phenyl (4j) derivatives were prepared in modest yields. 3746
DOI: 10.1021/acs.orglett.8b01300 Org. Lett. 2018, 20, 3745−3748
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Organic Letters
calculations on the conformer energetics of 3a′, see SI. Further, Sonogashira coupling of 4a led smoothly to the formation of product 7, which may possibly be used as an intermediate for the synthesis of fused helicene compounds.27 Optimized conditions (HOAc/Ac2O or dioxane) for the palladium-catalyzed acetoxylation reaction were established using 1f as the substrate (see SI), and the reaction was generalized for a variety of substrates (Scheme 5). The presence
Scheme 3. Scope of the C−H Activation/Iodination Reaction: Synthesis of Pyrimidines 4a−ja,b
Scheme 5. Scope of the C−H Activation/Acetoxylation Reaction: Synthesis of Pyrimidines 9a−j
a
Yield of isolated product. reaction.
b
Reaction time in parentheses. cNo
Using our iodinated products, we were able to explore additional reactivity (Scheme 4). Thus, anhydrous Suzuki− Scheme 4. Suzuki−Miyaura Reaction and Sonogashira Reaction of Iodopyrimidines 4a and 4j′ a
Yield of isolated product. bNo reaction.
of electron-donating (1o) or -withdrawing (1h) groups has no significant influence on the outcome, and the corresponding products 9c and 9d were obtained in similar yields. A steric effect was evident in the case of 1m (R3 = 2-Me), affording product 9f in 45% yield. Unfortunately, 1j (R2 = H) and 1n (R2 = SMe) failed to give corresponding products 9i and 9j for reasons not currently understood. With the aim of demonstrating scalability, we undertook 1 g (4.4 mmol) scale C−H arylation, iodination, and acetoxylation reactions of substrate 1f to obtain 3x (44%), 4a (63%), and 9a (76%), respectively (Scheme 6). These yields are comparable to those obtained on the 0.66−0.88 mmol scale.
Miyaura cross-coupling of mono- and di-iodo derivatives 4a and 4j′ with commercially available 4-methoxyphenyl boronic acid 525 furnished high yields of products 3i and 3a′, respectively. Aryl-substituted pyrimidines 8 (R = 4-Ar), with close resemblance to our substrate 3a′, are known to exhibit electroluminescent properties.26 The structure of 3a′ was determined using single crystal X-ray diffraction analysis (Figure 1). The analysis revealed that the asymmetric unit contains two
Scheme 6. Scale-up Reactions of Pyrimidine 1f
Figure 1. X-ray crystal structure (ORTEP diagram) of 3a′. Hydrogen atoms are omitted for clarity. The thermal ellipsoids are shown at the 50% probability level.
In conclusion, our present report establishes a new and general methodology for the direct ortho-arylation of 4-aryl pyrimidines with aryl iodides, which is mediated by a pyrimidinyl nitrogen directed C−H activation reaction. In addition, it provides new reactions for ortho-iodination and acetoxylation that are promoted by the same DG effect. In addition, the derived systems have been shown to be useful in further Suzuki−Miyaura and Sonogashira processes. The ready availability of the 4-aryl pyrimidine starting materials contributes to facilitating scale-up processes. The use and application of the reported methodology in the synthesis of bioactive and material science related molecules may be anticipated.
molecules of 3a′. The molecules differ in the orientation of the OMe group attached to the phenyl rings labeled as [C23, C24, C25, C26, C27, C28] (molecule A) and [C63, C64, C65, C66, C67, C68] (molecule B). A π−π interaction is observed between pairs consisting of two molecules of A related by symmetry (inversion and translation) and involves one of the aromatic rings attached to the pyrimidine ring (see SI). The distance of separation between the ring centroids is 3.769(11) Å. For DFT 3747
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Organic Letters
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8081. See also Cluster of papers, prefaced by: (c) Tobisu, M.; Chatani, N.; Snieckus, V. Synlett 2017, 28, 2559. (11) (a) Wang, Q.; Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45, 1257. (b) Ouyang, K.; Hao, W.; Zhang, W. X.; Xi, Z. Chem. Rev. 2015, 115, 12045. (12) (a) Pan, F.; Shi, Z. J. ACS Catal. 2014, 4, 280. (b) Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599. (13) For selected references on pyrazole-directed C−H activation, see: (a) Teskey, C. J.; Sohel, S. M. A.; Bunting, D. L.; Modha, S. G.; Greaney, M. F. Angew. Chem., Int. Ed. 2017, 56, 5263. (b) Li, Y. G.; Wang, Z. Y.; Zou, Y. L.; So, C. M.; Kwong, F. Y.; Qin, H. L.; Kantchev, E. A. B. Synlett 2017, 28, 499. (c) Doherty, S.; Knight, J. G.; Addyman, C. R.; Smyth, C. H.; Ward, N. A. B.; Harrington, R. W. Organometallics 2011, 30, 6010. (14) For selected references on pyrolidin-2-one-directed C−H activation, see: (a) Yeung, C. S.; Dong, V. M. Synlett 2011, 2011, 974. (b) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1, 331. (15) For selected references on quinoline-directed C−H activation, see: (a) Wang, H.; Yu, S.; Qi, Z.; Li, X. Org. Lett. 2015, 17, 2812. (b) Zhang, Y.; Feng, J.; Li, C. J. J. Am. Chem. Soc. 2008, 130, 2900. (16) For selected references on isoquinoline-directed C−H activation see: (a) Su, L.; Guo, D. D.; Li, B.; Guo, S. H.; Pan, G. F.; Gao, Y. R.; Wang, Y. Q. ChemCatChem 2017, 9, 2001. (b) Zhang, P.; Hong, L.; Li, G.; Wang, R. Adv. Synth. Catal. 2015, 357, 345. (17) (a) Nareddy, P.; Jordan, F.; Szostak, M. Org. Lett. 2018, 20, 341. (b) Zhu, X.; Su, J. H.; Du, C.; Wang, Z. L.; Ren, C. J.; Niu, J. L.; Song, M. P. Org. Lett. 2017, 19, 596. (c) Du, C.; Li, P. X.; Zhu, X.; Suo, J. F.; Niu, J. L.; Song, M. P. Angew. Chem., Int. Ed. 2016, 55, 13571. (d) Wu, Q.; Du, C.; Huang, Y.; Liu, X.; Long, Z.; Song, F.; You, J. Chem. Sci. 2015, 6, 288. (e) Lu, M. Z.; Lu, P.; Xu, Y. H.; Loh, T. P. Org. Lett. 2014, 16, 2614. (f) Punji, B.; Song, W.; Shevchenko, G. A.; Ackermann, L. Chem. - Eur. J. 2013, 19, 10605. (g) Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Synlett 2010, 2010, 313. (h) Cheng, K.; Zhang, Y.; Zhao, J.; Xie, C. Synlett 2008, 2008, 1325. (i) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (j) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (18) To date the pyrimidine directed C−H activation on aryl attached to C4 has been demonstrated only in three instances: (a) Štefane, B.; Fabris, J.; Požgan, F. Eur. J. Org. Chem. 2011, 2011, 3474. (b) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858. (c) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 2604. (19) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451. (20) Seki, M. Org. Process Res. Dev. 2016, 20, 867. (21) (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (22) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (23) (a) Aiso, H.; Kochi, T.; Mutsutani, H.; Tanabe, T.; Nishiyama, S.; Kakiuchi, F. J. Org. Chem. 2012, 77, 7718. (b) Huang, C.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Adv. Synth. Catal. 2011, 353, 1285. (c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (24) (a) Lakshman, M. K.; Zajc, B. ARKIVOC 2018, 2018, 252 and references therein. (b) Lu, W.; Xu, H.; Shen, Z. Org. Biomol. Chem. 2017, 15, 1261. (c) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790. (d) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (25) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899. (26) Schafer, T.; Bujard, P.; Rogers, J.; Bardon, K. PCT Int. Appl. WO 2004039786A1. (27) (a) Mohamed, R. K.; Mondal, S.; Guerrera, J. V.; Eaton, T. M.; Albrecht-Schmitt, T. E.; Shatruk, M.; Alabugin, I. V. Angew. Chem., Int. Ed. 2016, 55, 12054. (b) Feng, X.; Wu, J.; Ai, M.; Pisula, W.; Zhi, L.; Rabe, J. P.; Müllen, K. Angew. Chem., Int. Ed. 2007, 46, 3033.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01300. Full experimental details (PDF) NMR and HRMS spectra (PDF) Accession Codes
CCDC 1822991 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Victor Snieckus: 0000-0002-6448-9832 Present Addresses §
NMX Research and Solutions Inc., 500 Cartier Blvd. W., Laval, Québec, H7 V 5B7, Canada. # Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was funded by the Natural Sciences and Engineering Research Council of Canada−Collaborative Research and Development (NSERC−CRD).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01300 Org. Lett. 2018, 20, 3745−3748
