Subscriber access provided by WEBSTER UNIV
Letter
Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes Hao Chen, Arup Mondal, Philipp Wedi, and Manuel van Gemmeren ACS Catal., Just Accepted Manuscript • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis
Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes Hao Chen,† Arup Mondal,† Philipp Wedi,† Manuel van Gemmeren*†,‡ † Max Planck Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr (Germany) ‡ Organisch-Chemisches Institut Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster (Germany) ABSTRACT: Aromatic nitriles are key structural units in organic chemistry and thus highly attractive targets for C–H activation. Herein the development of an arene-limited, nondirected C–H cyanation based on the use of two complementary commercially available ligands is reported. The reaction enables the cyanation of arenes by C–H activation in the absence of directing groups and is thus complementary to established approaches. KEYWORDS: C–H activation; Cyanation; Dual-ligand catalysis; Palladium catalysis; Nitriles Aromatic nitriles are highly useful synthetic intermediates as well as important motifs in natural products and pharmacologically active compounds. Thus, it is not surprising that a variety of approaches have been pursued for their synthesis.1 Besides traditional functional group interconversions, such as benzamide to benzonitrile dehydrations, methods starting from non-functionalized arenes and building upon a C–H functionalization or activation are particularly attractive, due to their potential to introduce molecular complexity and utilize more easily available starting materials. Several approaches towards this goal are depicted in Scheme 1A. Firstly, it is not surprising that established methods for the introduction of other functional groups, such as boronic esters or halides, can be combined with the conversion of the respective functionality into a nitrile, e.g. by the Rosenmund-von Braun reaction in the case of aryl bromides (Approach 1).2 While this approach is suited to deliver a variety of aromatic nitriles, it faces the inherent disadvantage of requiring several steps and relying on another C–H functionalization as a source of the required reactivity and selectivity. It should be noted however, that in some cases the preceding functionalization step and the cyanation have elegantly been combined into one-pot procedures, for example by Hartwig and co-workers, who developed a sequence of Ircatalyzed borylation and subsequent Cu-mediated conversion of the resulting boronate esters to nitriles.3 Alternatively, arene C–H cyanations via radical pathways have been developed which, given that the substrate is suitably substituted to stabilize the radical intermediate, can deliver the desired benzonitrile derivatives (Approach 2).4 Two recent variants of these radical-involving processes are particularly noteworthy. McManus and Nicewicz have described a synthetically highly useful method based on photoredox catalysis, which allowed for the cyanation of a wide range of substrates, the regioselectivity being determined by the distribution of partial charges in a radical cation preceding radical formation, thus giving predominantly cyanation in the para- and orthopositions relative to the strongest donor substituent.4d
A
BR2/Hal
Approach 1: indirect synthesis
R
• Several steps required • Selectivity dictated by prefunctionalization method
H R
This work: non-directed C–H activation/cyanation
CN R
• No directing groups (DGs) • Selectivity controlled by sterics/electronics • Ar–H as limiting reagent Approach 2: via radical reactions • Scope limited by need for radical stabilization • Selectivity controlled by radical stability
R
DG CN
Approach 3: directing groups (DGs) • Scope limited by requirement for DG • Selectivity controlled by properties of DG
B Pd-source Pyridine ligand Ac-Gly-OH H
R
olefin
EWG R
•
H CN
R
Proposed mode of action R O N O R Pd R N
H O
Scheme 1. Established approaches for the C–H cyanation of arenes (A) and our proof of concept for the dual ligandenabled nondirected C–H activation of arenes (B). Recently, Gooßen and coworkers have disclosed an electrochemical method for the cyanation of arenes, which likewise proceeds through a sequence of first radical cation and then radical formation and features regioselectivity patterns analogous to the ones reported using photoredox catalysis.4e Thus, a complementary method based on a C–H activation remains highly desirable. However, to date methods based on a C–H activation have remained limited to substrates
ACS Paragon Plus Environment
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
bearing suitable directing groups (DGs) to enable the desired reactivity (Approach 3).5,6 We have recently developed a novel strategy for the Pdcatalyzed nondirected activation of aromatic C–H bonds that is based on the use of two complementary ligands and have applied it to the arene-limited nondirected olefination of arenes (Scheme 1B).7 Herein we report the development of an arene-limited nondirected C–H cyanation of arenes based on this dual ligand approach.8 Starting from the conditions reported in our study on the olefination of arenes, we could, through the introduction of suitable cyanide sources and an extensive optimization of the reaction conditions, develop two complementary sets of reaction conditions for the cyanation of arenes using copper(I) cyanide and zinc cyanide respectively. As can be seen from the results obtained for products 2a and 2b, Conditions A are particularly suited for alkyl-substituted arenes, while Conditions B deliver better results for functionalized arenes (Scheme 2). Having established reaction conditions that enable the nondirected arene-limited cyanation of arenes, we proceeded to explore the scope of our method. It should be noted that for both sets of reaction conditions, the mass balance is mostly accounted for by remaining starting material, although some non-specific decomposition was also observed, as can be seen from the difference between conversion and yield observed during the optimization studies (see the Supporting Information for details). We were pleased to find that benzene can be cyanated to give benzonitrile (2c) in a synthetically useful yield. The products derived of mono-alkyl substituted arenes (2a, 2d-f) were obtained in good yields. The decrease of ortho product from 6% in the toluene-derived product 2a to no detectable orthoproduct formation in the iso-propyl and tert-butyl substituted products 2e and 2f clearly highlights the influence of steric factors on the regioselectivity of the process. The hydrocinnamic acid-derived product 2b and phenethylaminederived products 2g and 2h could be obtained analogously, as well as the product 2i derived from protected phenyl alanine. We next examined the influence of non-alkyl substituents on the arene. A trimethylsilyl-substituent was tolerated by the reaction conditions to give the respective product 2j. The low amount of ortho product observed in this case is in good agreement with the steric demand of this substituent. The anisole-derived product 2k could be obtained under slightly modified reaction conditions and was formed as a mixture of ortho and para regioisomers, thus highlighting the influence of electronic effects on the regioselectivity of the reported method. As expected due to the analogy with our previous study on the olefination of arenes,7 a chloro substituent had an ortho-directing effect and the product 2l derived of chlorobenzene was obtained in an o:m:p-ratio of 46:22:32. We furthermore found that our protocol is suitable for the cyanation of electron-deficient substrates, as highlighted through the cyanation of fluorobenzene, giving 2m in good yield. In light of the particular attractiveness of arene-limited methods for the functionalization of multiply substituted starting materials, we proceeded to evaluate the performance of our method with di- and tri-substituted substrates. Both meta- and ortho-xylene were suitable substrates giving the products 2n and 2o respectively. The observation that 2n was obtained as a 79:21 ratio of regioisomers, while 2o was
Page 2 of 7 H
CF3
CN
Conditions A or B
R
R
N
1
2
L1
Mono-substituted arenes:
CO2Me
2a, 58%a, o:m:p = 6:52:42 38% (GC)b, o:m:p = 6:52:42
2d, 67%a o:m:p = 4:54:42
2b, 31% (GC)a , o:m:p = 12:53:35 71%b, o:m:p = 12:48:40
i-Pr
t-Bu
2e, 69%a m:p = 58:42
2f, 66%a m:p = 59:41
NHAc
2c, 48%a
NPhth
2g, 66%b,d (47%b) o:m:p = 7:53:40
SiMe3
CO2Me NPhth
2h, 51%b,e m:p = 60:40
2j, 51%a o:m:p = 2:63:35
2i, 37%b o:m:p = 9:48:43
Cl
O
F
2l, 47%b o:m:p = 46:22:32
2k, 53%c,f (37%c) o:p = 33:67
2m, 58%b,g (45%)b m:p = 41:59
Di- and tri-substituted arenes:
2n, 52%a : = 79:21
2o, 64%a as sole product
,
O
'
2p, 71%a : = 65:35
NTs '
'
2q, 70%a : = 91:9
NAc
'
Cl
'
2r, 51%b,d (41%b) 2s, 50%b,e (44%b) '(') = :, = 50:50 43:42:15
2t, 47%b,e ' = 50:50
2u, 53%b '' = 54:43:3
F
Cl
'
F ' b 2v, 52% '' = 41:39:16:4
2w, 67%a : > 95:5 3 mmol scale: 59%,
2x, 59%b : = 84:16
2y, 63%b : = 86:14
OMe Br
CO2Me
b
b,g
OMe MeO
2z, 65% : = 79:21
2aa, 29% : = 65:35
c
2ab, 69% : = 82:18
2ac, 61%
OMe b,g
(50%b)
Scheme 2. Scope of the dual ligand-enabled nondirected C–H cyanation of arenes. The reactions in this table were carried out on a 0.2 mmol scale. a Conditions A: Pd(OAc)2 (10 mol%), L1 (20 mol%), N-acetyl glycine (30 mol%), AgF (4 equiv), CuCN (2 equiv), HFIP (2 mL), 90 °C, 18 h. b Conditions B: Pd(OAc)2 (10 mol%), L1 (20 mol%), N-acetyl glycine (30 mol%), AgF (3 equiv), Zn(CN)2 (2 equiv), HFIP (2 mL), 80 °C, 18 h. c Conditions B were used with 2-
ACS Paragon Plus Environment
Page 3 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis methyl-5-nitropyridine instead of L1, due to the formation of inseparable mixtures between the product and L1. d 13 mol% of catalyst were used. e 15 mol% of catalyst were used. f 20 mol% of catalyst and 6 equiv AgF were used. g 20 mol% of catalyst were used.
formed as a single isomer can be rationalized by the competition between electronic and steric effects in the former case, while these effects work in the same direction in the latter case. We next explored fused bicyclic-substrates, leading to the formation of products 2p-t. The products 2p and 2q derived of indane and tetraline respectively were both obtained in good yields and with regioselectivities in favor of the less hindered position, albeit with a lower selectivity than for 2o, which reflects the reduction of steric demand in these substrates. Isochromane and protected tetrahydroisoquinoline could both be converted, giving 2r-t in moderate yield. Disubstituted substrates bearing halide substituents were also found to be tolerated, giving access to the products 2u and 2v with a chloride and fluoride substituent respectively. The trisubstituted product 2w was obtained in good yield and regioselectivity. Importantly, the synthesis of this product was shown to be scalable to a synthetically useful scale, giving a similar result on a 3 mmol scale. The electron deficient halidebearing products 2x-z were all obtained smoothly, while an even stronger electron-withdrawing ester functionality led to a moderate yield (2aa). The reduced reactivity of very electronpoor substrates also explains the perfect selectivity for monocyanation observed in all cases (benzonitrile itself was found to be unreactive as substrate). Finally, the methoxy-substituted products 2ab and 2ac were obtained in good yields. Overall, the studies on the scope of the developed protocol show its applicability to a wide range of substitution patterns as well as a functional group tolerance ranging from a strongly electron-donating methoxy group to moderately electronwithdrawing halide substituents. We could demonstrate that the reaction proceeds under a combined steric and electronic control that enables a high degree of predictability regarding the regioselectivity in future applications of this reaction. Although mixtures of regioisomers were obtained in most cases, high regioselectivity is possible in multiply substituted substrates. Additionally, in the context of late-stage diversification, the generation of mixtures including otherwise challenging to access regioisomers can in fact be an advantage, since it allows the rapid generation of samples that can be used for preliminary evaluation, for example with respect to their pharmacological activity. In this context it is remarkable that for mono-substituted substrates the metaproduct was often observed as the major component, which renders the reaction complementary to the existing methods based on directing groups or radical cation intermediates discussed above.9 Having studied the scope of this transformation, we became interested in further understanding the underlying mechanism, in particular the role of the two complementary ligands and the metal species involved. Towards this goal, we carried out a set of control experiments (Table 1).10 First, we confirmed that both ligands are essential for a satisfying reaction outcome (Entries 1-3). While in absence of N-acetyl glycine, no reaction occurred at all, the omission of L1 led to a drastically reduced yield and worsened o:m:p-selectivity. The use of quinoline instead of L1 still delivered a low yield, but restored the selectivity partially (Entry 4). Importantly, the omission of
the Pd-source led to no product formation (Entry 5). During the optimization of the reaction conditions, product formation was observed in the absence of a Ag-source (see Supporting Information, Scheme S1) and it was confirmed that an identical reaction outcome is obtained when the reaction is conducted in the dark (see Supporting Information, Scheme S6). Together with the fact that different cyanide sources with different metal cations can be used, these observations indicate that palladium is the catalytically active metal, since it is the only metal, which is found to be entirely essential for the reaction to occur. Together with the observed influence of both ligands, we thus propose a complex of palladium bearing both ligands as the active species. In this complex, the Nacetyl glycine would, in analogy to previous studies utilizing N-acylated amino acids as ligands,11 act as internal base in the key concerted metalation-deprotonation step. Due to the bidentate nature of the amino acid-derived ligand, L1 would necessarily be coordinated cis to the site of C–H activation, which is in good agreement with the strong influence of this ligand on the o:m:p-ratio. The pyridine-derived ligand would furthermore help to prevent catalyst decomposition and assist speciation as has been proposed for such ligands in preceding, non-arene-limited protocols.12 Based on this hypothesis, a comparable result would be expected, if the Pd-source and the two ligands were employed in a 1:1:1-ratio. Indeed, when we conducted this experiment, we observed the same o:m:p-ratio as in the reference reaction, albeit with a reduced yield. This suggests that the excess of these ligands employed under the optimized reaction conditions, while not altering the active species, helps to stabilize it or to increase its concentration under the reaction conditions (Entry 6). Although cases of Ag/Pd co-catalysis have been reported,13 the formation of product in the absence of silver indicates that the role of AgF in our reaction system is likely the re-oxidation of the palladium-based active species from Pd(0) to Pd(II) after the product forming step. Finally, we attribute the role of CuCN/Zn(CN)2 as the best reagents for this reaction to the need for control the precise quantity of cyanide anions in solution, which could otherwise act as a highly potent catalyst poison.14,2b,2c,5a,5v Table 1. Mechanistically relevant control experiments.a Pd(OAc)2 (10 mol%), L1 (20 mol%) N-Acetyl glycine (30 mol%)
CN Me
AgF (4 equiv), CuCN (2 equiv) HFIP (2 mL), 90 °C, 18 h
1a
2a
Entry
Deviation
GCYieldb
o:m:pb
1
None
57%
7:52:41
2
No Ac-Gly-OH
-
-
3
No L1
23%
32:31:37
4
Quinoline instead of L1
19%
14:49:37
5
No Pd(OAc)2
-
-
6
L1 (10 mol%), N-acetyl glycine (10 mol%)
17%
6:59:35
7
Addition of KCN (20 mol%)
-
-
a The reactions in this table were carried out on a 0.1 mmol scale. b GC-yields and o:m:p ratios were determined by GC-FID analysis using 1,3,5-trimethoxy-benzene as an internal standard.
ACS Paragon Plus Environment
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Accordingly, when we conducted a reaction in the presence of a catalytic amount of well-soluble KCN under otherwise optimized conditions, no product formation was observed, which highlights that catalyst poisoning is indeed possible under our reaction conditions, when cyanide concentrations become too high (Entry 7).15 At present, we can not fully rationalize the observation that different cyanide sources are best depending on the substrate class, but the sensitivity of the catalytic system to poisoning suggests that the choice of the cyanide source could serve to fine-tune the cyanide concentration.16 Finally, we conducted measurements of the kinetic isotope effect, which indicated that the C–H activation step is rate limiting (Scheme 3). Based on these findings, we propose the catalytic cycle shown in Scheme 3. Accordingly, the catalytically active complex I, consisting of palladium and both ligands employed, would engage in the rate-limiting C–H activation step, leading to an aryl-palladium species II, which would subsequently engage in a ligand exchange to give intermediate III. A subsequent reductive elimination would deliver the product and generate a Pd(0)-species IV, which would then be re-oxidized by the silver source as terminal oxidant, leading to the regeneration of the catalytically active species I. 2 Ag0
KIE Competition experiment:
Ar–H
PdIILn I oxidation rate-limiting C–H activation
2 AgI
kH/kD = 3.6 Separate experiments: kH/kD = 2.5 II
0
Pd Ln
Pd Ln R
IV
Product
reductive elimination
II
C–H Activation via CF3
ligand exchange
N
O N CN–
II
Pd Ln R
R
O Pd
N
H O
III
Scheme 3. Preliminary mechanistic data and proposed catalytic cycle. In summary, we have developed the first example of an arenelimited non directed cyanation of arenes through a C–H activation. The method is based on the use of a Pd(II) catalyst with two complementary commercially available ligands, both of which were shown to be essential for the success of the reaction. The protocol described is applicable to a broad range of substitution patterns and proceeds under a combination of electronic and steric control. The possibility to cyanate substrates bearing electron-donating as well as moderately electron-withdrawing substituents, both of which can be used as the limiting reagents, is expected to render this method attractive in the context of late-stage modification.
AUTHOR INFORMATION Corresponding Author *
[email protected].
Funding Sources We gratefully acknowledge financial support from the Max Planck Society (Otto Hahn Award to M.v.G.), FCI (Liebig Fellowship to M.v.G.), and WWU Münster.
ASSOCIATED CONTENT Supporting Information. Optimization of reaction conditions, experimental procedures, and analytical data for the compounds described. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT We thank the members of our NMR and MS departments for their excellent service. We thank Sabine Bognar and Kiron Kumar Ghosh for proof reading this manuscript. Furthermore, we are indebted to Prof. F. Glorius for his generous support.
ABBREVIATIONS HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol.
REFERENCES (1) (a) Larock, R. C. Comprehensive Organic Transformations: A guide to Functional Group Preparations; 2nd ed.; Wiley-VCH: Weinheim, 1999; (b) Olah, G. A.; Laali, K.; Farnia, M.; Shih, J.; Singh, B. P.; Christe, K. O. Onium Ions. 29. Cyanation and Nitration of Toluene with Cyanamide and Nitramide through Intermediate Cyano- and Nitrodiazonium Ions. Attempted Fluorination of Aromatics with Fluorodiazonium Ion. J. Org. Chem. 1985, 50, 1338-1339; (c) Wang, T.; Jiao, N. Direct Approaches to Nitriles via Highly Efficient Nitrogenation Strategy through C–H or C–C Bond Cleavage. Acc. Chem. Res. 2014, 47, 1137-1145. (2) (a) Ellis, G. P.; Romney-Alexander, T. M. Cyanation of aromatic halides, Chem. Rev. 1987, 87, 779-794; (b) Sundermeier, M.; Zapf, A.; Beller, M. Palladium-Catalyzed Cyanation of Aryl Halides: Recent Developments and Perspectives, Eur. J. Inorg. Chem. 2003, 3513-3526; (c) Anbarasan, P.; Schareina, T.; Beller, M. Recent Developments and Perspectives in Palladium-Catalyzed Cyanation of Aryl Halides: Synthesis of Benzonitriles, Chem. Soc. Rev. 2011, 40, 5049-5067; (d) Najam, T.; Shah, S. S. A.; Mehmood, K.; Din, A. U.; Rizwan, S.; Ashfaq, M.; Shaheen, S.; Waseem, A. An Overview on the Progress and Development on Metals/Non-Metal Catalyzed Cyanation Reactions, Inorg. Chim. Acta 2018, 469, 408-423. (3) (a) Liskey, C. W.; Liao, X.; Hartwig, J. F. Cyanation of Arenes via Iridium-Catalyzed Borylation, J. Am. Chem. Soc. 2010, 132, 11389-11391; (b) Ren, Y.; Yan, M.; Zhao, S.; Wang, J.; Ma, J.; Tian, X.; Yin, W. Selective para-Cyanation of Alkoxy- and Benzyloxy-Substituted Benzenes with Potassium Ferricyanide Promoted by Copper(II) Nitrate and Iodine, Adv. Synth. Catal. 2012, 354, 2301-2308; (c) Zhu, Y.; Zhao, M.; Lu, W.; Li, L.; Shen, Z. Acetonitrile as a Cyanating Reagent: Cu-Catalyzed Cyanation of Arenes, Org. Lett. 2015, 17, 2602-2605. (4) (a) Eberson, L.; Nilsson, S.; Rietz, B. Direct Cyanation of Aromatic Compounds. I. Diazotation of Cyanamide in the Presence of Aromatic Compounds., Acta Chem. Scand. 1972, 26, 3870-3870; (b) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. Direct Cyanation of Heteroaromatic Compounds Mediated by Hypervalent Iodine(III) Reagents: In Situ Generation of PhI(III)−CN Species and Their Cyano Transfer, J. Org. Chem. 2007, 72, 109-116; (c) Shu, Z.; Ji, W.; Wang, X.; Zhou, Y.; Zhang, Y.; Wang, J. Iron(II)-Catalyzed Direct Cyanation of Arenes with Aryl(cyano)iodonium Triflates, Angew. Chem. Int. Ed. 2014, 53, 2186-2189; (d) McManus, J. B.; Nicewicz, D. A. Direct C–H Cyanation of Arenes via Organic Photoredox Catalysis, J. Am. Chem. Soc. 2017, 139, 2880-2883; (e) Hayrapetyan, D.; Rit Raja, K.; Kratz, M.; Tschulik, K.; Gooßen, L. J. Electrochemical C−H Cyanation of Electron-Rich (Hetero)Arenes, Chem. Eur. J. 2018, 24, 11288-11291. (5) (a) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. ChelationAssisted Palladium-Catalyzed Direct Cyanation of 2-Arylpyridine C−H Bonds, Org. Lett. 2009, 11, 4716-4719; (b) Kim, J.; Chang, S. A New Combined Source of “CN” from N,N-Dimethylformamide and Ammonia in the Palladium-Catalyzed Cyanation of Aryl C−H Bonds, J. Am. Chem. Soc. 2010, 132, 10272-10274; (c) Ding, S.; Jiao, N. Direct Transformation of N,N-Dimethylformamide to −CN: Pd-
ACS Paragon Plus Environment
Page 4 of 7
Page 5 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis Catalyzed Cyanation of Heteroarenes via C–H Functionalization, J. Am. Chem. Soc. 2011, 133, 12374-12377; (d) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Copper-Catalyzed Cyanation of Arenes using Benzyl Nitrile as a Cyanide Anion Surrogate, Chem. Commun. 2012, 48, 9933-9935; (e) Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Palladium-Catalyzed C(sp2)–H Cyanation Using Tertiary Amine Derived Isocyanide as a Cyano Source, Org. Lett. 2012, 14, 49664969; (f) Xu, S.; Huang, X.; Hong, X.; Xu, B. Palladium-Assisted Regioselective C–H Cyanation of Heteroarenes Using Isonitrile as Cyanide Source, Org. Lett. 2012, 14, 4614-4617; (g) Chaitanya, M.; Yadagiri, D.; Anbarasan, P. Rhodium Catalyzed Cyanation of Chelation Assisted C–H Bonds, Org. Lett. 2013, 15, 4960-4963; (h) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y. Rhodium-Catalyzed Directed C–H Cyanation of Arenes with N-Cyano-N-phenyl-p-toluenesulfonamide, J. Am. Chem. Soc. 2013, 135, 10630-10633; (i) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Copper-Catalyzed Aromatic C-H Bond Cyanation by C-CN Bond Cleavage of Inert Acetonitrile, Chem. Eur. J. 2013, 19, 16880-16886; (j) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. CopperMediated Direct Aryl C–H Cyanation with Azobisisobutyronitrile via a Free-Radical Pathway, Org. Lett. 2013, 15, 3354-3357; (k) Han, J.; Pan, C.; Jia, X.; Zhu, C. Rhodium-Catalyzed Ortho-Cyanation of Symmetrical Azobenzenes with N-Cyano-N-phenyl-ptoluenesulfonamide, Org. Biomol. Chem. 2014, 12, 8603-8606; (l) Hong, X.; Wang, H.; Qian, G.; Tan, Q.; Xu, B. Rhodium-Catalyzed Direct C–H Bond Cyanation of Arenes with Isocyanide, J. Org. Chem. 2014, 79, 3228-3237; (m) Liu, W.; Ackermann, L. Versatile Ruthenium(II)-Catalyzed C–H Cyanations of Benzamides, Chem. Commun. 2014, 50, 1878-1881; (n) Yan, Y.; Yuan, Y.; Jiao, N. CuMediated C–H Cyanation of Arenes Using N,N-Dimethylformamide (DMF) as the “CN” Source, Org. Chem. Front. 2014, 1, 1176-1179; (o) Yu, D.-G.; Gensch, T.; de Azambuja, F.; Vásquez-Céspedes, S.; Glorius, F. Co(III)-Catalyzed C–H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation, J. Am. Chem. Soc. 2014, 136, 17722-17725; (p) Dong, J.; Wu, Z.; Liu, Z.; Liu, P.; Sun, P. Rhodium(III)-Catalyzed Direct Cyanation of Aromatic C–H Bond to Form 2(Alkylamino)benzonitriles Using N-Nitroso As Directing Group, J. Org. Chem. 2015, 80, 12588-12593; (q) Guan, D.; Han, L.; Wang, L.; Song, H.; Chu, W.; Sun, Z. Direct Cyanation of Picolinamides Using K4[Fe(CN)6] as the Cyanide Source, Chem. Lett. 2015, 44, 743-745; (r) Li, J.; Ackermann, L. Cobalt-Catalyzed C-H Cyanation of Arenes and Heteroarenes, Angew. Chem. Int. Ed. 2015, 54, 3635-3638; (s) Pawar, A. B.; Chang, S. Cobalt-Catalyzed C–H Cyanation of (Hetero)arenes and 6-Arylpurines with N-Cyanosuccinimide as a New Cyanating Agent, Org. Lett. 2015, 17, 660-663; (t) Zhang, L.; Lu, P.; Wang, Y. Copper-Mediated Cyanation of Indoles and Electron-Rich Arenes Using DMF as a Single Surrogate, Org. Biomol. Chem. 2015, 13, 8322-8329; (u) Chen, Z.-B.; Zhang, F.-L.; Yuan, Q.; Chen, H.-F.; Zhu, Y.-M.; Shen, J.-K. α-Iminonitrile: A New Cyanating Agent for the Palladium Catalyzed C–H Cyanation of Arenes, RCS Adv. 2016, 6, 64234-64238; (v) Bag, S.; Jayarajan, R.; Dutta, U.; Chowdhury, R.; Mondal, R.; Maiti, D. Remote meta-C–H Cyanation of Arenes Enabled by a Pyrimidine-Based Auxiliary, Angew. Chem. Int. Ed. 2017, 56, 12538-12542. (6) While this manuscript was under consideration for publication, two contemporary studies on the nondirected cyanation of arenes appeared online as accepted articles: (a) Zhao, D.; Xu, P.; Ritter, T. Palladium-Catalyzed Late-Stage Direct Arene Cyanation, Chem, 2019, 5, 97-107. (b) Liu, L.-Y.; Yeung, K.-S.; Yu, J.-Q. Ligand-Promoted Non-Directed C–H Cyanation of Arenes, Chem. Eur. J., early view, DOI: 10.1002/chem.201805772. (7) (a) Chen, H.; Wedi, P.; Meyer, T.; Tavakoli, G.; van Gemmeren, M. Dual Ligand-Enabled Nondirected C−H Olefination of Arenes, Angew. Chem. Int. Ed. 2018, 57, 2497-2501. For contemporary studies on the nondirected arene-limited C–H olefination of arenes, see: (b) Naksomboon, K.; Valderas, C.; GómezMartínez, M.; Álvarez-Casao, Y.; Fernández-Ibáñez, M. Á. S,OLigand-Promoted Palladium-Catalyzed C–H Functionalization Reactions of Nondirected Arenes, ACS Catal. 2017, 7, 6342-6346; (c) Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P.
T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. LigandAccelerated Non-Directed C–H Functionalization of Arenes, Nature 2017, 551, 489-493. (8) For selected reviews on nondirected C–H activation, see: (a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Beyond Directing Groups: Transition-Metal-Catalyzed C–H Activation of Simple Arenes, Angew. Chem. Int. Ed. 2012, 51, 1023610254; (b) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C–H Bond Functionalization: Challenges and Opportunities, ACS Cent. Sci. 2016, 2, 281-292; (c) Wedi, P.; van Gemmeren, M. AreneLimited Nondirected C-H Activation of Arenes, Angew. Chem. Int. Ed. 2018, 57, 13016-13027. (9) While we have isolated the mixtures of regioisomers during our scope studies, in order to obtain data on the overall yield and unperturbed information on the regioselectivity, we could demonstrate on selected examples (2d, 2e, 2p) that the separation of the isomers is possible through chromatographic techniques. For details, see the Supporting Information. (10) Table 1 shows the results obtained using Conditions A. Analogous results were obtained for the synthesis of 2b using Conditions B. For details, see the Supporting Information. (11) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Pd(II)-Catalyzed Olefination of Electron-Deficient Arenes Using 2,6-Dialkylpyridine Ligands, J. Am. Chem. Soc. 2009, 131, 5072-5074; (b) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Remarkably High Reactivity of Pd(OAc)2/Pyridine Catalysts: Nondirected C-H Oxygenation of Arenes, Angew. Chem. Int. Ed. 2011, 50, 9409-9412; (c) Zhang, S.; Shi, L.; Ding, Y. Theoretical Analysis of the Mechanism of Palladium(II) Acetate-Catalyzed Oxidative Heck Coupling of Electron-Deficient Arenes with Alkenes: Effects of the Pyridine-Type Ancillary Ligand and Origins of the metaRegioselectivity, J. Am. Chem. Soc. 2011, 133, 20218-20229; (d) Kubota, A.; Emmert, M. H.; Sanford, M. S. Pyridine Ligands as Promoters in PdII/0-Catalyzed C–H Olefination Reactions, Org. Lett. 2012, 14, 1760-1763; (e) Engle, K. M.; Yu, J.-Q. Developing Ligands for Palladium(II)-Catalyzed C–H Functionalization: Intimate Dialogue between Ligand and Substrate, J. Org. Chem. 2013, 78, 8927-8955; (f) Cook, A. K.; Sanford, M. S. Mechanism of the Palladium-Catalyzed Arene C–H Acetoxylation: A Comparison of Catalysts and Ligand Effects, J. Am. Chem. Soc. 2015, 137, 31093118. (12) (a) Malkov, A. V.; Hand, J. B.; Kočovský, P.; A LongRange Chiral Relay via Tertiary Amide Group in Asymmetric Catalysis: New Amion Acid-Derived N,P-Ligands for CopperCatalysed Conjugate Addition, Chem Commun. 2003, 15, 1948-1949; (b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Ligand-Accelerated C−H Activation Reactions: Evidence for a Switch of Mechanism, J. Am. Chem. Soc. 2010, 132, 14137-14151; (c) Cheng, G.-J.; Yang, Y.-F.; Liu, P.; Chen, P.; Sun, T.-Y.; Li, G.; Zhang, X.; Houk, K. N.; Yu, J.Q.; Wu, Y.-D. Role of N-Acyl Amino Acid Ligands in Pd(II)Catalyzed Remote C–H Activation of Tethered Arenes, J. Am. Chem. Soc. 2014, 136, 894-897; (d) Cheng, G.-J.; Chen, P.; Sun, T.-Y.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D. A Combined IM-MS/DFT Study on [Pd(MPAA)]-Catalyzed Enantioselective C-H Activation: Relay of Chirality through a Rigid Framework, Chem. Eur. J. 2015, 21, 1118011188; (e) Zhong, X.-M.; Cheng, G.-J.; Chen, P.; Zhang, X.; Wu, Y.D. Mechanistic Study on Pd/Mono-N-protected Amino Acid Catalyzed Vinyl–Vinyl Coupling Reactions: Reactivity and E/Z Selectivity, Org. Lett. 2016; 18, 5240-5243 (f) Yang, Y.-F.; Hong, X.; Yu, J.-Q.; Houk, K. N. Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups, Acc. Chem. Res. 2017, 50, 2853-2860; (g) Zhao, L.; Zhou, S.; Tong, J.; Wang, J.; Liu, H. Asymmetric Synthesis of Chiral Trifluoromethyl Containing Heterocyclic Amino Acids, Chinese J. Chem. 2017, 35, 1540-1548; (h) Park, Y.; Niemeyer, Z. L.; Yu, J.-Q.; Sigman, M. S. Quantifying Structural Effects of Amino Acid Ligands in Pd(II)Catalyzed Enantioselective C–H Functionalization Reactions, Organometallics 2018, 37, 203-210; (i) Liu, X.; Dong, S.; Lin, L.; Feng, X. Chiral Amino Acids-Derived Catalysts and Ligands, Chinese J. Chem. 2018, 36, 791-797.
ACS Paragon Plus Environment
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
(13) (a) Politova, T. I.; Gal’vita, V. V.; Belyaev, V. D.; Sobyanin, V. A. Non-Faradaic Catalysis: The Case of CO Oxidation Over Ag-Pd Alloy Electrode in a Solid Oxide Electrolyte Cell, Catalysis Lett. 1997, 44, 75-81; (b) Radev, L.; Khristova, M.; Mehandjiev, D.; Sumuneva, B. Sol-Gel Ag + Pd/SiO2 as a Catalyst for Reduction of NO with CO, Catalysis Lett. 2006, 112, 181-186; (c) Lee, S. Y.; Hartwig, J. F. Palladium-Catalyzed, Site-Selective Direct Allylation of Aryl C–H Bonds by Silver-Mediated C–H Activation: A Synthetic and Mechanistic Investigation, J. Am. Chem. Soc. 2016, 138, 15278-15284; (d) Whitaker, D.; Burés, J.; Larrosa, I. Ag(I)Catalyzed C–H Activation: The Role of the Ag(I) Salt in Pd/AgMediated C–H Arylation of Electron-Deficient Arenes, J. Am. Chem. Soc. 2016, 138, 8384-8387; (e) Lotz, M. D.; Camasso, N. M.; Canty, A. J.; Sanford, M. S. Role of Silver Salts in Palladium-Catalyzed Arene and Heteroarene C–H Functionalization Reactions, Organometallics 2017, 36, 165-171; (f) Gao, X.; Zhou, Y.; Jing, F.; Luo, J.; Huang, Q.; Chu, W. Layered Double Hydroxides Derived ZnO-Al2O3 Supported Pd-Ag Catalysts for Selective Hydrogenation of Acetylene, Chinese J. Chem. 2017, 35, 1009-1015; (g) Bay, K. L.; Yang, Y.-F.; Houk, K. N. Multiple Roles of Silver Salts in PalladiumCatalyzed C–H Activations, J. Organomet. Chem. 2018, 864, 19-25. (14) Sundermeier, M.; Zapf, A.; Beller, M. A Convenient Procedure for the Palladium-Catalyzed Cyanation of Aryl Halides, Angew. Chem. Int. Ed. 2003, 42, 1661-1664. (15) (a) Bertz, S. H.; Fairchild, E. H. Copper(I) Cyanide, Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; John Wiley & Sons Ltd. 2001; (b) Heaney, H. Zinc Cyanide, Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; John Wiley & Sons Ltd. 2001; (c) Haroutounian, S. A. Potassium Cyanide, Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; John Wiley & Sons Ltd. 2001. (16) The use of HFIP as solvent was found to be crucial in this reaction. The unique suitability of this solvent for selective C–H activation processes has been well documented. Multiple rationalizations such as possible hydrogen bonds with the catalytically active species or an ideal balance of solubilizing ability and polarity offered by this solvent have been proposed, but no conclusive statement can be made regarding the precise role of this solvent in such reactions. For reviews on the role of HFIP in C–H activation, see: (a) Wencel-Delord, J.; Colobert, F. A Remarkable Solvent Effect of Fluorinated Alcohols on Transition Metal Catalysed C–H Functionalizations, Org. Chem. Front. 2016, 3, 394-400; (b) Sinha, S. K.; Bhattacharya, T.; Maiti, D. Role of hexafluoroisopropanol in C‒H activation, React. Chem. Eng. 2019, advance article, DOI: 10.1039/C8RE00225H.
ACS Paragon Plus Environment
Page 6 of 7
Page 7 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis
Preferred TOC Graphic Pd(OAc)2, Ac-Gly-OH CF3 H R
N CN-source Ag-salt
CN R
• Arene as limiting reagent • No need for directing groups • Steric/electronic control
Alternative TOC: Pd(OAc)2, Ac-Gly-OH CF3 H R
N CN-source Ag-salt
CN R
• Arene as limiting reagent • No need for directing groups • Steric/electronic control
ACS Paragon Plus Environment
