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Nickel-Catalyzed 1,2-Aminoarylation of Oxime Ester-Tethered Alkenes with Boronic Acids Hai-Bin Yang, Stalin R. Pathipati, and Nicklas Selander ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03432 • Publication Date (Web): 08 Nov 2017 Downloaded from http://pubs.acs.org on November 8, 2017
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Nickel-Catalyzed 1,2-Aminoarylation of Oxime Ester-Tethered Alkenes with Boronic Acids Hai-Bin Yang, Stalin R. Pathipati, and Nicklas Selander* Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, SE-106 91 Stockholm, Sweden ABSTRACT: A nickel-catalyzed 1,2-aminoarylation of oxime ester- tethered alkenes with boronic acids was developed. A variety of pyrroline derivatives were synthesized in good yields via the successive formation of C(sp3)-N and C(sp3)-C(sp2) bonds. For cyclobutanone-derived oxime esters, the reaction provided aliphatic nitriles incorporating an aromatic group in the γ-position. A mechanism involving iminyl radical and carbon-centered radical intermediates was proposed. KEYWORDS: Aminoarylation, Nickel Catalysis, Oximes, Pyrrolines, Radicals
Five-membered N-heterocycles (e.g., pyrrolidine, pyrrole, and imidazole) as privileged structural motifs can be found in more than 3000 biologically active compounds, including >500 marketed drugs, according to the PubChem database. Thus, it is highly desirable to develop general and practical methodologies to access such targets.1 Among those, Wolfe developed an elegant Pd-catalyzed 1,2-aminoarylation of δ,εunsaturated amine derivatives with aryl halides for the synthesis of pyrrolidines.2 In addition to this strategy, involving a nucleophilic amino source, an umpolung approach using γ,δunsaturated oxime derivatives as amino source has recently received an increased attention.3 An important advantage of this strategy is the reliable 3-step preparation of the γ,δunsaturated oxime derivatives from methyl ketones.4 In addition, the cyclization products contain an imine moiety as a useful handle for further transformations, as demonstrated in the synthesis of cycloheptylprodigiosin5 and gelsenicine.6 The N-O bond cleavage of γ,δ-unsaturated oxime derivatives with transition metals (e.g., palladium,7 copper8 and iron9) followed by an intramolecular aminative functionalization delivers diverse molecules incorporating a pyrroline moiety. Among these protocols, palladium catalysis plays an important role since the alkyl-Pd intermediate formed after cyclization (A to B, Scheme 1a) can be coupled with external nucleophiles to rapidly access various N-heterocycles. In the pioneering work by Narasaka, it was demonstrated that γ,δunsaturated oximes led to the formation of pyrroles as the major product, through a β-H elimination process using Pd catalysis (Scheme 1a).10 Recently, the Bower group discovered that the selectivity can be altered by varying the substrate, ligand or metal to provide pyrrolines as the major product (Scheme 1a).8a,11 Additionally, Watson and Bower independently expanded the Pd-catalyzed intramolecular aza-Heck reaction to include hydroxamate derivatives.12 In 2015, Bower reported an elegant Pd-catalyzed 1,2aminoarylation of oxime ester-tethered alkenes with pinacol arylboronates and other boron reagents (Scheme 1b).13 However, the protocol is limited to 1,1-disubstituted terminal alkenes due to competing β-H elimination. Furthermore, the protocol is not efficient for electron-poor arylboronates. The same issue with β-H elimination exists in the Pd-catalyzed
iminohalogenation of oxime ester-tethered alkenes, reported by Tong (Scheme 1b).14
Scheme 1. Cyclization of γ,δ-Unsaturated Oxime Esters for the Synthesis of Five-membered N-Heterocycles To overcome the long-standing challenge of β-H elimination in cross-coupling reactions, nickel catalysis is a promising solution. The Baran and Weix groups have demonstrated the reduction of the N-O bond in NHPI esters using Ni-complexes to provide carbon-centered radical intermediates.15 For transmetallation-based reactions, the higher energy of the vacant d-orbital of nickel is important to avoid competing β-H elimination processes.16 As a part of our research program on radical transformations of N-O bonds,9,17 we envisaged a 1,2aminoarylation of oxime ester-tethered alkenes with boronic
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acids to be possible through Ni-catalysis. We hypothesized a NiI/NiIII pathway,18 involving iminyl radical C19 and the carbon-centered radical D as key intermediates (Scheme 1c). Although nickel-catalyzed cross-coupling reactions are well established, existing protocols are focused on the formation of C-C bonds.20 Moreover, the reactivity of iminyl radicals under nickel catalysis has remained unexplored. The key challenge in developing new reactions based on this concept lies in controlling the reactivity of intermediates C and D (Scheme 1c). The combination of iminyl radical C with a NiII species may lead to imine side products through reductive elimination.21 Furthermore, the highly reactive alkyl radical D can easily abstract an H-atom from the reaction media instead of recombining with the productive NiII species.22 We commenced our studies on the cross-coupling of γ,δunsaturated oxime ester 1 with boronic acid 2a (Table 1).23 Table 1. Selected Screening Data
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Table 2. Substrate Scopea N R1
OBzF
Z R2 1 (0.20 mmol)
2 (0.60 mmol)
boronic acids N Ph
Ph
3a, 72% (L1, 36 h) 2.80 mmol scale Ph
F
3d, 52% (L1, 24 h)
Ph
OMe
N
Ph
Br
3h, 38% (L1, 24 h) 3h, 68% (L3, 24 h) Cl N Ph
Ac
N
N
3 N
N R
Ac
3j, 53% (L1, 48 h)
N
N
Ph
N 3l, 62% (L1, 24 h) Me
3k, 31% (L1, 36 h)
R4
Z
3f, R= OMe, 57% (L1, 24 h) 3g, R= Me, 62% (L1, 24 h) N Ph
3i, 51% (L1, 24 h) Ph
3 R2 R
3c, 40% (L1, 24 h) Br 3c, 55% (L3, 24 h) Ph
3e, 61% (L1, 24 h)
N
Ph
N
N
R1
Et3N (10.0 equiv) 1,4-dioxane (6.0 mL), 90 oC
3b, 51% (L1, 24 h)
N
Ph
NiBr2 (20 mol%) L1 or L3 (20 mol%)
R4 B(OH)2
+
R3
3m, 63%b (L1, 24 h) 3m, 75%b/56% (L3, 24 h)
oxime esters R
N
S
N Ph
3n, R = Cl, 60% (L1, 24 h) 3o, R = OMe, 67% (L1, 24 h)
entry
1, R1
catalyst
ligand
T (oC)
3a/4/5 (%)
1
1a, Bz
NiCl2·glyme
L1
80
25/10/5
2
1b, BzF
NiCl2·glyme
L1
80
45/34/5
3
1b, BzF
NiBr2
L1
80
67/18/12
3r, 67% (L1, 24 h)
4
1b, Bz
F
Ni(OTf)2
L1
80
40/45/15
N
5
1b, BzF
Ni(COD)2
L1
80
0/0/0
6
1b, BzF
NiBr2
L2
80
45/14/25
7
1b, BzF
NiBr2
L3
80
65/15/10
8
1b, BzF
NiBr2
L4
80
43/15/16
9
1b, BzF
NiBr2
L5
80
28/13/29
10
1b, BzF
NiBr2
L6
80
44/14/22
11
1b, BzF
NiBr2
L1
70
64/25/10
12
1b, BzF
NiBr2
L1
90
70/12/10
13b
1b, BzF
NiBr2
L1
90
80/11/7
a
a
1
Yields determined by H NMR analysis using 1,3,5trimethoxy benzene as an internal standard. BzF = 2,3,4,5,6pentafluoro-benzoyl. b3.0 mL 1,4-dioxane was used.
By reacting 1a and 2a in the presence of NiCl2·glyme, Et3N, and ligand L1 in 1,4-dioxane at 80 oC, pyrroline 3a was obtained in 25% yield along with 4 (formed via imine hydrolysis) and 5 as side products in 10% and 5% yield, respectively (Table 1, entry 1). The conversion of substrate 1a was slow, even at elevated temperatures. However, changing the R group of oxime ester 1 from Bz to the perfluorinated analogue BzF led to a higher yield (45%) of 3a (Table 1, entry 2). Further screening of other nickel(II) salts showed NiBr2 to be a better catalyst, obtaining 3a in 67% yield (Table 1, entry 3). With the electron-poor ligand L3, a comparable yield of 3a (65%) was obtained (Table 1, entry 7). The yield of 3a increased to 80%, with a slight suppression of 4 and 5, upon performing the reaction with L1 at 90 oC and by dilution (Table 1, entry 13). With the optimized reaction conditions in hand, we continued to investigate the substrate scope with respect to various boronic acids and oxime esters (Table 2).23
O
3p, 62% (L1, 24 h)
Ph 3q, 60% (L1, 24 h)
N
N Ph
Ph
Ph
3u, 32% (L1, 24 h) 3u, 55% (L3, 24 h) N
N
Ph
Me Ph
3y, 25% (L1, 24 h) 3y, 45% (L3, 24 h) 3y, 53%d
N Ph
Ph
Me
Me 3s, 64% (L1, 24 h) N
3t, 82% (L1, dr = 1.4:1, 24 h) Ph N Ph
R
Ph Me Me 3v, R = Me, 71% (L1, dr = 2.8:1, 24 h) 3x, 40% 3w, R =Ph, 10% (L1, 24 h)c (L1, dr =1.5:1, 48 h) Ph Me N N Ph Ph C6F5 N 3z, 30% (L1, 24 h) 3z, 0%d
Ac
O 3aa, 65% (L1, 24 h)
a
Isolated yields. bNMR yield. cSolvent: tBuOH. dPd2(dba)3 (5 mol%), P(3,5-(CF3)2C6H3)3 (20 mol%), ArBPin (2.0 equiv), Et3N (2.0 equiv), DMF, 80 oC, 14 h.
Upon performing the cross-coupling of 1b and phenylboronic acid on a larger scale (2.80 mmol), 3a was isolated in 72% yield. Various substituted arylboronic acids (OMe, Br, F, Ac, Me) participated in the reaction with oxime ester 1b, affording the desired pyrrolines 3b-3i in moderate to good yields. Interestingly, the previously unexplored ligand L3 performed better than L1 (less of side product 4, 15% vs. 30% for 3h) for bromine-substituted phenylboronic acids (3c and 3h). Furthermore, the reaction is suitable for fused aromatic, heteroaromatic and vinylic boronic acids, providing diverse pyrrolines 3j-3m in 31-75% yield. Next, we investigated the reaction employing various oxime esters (Table 2, 3n-3z and 3aa). For aryl- and heteroarylsubstituted oxime esters (R1), the reaction proceeded well to provide 3n-3s in 60-67% yield, without any noticeable electronic effects.24 Product 3t was obtained in a higher yield (82%, 1.4:1 dr) possibly due to a closer proximity of the olefin motif. For aliphatic substituents (R1 = Bn), L3 gave a higher yield of 3u (55%) than L1 (32%). However, a mixture of
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products was obtained when R1 = Me. Non-terminal alkenes were also investigated; the reaction provided 3v and 3w in 71% (2.8:1 dr) and 10% yield, respectively. For the cyclic alkene substrate, the reaction provided cross-coupling product 3x in 40% yield (1.5:1 dr), rather than a Heck-type product. Compared to Bower’s protocol13 for the arylation of 1,1disubstituted olefinic substrates, our protocol was less efficient for phenylboronic acid (3y, 45% vs. 53%) while it performed better for an electron-poor boronic acid (3z, 30% vs. 0%). We were also pleased to find that an amidooxime, previously unexplored in cross-coupling reactions, could be transformed into the arylated imidazoline derivative 3aa (65% yield).25 Inspired by Uemura’s seminal work26 on the ring-opening of cyclobutanone derived O-acyloximes with palladium, and our recent study on the iron-catalyzed cross-coupling with silyl enol ethers,9 we subjected 1r to the standard reaction conditions. The construction of a new C(sp3)-Ar bond took place efficiently to provide nitriles 6a-c in high yields (Scheme 2), representing the first Suzuki-type reaction via a ring-opening of an O-acyloxime to produce an electrophilic coupling partner.
Scheme 2. Synthesis of Aliphatic Nitriles
N p-tol
OCOC6F5 N COC6F5 1q
3,4,5-trimethoxyphenylboronic acid (3.0 equiv) NiBr2 (20 mol%) L1 (20 mol%) Et3N (10.0 equiv) 1,4-dioxane 90 oC, 24 h
O p-tol
OMe
N HN
ABI-274, 61%
Co(OAc)2 (20 mol%) NHPI (40 mol%) O2, EtOAc
p-tol
OMe
N
N OMe C6F5OC 3ab, 32% OMe 1) NaOH (3.0 equiv), MeOH 2) (COCl)2 (1.0 equiv) DMSO (2.0 equiv) Et3N (4.5 equiv), DCM p-tol
OMe OMe
OMe
N HN
OMe 10, 47%
OMe
Scheme 4. Total Synthesis of ABI-274 To probe for insights into the reaction mechanism, a series of experiments were conducted (Scheme 5).31
Scheme 5. Mechanistic Probing Experiments
Several synthetic transformations were carried out to demonstrate the product utility. Pyrroline 3a underwent a quantitative [3+2] cycloaddition with N-hydroxybenzimidoyl chloride to yield the biologically relevant 1,2,4-oxadiazoline 7.27 Furthermore, the corresponding pyrrole 8, and pyrrolidine 9 were accessed through a Pd/C-catalyzed aromatization28 and a DIBAL-mediated reduction11a (Scheme 3).
Scheme 3. Synthetic Applications of 3a. To further demonstrate the synthetic utility of our protocol, we targeted the total synthesis of ABI-274, a potent tubulin inhibitor, effective for multidrug resistant cancer cells.29 Our synthetic strategy commenced from compound 1q, which underwent a cross-coupling with (3,4,5trimethoxyphenyl)boronic acid to provide compound 3ab in 32% yield. Removal of the protecting group, followed by a Swern oxidation, yielded imidazole 10 in 47%. The target compound ABI-274 was obtained in 61% yield via a Co/NHPI-mediated selective aerobic oxygenation.30 Although the total yield is low, as for the reported synthesis,29a our strategy offers an alternative route for the synthesis of ABI analogues (Scheme 4).
When performing the 1,2-aminoarylation reaction of oxime ester 1b in the presence of 1.0 equiv of TEMPO, product 3a was not detected (Scheme 5a). Instead, TEMPO adduct 12 was isolated in 42% yield, indicating the plausibility of carboncentered radical D, presumably forming in a 5-exo-trig cyclization of iminyl radical intermediate C (Scheme 1). Upon subjecting the saturated analogue 1s to the standard reaction conditions, imines 13 and 14 were obtained in 68% and 6% yield, respectively (Scheme 5b). By the addition of tBuSH as a hydrogen atom donor, the yield of 13 decreased, indicating the possibility of an iminyl radical (C) to be involved.32 Furthermore, the involvement of a brominated pyrroline intermediate (c.f., Scheme 1b) was ruled out.31 Based on the observations above and that Ni0 was ineffective for the reaction (Table 1, entry 5), a NiI/NiIII catalytic cycle via radical intermediates C and D (Scheme 1c) is proposed.31 The existence of C and D reflects the intrinsic mechanistic difference with the Pdcatalyzed reaction.13 However, alternative pathways can not be ruled out at this point.33 In summary, a nickel-catalyzed 1,2-aminoarylation of oxime ester-tethered alkenes with boronic acids was developed. The reaction displays a broad scope, with respect to both coupling partners, for the synthesis of pyrroline derivatives. The protocol was also extended to imidazolines, and arylated aliphatic nitriles using a cyclobutanone-derived oxime ester. Mechanistic probing experiments indicated the likeliness of iminyl and carbon-centered radicals to be involved. The results demonstrate the utility of Ni-catalysis for radical coupling reactions using oxime esters, and the protocol displays several synthetic advantages over Pd-catalyzed transformations of oxime ester derivatives.
AUTHOR INFORMATION
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Corresponding Author * E-mail:
[email protected] Notes The authors declare no competing financial interests.
ASSOCIATED CONTENT Supporting Information. Experimental details, characterization data, NMR spectra (PDF) This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT Financial support from the Swedish Research Council, VR (6212012-2981), the Carl Trygger foundation, and the Wenner-Gren Foundations is gratefully acknowledged.
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Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016, 352, 801−805. (16) Koga, N.; Obara, S.; Kitaura, K.; Morokuma, K. J. Am. Chem. Soc. 1985, 107, 7109−7116. (17) Yang, H.-B.; Selander, N. Org. Biomol. Chem. 2017, 15, 1771−1775. (18) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126, 8100−8101. (19) (a) Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2008, 81, 539−547. (b) Walton, J. C. Acc. Chem. Res. 2014, 47, 1406−1416. (c) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603−1618. (20) Leading references: (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726−14727. (b) Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387−2390. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340−1341. (d) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076−8077. (e) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698−3699. Selected recent examples: (f) García-Domínguez, A.; Li, Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835−6838. (g) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Science 2016, 354, 1265−1269. (h) Juliá-Hernández, F.; Moragas, T.; Cornella, J.; Martin, R. Nature 2017, 545, 84−88. (i) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. J. Am. Chem. Soc. 2017, 139, 5313−5316. (j) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D. H.; Wei, F. L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213−218. (k) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc. 2017, 139, 5684−5687. (l) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org. Lett. 2017, 19, 2150−2153. (m) Wu, K.; Doyle, A. G. Nat. Chem. 2017, 9, 779−784. (n) Weires, N. A.; Baker, E. L.; Garg, N. K. Nat Chem 2016, 8, 75−79. (o) Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Angew. Chem. Int. Ed. 2016, 55, 15544−15548. (p) Eno, M. S.; Lu, A.; Morken, J. P. J. Am. Chem. Soc. 2016, 138, 7824−7827. (q) Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Angew. Chem. Int. Ed. 2016, 55, 6730−6733. (r) Tobisu, M.; Takahira, T.; Morioka, T.; Chatani, N. J. Am. Chem. Soc. 2016, 138, 6711−6714. (s) Rezazadeh, S.; Devannah, V.; Watson, D. A. J. Am. Chem. Soc. 2017, 139, 8110−8113. (21) (a) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947−1950. (b) Yue, H.; Guo, L.; Liao, H.-H.; Cai, Y.; Zhu, C.; Rueping, M. Angew. Chem. Int. Ed. 2017, 56, 4282−4285. (22) Yotsuji, K.; Hoshiya, N.; Kobayashi, T.; Fukuda, H.; Abe, H.; Arisawa, M.; Shuto, S. Adv. Synth. Catal. 2015, 357, 1022−1028. (23) For additional screening data, see the Supporting Information. For substrates giving a lower yield of 3, we observed an increased amount of 4 and 5; no starting material 1 could be recovered. (24) Portela-Cubillo, F.; Lymer, J.; Scanlan, E. M.; Scott, J. S.; Walton, J. C. Tetrahedron 2008, 64, 11908−11916. (25) Zaman, S.; Mitsuru, K.; Abell, A. D.; Org. Lett. 2005, 7, 609−611. (26) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049−12050. (27) Dannhardt, G.; Mayer, K. K.; Sommer, I. Sci. Pharm. 1984, 52, 280−290. (28) Geier, G. R.; Grindrod, S. C. J. Org. Chem. 2004, 69, 6404−6412. (29) (a) Chen, J.; Wang, Z.; Li, C.-M.; Lu, Y.; Vaddady, P. K.; Meibohm, B.; Dalton, J. T.; Miller, D. D.; Li, W. J. Med. Chem. 2010, 53, 7414−7427. (b) Wang, J.; Chen, J.; Miller, D. D.; Li, W. 2014, WO 2014/138279. (c) Dalton, J. T.; Miller, D. D.; Ahn, S.; Chen, J.; Duke, C.; Li, C.; Li, W.; Lu, Y.; Wang, Z. 2011, WO 2011/109059. (30) Hruszkewycz, D. P.; Miles, K. C.; Thiel, O. R.; Stahl, S. S. Chem. Sci. 2017, 8, 1282−1287. (31) For additional details and a full proposed mechanism, see the Supporting Information. (32) (a) Dang, H.-S.; Roberts, B. P. Tetrahedron Lett 1995, 36, 2875−2878. (b) Le Tadic-Biadatti, M.-H.; Callier-Dublanchet, A.-C.; Horner, J. H.; Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997, 62, 559−563.
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ACS Catalysis
(33) An alternative Nii/NiII/NiIII catalytic cycle involving an aminometallation can be found in the Supporting Information.
Insert Table of Contents artwork here
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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
TOC 81x32mm (300 x 300 DPI)
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a) Pd-catalyzed Narasaka–Heck cyclization of γ,δ-unsaturated oxime esters10-11
Page 7 of 13 R2 OBz
F
Pd
ACS Catalysis OBzF PdII
N
R2
R2
b
H
R1 PdII Ha
R2
pyrroline
β-Hb elimination R2 +
1N N N HN 2 1 1 R R R1 pyrrole R1 A B 3 β-Ha elimination 4 b) Pd-catalyzed intramolecular aminative functionalization of γ,δ-unsaturated oximes13-14 52e- mechanism OCOR N 61 N R2 R1 N R2 NaX, Pd R ArBPin, Pd 1 7 R Ar = Ph or X Ar R2 ≠ H e-rich hetAr 8 X = I, Br, Cl 1,1-disubst. olefins c) 9 This work: Ni-catalyzed 1,2-aminoarylation of oxime ester-tethered alkenes with R-B(OH)2 SET mechanism 10 F Ni N OBz R1 N R2 R3 11 R4 B(OH)2 + 1 3 R12 Z R Z Z = C, N R4 R4 = Ar, hetAr, vinyl R2 = H, Alk 13 R4NiIL SET NiILX 14 R4NiIILX 15 R1 N R2 R3 R1 N R2 R4NiIILX 16R1 N R3 Z Z NiIIILX 17 Z R3 R2 R4 E D 18 C 4NiIILX R mechanistically distinct from Pd "H " 19 (HAT) NiILX more viable boronic acid reagents 20 R4 ACS Paragon Plus Environment 1st case of Ni-catalyzed reaction R1 N R2 21R1 N R3 involving nitrogen-centered radical Z 1st case of C(sp3)-N bond formation 22 Z R2 3 R
using Ni-catalysis
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
NOAc
+
1r (0.20 mmol)
Ar B(OH)2 2 (0.60 mmol)
NiBr2 (20 mol%) L1 (20 mol%) Et3N (10.0 equiv) 1,4-dioxane (6.0 mL) 90 oC, 24 h
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R CN 6a, R = H, 65% 6b, R = Ac, 76% 6c, R = OMe, 53%
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ACS Catalysis
Ph
N O Ph
Ph
N Bn
NOH (1.5 equiv) Ph Cl
Pd/C (12.5 mol%)
N
Ph
NH
Bn diglyme, 160 oC, 2 h
Et3N (2.0 equiv) DCM, rt, 2 h
Bn 8, 47%
3a
7, 99% (dr = 5.50:1)
DIBAL-H (4.0 equiv) DCM, -78 oC, 4 h Ph
H N
Bn
9, 91%
ACS Paragon Plus Environment
N p-tol
OCOC6F5 N COC6F5
3,4,5-trimethoxyphenylboronic acid (3.0 equiv) NiBr2 (20 mol%) L1 (20 mol%)
ACSCatalysis
Et3N (10.0 equiv) 1,4-dioxane 90 oC, 24 h
p-tol
Page 10of13 OMe N
N OMe C6F5OC 3ab, 32% OMe
1 1q 1) NaOH (3.0 equiv), MeOH 2 2) (COCl)2 (1.0 equiv) DMSO (2.0 equiv) 3 Et3N (4.5 equiv), DCM O Co(OAc)2 (20 mol%) 4 OMe NHPI (40 mol%) N OMe N ACSParagonPlu sEnvironment p-tol 5 O2, EtOAc p-tol HN HN OMe 6 OMe OMe ABI-274, 61% OMe 7 10, 47%
a) Trapping of the radical intermediate with TEMPO
Page 11 of 13 N
Ph
N
Et3N, 1,4-dioxane, 90 oC TEMPO (1.0 equiv)
Ph
1 2 3 N 4 Ph 5 6 7
ACS Catalysis
PhB(OH)2 NiBr2 (20 mol%) L1 (20 mol%)
OBzF
1b
O N
+
4, 23% (3a, 0%)
12, 42%
b) Coupling of PhB(OH)2 with saturated oxime acetate OBzF + PhB(OH)2
NiBr2 (20 mol%) L1 (20 mol%)
NPh
ACS Paragon Plus Environment nBu 90 oC Et3N, 1,4-dioxane, Ph Me 1s
13
68% GC-MS without tBuSH: yield with tBuSH (2.0 equiv): 28%
NH + Ph 14
nBu
6% 33%
N-OR1
NiX2 (20 mol%) Ph Ph L (20 mol%) 1 (0.10 mmol) 1,4-dioxane (2.0 mL) + Et3N (10 equiv) PhB(OH)2 T oC, 24 h 2a (0.30 mmol)
ACS Catalysi
1 2 3 4
ACS RPar agon Pl EntBu vironmet 2 L1, R2us =
R2
N
N
L2, R2 = H L3, R2 = CO2Me L4, R2 = OMe
PagOe 12 of 13 Ph
N
Ph +
+
N
Ph 3a
4
R2
5 R2
L5, R2 = H L6, R2 = Ph N
N
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ACS Catalysis
N R1
OBzF R3
Z R2 1 (0.20 mmol)
2 (0.60 mmol)
boronic acids N Ph
Ph
3a, 72% (L1, 36 h) 2.80 mmol scale Ph
F
3d, 52% (L1, 24 h)
Ph
Br
3h, 38% (L1, 24 h) 3h, 68% (L3, 24 h) Ph
N
Ph
N
N
N
N R
3f, R= OMe, 57% (L1, 24 h) 3g, R= Me, 62% (L1, 24 h) N Ph
Ac
3j, 53% (L1, 48 h)
N
N
Ph
N 3l, 62% (L1, 24 h) Me
3k, 31% (L1, 36 h)
3
Ph
Ac
R4
3c, 40% (L1, 24 h) Br 3c, 55% (L3, 24 h)
3i, 51% (L1, 24 h)
Cl
N
OMe
3 R2 R
Z
Ph
3e, 61% (L1, 24 h)
N
Ph
N
N
R1
Et3N (10.0 equiv) 1,4-dioxane (6.0 mL), 90 oC
3b, 51% (L1, 24 h)
N
Ph
NiBr2 (20 mol%) L1 or L3 (20 mol%)
R4 B(OH)2
+
3m, 63%b (L1, 24 h) 3m, 75%b/56% (L3, 24 h)
oxime esters R
N
S
N Ph
3n, R = Cl, 60% (L1, 24 h) 3o, R = OMe, 67% (L1, 24 h) O
3p, 62% (L1, 24 h)
Ph 3q, 60% (L1, 24 h)
N
N Ph
3r, 67% (L1, 24 h) N Ph
Ph
3u, 32% (L1, 24 h) 3u, 55% (L3, 24 h) N
N
Ph
Me Ph
3y, 25% (L1, 24 h) 3y, 45% (L3, 24 h) 3y, 53%d
N Ph
Ph
Me
Me 3s, 64% (L1, 24 h) N
3t, 82% (L1, dr = 1.4:1, 24 h) Ph N Ph
R Ph
Me Me 3v, R = Me, 71% (L1, dr = 2.8:1, 24 h) 3x, 40% c 3w, R =Ph, 10% (L1, 24 h) (L1, dr =1.5:1, 48 h) Ph Me N N Ph Ph C6F5 N 3z, 30% (L1, 24 h) 3z, 0%d
Ac
O 3aa, 65% (L1, 24 h)
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