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Sequential Functionalization of meta-C–H and ipso-C–O Bonds of Phenols Jiancong Xu, Jingjing Chen, Feng Gao, Shuguang Xie, Xiaohua Xu, Zhong Jin, and Jin-Quan Yu J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2019 Downloaded from http://pubs.acs.org on January 22, 2019
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Journal of the American Chemical Society
Sequential Functionalization of meta-C–H and ipso-C–O Bonds of Phenols Jiancong Xu,┴,† Jingjing Chen,┴,† Feng Gao,† Shuguang Xie,† Xiaohua Xu,*,†,‡ Zhong Jin,*,†,‡ and JinQuan Yu*,⁋ †State
Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China ‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China ⁋Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Supporting Information Placeholder ABSTRACT: The use of a template as a linchpin motif in directed remote C–H functionalization is a versatile yet relatively underexplored strategy. We have developed a template-directed approach to realizing one-pot sequential palladium-catalyzed meta-selective C–H olefination of phenols, and nickel-catalyzed ipso-C–O activation and arylation. Thus, this bifunctional template converts phenols to synthetically useful 1,3-disubstituted arenes.
lifetime.3f For example, we3f,8 and others9 have found that the use of a relatively ri(a) Previous work (Chatani et al.): O H
FG2
[Rh] or [Ni]
N FG1
N ortho-C-H functionalization
FG1 ipso-C-O functionalization
(b) Sequential Functionalization of meta-C-H and ipso-C-O Bonds of Phenols: N
O N
m N H
Realizing remote selective C–H functionalization is essential for broad application of directed C–H activation reactions in the presence of multiple C–H bonds.1 Over the past two decades, transition-metal-catalyzed arene ortho-C–H functionalization has been extensively exploited via σ-chelation-assisted directing effect.2 More recently, directed remote meta- and para-C–H functionalization of arenes has also been achieved using distance and geometry as the key recognition parameters.3–5 However, the installation and removal of these templates for remote C–H activation reduces the step economy in synthetic applications. Therefore, a one-pot procedure that can both directly remove the directing group and install additional desired functionality would greatly improve the synthetic efficacy of directed arene C–H activation. In this context, Chatani and others have demonstrated a commendable example with the ortho-selective directing group 2pyridyloxy (OPy) (Figure 1a).6 Herein we report the development of a palladium-catalyzed remote meta-C–H olefination of phenols enabled by a novel bifunctional template, which can also be directly converted into other functional groups, i.e. an aryl group (vide infra), via the catalytic cleavage of the ipso-C–O bonds in the meta-functionalized phenols (Figure 1b). Notably, this template is easily installed in a single step from the commercially available 2,4-dichloro-6-methoxy-1,3,5-triazine (Figure 1c). It is well established that the positional selectivity of templateassisted remote C–H activation is highly associated with the template geometry.3,4 An appropriate template facilitates the assembly of a conformationally favored macrocyclic metallocycle that enables the metal catalyst to activate the remote C–H bond of the arene through an agnostic interaction.7 Moreover, a rigid backbone in the template readily forms a large yet less strained macrocyclic pre-transition state, and therefore provides the palladacycle intermediate with higher stability and a longer
O
[Pd]
OMe N
meta-C-H
ipso-C-O
directed remote C-H functionalization
functionalized removal of directing template
[Pd]
[Ni]
R2
R R1
(c) Synthesis of Template: OMe
OMe N Cl
2-CN-ArBpin PdCl2(PPh3)2
N N
Cl
65-85%
N Cl
OMe
N N NC
R
T1 R = H T2 R = 5-OMe T3 R = 4,5-(OMe)2
N Cl
N N
> 10 g NC
Figure 1. Development of new bifunctional templates for sequential meta-C–H/ipso-C–O functionalization of phenols. gid template could functionalize remote meta-C–H bonds in longchain aromatic alcohols. Bearing in mind that the unreactive C–O bonds in phenols may be directly functionalized via transitionmetal-catalyzed C–O cleavage of aryl ethers, such as 2pyridyloxy,6,10 and 2-triazinyloxy groups11, we strove to develop a bifunctional template that could both direct the meta-C–H functionalization of phenols and be subsequently removed through a transition-metal-catalyzed ipso-C–O cleavage, consisting of a 1,3,5-triazine-derived rigid biaryl scaffold (Figure 1b). Initially, the biaryl templates T1–T3 were synthesized via a Suzuki coupling from the commercially available 2,4-dichloro-6methoxy-1,3,5-triazine (Figure 1c), and the latter can also be prepared from inexpensive cyanuric chloride in almost quantitative yield (see the SI). The substrate bearing the template T1 was subjected to the previously established meta-C–H olefination conditions.3,8 Much to our delight, the C–H olefination occurred exclusively at the meta-position with meta:others > 20:1 regioselectivity. Ortho-C–H functionalization directed by the donor heteroatom of 1,3,5-triazine was not observed under the reaction conditions.12 Not surprisingly, using templates T2 and T3 also afforded the products in >20:1 meta-selectivity. Increasing the electron density of the phenyl rings in the templates T2 and T3
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did not significantly improve the reactivity, but led to a lower ratio of mono- to di-olefinated products (Scheme 1). With the template T1, however, the desired meta-C–H olefination product could be obtained in 82% yield after an elongated reaction time (36 h). Thus, T1 was selected as the optimal template.
arylboronic acid was investigated. Reaction parameters such as metal catalysts, ligand, base, solvent, and temperature were examined (see SI for details), showing that Ni(xantphos)Cl2 (10 mol%), K3PO4 (7.0 eq), in toluene at 120 oC comprised the optimal reaction conditions.
Scheme 1. Design of New Template for meta-C-H Olefination of Phenola
Table 1. Pd-Catalyzed Template-Directed meta-C–H Olefination of Phenolsa
O
T +
H m'
mH
CO2Et (3 eq.)
OMe N
N N
N T1 65% (mono:di = 2.8:1) 82% (mono:di = 3.4:1)b (meta:others > 20:1)
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 eq.) HFIP, 80 oC, 24 h
O
O
N
m
N
N T2 58% (mono:di = 2.6:1) (meta:others > 20:1)
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (1.5 eq.)
CO2Et (3 eq.)
O
T1
T1
O
OMe
N T3 66% (mono:di = 2.3:1) (meta:others > 20:1)
CO2Et
O
T1
O
Having identified the optimal template, we further investigated the generality of the template-assisted meta-C–H olefination (Table 1). Both electron-donating and -withdrawing groups are well tolerated with predominant meta-selectivity. Excluding alkyl and alkoxyl groups, a variety of functional groups such as halogen (2e, 2f, 2j, 2n and 2o), ester (2g), and acetyl (2p) groups afforded the meta-olefinated products in isolated yields of 49–89%. Substrates bearing two groups in different substitution patterns are also compatible with the present protocol (2q–s). Compared with meta- and para-substituted phenols, substrates derived from ortho-substituted phenols delivered the meta-C–H olefination products in higher yields (2b–g). The presence of an orthosubstituent significantly improves the mono-selectivity as the dimeta-C–H olefination will be subjected to steric hindrance from the adjacent ortho-substituent. It is noteworthy that, using template T1, naturally occurring L-tyrosine (2t) and estrone (2u) also yielded the corresponding olefination products in exclusive meta-selectivity. The synthetically valuable meta-olefinated phenols could be readily obtained through removing the template (See SI for details). In addition, the olefin coupling partner scope was examined. Various α,β-unsaturated esters, amide, sulfone, and phosphonate olefins were reactive, affording the metaolefinated products in good yields (2v1–2v6). Under the reaction conditions, α- or β-substituted olefins proved to be compatible substrates (2v7 and 2v8). Moreover, C–H olefination with cyclic α,β-unsaturated esters and 2-amidoacrylates also provided the desired meta-products with exclusive Z-selectivity in satisfactory yields (2v9–2v12). The stereochemistry of the double bond is determined by the two competing transition state energy of the hydride elimination, analogous to the Heck Coupling. The transition state with the electron-withdrawing ester group being anti to the phenyl group is generally favored which accounts for the observed Z-selectivity of meta-C–H olefinated products (for stereochemistry assignment, see the SI). In template-directed C–H functionalization, an additional step is typically required to remove the template and release the C–H functionalized product.3–5 We wonder whether the template could serve as a linchpin to enable further elaboration of the product via C–O activation. Undoubtedly, direct functionalization via template-induced ipso-C–O bond cross-coupling will not only reduce the cost of the process, but also improve the synthetic efficacy. Therefore, transition-metal-catalyzed direct ipso-C–O cross-coupling of the meta-C–H olefinated phenol 2a with
O
F
O
O
O
T1
CO2Et
CO2Et
Me 2l: 69%
T1
O
CO2Et
2h (R = Me): 65% 2i (R = OMe): 71%
T1
CO2Et 2k: 62%
T1
T1
R
CO2Et 2gmono: 61% 2gdi: 17%
T1
CO2Et F3C 2j: 67% O
T1
CO2Et 2fmono: 68% 2fdi: 17%
T1
O
CO2Et 2d: 75%
EtO2C
CO2Et 2emono: 75% 2edi: trace
and regioselectivity were determined by 1H NMR with CH2Br2 as an internal standard. bReaction time: 36 h.
T1
CO2Et 2c: 89%
Cl
aYield
O MeO
2b: 81%
T1
O F
T1
O
CO2Et
CO2Et
m 2
tBu
2amono: 54%, 2adi: 16%
T1
R
HFIP, 80 oC, 36 h
Me
OMe
O
1
N N
OMe
+ mH
CO2Et
OMe
N
T1
R
H m'
OMe N
T
O
OMe 2m: 69%
T1
O
T1
Me CO2Et
CO2Et
F
CO2Et
Cl 2n: 71% O
T1
Cl CO2Et
CO2Et
CO2Et
NPhth T1
O
O
T1
O
2u: 65%
T1
O
Me
2v4 (R = CONMe2): 69% 2v5 (R = SO2Ph): 76% 2v6 (R = P(O)(OEt)2): 79% T1 O Me Me CO2Me
CO2nBu
CO2Me Me
2v7 : 68% O
2v8 : 66%
T1
O NHTFA
Me
CO2Me 2v10 : 71%
T1
Me
R
CO2R
H
H O
2t: 59%
Me
2v9 : 65%
O H
CO2Me T1
2s: 53%
2v1 (R = Me): 73% 2v2 (R = Bn): 76% 2v3 (R = tBu): 44% T1 O Me CO2Me
CO2Et
Me
Cl 2r: 55% olefin partner: T1 O Me
CO2Et Me 2q: 70%
COMe 2p: 49%
2o: 57% T1 O Me
2v11 : 65%
T1 NHAc CO2Me
2v12 : 41%
aIsolated
yield. Regioselectivity was determined to be meta:others > 20:1 by 1H NMR using CH2Br2 as an internal standard. Next, the substrate scope and the functional group tolerance of this nickel-catalyzed transformation were also surveyed (Table 2). Using p-methoxyl phenylboronic acid as a coupling partner, Nicatalyzed C–O cross-coupling with various o-, m-, and psubstituted phenol substrates provided the biaryl products 3 in good to excellent yields under the optimized reaction conditions (3b–k). Various functional groups, such as alkyl, alkoxyl, halogen, trifluoromethyl, and ester groups, are tolerated in this transformation. Moreover, m-, m′-diolefinated phenol substrates successf-ully underwent the reaction in good yield (3l). Using the meta-C–H olefinated product of N-protected L-tyrosine, it was also possible to synthesize an unnatural amino acid (3m). Single crystal X-ray diffraction analyses of compounds 3i (p-OMe) and 3j (p-F) validated the exclusive meta-selectivity of C–H functionalization and ipso-C–O cross-coupling (see SI for details).
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Journal of the American Chemical Society The scope of organoboron reagents was also evaluated: both mand p-substituents on arylboronic acids including alkyl, halogen, trifluoromethyl, and ester groups were tolerated (3n–t). Notably, heteroarylboronic acid (3u) afforded the biaryl product in 83% yield. Regrettably, o-substituted arylboronic acids give the target products in poor yields, probably due to the steric congestion.
O
mH 2 Ar
O R
+
ArB(OH)2
Ni(Xantphos)Cl2 (10 mol%) K3PO4 (7 eq)
(4 eq)
toluene, 120 oC, 24 h
CO2Et
m 2 Ar
m 3
3c, 80%
Ar
4b, 58% Me
Ar
CO2Me
aOverall
CO2Et
Ar
CO2Bn
CO2Me
MeO 4d, 47%
4e, 43%
yield for two steps.
Scheme 2. Recovery and Regeneration of Template
3d, 88%
Ar
OMe
Ar
N
3e, 85%
CO2Et F3C 3f, 89%
Ar
CO2Et
EtO2C
CO2Et
NPhth
Ar CO2Et
CO2Et
Ar
R 3j (R = F), 87% (X-ray) 3k (R = Cl), 70%c
Me
F
CO2Et 3o, 85% F3C
3m, 52%
Cl
CO2Et
3n, 89%
CO2Et
3l, 85%
CO2Et
CO2Et 3p, 75%
CO2Et
S
CO2Et 3s, 82%
CO2Et 3q, 85%
EtO2C
CO2Et 3t, 75%c
2) 1N HCl
CO2Et 3u, 83%
aIsolated
yield. b110 oC, 36 h. c110 oC. To improve the synthetic utility of this strategy and avoid the tedious separation of C–H olefination products, a one-pot metaC–H/ipso-C–O functionalization procedure was pursued (Table 3). Following palladium-catalyzed meta-C–H olefination, the unpurified intermediate was subjected to nickel-catalyzed ipso-C– O cross-coupling reaction with an arylboronic acid. Gratifyingly, this one-pot procedure furnished the desired m-substituted biaryls in good overall yields (3a, 4a–e). These results further demonstrated the synthetic applicability of this template-assisted transformation. More importantly, template T1 can be recovered and regenerated after nickel-catalyzed C–O coupling in excellent yield (Scheme 2), which further enhances the synthetic efficacy and atom-economy of the strategy.
Table 3. Template-Assisted Tandem meta-C–H/ipso-C–O Functionalization of Phenolsa
N 3a + HO
OMe
N
PhNMe2 80 oC, 6 h, Ar
NC
2a
N
POCl3
N
90%
CO2Me
CO2Me
CO2Et
1) C-O coupling
NC
Me 3h, 78%b
3g, 86%
OMe
N N
O
CO2Et F
3r, 81%
4a, 55%
SO2Ph
Me
MeO
CO2Et Me
3b, 73%
Ar
F
Ar
CONMe2
CO2Et
Ar
CO2Et
3a, 90%
OMe 3i, 89% (X-ray)
Ar = 4-OMe-C6H4Ar
CO2Et
m 4
(intermediate not isolated)
4c, 54%
Ar
CO2Et
Ar
Ar R
F
MeO
MeO
Ni
3a, 48%
R
Ar = 4-OMe-C6H4Ar
ipso-C-O
Pd
CO2Et
Ar
Ar
meta-C-H
R
Table 2. Ni-Catalyzed C–O Cross-Coupling of metaOlefinated Phenolsa T1
T1
N N
Cl
NC T1, 90%
5, 88%
Finally, this template-directed remote C–H functionalization strategy was tested in the synthesis of key building blocks of natural products. Template-assisted meta-C–H olefination of the substrate derived from guaiacol afforded the olefinated product 6 in 68% yield. While direct C–O coupling of compound 6 with arylboronate 9 under the present conditions gave the biaryl scaffold 10 in low yield (18%), an alternative route featuring quantitative removal of the template T1, borylation, and palladium-catalyzed Suzuki coupling with bromide 8 efficiently delivered the left-hand moiety 10 of TMC-95 A–D (Scheme 3), a small class of naturally occurring selective proteasome inhibitors with IC50 values of 5–60 nM.13 The synthetic strategy allows for facile modification of the biaryl units and the amino acid residue, for such purposes as a structure-activity relationship (SAR) study for this family of natural products.
Scheme 3. Application to Synthesis of the Central Scaffold of Natural Antibiotic TMC-95a OH MeO
guaiacol
O 1) T1, KOH
T1
MeO
NHCbz
2) meta-C-H olef ination
6
O O Bpin
N H 9
TMC-95 A-D
CO2Me
Bpin
3) morpholine 4) Tf 2O, py
MeO
5) Pd(OAc)2/DPEphos B2(pin)2
O
7) ipso-C-O coupling
MeO
CO2Me 7
O
6) Pd(dppf)Cl2 O
steps
NHCbz
N H
O Br
N H 8
NHCbz CO2Me 10
aConditions:
(1) T1 (1 eq), KOH (1 eq), THF, rt, 95%. (2) olefin (3 eq), Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%), AgOAc (1.5 eq), HFIP (0.2 M), 80 oC, 36 h, 68%. (3) morpholine (1 eq), dioxane, 100 oC, 12 h, 99%. (4) Tf2O (1.1 eq), Pyridine (2.5 eq), CH2Cl2, 0 oC to rt, 3 h, 75%. (5) B2(pin)2 (2 eq), Pd(OAc)2 (10 mol%), DPEphos (20 mol%), TEA (4 eq), dioxane, 80 oC, 16 h, 90 %. (6) ArBr 8 (1.1 eq), Pd(dppf)Cl2 (20 mol%), K2CO3 (4 eq), DME, 80 oC, 14 h, 92%. (7) ArBpin 9 (4 eq), Ni(xantphos)Cl2 (10 mol%), K3PO4 (7 eq), toluene, 120 oC, 24 h, 18%. In summary, a robust bifunctional template has been developed for the palladium-catalyzed remote meta-C–H olefination of phenols. The template can be synthesized concisely in a two-step sequence from inexpensive cyanuric chloride, and is easily
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installed and removed. In addition, this bifunctional template is amenable to nickel-catalyzed ipso-C–O cross-coupling. This template-assisted one-pot sequential meta-C–H/ipso-C–O functionalization methodology allows for the expedited synthesis of multiply substituted arenes from simple phenol substrates. Further applications of this template-assisted strategy are under investigation in our laboratory.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures, characterization data, NMR spectra for new compounds (PDF) Crystal data for compounds 3i and 3j (CIF)
AUTHOR INFORMATION Corresponding Author *
[email protected] *
[email protected] *
[email protected] Author Contributions ┴These
authors contributed equally.
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We thank the NSF of China (20502012, 21172111 and 21672116) for financial support of this work. We gratefully acknowledge The Scripps Research Institute, the NIH ((National Institute of General Medical Sciences grant 5R01GM102265).
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Table of Contents (TOC) O
meta-C-H T
Pd
ipso-C-O
FG2
Ni
OMe N
N N
m H
Enabled by a bifunctional template
FG1
N O
CO2Et
O H
Ar H
H HO
CO2Me
O N H
NPhth MeO
NHCbz
CO2Et
CO2Me from estrone
from L-tyrosine
from guaiacol
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