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Chemoselective Activation of sp3 vs sp2 C-H Bonds with Pd(II) John M. Curto, and Marisa C Kozlowski J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5093166 • Publication Date (Web): 25 Nov 2014 Downloaded from http://pubs.acs.org on November 27, 2014
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Chemoselective Activation of sp3 vs sp2 C−H Bonds with Pd(II) John M. Curto, Marisa C. Kozlowski* Department of Chemistry and Penn Merck High Throughput Experimentation Laboratory, University of Pennsylvania, Philadelphia, Supporting Information Placeholder However, activation of toluene by non-radical processes is a ABSTRACT: The first selective coupling of a carbon nucleophile long-standing challenge. 11 , 12 White and Shi have developed an with methyl, ethyl, propyl and butyl arenes in the absence of a elegant system for the C−H activation of the doubly activated directing group is described. The Pd(OAc)2 double C-H activation allylbenzene.13 Since the discovery of Pd catalyzed acetoxylation of process was found to display remarkable selectivity for the terminal toluene in 1968 by Bryant, few advances have been made (Scheme methyl sites in alkyl arenes, rather than the more commonly 1, eq 3). 14 In fact, toluene is considered benign in most Pdobserved arene sp2 C–H activation. Mechanistic studies indicate catalyzed processes, and is frequently used as solvent. Our the intermediacy of an azlactone dimer, obtained from oxidation longstanding interest 15 in metal catalyzed C−H activation with Pd(OAc)2, and are consistent with a Pd-catalyzed C–H prompted our investigation of the Pd catalyzed oxidative coupling activation vs a radical process. The observed reactivity establishes of toluene. Herein, we disclose the discovery of selective Pd that typical reaction solvents (e.g. toluene) can readily participate in C–H activation chemistry. activation of benzylic and alkyl sp3 C−H bonds relative to arene sp2 C−H bonds to achieve CDC coupling reactions with a carbon nucleophile (Scheme 1, eq 4). The ability of metals, and particularly Pd catalysts, to selectively insert into C–H bonds has provided a host of new, useful methods for the construction of organic structures.1 C–H activation is highly significant because additional steps to preactivate a center for a bond construction (e.g., halogenation) can be avoided, thereby increasing efficiency by reducing step-count and decreasing waste. Catalytic dehydrogenative cross-coupling (CDC) is the ideal version of this process where C–H bonds from each of two reacting partners are selectively cleaved, accompanied by an oxidative fragment union.2 In this strategy, coordinating groups play a key role by complexing the substrate with the catalyst and thus lowering the energy barrier for C−H activation.3 Advances in such alkyl C−H activation are considerable, but much less progress has been made in systems lacking coordinating groups.4 Toluene compounds are easy-to-handle, stable, and commercially available rendering them ideal as benzylation reagents, and far more atom-economical than the corresponding benzyl halides. Even though the benzylic C−H bond in toluene is 20-30 kcal/mol weaker than the arene C−H, Pd displays a remarkable selectivity for arene C−H activation (Figure 1).5 In fact, methyl and other alkyl substituents on arenes are compatible with Pd-catalyzed sp2 C−H functionalization. Presumably, coordination of a Pd catalyst to the π-system of the arene positions the metal carboxylate for a favorable deprotonative metalation (Figure 1).6 H H
H
H
H
O weakest C-H bond H Me bond strength H H ~ 85-90 kcal/mol Pd O least hindered OAc arene C-H bond bond strength ~110-115 kcal/mol H
H
H
Scheme 1. sp 3 C−H Activation of toluene with Pd. CDC via diradical formation CH 3 +A H
Pd
O Me
H
O
Benzylic Activation Arene Activation
Figure 1. sp3 C−H vs sp2 C−H activation of toluene with Pd.
Of late, radical mediated processes for activation of toluene have shown considerable promise in CDC (Scheme 1, eq 1 and 2).7,8,9 A benzylic radical is easily formed at elevated temperatures with ditert-butylperoxide and can merge with Pd-catalyzed processes. Cu catalysts have also been reported to form benzylic amines and alcohols from toluene and stabilized heteroatom radicals.10
+
Δ
A
Pd(II) CO
A
O
(1)
A = NR 2, NHR, OR CDC via radical mediated oxidation CH 3 CH2 (t-BuO)2
[O]
DG O
O
H
CDC via Pd catalyzed C-H activation CH 3 Pd(II) O2 RCOOH + Δ (excess) This work CH 3
DG
Pd(II) (2)
Δ
DG = Directing Group O O
R
(3)
A = carbon Nu
+
A H
Pd(II) oxidant Δ
A
(4)
We initially explored the coupling of phenylglycine azlactone and toluene with late-transition metals based on their propensity for C–H activation (Table 1). Notably, only Pd(II) carboxylates provided any cross-coupled product (Table 1, entries 6-7). PdCl2 provided the azlactone dimer, but all other Pd sources were inactive (Table 1, entries 8-12). Surprisingly, the coupling product 2a arose from deprotonative metalation into the sp3 C−H bond rather than the typical sp2 C−H activation.5-6 Table 1. Metal sources for C−H activation of toluene. PMP O PMP = p-MeOPh O [M] Source H N N H 90 °C, 12 h H Ph H H H Ph (0.05 M) 1 2a [M] source [M] source entry entry yield (%) a yield (%) a (100 mol %) (100 mol %) Pd(TFA) 2 Au(OAc)3b 7 1 0 81 PdCl 2 Cu(OAc)2b 0 0 2 8 PdCl 2(MeCN) 2 Rh 2(OAc) 4b 0 0 3 9 b PdCl2(COD) 2 Ni(OAc)2 0 10 0 4 b [Pd(allyl)Cl 2]2 5 [Pt 4(OAc) 8] HOAc 0 11 0 Pd 2dba3 77 Pd(OAc) 2 0 6 12
PMP
AcO
CH2
(t-BuO)2
O
O +
aIsolated
yield. b Azlactone dimer as substrate, 20 mol % metal source, 5 h.
With this rare example of selective C−H activation of the benzylic position of toluene,12 we attempted to minimize the amount of toluene. A screen of co-solvents 16 revealed that 1,4-
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dixoane was optimal to reduce toluene from 80 to 20 equiv while efficiently providing the benzylated product (Scheme 2, 2a). These conditions also proved successful for several toluene derivatives. In contrast to Bryant’s results with acetoxylation of xylenes, the monobenzylated product was the only product observed (Scheme 2, 2b2d).14a Although meta-xylene (2c) was highly effective, mesitylene proceeded in only 14% yield; increased temperature and longer reaction times did not improve the outcome. We speculate that the three alkyls of mesitylene hinder the coordination of the palladium to the π-system needed to initiate C–H activation (Figure 1).
identifying a suitable oxidant to allow turnover. Scheme 3. Selective primary C−H activation. PMP
O O + H3C
N H
Ph PMP
PMP OH 2
H
1
H H 3 72% PMP
CH3
PMP O Pd(OAc)2 O (100 mol %) N O + R N 1,4-dioxane (0.3 M) Ph H H H 90 °C, 24 h Ph (20 equiv) 1 2a-2j PMP O PMP PMP O O O O O CH3 N N N
PMP N
H H 2a 83% 83%a O O
Ph
PMP N
Ph H H 2d CH3 67%a PMP N Ph
Ph H H
PMP
O O
H H 2b 78% 83%a O O
N
2e 71% (74%a) O H3C O
Ph
PMP
OMe N
H H 2c 78% 75%a O O
Ph H H 2f 68% 65%a PMP O O N
Ph H H H H 2g 2h 96% 98% 78%a 80%a aNeat reaction solution with 80 equiv of tolyl analog.
R
OH 2
H
1
H H 4 65% PMP
O N Ph
O 3
R
O N Ph
O
Ph
n
O N Ph
PMP O Pd(OAc)2 O (100 mol %) N R () 1,4-dioxane (0.3 M) n Ph 90 °C, 24 h H H 3-6
()
(20 equiv) n = 1, 2, 3
1
Scheme 2. C−H Activation of tolyl analogs. PMP
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O N Ph
2 1
H H 5 62%
O 4 3
H H 6 46%
2 1
A PME screen21 with 23 diverse oxidants (2 equiv) and 2 Pd carboxylates (30 mol %)16 revealed that 2,6-dimethylbenzoquinone was superior, providing the benzylated product in 73% yield. Further reduction of the Pd loading to 10 mol % and 2,6-DMBQ to 1 equiv was still effective, but with lower yield (56%). 2,6-DMBQ loading could be reduced with a co-oxidant, MnO2, but the most successful additive was PivOH.16 Presumably, this additive promotes dissociation of the hydroquinone anion from Pd(II).22
CH3
CH3
Ph H H 2i 76% 80%a
Naphthalene analogs of benzyl bromide are relatively unstable for SN2 transformations and are not widely available. The use of 1and 2-methyl naphthalene in CDC via radical mediated processes is uncommon because the tolyl analog is typically used neat, a difficult proposition with these solids. With the optimal conditions, naphthyl derivatives of phenylglycine azlactone were formed in good yield (Scheme 2). Hydrolysis of these compounds permits facile access to unnatural α,α-disubstituted α-amino acids.17 The success with the selective sp3 C−H bond activation of primary benzylic sites prompted exploration of secondary benzylic compounds (Scheme 3).18 Unexpectedly, the secondary benzylic product was not observed; rather, with each substrate, substitution occurred at the primary methyl.19 Most surprising, propylbenzene and butylbenzene gave rise to the product (5 and 6) while 5.7a,10b The absence of an isotope effect and deuterium scrambling with d5toluene indicates that initial Pd metalation of an arene C−H is unlikely.
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Scheme 5. Kinetic isotope studies.
PMP
O O
N H
Ph
O C7H 8/C7D 8 PMP O (0.1 M) N Pd(OAc) 2 (100 mol %) Ph H H 95 °C, 7 h
PMP
O
D
D O
D
+ N Ph D D D kH /kD = 3.55 PMP
C7H 8/C7H 3D 5PMP O (0.1 M) O N Pd(OAc) 2 (100 mol %) Ph H H 95 °C, 7 h
+
O N Ph
kH /kD = 1.09
D
D O
H H
D
D D
D
In the course of these studies, the dimer of the azlactone was observed frequently, prompting further studies to determine if it was necessary for benzylation or was a side-product. Dimer formation can be initiated with a metal oxidant (e.g., NiO2, MnO2) or with air in a polar solvent (DMSO).24 We thus developed mild conditions to form the azlactone dimer (8) in 83% yield with Pd(OAc)2 (5 mol %) using Ag2O (100 mol %) at rt.16 When this dimer was subjected to catalytic Pd(OAc)2 and toluene (no added oxidant), the benzylated product was formed in 72% yield (Scheme 6, top). 25 The high yield in the absence of additional oxidant suggests that once the azlactone dimer is formed, the benzylation is redox neutral unlike other processes involving dimeric Pd.26
Pd(OAc)2 at elevated temperatures to generate benzylic Pd(II) A.12,14 The electron-rich A may undergo metathesis with the azlactone dimer (path a or c ). Displacement of the better acetate leaving group (path a ) would generate B, which would provide product upon reductive elimination. However, the C-acetoxy byproduct (C) of this event was not observed. Alternatively, Pd(IV) intermediate D may form by oxidative addition of the labile C−C bond of the azlactone dimer to A (path b ). Reductive elimination would yield the benzylated azlactone product and E, both of which could also form via metathesis path c . Pd(OAc)2 would be regenerated from E in the presence of AcOH. Reformation of phenylglycine azlactone consumes the remaining Pd(OAc)2, accounting for the 72% yield observed commencing from the azlactone dimer in the absence of oxidant (Scheme 6). a)
PMP
PMP
Ph
PMP Pd(OAc)2 (25 mol%)
O O Ph
N Ph O
toluene 95 °C, 5 h 72%
N O
PMP 8 azlactone dimer
Pd(TFA)2 benzene rt to 60 °C
O O Ph Ph O O
N
CH3
1
Ph C
HOAc
O
CF3
O
1
O
Ph
AcOH
O
PMP
Pd
O
N
+
Phenylalanine azlactone dimer is known to undergo homolytic cleavage at temperatures above 115 °C.24b The possibility of such an event being closely coupled to C–H activation was therefore considered. Evidence found against such a path includes the transformation proceeding below the dimer homolysis temperature and not proceeding in the absence of Pd(II). Further, studies with the PMP-phenylglycine dimer (8) and Ph-phenylglycine dimer at 85-95 °C with and without Pd(OAc)2 reveal no dimer recombination characteristic of such a homolytic cleavage.16 Although the full mechanistic details of this transformation remain to be elucidated, the following mechanism accounts for the observations to date (Figure 2a). 1H NMR spectroscopic monitoring reveals that the phenylglycine azlactone 1 is converted to the azlactone dimer 8 in the first 30 min when exposed to Pd(OAc)2 and heat. Toluene can undergo C−H activation with
b)
O
Ph
H H 2a
Ph
Pd(OAc)2
H3C
HOAc PMP
O N
3
OAc Ph N PMP Pd N Ph O O D Ph
O N
PMP E
The azlactone dimer was discovered to form metal complex 9 upon treatment with Pd(TFA)2, (Scheme 6, bottom) as judged by a downfield 1H NMR shift of the C-4 phenyl ortho-hydrogen (7.31 to 9.47 ppm) and X-ray crystallography.16 Treatment of this complex with toluene at elevated temperatures provided the benzyl product (Scheme 6, bottom), although in lesser yield (c.f. Table 1, entry 7). Monitoring of complex 9 at rt with d8-toluene revealed dissociation of the complex within 30 min. From these results, it appears that complex 9 is not a reactive intermediate.
Ph
O
O
OAc
Ph
N
Pd
path b
Ph
PMP
H
PMP
B
Pd A
O
(40 equiv) 95 °C, 4h 37%
O
path a
Pd(OAc)2 CF3
O N Ph
OAc
AcO
H
O
O
PMP 9
O
N
PMP
H H 2a
PMP
O
path c
Pd N
PMP
Ph N
8 H H
Ph
[O]
O
O
O
Ph H H 2a PMP
H Pd(OAc)2
1
O
O
O N
O
N
Pd(0)
N Ph
Scheme 6. Involvement of the azlactone dimer. PMP
O
2 equiv N
PMP
O
O
Ph
O H H
AcO Pd A'
AcO Pd
CH3
CH3
AcO
Ph
Pd H H
Ph A"
AcO Pd H
H
H
Figure 2. Proposed mechanism for tolyl C–H activation.
A deuterium labeling study conducted with d2-ethylbenzene revealed positional deuterium scrambling (eq 5), which supports initial Pd metalation of the benzylic C−H bond (Figure 2b). Subsequent β-hydride elimination to a styrene, readdition of Pd onto the terminal carbon, and cross-coupling with the azlactone would account for the ethylated product (Figure 2b); however, styrenes added to the reaction did not incorporate into the product. The selective sp3 C−H activation of ethylbenzene provided a unique opportunity to interrogate potential radical pathways. When phenylglycine azlactone was treated with ethylbenzene at 90 °C with Pd(OAc)2 and (t-BuO)2 , only reaction at the terminal site (2a) was observed (Table 2, entry 1). In the absence of Pd, but above the homolysis temperature of (t-BuO)2, 27 only the benzylated product was seen (entry 2).28 With Pd(OAc)2 and (tBuO)2 together at this higher temperature, products from both the
3
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metal-mediated and radical pathways were seen (entry 3). Radical scavengers also had no effect on the toluene reaction.29 Altogether, these results contraindicate a radical mechanism for this process. PMP
O
D
D O + H C 3
N
Pd(OAc) 2 (100 mol %) 24 h, 95 °C
H
Ph
PMP
38% H
O
OH(D) H(D)
N Ph (D)H H(D)
(5)
62% H
Table 2. Probing radical pathways with ethylbenzene. PMP
O
H O + H 3C
N
H
Pd(OAc) 2 PMP (t-BuO)2 (2 equiv) 14 h
H
Ph
O
1
+
entry T (°C) Pd (mol %) observed product 1 2 3
OH
N Ph
90 125 125
20 0 20
2a 7 2a and 7
PMP
H
H H 2a
O N
O
Ph H CH 3 7
In summary, a novel reactivity mode for alkylarene derivatives has been discovered. With a simple system consisting of Pd(OAc)2 and pivalic acid, CDC with a carbon nucleophile occurs readily for the terminal methyl positions of methyl, ethyl, propyl and butyl arenes. The resultant azlactone products are masked α-amino acids, with hindered α,α-disubstitution patterns that are difficult to achieve via other means. 30 Notably, selective sp3 C–H activation is observed in benzylic systems even though Pd(OAc)2 typically causes arene C–H activation. Further studies to understand the mechanism and, in particular, the role of an observed azlactone dimer on the sp3 vs sp2 C–H activation selectivity are underway. These studies provide a cautionary tale against use of methyl arene solvents, such as toluene and xylenes, in Pd-catalyzed C–H activation chemistry. Studies are ongoing to improve turnover and to extend the scope of the acidic C−H partner in these couplings
ASSOCIATED CONTENT Supporting Information. Experimental details, spectral data, full citation of ref 25. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Authors
[email protected] ACKNOWLEDGMENT We are grateful to the NIH (GM-087605) and the NSF (CHE1213230) for financial support of this research. Partial instrumentation support was provided by the NIH for MS (1S10RR023444) and NMR (1S10RR022442) and by the NSF for an X-Ray Diffractometer (CHE 0840438) and HTE facilities (GOALI CHE-0848460). We thank Dr. Simon Berritt (Penn Merck HTE Laboratory) for helpful discussions.
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(2) (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011 , 111, 1215. (b) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (3) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744. (4) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075. (b) Waltz, K. M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 11358. (c) Chen, M. S.; White, M. C. Science 2007, 318, 783. (5) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255. (6) (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. (b) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110, 749. (c) Ackerman, L. Chem. Rev. 2011, 111, 1315. (7) (a) Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902. (b) Xie, P.; Xia, C.; Huang, H. Org. Lett. 2013, 15, 3370. (c) Liu, H.; Laurenczy, G.; Yan, N.; Dyson, P. J. Chem. Commun. 2014, 50, 341. (8) Yin, Z.; Sun, P. J. Org. Chem. 2012, 77, 11339. (9) (a) Wu, Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y Chem. Comm. 2013, 49, 689. (b) Xiong, F.; Qian, C.; Lin, D.; Zeng, W.; Lu, X. Org. Lett 2013, 15, 5444. (c) Xu, Z.; Xiang, B.; Sun, P. RSC Advances 2013, 3, 1679. (10) (a) Powell, D. A.; Fan, H. J. Org. Chem. 2010, 75, 2726. (b) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2012, 14, 3982. (11) For reviews on sp3 C-H activation, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. (c) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191. (12) For toluene self-coupling to a 6:94 mixture of benzylic-arene and arene-arene product with Pd(OAc)2 and TFA, see: Rong, Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376. (13) (a) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901. (b) Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 130, 14090. (14) (a) Bryant, D. R.; McKeon, J. E.; Ream, B. C. J. Org. Chem. 1968, 33, 4123. (b) Liu, H.; Shi, G.; Pan, S.; Jiang, Y.; Zhang, Y. Org. Lett. 2013, 15, 4098. (15) (a) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137. (b) Lee, Y. E.; Cao, T.; Toruellas, C.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136, 6782. (16) See Supporting Information. (17) Trost, B. M.; Xavier, A. J. Am. Chem. Soc. 1999, 121, 10727. (18) Diphenylmethane and cumene were explored with the optimal conditions but did not provide the benzyl product. (19) In ref. 14a, acetoxylation of ethylbenzene at the terminal methyl was observed as a complex product mixture in 8.3% overall yield. (20) Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213. (21)Schmink, J.R.; Bellomo, A.; Berritt, S. Aldrichim. Acta 2013, 46, 71. (22) Grennberg, H.; Gogoll, A.; Backvall, J.-E. Organometallics 1993, 12, 1790. (23)Simmons, E.M.; Hartwig, J.F. Angew. Chem. Int. Ed. 2012, 3066. (24) (a) Rodriguez, H.; Marquez, A.; Chuaqui, C. A.; Gomez, B. Tetrahedron 1991, 47, 5681. (b) Andersen, K. K.; Gloster, D. F.; Bray, D. D.; Shoja, M. J. Het. Chem. 1998, 35, 317. (25) Pd(0) sources did not provide 2a from dimer and toluene. (26) Powers, D. C.; Ritter, T. Nature 2009, 1, 302. (27) Pryor, W. A.; Lee, A.; Witt, C.E. J. Am. Chem. Soc. 1964, 86, 4229. (28) Six diasteromers of C- and O-benzylation were observed, see: Regalado, E. L.; Kozlowski, M. C.; Curto, J. M.; Ritter, T.; Campbell, M. G.; Mazzotti, A. R.; Hamper, B. C.; Spilling, C. D.; Mannino, M. P.; Wan, L.; Yu, J.-Q.; Liu, J.; Welch, C. J. Org. Biomol. Chem. 2014, 12, 2161. (29) 2a was obtained in 54, 85, and 59% yield with TEMPO, 1,1diphenylethylene and BHT, respectively. (30) (a) Curto, J. M.; Dickstein, J. S.; Berritt, S.; Kozlowski, M. C. Org. Lett. 2014, 16, 1948. (b) Dickstein, J. S.; Fennie, M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 15794.
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PMP
O O
N Ph
+
H 3C
conditions A Pd(OAc) 2 1,4-dioxane 90 °C, 24 h
()
n
H (~20 equiv) n = 0, 1, 2, 3
R
conditions B Pd(OAc) 2 2,6-DMBQ, PivOH activated carbon 1,4-dioxane 95 °C, 45 h
PMP
PMP
O O
N
Ph H H
R PMP
PMP
O N Ph
O
O N Ph
O
H H
O N Ph
R
O
H H
H H
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