Copper-Catalyzed Desaturation of Lactones, Lactams and Ketones

Subscriber access provided by UNSW Library

Article

Copper-Catalyzed Desaturation of Lactones, Lactams and Ketones under pH-Neutral Conditions Ming Chen, and Guangbin Dong J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07932 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 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 15 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

Journal of the American Chemical Society

Copper-Catalyzed Desaturation of Lactones, Lactams and Ketones under pHNeutral Conditions Ming Chen† and Guangbin Dong*,† †Department

of Chemistry, University of Chicago, Chicago, Illinois, 60637, United States

Abstract A copper-catalyzed desaturation method is reported, which is suitable for converting lactones, lactams and cyclic ketones to their α,β-unsaturated counterparts. The reaction does not require strong base/acid or sulfur/selenium reagents, and can be carried out through a simple one-step operation. The protocol uses inexpensive catalysts and reagents, exhibits excellent scalability and functional group tolerance. Notably, t-butanol is the only stoichiometric byproduct produced, and over oxidation is not observed. The reaction mechanism has been investigated through control experiments, deuterium labelling, radical clock, EPR, HRMS and kinetic studies. The data obtained are consistent with a reaction pathway involving a reversible α-deprotonation by a Cu(II)-OtBu species, followed by further oxidation of the resulting Cu enolate.

Introduction Methods that prepare and modify carbonyl compounds have been critical in organic synthesis.1 Among numerous carbonyl-involved transformations, desaturation reactions, namely converting a saturated carbonyl compound to the corresponding α,β-unsaturated counterpart, is of particular interest for syntheses of complex and biologically relevant molecules.2 First, the electrophilic α,βunsaturated structural motif is commonly found in many bioactive natural products (Fig. 1), which has been an important inspiration for developing new pharmaceutical agents.3 On the other hand, the desaturation process could be coupled with other transformations, which leads to β-functionalization2a,4 or simultaneous α,β-difunctionalization of carbonyl compounds.5 O

O

O

Ph (-)-massioalactone O

O

O

O

O

MeOOC

(R)-(+)-goniothalamin

O

O

OMe

N

O

N xylogranatopyridine B

O OMe

piperlongumine OMe

O Apocarotenoid

Figure 1. Representative natural products containing α,β-unsaturated carbonyl moieties. To date, desaturation of ketones and aldehydes has been extensively developed;2 among various creative strategies, the palladium-catalyzed oxidation offers a direct, efficient and mild approach, and has been widely utilized in complex molecule syntheses.6 By contrast, the corresponding reactions with common esters and amides have been much less developed. Classical approaches typically involve introducing a sulfur or selenium-based leaving group to the α-carbon followed by an elimination process.7 Recently, through an electrophilic activation approach, an impressive one-pot chemoselective ACS Paragon Plus Environment

Journal of the American Chemical Society 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

Page 2 of 15

selenium(IV)-mediated amide-desaturation was reported by Maulide and co-workers (Scheme 1a).8 Regarding catalytic strategies, Newhouse has systematically developed a suite of palladium-catalyzed dehydrogenation of esters, amides, nitriles, ketones and carboxylic acids,9 which were effectively enabled by enolate formation with a novel lithium anilide and subsequent transmetalation to zinc (Scheme 1b). Alternatively, a soft enolization approach has been adopted by us for direct desaturation of various esters and amides under either palladium10 or platinum catalysis11 (Scheme 1c). While effective, these established catalytic methods require either stoichiometric strong bases or strong Lewis acids for carbonyl enolization due to reduced acidity of the α C−H bonds in esters and amides (compared to ketones and aldehydes); as a consequence, byproducts are heavily produced in these processes. Scheme 1. Recent Advances on Desaturation of Esters and Amides a) Maulide: O NR'2

R

R' N

Tf2O, 2-I-pyr R

R'

O Ph SeOH

O

ZnCl2

O

NR'2

oxidant, base R

electrophilic activation b) Newhouse: O

OLi

LiNR"2

XR'

R

X = O, NR'

Pd cat., oxidant

XR'

R

enolization by strong bases

c) our previous work: O Bu2BOTf, DIPEA

X

XR'

R

[B]

Pd or Pt cat., oxidant

O

X X = O, NR

O X

enolization by strong lewis acids

d) this work: O

O

R3P-Cu(I) cat t BuOOtBu

X

X

PhH, 80 oC

X

[Cu] O H

+

BuOH

2 equiv

X = CH2, O, NR O

waste t

O X

catalytic enolization

[Cu]

 strong base and acid free  sulfur and selenium free  simple one-step operation  inexpensive catalyst/reagent  scalable and chemoselective  no over-oxidation

Inspired by Stahl’s seminal mechanistic studies on the palladium-catalyzed ketone dehydrogenation,6g an intriguing question is whether catalytic enolization of lactones and lactams could be realized using a dual functional catalyst that contains a more Lewis acidic metal and a more basic X ligand (better than carboxylates). Serving as both a Lewis acid and an oxidation catalyst, the metal complex could first activate the carbonyl substrate through soft enolization and then participate in the subsequent dehydrogenation process. To continuously supply the base, as well as to maintain a relatively neutral reaction medium and minimize byproduct formation, it could be strategically attractive to slowly generate the basic X ligand from the oxidant. In addition, it would also be appealing if earth abundant first-row transition metals could be employed as catalysts. Herein, we describe our initial development of a copper-catalyzed oxidation method that can effectively convert a range of saturated lactones, lactams and ketones to the corresponding unsaturated conjugated carbonyls (Scheme 1d). The reaction is operated under near pH-neutral conditions with t-butanol as the only stoichiometric byproduct formed.

ACS Paragon Plus Environment

Page 3 of 15 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


Results and Discussion In 2014, Han,12 Patel13 and Hartwig14 independently reported a Cu-catalyzed sequential dehydrogenation of simple alkanes followed by Kharasch−Sosnovsky-type15 allylic functionalization. Shortly after, the Antonchick group disclosed a single example of a Cu-catalyzed dehydrogenation of a special 1,4-diketone.16 Concurrently, the Su group reported a novel Cu/2,2’-bipyridine (bpy)-catalyzed TEMPO-mediated system for dehydrogenative β-functionalization17 and later multi-desaturation reactions18 via radical abstractions. While highly efficient, the scope has been mainly focused on ketones/aldehydes and selective mono-dehydrogenation was difficult. The challenge for the selective mono-dehydrogenation is likely due to that, comparing to the α C−H bond in the substrate (~89-94 kcal/mol), the allylic C−H bond of the initially formed unsaturated product is typically weaker (~87 kcal/mol) and tends to be more reactive with radical species.19 In addition, from the prospect of polar effect,20 the α C−H bond is generally more electronically deficient than allylic C−H bonds, therefore less competitive to be abstracted by an electrophilic oxygen-based radical. Table 1. Selected Optimization Studiesa O O C7H15 1a

Entry

O

20 mol% CuTc 20 mol% CyPPh2

O

1.5 equiv DTBP PhH, 80 oC, 12 h 'standard' conditions 0.1 M

S

C7H15 2a, 82% (81% isolated)

Without CuTc Without CyPPh2

2

CuTc

Yield (%) of 2aa,b

Variations from the 'standard' conditions

1

0 trace

3

Without DTBP

0

4 5 6 7

C1-6 instead of CuTc L1-16 instead of CyPPh2 Ox1-4 instead of DTBP

Listed below Listed below Listed below

10 mol% CuTc and 10 mol% CyPPh2

58

solvent = toluene solvent = PhF solvent = 1,4-dioxane solvent = DCE temp = 70 oC temp = 60 oC C = 0.05 M C = 0.2 M none

60 68 0 20 76 42 48c 72 82

8 9 10 11 12 13 14 15 16

O

Cu O

CuSPh Cu(CH3CN)4PF6 Cu(OAc)2 Cu2(OTf)2PhMe CuCl CuOAc C1, 78% C2, 20% C3, 0% C6, trace C5, trace C4, 0% PAr3 (L4-L9) Ar = Ph, 64% N L1, 10% bpy L2, 14%

Ar = p-Me-C6H4, 66% Ar = p-F-C6H4, 68%

XPhos, L14, 0%

Ar = p-CF3-C6H4, 48%

XantPhos, L15, 0%

Ar = 3,5-di-CF3-C6H3, 28%

dppb, L16, 0%

Ph O

SPhos, L13, 0%

Ar = p-OMe-C6H4, 72%

1,10-phen L3, trace O

i PrPPh2 BuPPh2 Cy3P L10, 76% L11, 82% L12, 56%

t

Ph

Ox1, 58%

O

O

O Ox2, 0%

O

Ph Ph

O

O

Ph

Ox3, 0% O

a Each

OH O Ox4, 0%

reaction was run on a 0.2 mmol scale in a sealed 4 mL vial for 12 h. b Yields were determined by 1H NMR using CH2Br2 as the internal standard. c 50% of 1a was observed.



To address the selectivity challenge, we hypothesized that, using a more basic X ligand, such as tbutoxide, and a softer L ligand (that can have a stronger trans influence), deprotonation of the α C−H bond could be achieved in a cooperative manner under relatively mild conditions (i.e. lower reaction temperature). As a consequence, it is expected that the undesired radical-mediated further oxidation could be minimized. To test this hypothesis, phosphines were first examined as the ancillary ligand and di-t-butylperoxide (DTBP) was employed as the oxidant in order to slowly generate the basic t-butoxide ligand. To our delight, when using lactone 1a as the model substrate, the desired α,β-unsaturated lactone product 2a was isolated in 81% yield at 80 oC when using copper(I) thiophene-2-carboxylate (CuTc)/CyPPh2 (20 mol%) as the metal/ligand combination (Table 1). The role of each reactant was then explored through control experiments. Clearly, the copper catalyst, the phosphine ligand and DTBP are all essential to this transformation (entries 1-3). Besides CuTc, a variety of other copper (I) and (II) complexes has also been tested as catalysts (entry 4). While CuOAc was almost equally effective, other Cu(I) species, such as CuCl, CuSPh and Cu(MeCN)4PF6, were much less efficient, suggesting the importance of the carboxylate ligand (vide infra, Mechanistic Studies). Cu(II) complexes, including Cu2(OTf)2•PhMe and Cu(OAc)2 (effective catalyst in Su’s reactions17,18), gave no or trace desired product. While the majority of the prior Cu-mediated oxidation reactions employ pyridine-type ligands,21 phosphine ligands were found to be more effective in this transformation (entry 5).22 Pyridine, bpy and 1,10-phen (L1-L3) all gave low yields of the product. Simple triarylphosphines are excellent ligands. Regarding the electronic effect of the ligand (L4-L9), the more electron-rich PAr3 outperformed the electron-deficient ones. Interestingly, the monoalkyl diarylphosphines were found most efficient. Both tBu and iPr-substituted phosphines (L10 and L11) can give comparable yields to CyPPh , but the trialkyl 2 PCy3 ligand (L12) gave a lower yield. In addition, Buchwald ligands (L13 and L14) and bidentate phosphine ligands (L15 and L16) have also been examined, whereas all gave low efficiency or no reactivity. As one of the most stable peroxide species with decomposition temperature over 100oC, DTBP was found to be a superior oxidant. Cumyl peroxide (Ox1) delivered the desired product in a moderate yield; other peroxides, including tBuOOBz (Ox2), BPO (Ox3) and TBHP (Ox4), failed to yield any product (entry 6). Decreasing the catalyst/ligand loading to 10 mol% still afforded 2a in 58% yield (entry 7). A survey of different solvents suggested aromatic solvents to be optimal (entries 8-11); in contract, the more polar solvents, e.g. 1,4-dioxane and DCE, gave no product or only 20% yield, respectively. Although 80 oC was the best reaction temperature, the reaction can still proceed even at 60 oC (entries 12 and 13). Finally, running the reaction at a lower concentration gave a lower conversion with most of the starting material recovered (entry 14), while a higher concentration led to more substrate decomposition (entry 15). With the optimized conditions in hand, the substrate scope was explored (Table 2). First, substitutions at the various positions of δ-lactones were tolerated (2a-2ah). 23 δ-Alkyl- or arylsubstituted substrates all worked well, giving satisfactory yields of the corresponding products. In the presence of an additional enolizable linear ester, the desaturation of δ-lactones (1j) still occurred selectively at the lactone moiety. The α-phenyl substituted δ-lactone gave no desired product (2k); instead, the α-dimer was formed as the major side product (vide infra, Scheme 4). When the phenyl group was replaced with a benzyl group, a pair of isomers of dehydrogenation products was obtained in low yields (2l). The β-methyl substituted δ-lactone afforded a high yield (2m) using i-PrPPh2 as the ligand. The fused lactone (1n) was also a suitable substrate. The functional group compatibility was examined based on β-aryl-substituted δ-lactones (2o-2ah). Gratifyingly, a wide range of functional groups were Table 2. Substrate Scope with Lactones, Lactams and Ketones


Page 4 of 15

Page 5 of 15

Journal of the American Chemical Society O

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

O

O O

R

R

n = 0, 1 1

'standard' conditions

R

O

n = 0, 1 5

n = 0, 1 3

O

O PG

N

O

n = 0, 1 4

n = 0, 1 2

PG

N

R

R

R

n = 0, 1 6

Lactones O

O

O

O

O

O

C7H15 2b, 73%

O

O O

2d, 71%

O O

Ph

O

O

Ph

2l, 25%

Me

C7H15

2r, 51% O OPh

O

O C7H15

C7H15

C7H15

C7H15

I

2u, 57%

2t, 53%

C7H15

O O

Br

O

2q, 50%

O O

Br

O F C7H15

2p, 57%

O O

2m, 80%c

O

Me C7H15

C7H15

O

2l', 9%

O O

2o, 60%

2s, 55%

O

O O

2n, 51%

O

O

Ph

2k, 0%

O

O

2g, 78%

Me

2j, 72%c

O

2v, 49%

c

2w, 61% O

O

O

O

O

O C7H15

MeO

O

CO2Et

OEt

2i, 41%

O

O

2f, 69%

O

Ph

O

Bn 2h, 73%

OMe

2e, 72%

O Bn

O O

Ph

2c, 68%

O

O O

Me

2a, 81%

Cl

O O

O

O C7H15

F3CO

2x, 52%

O

O O

C7H15 TMS

2y, 58%

C7H15

C7H15

2ab, 42%

2aa, 64%

2z, 62%

O O

O Me

O

O

C7H15

O O

NC

O C7H15

2ac, 53%c O

O

2ai, 54%

O

O

H

O

O

H

H

AcO

O

H

H AcO

H 2al, 75%c

2ak, 56%

O

H

H

H O

O

2aj, 43%

d

O O

2ag, 62%

O

O

Me

2ah, 58%

2af, 58%

N

O Me

N

C7H15 C7H15 Me

F3C

2ae, 50%

O C7H15

O

MeO2C

O O

O O

C7H15

2ad, 44%c

O

O

H

O 2am, 64%c

Ketones and Lactams O

O

O N

O

O

O C6F5

N

4b, 60%

H

O C6F5

H

H c

AcO

O

H

H 4e, 55%

AcO

O

Me

H

H

H

4d, 62% from epiandrosterone acetate

d

N

N

Ts

H

H

H

MeO 4f, 52%

from Dehydroepiandrosterone acetate

4g, 41% from estrone

6e, 42%c,d

6d, 48%c,d

6c, 59%c

O

O

H

H

6b, 62%c

6a, 48%c

4c, 57%

O

a

N

Ts

Me

Ph 4a, 52%

AcO

O

O

O Ts

O Me

Me

Me

H

CO2Me

Me H Me Me 4h, 45% from oleanolic acid

Each reaction was run on a 0.2 mmol scale in a sealed 4 mL vial for 12 h. b Isolated yields. c 20 mol% iPrPPh2 was used. The reaction was run at 100 oC. Ts= p-toluenesulfonyl.



tolerated, including aryl fluoride (2r), chloride (2s), bromide (2t and 2u), iodide (2v), ethers (2w, 2x and 2y), silyl (2z), nitrile (2ad), ester (2ae), trifluoromethyl (2af), electron-rich arenes (2w, 2x and 2ac), polyaromatic (2ab) and tertiary amides (2ag and 2ah). Five and seven-membered lactones were found less reactive, though unsaturated γ-lactone (2ai) was still obtained in a moderate yield. Gratifyingly, δlactones derived from bioactive natural products, such as α-tocopherol (2aj), cholesterol (2ak), androsterone (2al), and dehydroepiandrosterone (2am), also smoothly afforded the desired desaturation products. Note that the allylic and benzylic C−H bonds in these substrates were tolerated. The feasibility of desaturating ketones and lactams was also tested with the Cu-catalyzed protocol. β,βdisubstituted or α,α-disubstituted cyclopentanones and cyclohexanones were competent substrates (4a-4c). Particularly, this method could be employed to desaturate a number of sterically encumbered steroid-based substrates (4d-4h). In addition, protected six- or seven- membered lactams could all afford the corresponding unsaturated products in moderate yields (6a-6e). Reactions with linear esters and amides were not fruitful under the current conditions likely due to further reduced acidity of the α hydrogens, which is the topic of the ongoing study. Scheme 2. Gram-scale Reactions 20 mol% CuTc 20 mol% [P] 1.5 equiv tBuOOtBu

O O 1a

C7H15

O O

PhH, 80 oC, 24 h 2a

C7H15

20 mmol, [P] = CyPPh2 : 86%, 3.4 g 100 mmol, [P] = PPh3 : 68%, 13.4 g

To investigate the practicality of this method, gram and decagram-scale reactions were carried out. On a 20.0 mmol scale, the desired α,β-unsaturated lactone 2a was isolated in 86% yield when CyPPh2 was used (Scheme 2). The 100 mmol scale reaction employed inexpensive PPh3 as the ligand,24 which afforded 13.4 g of product 2a. Mechanistic Studies Efforts were then carried out to obtain some mechanistic insights into the Cu-catalyzed dehydrogenation reaction. First, perhaps, the most interesting question is how the α C−H bond is cleaved. To address this question, a number of control experiments were conducted (Scheme 3). Running the reaction of substrate 1b under the standard reaction conditions except in the presence of 3 equiv tBuOD in 4 h provided the desaturated product in 58% yield with 20% D incorporation at the α position (Eq 1). The recovered 1b was found to contain 40% D at the α position. On the other hand, no deuterium incorporation was found when running the same reaction in the absence of DTBP or Cu (Eq 2), suggesting an important role of the proposed [tBuO-Cu] species. The H/D exchange phenomenon indicates that the copper enolate formation is likely reversible. Thus, from a microscopic reversibility viewpoint, the cleavage of the α C−H bond should come from a deprotonation process,25,16 which could be the key for the proposed catalytic enolization. In addition, given that over-oxidation was not observed even after subjecting the unsaturated product (2a) to the standard condition (Eq 3), as well as the tolerance of weak benzylic and allylic C−H bonds (2d-2f and 2ak), the alternative α C−H abstraction pathway by highly reactive free tBuO· radical is unlikely. Scheme 3. Cleavage of the α C−H Bond


Page 6 of 15

Page 7 of 15 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

Journal of the American Chemical Society O

20%D

standard condition 3 equiv tBuOD

O

40%D

O

D

2b-d1, 58% 0% D

no DTBP

O O 1b

1b-d2, 18%

O H H

standard condition 3 equiv tBuOD 4h

(1)

O

D

+

4h 1b

O

D

O

2b (not observed)

O

(2)

1b

no CuTc

O O 2a

standard condition 12 h

C7H15

proposed:

[Cu] O H

O O

over-oxidation: not observed 2a, 94%

O

(3)

[Cu] +

O

HO

The second question is how the β C−H bond is cleaved. To answer this question, understanding the property of the generated copper enolate would be important. Similar to Su’s observation,17a the copper enolate also exhibits sufficient radical character (Scheme 4). First, the reaction of the cyclopropanecontaining lactone (7) gave a transient ring-opening product (8), which decomposed after a longer reaction time (Eq 4). The C−C cleavage pattern for such a ring-fused cyclopropane is consistent with the previously reported radical-mediated pathway.26 In addition, a persistent radical, e.g. TEMPO, can effectively trap the α radical generated in the reaction (Eq 5). Moreover, when the α-phenyl substituted δ-lactone (1k) was employed, the α dimer was formed in 60% yield (Eq 6). This is likely due to that such α radical species is stable enough to dissociate and form a dimer. Thus, in addition to being basic, the copper enolate intermediate also has a notable radical property. Scheme 4. Radical Character of the Copper Enolate O

O standard condition

O

O

+

(4)

7

3h

62%

7

8, 21%

O

O

standard condition additive

O

2a

12 h 1a

N

+

40% 0%

(5)

44% 74%

O

O standard condition

O

O

9

additive 50 mol% TEMPO : 100 mol% TEMPO:

Ph

O

O Ph Ph

O

O

(6)

O

[Cux-1]

60% 1k

2k'

X-ray of 2k' proposed: O O

[Cux]

O O

[Cux] O

Given the radical character of the copper enolate, the β C−H bond of the enolate is anticipated to be significantly weakened. Early studies by Kochi show that alkyl radicals can react with Cu(II) salts to give olefins; this process was described as a “oxidative elimination” reaction (Scheme 5).27 A transient Cu(III)alkyl intermediate was proposed and carboxylate ligands on copper (e.g. OAc) were critical for this ACS Paragon Plus Environment


Page 8 of 15

transformation. Similarly, in this Cu-catalyzed dehydrogenation reaction, carboxylate-type X ligands were also found to be essential (vide supra, Table 1). Thus, we questioned whether a similar “oxidative elimination” process could have occurred in this system.28 A number of experiments were then carried out. While it is difficult to quantify the tBuOH generated in the reaction, the use of heavier cumyl peroxide (Ox1) afforded the corresponding alcohol 10 in 94% yield based on the desaturated product generated (Eq 7). In the prior Cu(OAc)2/TEMPO-assisted dehydrogenation, the β C−H abstraction occurred with an α-oxygenated species (e.g. TMEPO-substituted ketones).17a In our system, the αoxygenated species was not observed with lactones. In contrast, the α-tBuO-substituted product (11) was only observed when treating lactam 5a with stoichiometric CuOAc in the absence of phosphine ligands (Eq 8); however, subjecting compound 11 to the standard catalytic conditions gave no desired desaturation product (Eq 9). These results indicate that the α-oxygenated species is unlikely to be an intermediate in this reaction, which represents a main difference from the Cu(OAc)2/TEMPO system.17a Hence, in our system the β C−H scission possibly occurs with either the copper enolate or the enolate radical species. Scheme 5. Cleavage of the β C−H bond Established: (by Kochi) OAc R

R

H

[Cu(II)(OAc)2]

R

[CuIII]

oxidative elimination

HOAc

OAc

I

[Cu OAc] Ph O

O

1a

Ph Ph

20 mol% CuOAc 20% CyPPh2

O

O

O

o C7H15 PhH, 80 C, 12 h

O N

HO

O C6F5

t

1 equiv CuOAc 1.5 equiv DTBP

BuO

O N

C6F5 +

PhH, 80 oC, 12 h

5a, 14% + 6a, 20%

(8)

11, 27%

5a O t

(7)

x2 10 94% (based on 2a)

2a, 62% +

BuO

O N

O C6F5

standard condition

O N

12 h 11 proposed: O

6a O

[CuIII]

O

OR H

O

[CuII] H

not observed

oxidative elimination

OR

(9)

C6F5

O O

Kinetic studies. To better understand the catalytic system, the kinetic profiles of the reaction were obtained (Fig. 2). A short induction period (~10 min) was observed. The reaction then proceeded with a fast initial rate (0.4 mM/min), and became slower after 3 hours (at around 50% conversion). The production formation was plateaued after 6 hours. Notably, in the first 6 hours, the mass balance was nearly perfect, indicating that there was almost no decomposition of the starting material in this period. The catalyst system then became inactive after 6 hours; the 31P NMR of the reaction mixture suggests that a significant amount of phosphine oxide was formed at this stage. It is also not surprising that decomposition of 1a started to occur after the death of the catalyst.


Page 9 of 15 20 mol% CuTc 20 mol% CyPPh2 1.5 equiv t BuOOt Bu

O O 1a

C7H15

110 90

O O

o

PhH, 80 C

2a

C7H15

12 10 8 6 4 2 0 0

10

20

30

Yield (%)

70 2a 50

1a

30 10 -10 0

200

400

600

800

t / (min)

Figure 2. The Kinetic Profile of the Cu-Catalyzed Desaturation of Lactone 1a under the Standard Conditions

0.00045

Initial rate ( M/min )

DTBP: first order 0.00040

0.00035

0.00030

0.00025

0.00020

0.10

0.12

0.14

0.16

0.18

0.20

DTBP ( M )

0.00050

CuTC-CyPPh2: first order

Initial Rate ( M/min )

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


0.00045

0.00040

0.00035

0.00030

0.00025

0.016

0.020

0.024

0.028

0.032

CuTc-CyPPh2 ( M )



0.0010 0.0008

Initial Rate ( M/min )

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

Page 10 of 15

1b : zero order

0.0006 0.0004 0.0002 0.0000 0.0002 0.0004

0.02

0.04

0.06

0.08

0.10

0.12

0.14

1b (M)

Figure 3. Measurement of the Reaction Rate Dependence of the Oxidant (DTBP), the Copper Catalyst and the Substrate (1b) To gain insights into the turnover limiting step (TLS) and the resting state of the catalyst, the reaction orders of each component have been determined using the initial-rate method (Fig. 3). The rate of reaction shows first-order dependences on the catalyst and the oxidant (DTBP), but pseudo zeroorder on the lactone substrate (1b). In addition, the parallel kinetic isotope eﬀect (KIE) studies show that no primary KIE was observed at either the α or β position (Scheme 6), which indicates that C−H bond cleavage is unlikely involved in the TLS, though a small KH/KD ratio (1.2, repeated twice) was observed at the α position. The kinetic feature of this reaction represents another difference from the Cu(OAc)2/TEMPO system,17a which has the α C−H cleavage as the TLS. Scheme 6. Kinetic Isotope Eﬀect Studies. A)

O O 1a

O

D

O

D D

1a-d2

O O

1a-d2

D

O O

2a

KH / KD = 1.2  0.1

O D

B)

O

D

KH / KD = 1.0  0.1

O O

2a-d2

D D D

O 2a-d2 O

O

D 1a-d 4

D

O

D 2a-d4

Based on the results of the kinetic study, further experiments have been carried out to probe the TLS and resting state of the catalyst. First, the induction period was found to be notably shortened under a higher concentration of DTBP. In addition, when first mixing CuTc and CyPPh2 in benzene at 80 oC for 0.5 h and then adding the substrate and DTBP, the induction period still existed. However, when mixing CuTc, CyPPh2 and DTBP at 80 oC first before adding the substrate,29 no induction period was observed (for details, see Supporting Information). These results suggest that the copper (I) species, i.e. [LCu(I)OAc], is unlikely to be involved in the catalytic cycle. To examine whether the TLS involves participation of the lactone substrate, stoichiometric phosphine ligand, Cu(I)Tc and DTBP were first stirred at 80 oC for 1 h before reacting with substrate 1b at room temperature, 40 oC and 50 oC, respectively (Eq 10). No desired desaturation product was observed with most substrate 1b untouched in all these reactions after 24 h, which implies that the TLS should not be a step before the substrate enters the catalytic cycle. Considering the pseudo-zero order dependence with the substrate concentration as well as a small KIE at the α position and no KIE at the β position, we postulated that the ACS Paragon Plus Environment

Page 11 of 15 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


TLS could be a step after the α C−H deprotonation but before the β C−H cleavage, which also involves reaction with DTBP (due to the first order dependence on [DTBP]). O 1 equiv CuTc 1 equiv CyPPh2 1.1 equiv DTBP

O

1 equiv 1b 80 oC, 1 h then r.t.

1b

+

in r.t. or 40 oC or 50 oC

(10)

94-97%

2b not observed

Proposed catalytic cycle. While some mechanistic details of this reaction remain unclear and still under investigation, the data above allow us to propose a hypothesis for the Cu-catalyzed desaturation of lactones (Fig. 4). Elegant mechanistic studies by Warren show that Cu(I) could react with DTBP to generate a LCu(II)OtBu species (B) and a t-butyl oxo-radical that can undergo quick combination with another equivalent of Cu(I) to give the same species B.21e,f This process is anticipated to be the reason for the induction period, which is consistent with a fact that higher [DTBP] shortened the induction period. The LCu(II)OtBu species B could then coordinate to the carbonyl substrate and promote the subsequent reversible deprotonation of the α-C−H bond. The resulting LCu(II)-enolate D or E could then react with DTBP to afford a Cu(III) intermediate F that undergoes fast oxidative elimination, according to Kochi’s study,27,30 to afford the desaturated product and ultimately regenerate the LCu(II)OtBu species B.31 2 [LCuIY] A BuO OtBu induction period

O

t

O

X

OtBu 2 L CuII Y B

X + tBuOH t

t

BuO L O CuIII X Y H

F

C

[CuIII] OtBu G L

[CuII]

TLS t

t

BuO O Bu

L

Y O CuII H

X = O, N, C Y = OAc, Tc L = phosphine

L Y CuII O BuO H

Y CuII

O X

X

X

+ tBuOH

D

E O

O X

A +

TEMPO

X

TEMPO H

Figure 4. Proposed Simplified Catalytic Cycle Based on the kinetic studies, the TLS is proposed to be the reaction between the LCu(II)-enolate and DTBP. This proposal is consistent with the KIE experiments (vide supra, Scheme 6), as the β C−H cleavage is expected to be after the TLS and the α C−H cleavage to be before the TLS and reversible (equilibrium isotope effect). In addition, peroxides are known to be capable of oxidizing Cu(II) to Cu(III),32 though other pathways involving oxidation of the potential α radical intermediate H cannot be excluded at this stage. Consequently, the resting state of the catalyst is postulated to be the LCu(II)-enolate and/or other Cu(II) species (B or C), given that these species could all be in equilibrium. While it remains difficult to identify the exact Cu(II) species as the resting state(s),33 EPR spectrum of the reaction mixture clearly indicated the existence of Cu(II) species (see Supporting Information). In addition, ESI high-resolution mass spec (HRMS) of the reaction mixture captured the masses of the Cu(II) species instead of Cu(I) or Cu(III) species (see Supporting Information). Taken together, all the data are consistent with the proposed reaction pathway. Finally, it is noteworthy that copper carboxylates often exist in a dimeric ACS Paragon Plus Environment


form,34 thus it is highly possible that dinuclear copper species are involved and the actual catalytic cycle is much more complex. Further detailed characterization of the reaction intermediates is underway. Conclusion In summary, the development of a Cu-catalyzed desaturation of lactones, lactams and cyclic ketones is described. The reaction does not require stoichiometric strong bases or acids, and is sulfur/seleniumfree, showing high functional group tolerance. It uses a first-row transition-metal catalyst and an inexpensive reagent with t-butanol formed as the only stoichiometric byproduct. In addition, this method is scalable, operationally simple, and avoids over-oxidation. Preliminary mechanistic studies reveal an unusual reversible deprotonation of the carbonyl α C−H bonds, radical character of the copper enolate intermediate, and a critical role of the DTBP oxidant. Future efforts will involve further enhancement of the reaction efficiency and substrate scope through catalyst design and better understanding of the structure and reactivity of the copper enolate intermediate.

ASSOCIATED CONTENT Text, figures, tables, and CIF files giving experimental procedures, kinetics data, and crystallographic information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author

*[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank University of Chicago for the research support. Dr. Jianchun Wang, Dr. Yan Xu, Mr. Chengpeng Wang and Prof. Guosheng Liu are acknowledged for helpful discussions of the reaction mechanism. Dr. Zhao Wu is thanked for checking the experiments. We also thank Dr. Ki-Young Yoon for the X-ray crystallography and Mr. Xuanyu Feng for the EPR experiments.

REFERENCES (1) Otera, J. Modern Carbonyl Chemistry; Wiley: Weinheim, 2000. (2) For representative reviews, see: (a) Muzart, J.; One-Pot Syntheses of α,β-Unsaturated Carbonyl Compounds through Palladium-Mediated Dehydrogenation of Ketones, Aldehydes, Esters, Lactones and Amides. Eur. J. Org. Chem. 2010, 3779. (b) Stahl, S. S.; Diao, T. Oxidation Adjacent to C-X Bonds by Dehydrogenation. Comp. Org. Synth. 2014, 7, 178. (c) Iosub, A. V.; Stahl, S. S. Palladium-catalyzed aerobic dehydrogenation of cyclic hydrocarbons for the synthesis of substituted aromatics and other unsaturated products. ACS Catal. 2016, 6, 8201. (d) Turlik, A.; Chen, Y.; Newhouse, T. R. Dehydrogenation Adjacent to Carbonyls Using Palladium-Allyl Intermediates. Synlett 2016, 331. (3) (a) Pirkle, W. H.; Adams, P. E. Enantiomerically pure lactones. 3. Synthesis of and stereospecific conjugate additions to .alpha.,.beta.-unsaturated lactones. J. Org. Chem. 1980, 45, 4117. (b) de Fátima, Â.; Kohn, L. K.; de Carvalho, J. E.; Pilli, R. A. Cytotoxic activity of (S)-goniothalamin and analogues against human cancer cells. Bioorg. Med. Chem. 2006, 14, 622. (c) Zhou, Z.-F.; Liu, H. L.; Zhang, W.; Kurtán, T.; Mándi, A.; Bényei, A.; Li, J.; Taglialatela-Scafati, O.; Guo, Y.-W. Bioactive rearranged limonoids from the Chinese mangrove Xylocarpus granatum Koenig. Tetrahedron 2014, 70, 6444. (d) Barcelos, R. C.; Pastre, J. C.; Vendramini-Costa, D. B.; Caixeta, V.; Longato, G. B.; ACS Paragon Plus Environment

Page 12 of 15

Page 13 of 15 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


Monteiro, P. A.; de Carvalho, J. E.; Pilli, R. A. Design and Synthesis of N-Acylated Aza-Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity. ChemMedChem 2014 , 9 , 2725. (e) Méndez-Robles, M. D.; Permady, H. H.; Jaramillo-Flores, M. E.; Lugo-Cervantes, E. C.; Cardador-Martinez, A.; Canales-Aguirre, A. A.; Lopez-Dellamary, F.; Cerda-Garcia-Martinez, C. M.; Tamariz, J. C-26 and C-30 Apocarotenoids from Seeds of Ditaxis heterantha with Antioxidant Activity and Protection against DNA Oxidative Damage. J. Nat. Prod. 2006, 69, 1140. (4) (a) Le Bras, J.; Muzart, J. Palladium-Catalyzed Domino Dehydrogenation/Heck-Type Reactions of Carbonyl Compounds. Adv. Synth. Catal. 2018, 360, 2411. (b) Huang, Z.; Dong, G. Catalytic C−C Bond Forming Transformations via Direct β-C−H Functionalization of Carbonyl Compounds. Tetrahedron Lett. 2014, 55, 5869. (5) (a) Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Allyl-Palladium-Catalyzed Ketone Dehydrogenation Enables Telescoping with Enone a,b-Vicinal Difunctionalization. Angew. Chem., Int. Ed. 2017, 56, 8258. (b) For a review on α,β-vicinal difunctionalization of enones, see: M. J. Chapdelaine, M. Hulce in Organic Reactions, Vol. 38 (Eds.: Paquette, L. A.), Wiley, New York, 1990, 225. (6) For seminal works on Pd-catalyzed ketone dehydrogenation, see: (a) Theissen, R. J. Preparation of. alpha.,. beta.-unsaturated carbonyl compunds. J. Org. Chem. 1971, 36, 752. (b) Ito, Y.; Hirao, T.; Saegusa, T. Synthesis of. alpha.,.beta.-unsaturated carbonyl compounds by palladium (II)-catalyzed dehydrosilylation of silyl enol ethers. J. Org. Chem. 1978, 43, 1011. (c) Shimizu, I.; Minami, I.; Tsuji, J. Palladium-catalyzed synthesis of α, β-unsaturated ketones from ketones via allyl enol carbonates. Tetrahedron Lett. 1983, 24, 1797. (d) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. A simple, effective, new, palladium-catalyzed conversion of enol silanes to enones and enals. Tetrahedron Lett. 1995, 36, 2423. (e) Diao, T. N.; Stahl, S. S. Synthesis of cyclic enones via direct palladium-catalyzed aerobic dehydrogenation of ketones. J. Am. Chem. Soc. 2011, 133, 14566. (f) Diao, T. N.; Wadzinski, T. J.; Stahl, S. S. Direct aerobic α, β-dehydrogenation of aldehydes and ketones with a Pd (TFA)2/4,5-diazafluorenone catalyst. Chem. Sci. 2012, 3, 887. (g) Diao, T. N.; Pun, D.; Stahl, S. S. Aerobic Dehydrogenation of Cyclohexanone to Cyclohexenone Catalyzed by Pd(DMSO)2(TFA)2: Evidence for Ligand-Controlled Chemoselectivity. J. Am. Chem. Soc. 2013, 135, 8205. (h) Sakamoto, Y.; Amaya, T.; Suzuki, T.; Hirao, T. Palladium (II)-Catalyzed Dehydroboration via Generation of Boron Enolates. Chem. Eur. J. 2016, 22, 18686. (7) (a) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. Electrophilic and nucleophilic organoselenium reagents. New routes to. alpha.,. beta.-unsaturated carbonyl compounds. J. Am. Chem. Soc. 1973, 95, 6137. (b) Trost, B. M.; Salzmann, T. N.; Hiroi, K. New synthetic reactions. Sulfenylations and dehydrosulfenylations of esters and ketones. J. Am. Chem. Soc. 1976, 98, 4887. (c) Matsuo, J.-i.; Aizawa, Y. One-pot dehydrogenation of carboxylic acid derivatives toa,b-unsaturated carbonyl compounds under mild conditions. Tetrahe-dron. Lett. 2005, 46, 407. (8) Teskey, C. J.; Adler, P.; Goncalves, C. R.; Maulide, N. Chemoselective α,β-Dehydrogenation of Saturated Amides. Angew. Chem., Int. Ed. 2019, 58, 447. (9) (a) Chen, Y.; Romaire, J. P.; Newhouse, T. R. Palladium-Catalyzed α,β-Dehydrogenation of Esters and Nitriles. J. Am. Chem. Soc. 2015, 137, 5875. (b) Chen, Y.; Turlik, A.; Newhouse, T. R. Amide α,βDehydrogenation Using Allyl-Palladium Catalysis and a Hindered Monodentate Anilide. J. Am. Chem. Soc. 2016 , 138, 1166. (c) Zhao, Y.; Chen, Y.; Newhouse, T. R. Allyl-Palladium-Catalyzed a,bDehydrogenation of Carboxylic Acids via Enediolates. Angew. Chem., Int. Ed. 2017 , 56, 13122. (d) Huang, D.; Zhao, Y.; Newhouse, T. R. Synthesis of Cyclic Enones by Allyl-Palladium-Catalyzed α,βDehydrogenation. Org. Lett. 2018, 20, 684. (e) Szewczyk, S. M.; Zhao, Y.; Sakai, H. A.; Dube, P.; Newhouse, T. R. α,β-Dehydrogenation of esters with free O-H and N-H functionalities with allylpalladium catalysis. Tetrahedron 2018, 74, 3293. (10) Chen, M.; Dong, G. Direct catalytic desaturation of lactams enabled by soft enolization. J. Am. Chem. Soc. 2017, 139, 7757. (11) Chen, M.; Rago, A.; Dong, G. Platinum-catalyzed Desaturation of Lactams, Ketones and Lactones. Angew. Chem., Int. Ed. 2018, 57, 16205. (12) Zhao, J.; Fang, H.; Han, J.; Pan, Y. Cu-Catalyzed C(sp3)−H Bond Activation Reaction for Direct Preparation of Cycloallyl Esters from Cycloalkanes and Aromatic Aldehydes. Org. Lett. 2014, 16, 2530. ACS Paragon Plus Environment


(13) Rout, S. K.; Guin, S.; Ali, W.; Gogoi, A.; Patel, B. K. Copper-Catalyzed Esterification of Alkylbenzenes with Cyclic Ethers and Cycloalkanes via C(sp3)-H Activation Following Cross-Dehydrogenative Coupling. Org. Lett. 2014, 16, 3086. (14) Tran, B. L.; Driess, M.; Hartwig, J. F. Copper-Catalyzed Oxidative Dehydrogenative Carboxylation of Unactivated Alkanes to Allylic Esters via Alkenes. J. Am. Chem. Soc. 2014, 136, 17292. (15) Kharasch, M. S.; Sosnovsky, G. The Reactions of t-Butyl Perbenzoate and Olefines-A Stereospecific Reaction. J. Am. Chem. Soc. 1958, 80, 756. (16) Manna, S.; Antonchick, A. P. [1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes. Angew. Chem., Int. Ed. 2016, 55, 5290. (17) (a) Jie, X.; Shang, Y.; Zhang, X.; Su, W. Cu-Catalyzed Sequential Dehydrogenation-Conjugate Addition for β-Functionalization of Saturated Ketones: Scope and Mechanism. J. Am. Chem. Soc. 2016, 138, 5623. (b) Li, H.; Jiang, Q.; Jie, X.; Shang, Y.; Zhang, Y.; Goossen, L. J.; Su, W. Rh/Cu-Catalyzed Ketone β-Functionalization by Merging Ketone Dehydrogenation and Carboxyl-Directed C–H Alkylation. ACS Catal. 2018, 8, 4777. (18) Shang, Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su, W. Dehydrogenative desaturation-relay via formation of multicenterstabilized radical intermediates. Nat. Commun. 2017, 8, 2273. (19) Roberts, B. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 1999, 28, 25. (20) (a) Russell, G. A. Nature of the Polar Effect in Reactions of Atoms and Radicals. J. Org Chem. 1958, 23, 1407. (b) Zavitsas, A. A.; Pinto, J. A. The Meaning of the “Polar Effect” in Hydrogen Abstractions by Free Radicals. Reactions of the tert-Butoxy Radical. J. Am. Chem. Soc. 1972, 94, 7390. (c) Grob, C. A. Polar Effects in Organic Reactions. Angew. Chem., Int. Ed. Engl. 1976, 15, 569. (d) Paul, V.; Roberts, B. Polarity reversal catalysis of hydrogen atom abstraction reactions. J. Chem. Soc., Chem. Commun. 1987, 1322. (21) For reviews, see: (a) Gephart, R. T., III; Warren, T. H. Copper-Catalyzed sp3 C–H Amination. Organometallics 2012, 31, 7728. (b) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Aerobic Copper-Catalyzed Organic Reactions. Chem. Rev. 2013, 113, 6234. (c) Guo, X. X.; Gu, D. W.; Wu, Z.; Zhang, W. Copper-Catalyzed C-H Functionalization Reactions: Efficient Synthesis of Heterocycles. Chem. Rev. 2015, 115, 1622. For selected examples, see: (d) Wiese, S.; Badiei, Y. M.; Gephart, R. T.; Mossin, S.; Varonka, M. S.; Melzer, M. M.; Meyer, K.; Cundari, T. R.; Warren, T. H. Catalytic C-H Amination with Unactivated Amines through Copper(II) Amides. Angew. Chem., Int. Ed. 2010, 49, 8850. (e) Gephart, R. T., III; Mcmullin, C. L.; Sapiezynski, N. G.; Jang, E. S.; Aguila, M. J. B.; Cundari, T. R.; Warren, T. H. Reaction of CuI with Dialkyl Peroxides: CuII-Alkoxides, Alkoxy Radicals, and Catalytic C–H Etherification. J. Am. Chem. Soc. 2012, 134, 17350. (f) Jang, E. S.; McMullin, C. L.; Kass, M.; Meyer, K.; Cundari, T. R.; Warren, T. H. Copper(II) Anilides in sp3 C-H Amination. J. Am. Chem. Soc. 2014, 136, 10930. (g) Salvador, T. K.; Arnett, C. H.; Kundu, S.; Sapiezynski, N. G.; Bertke, J. A.; Boroujeni, M. R.; Warren, T. H. Copper Catalyzed sp3 C–H Etherification with Acyl Protected Phenols. J. Am. Chem. Soc. 2016, 138, 16580. (h) Zhang, C.; Zong, X.; Zhang, L.; Jiao, N. Copper-Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling of Amine and r-Carbonyl Aldehyde: A Practical and Efficient Approach to α-Ketoamides with Wide Substrate Scope. Org. Lett. 2012, 14, 3280. (i) Zhang, C.; Jiao, N. Copper-Catalyzed Aerobic Oxidative Dehydrogenative Coupling of Anilines Leading to Aromatic Azo Compounds using Dioxygen as an Oxidant. Angew. Chem., Int Ed. 2010, 49, 6174. (j) McCann, S. D.; Stahl, S. S. Copper-Catalyzed Aerobic Oxidations of Organic Molecules: Pathways for Two-Electron Oxidation with a Four-Electron Oxidant and a One-Electron Redox-Active Catalyst. Acc. Chem. Res. 2015, 48, 1756. (k) McCann, S. D.; Stahl, S. S. Mechanism of Copper/ AzodicarboxylateCatalyzed Aerobic Alcohol Oxidation: Evidence for Uncooperative Catalysis. J. Am. Chem. Soc. 2016, 138, 199. (l) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Enantioselective cyanationof benzylic C-H bonds viacopper-catalyzed radical relay. Science 2016, 353, 1014. (m) Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed Radical Relay for Asymmetric Radical Transformations. Acc. Chem. Res. 2018, 51, 2036. (22) Tereniak, S. J.; Landis, C. R.; Stahl, S. S. Are phosphines viable ligands for Pd-Catalyzed aerobic oxidation reactions? Contrasting insights from a survey of six reactions. ACS Catal. 2018, 8, 3708. ACS Paragon Plus Environment

Page 14 of 15

Page 15 of 15 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


(23) The reactions were run with an extended reaction time to allow for full conversions. Otherwise, separation of pure products from unreacted starting materials would be very difficult. (24) While the larger scale reactions were always run with caution and protecting equipment, safety issues with the use of DTBP were not observed in our hands. (25) Bailey, W. D.; Gagnon, N. L.; Elwell, C. E.; Cramblitt, A. C.; Bouchey, C. J.; Tolman, W. B. Revisiting the Nucleophilic Reactivity of an Anionic Copper-Superoxide Complex. Inorg. Chem. 2019, 58, 4706. (26) (a) Groves, J. T.; Kruper, W. J.; Haushalter, R. C. Hydrocarbon oxidations with oxometalloporphinates. Isolation and reactions of a (porphinato)manganese(V) complex. J. Am. Chem. Soc. 1980, 102, 6375. (b) Chakrabarty, S.; Austin, R. N.; Deng, D.; Groves, J. T.; Lipscomb, J. D. Radical Intermediates in Monooxygenase Reactions of Rieske Dioxygenases. J. Am. Chem. Soc. 2007, 129, 3514. (c) Nagahara, S.; Yamakawa, T.; Yamamoto, H. Aluminum chloride catalyzed hydrosilylation of cyclopropanes with chlorodimethylsilane. Tetrahedron Lett. 2001, 42, 5057. (d) Liu, W.; Groves, J. T. Manganese Porphyrins Catalyze Selective C-H Bond Halogenations. J. Am. Chem. Soc. 2010, 132, 12847. (27) Kochi, J. K.; Bemis, A.; Jenkins, C. L. Mechanism of electron transfer oxidation of alkyl radicals by copper(II) complexes. J. Am. Chem. Soc. 1968, 90, 4616. (28) Notably, direct β-hydrogen elimination of a high valent copper species is rare. (29) A immediate color change from colorless to green was observed when mixing the Cu(I) complex with DTBP. (30) Kochi, J. K. Electron-transfer mechanisms for organometallic intermediates in catalytic reactions. Acc. Chem. Res. 1974, 7, 351. (31) The details for the regeneration of Cu(II) species B are unclear at this stage. We hypothesized that another Cu(II) species is probably involved in this process. (32) Wang, J.; Liu, C.; Yuan, J.; Lei. A. Copper-Catalyzed Oxidative Coupling of Alkenes with Aldehydes: Direct Access to α,β-Unsaturated Ketones. Angew. Chem. Int. Ed. 2013, 52, 2256. (33) 31P NMR of the reaction mixtures showed close and broad peaks. Thus, it was not trivial to use NMR to identify the resting state. (34) Brown, G. M.; Chidambaram, R. Dinuclear Copper(II) Acetate Monohydrate: A Redetermination of the Structure by NeutronDiffraction Analysis. Acta Crystallogr. B 1973, 29, 2393. O

O

R3P-Cu(I) cat t BuOOtBu

X

X

PhH, 80 oC

waste +

X

O X

catalytic enolization

BuOH

2 equiv

X = CH2, O, NR [Cu] O O H

t

[Cu]

 strong base and acid free  sulfur and selenium free  simple one-step operation  inexpensive catalyst/reagent  scalable and chemoselective  no over-oxidation


Copper-Catalyzed Desaturation of Lactones, Lactams and Ketones

Recommend Documents