A diverse range of copper complexes in both the S = 0 and S = 1/2 states are reported, including a rare, paramagnetic copper-phosphine complex that can serve as a structural model for important copper intermediates of the enantioselective Csp³-N linkages of carbazoles. Photoinduced copper-catalyzed alkylation of amines: a mechanistic study of the cross-coupling of carbazole with alkyl bromides.
Introduction
- Transition metal-catalyzed coupling reactions of organohalides
- Photoinduced, copper-catalyzed C–N couplings
- Chemistry of carbazole
- Overview of individual chapters
- Notes and references
Selected examples of nucleophiles used in photoinduced, copper-catalyzed couplings in the absence of exogenous ligands. In Chapter 4, we build on the results described in Chapter 3 and communicate the development of the photoinduced, copper-catalyzed couplings of carbamates with unactivated alkyl bromides (Scheme 1.6).
Mechanistic insights on copper-catalyzed alkylations of amines: photoinduced
Introduction
This key observation inspired the development of general, photoinduced, copper-catalyzed couplings of carbazoles and alkyl halides (Scheme 2.1b).2. 20 that the photoinduced, copper-catalyzed couplings of carbazole with alkyl halides proceed via a predominantly off-cage process.
Results and Discussions
- Optimization of conditions for mechanistic studies
- Stoichiometric reactivity of [Cu I (carb) 2 ]Li
- Single electron transfer from [Li(carb)]*
- Characterization of [Cu II (carb) 3 ] –
- Evidence for out-of-cage coupling via free radical intermediate
In the absence of light, stirring a mixture of Li(carbohydrate) and the alkyl bromide does not lead to the consumption of the electrophile. Outcome of the irradiation of a mixture of Li(carb) and 2-bromo-4-phenylbutane in the absence of copper.
Conclusions
Using ESI-MS, we obtained evidence for the presence of [CuI(carb)2]– under catalysis conditions. Using EPR spectroscopy, we obtained evidence for the formation of a copper(II) complex during catalysis; we hypothesized that this intermediate was [CuII(carb)3]– (formed by the reaction of the carbazyl radical with [CuI(carb)2]–), which was then independently synthesized and structurally characterized.
Experimental section
- General information
- Procedures for photoinduced cross-couplings
- Preparation of metal carbazolides
- Procedures for freeze-quench EPR studies
- Procedures for UV-vis studies
- Actinometry
- Procedures for Stern-Volmer analysis
- Reactivity of [Cu II (carb) 3 ]Li
- Computational methods
- X-ray crystallographic data
A 10 mM solution of Li(carb) in CH3CN was made and this solution was used as a stock to create Li(carb) solutions of lower concentration. 30 For [CuII(carb)3]– , the Loewdin spin density was derived from a constrained optimization where the N–Cu–N angles and C(1)–C(9a)–N–Cu dihedrals along each carbazole were constrained. to match the experimentally determined solid crystal structure.
Notes and References
18 For examples of other copper(II) amido complexes where a significant spin density is assumed to be on nitrogen, see (a) ref 9. 19 For examples of other copper(II) amido complexes that abstract hydrogen atoms, see ref. 8 and 18b.
Copper complexes supported by tridentate bis(phosphino)carbazole ligands
Introduction
However, the N-substitution of carbazole and competing ligand substitution reactions may present a significant challenge in the selective coupling of the desired nucleophile under this hypothetical reaction condition. Since lithium carbazolide is able to engage in SET with unactivated alkyl bromides, we envisioned that the inherent photoproperties of the carbazole scaffold could be used to advantage in the design of a new photocatalyst capable of copper-catalyzed cross-coupling reactions of non-photoactive nucleophiles initiate. .
Results and Discussions
- Synthesis and characterization of copper(I) complexes supported by tridentate
- Reactivity of complex 3.1
- Catalytic C–N coupling enabled by complex 3.1 and light
The 1H NMR spectrum of the reaction mixture shows the intact N-H resonance, unlike the preparation of 3.1 (Scheme 3.3). The feasibility of transforming the decomposition product of the one-electron oxidation from 3.1 (e.g. 3.8) back to 3.1 is advantageous in the context of developing catalytic transformations using 3.1.
Conclusions
Ligand structures and combinations ineffective for the coupling of t-butyl carbamate with 2-bromo-4-phenylbutane under conditions related to those shown in Scheme 3.5. The design of complex 3.1 is essential to elicit the observed photochemical transformation, as copper, bis(phosphino)carbazole, and light are all required for the formation of C–N bonds.
Experimental section
- General information
- Preparation of ligands
- Preparation of copper complexes
- Photoproperties of complexes
- EPR spectroscopy
- DFT calculations
- General procedure for the photoinduced alkylations
- X-ray crystallographic data
Then 1 mL of THF was added, and the mixture was allowed to stir overnight at room temperature. Next, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo.
Notes and References
1 There are conflicting values of the standard reduction potentials of alkyl halides in the literature. 8 For an example of the deleterious impact of a substitution in the 1-position on the reactivity of the carbazole nitrogen in a photoinduced, copper-catalyzed N-alkylation, see Bissember, A.
Synthesis of carbamate-protected primary amines via photoinduced, copper-
- Introduction
- Results and Discussions
- Optimization
- Scope
- Mechanistic studies
- Stereoselective N–alkylations of ammonia surrogates
- Conclusions
- Experimental Section
- General information
- Photoinduced, copper-catalyzed alkylations
- Effect of reaction parameters
- Effect of additives
- Mechanistic studies
- Stereoselective N–alkylations of ammonia surrogates
- X-ray crystallographic data
- Notes and References
The presence of complex 4.1 at the beginning of the reaction and in the ongoing reaction is also confirmed by ESI-MS analysis.12. 171 similar to the stereoselectivity reported for the cyclization of the derivatized secondary alkyl radical, this finding supports the hypothesis that the secondary alkyl radical is an intermediate in the photoinduced, copper-catalyzed couplings we report.
Copper complexes supported by bidentate (phosphino)carbazole ligands
Introduction
Results and Discussions
- Synthesis and characterization of S = 1/2 complexes supported by bidentate
- Reactivity of S = 1/2 complexes supported by bidentate (phosphino)carbazoles
- Investigation of mononuclear S = 1/2 copper complexes supported by
Concluding Remarks
Experimental Section
- General information
- Synthesis of (phosphino)carbazole ligands
- Synthesis of bimetallic complexes supported by (phosphino)carbazoles
- Photoinduced, copper-catalyzed cyanomethylations
- Generation of S = 1/2 copper complexes supported by (phosphino)carbazoles
- X-ray crystallographic data
Notes and References
Examples of pathways by which the formation of a radical (•R) from an organohalide
A representative proof-of-principle study that demonstrated the viability of a radical pathway in the copper-catalyzed Csp²-N coupling of an aryl halide with an amine (also known as the Ullmann coupling) was communicated by the Peters and Fu laboratories in 2012.8 Prior to this report , the Peters group had examined the use of their luminescent copper complexes to facilitate light-initiated multielectron processes,9 and observed that irradiation of complex 1.1 and iodobenzene gave N-phenyl carbazole (Scheme 1.3, top).8 In 2012 study, the Fu and Peters groups showed that a wide range of mechanistic data is consistent with a radical pathway,10 in contrast to the pair-electron pathways that had been suggested in thermal Ullmann bonds,11 en route to Csp² bond formation -N. Furthermore, they demonstrated that N-phenyl carbazole can be detected in 64% yield when lithium carbazolide is irradiated in the presence of iodobenzene and a substoichiometric amount (10 mol%) of CuI (Scheme 1.3, bottom).
Photoinduced Ullmann coupling reported in 2012 by the Fu and Peters laboratories
We begin our account in Chapter 2 by presenting an in-depth mechanistic investigation of the photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides (Scheme 1.4). Optimized reaction conditions for an in-depth mechanistic study on photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides.
Optimized reaction conditions for an in-depth mechanistic study on photoinduced,
Application of a newly-designed copper-based photoredox catalyst 3.1 ligated by a
Photoinduced, copper-catalyzed couplings of carbamates with unactivated alkyl
The probability of photoinduced one-electron oxidation of copper is further confirmed by the reduction of the lifetime of [CuI(carb)2]Li* in the presence of alkyl bromide. 36 reviewed the photoinduced copper-catalyzed coupling of a deuterium-labeled analogue of 6-bromo-1-heptene (Scheme 2.8).
Evolution of N–functionalizations of carbazole
Photostability of 6-halo-1-heptenes
To further simplify the reaction conditions for mechanistic studies, separate reaction components were used ([CuI(carb)2]Li as catalyst and Li(carb) as nucleophile; carb = carbazolide),11 instead of the mixture of CuI, carbazole. and LiOt-Bu that were described in the previous study. Under the new conditions, carbazole undergoes alkylation with 2-bromo-4-phenylbutane in 64% yield at 0 °C in the presence of 5 mol% catalyst (Scheme 2.3).
New conditions for the mechanistic studies
The lifetime of a non-emissive excited state of [Li(CH3CN)][Cu(carb)2] as a function of electrophile concentration was measured by transient absorbance spectroscopy (λpump = 355 nm, λprobe = 580 nm); the data are summarized in table 2.6. 92 secondary bromide using blue LEDs as a light source can be achieved in the presence of 3,1, although the yield of the observed C–N coupling is modest (33%, Scheme 3.5).
Stoichiometric reaction between [Cu I (carb) 2 ]Li and 2-bromo-4-phenylbutane
Outcome of the irradiation of a mixture of Li(carb) and 2-bromo-4-phenylbutane in the
As with the original mechanism (Figure 2.1), the key step for forming C-N bonds is still the reaction of an alkyl radical with a copper(II) carbazolide complex, but the route for forming these intermediates is different. Then, 1 ml of the resulting green solution of CuBr2 (0.010 mmol) was added dropwise to the thawing CH3CN solution of Li(carb).
Hydrogen atom transfer by TEMPO–H to [Cu II (carb) 3 ]Li, resulting in the full
The coupling of 6-bromo-1-heptene, yielding the cyclization product
Trans-deuterium-labeled analog of 6-bromo-1-heptene resulting in loss of stereochemical information upon coupling under standard conditions.
Trans-deuterium-labeled analogue of 6-bromo-1-heptene resulting in the loss of
37 a photoinduced, copper-catalyzed cross-coupling is performed in the presence of TEMPO, further supporting the possibility of coupling outside the cage.
The effect of overall reaction concentrations on the extent of cyclization
TD-DFT results: Orbital compositions of the calculated singlet excitations (first three) of copper complex 3.1. In reactions of sterically hindered electrophiles (e.g. Scheme 4.4), electrophilic homocoupling products are detected via the GC analysis of the crude reaction mixtures, consistent with the intermediation of alkyl radicals.14 The presence of alkyl radicals is also evident in the stereochemical outcome of the C–N linkages of 3-substituted cyclohexyl bromide (Table 4.3 entry 9; starting material: 1:5.4 cis/trans; product: .. 6.5:1 cis/trans) and that of the pregnenolone-derived electrophile (Scheme 4.5); the latter yields mainly the stereoretention product of the substitution reaction.
Photosensitization by carbazole in the coupling of benzimidazole and iodobenzene
Preparation of PNP ligands
When ligands L3.1-L3.6 are treated with mesityl copper or with a mixture of CuCl and LiOt-Bu in benzene, the raw 1H NMR spectra of the resulting solutions show the disappearance of N-H resonances of free ligands (Scheme 3.3) . The 31P NMR spectra also reveal the downfield shift and broadening of the phosphor resonances, consistent with the ligation to the copper center.
Synthesis of mononuclear, three-coordinate copper complexes
Based on the cross section of the excitation and the emission profiles10 (Figure 3.4, right) and the electrochemical data, we estimate that complex 3.1 has an excited-state reduction potential of –2.5 V vs SCE. Based on the estimated excited-state reduction potential of complex 3.1, we postulate that this quenching is likely due to single electron transfer from the 3.1* to the alkyl bromide.
Formation of complex 3.8–BF 4
Pleasingly, we have found that 3.1 can be used as an effective catalyst for the photoinduced copper-catalyzed couplings of carboxamide-type nucleophiles with unactivated alkyl halides. In the absence of light, no reaction is observed and the alkyl bromide can be recovered quantitatively.
Catalytic C–N coupling of t-butyl carbamate with 2-bromo-4-phenylbutane
The 1H NMR spectrum of the residue showed the clean formation of the target compound, which could be further purified by recrystallization from a mixture of benzene/n-hexanes, Et2O or CH3CN at –35 °C to provide colorless crystals of copper complexes . 104 Colorless crystals of the target complex after recrystallization in a mixture of benzene/n-hexanes at –35 °C (260 mg, 76% yield).
Primary amine synthesis by substitution reactions with alkyl halides
Because primary amines play an important role in many fields of science, including biology, medicinal chemistry, and materials science, the selective synthesis of primary amines is an important challenge in organic chemistry.1 Perhaps the most obvious route is the nucleophilic substitution of an alkyl electrophile. with ammonia (a commodity) can be problematic due to problems such as overalkylation with strong electrophiles and insufficient reactivity with weak electrophiles (Scheme 4.1, above).2 As a result, a number of useful alternative approaches have been developed, including the Gabriel synthesis, which allows direct access to protected primary amines via an SN2 reaction between the phthalimide anion and the corresponding alkyl electrophile (Scheme 4.1, middle).3. Here, we extend the catalytic reactivity of the new photocatalyst presented in Chapter 3 (complex 3.1) and reveal the development of a copper-catalyzed method for the selective mono-alkylation of primary carbamates with unactivated secondary alkyl halides induced by blue LED irradiation. lamps.
Attempted alkylation of t-butyl carbamate under amide alkylation conditions
To suppress the formation of elimination products, the coupling of the sterically demanding substrate requires a slowing down of the reaction. For the coupling of the pregnenolone-derived alkyl bromide, the major diastereomer of the product can be isolated as a single isomer (>20:1) via column chromatography followed by recrystallization.
Effect of added CuBr on the photoinduced coupling of t-butyl carbamate catalyzed by
Coupling of a hindered substrate under modified reaction conditions
Application of the method to the derivatization of a complex alkyl bromide
169 carboxamides, in which a copper nucleophile complex is proposed to be involved in both electron transfer and bond formation.7 A 31P NMR study establishes that complex 4.1 does not dissociate ligand L4.1 or bind t-butyl carbamate to a significant extent in the presence of 3.0 equiv. of the carbamate/LiOt-Bu. The EPR spectrum of the standard reaction mixture (Table 4.1, entry 1) reveals an S = 1/2 species with hyperfine coupling to a mononuclear Cu center (I = 3/2) (Figure 4.2, black trace).
Observation of cyclized alkyl radical coupling products
In particular, the secondary alkyl radical derived from 6-bromo-1-heptene cyclizes with a rate constant of 1.0 × 105 s-1 at 25 °C.15 Because this is much slower than typical diffusion rates (generally >108 s-1 ),16 the radical has sufficient time to diffuse before being involved in C–N bond formation, as required by the mechanism depicted in Figure 4.1. In light of the successful reactions between carbamates with unactivated secondary alkyl bromides that occur via an off-cage radical coupling mechanism, we sought to extend the strategy to prepare stereoprotected primary amines.
Stereoconvergent coupling of racemic secondary electrophiles
Chiral nucleophiles that have been unsuccessful in the synthesis of stereoprotected primary amines and possible reasons for their shortcomings. In contrast, stereoselectivity has been observed when methyl carbamate is used in the coupling of an unactivated alkyl bromide with an ether directing group.
Stereoselective coupling of methyl carbamate in the presence of a chiral diamine
CuBr, ligand L4.1, LiOt-Bu and the carbamate were added to an 8 mL borosilicate glass vial containing a magnetic stir bar. CuBr, ligand L4.1, LiOt-Bu, the carbamate, and the electrophile were added to an 8 mL borosilicate glass vial containing a magnetic stir bar.
Enantioconvergent copper catalysis: the alkylation of carbazole with a tertiary α-
CN in the presence of an equivalent of LiOt-Bu
![Figure 2.7. Characterization of the copper(II) intermediate. Left: solid-state molecular structure of [Cu II (carb) 3 ][K(THF) 6 ] as determined by single crystal X-ray diffraction (countercation and H atoms are omitted for clarity)](https://thumb-ap.123doks.com/thumbv2/123dok/10403007.0/52.918.212.765.111.332/figure-characterization-intermediate-molecular-structure-determined-diffraction-countercation.webp)
