共查询到20条相似文献,搜索用时 46 毫秒
1.
2.
3.
4.
5.
CaO solubility in equimolar molten salts CaCl2–x (x = 0, NaCl, KCl, SrCl2, BaCl2 and LiCl) was determined at 873–1223 K and activity coefficient calculated. CaO solubility in the binary salts is less than in CaCl2, and the activity coefficient is greater than one. With increasing temperature CaO solubility increases and the activity coefficient decreases. The dependency of CaO activity coefficient on temperature in equimolar molten salts CaCl2–x is
相似文献
CaCl2 | RTln γCaO = 6961 + 5.06 T (K) | 1123–1223 K |
CaCl2–NaCl | RTln γCaO = 3985 + 17.67 T (K) | 923–1123 K |
CaCl2–KCl | RTln γCaO = 2384 + 22.72 T (K) | 1073–1223 K |
CaCl2–SrCl2 | RTln γCaO = 27245–1.13 T (K) | 1073–1223 K |
CaCl2–BaCl2 | RTln γCaO = 17068 + 10.19 T (K) | 1223–1273 K |
CaCl2–LiCl | RTln γCaO = 14724 + 0.72 T (K) | 923–1073 K |
Full-size table
6.
7.
8.
The overall photobromination reactions have been studied using a competitive technique. Relative Arrhenius parameters were obtained for the rate-determining step These were placed on an absolute basis using previous-absolute values of A and E for RFI=CF3I. The activation energies were used to calculate bond dissociation energies D(R? I) with the following results:
RF? | E16 | D(RF?I)(kcal/mole) |
---|---|---|
CF3I a a E16 from [1] | 10.8 | 52.6 |
C2F5I | 8.8 | 50.6 |
n-C3F7I | 7.4 | 49.2 |
i-C3F7I | 7.5 | 49.2 |
n-C4F9I | 6.7 | 48.4 |
- a E16 from [1]
9.
Ke Yang Zhi Li Chong Liu Yunjian Li Qingyue Hu Mazen Elsaid Bijin Li Jayabrata Das Yanfeng Dang Debabrata Maiti Haibo Ge 《Chemical science》2022,13(20):5938
The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp3)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.1 Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).2 Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.3 Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.6 Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.7 Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.8 Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.9 Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.10 The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.11 Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.12Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.17 This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.18We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)2 and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)2 to be the optimal catalyst, while Pd(TFA)2, PdCl2 and PdBr2 provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)2 was instead used (entry 15).Optimization of reaction conditionsa
Open in a separate windowaReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by 1H-NMR using dibromomethane as an internal standard.bIsolated yield.cPd(OAc)2 (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp3)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol−1). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)2]3, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol−1. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp3)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG‡ = 37.4 kcal mol−1). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol−1. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp3)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol−1, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp3)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol−1. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG‡ = 27.4 kcal mol−1) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol−1 (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol−1) and thermodynamically favorable (30.7 kcal mol−1). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol−1). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced. 相似文献
Entry | Pd source | L (mol%) | TDG1 (mol%) | Solvent (v/v, mL) | Yield (%) |
---|---|---|---|---|---|
1 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP | 30 |
2 | Pd(OAc)2 | L1 (30) | TDG1 (40) | AcOH | <5 |
3 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (1 : 1) | 28 |
4 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (9 : 1) | 47 |
5 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (1 : 9) | <5 |
6 | Pd(OAc)2 | L1 (30) | TDG1 (60) | HFIP/AcOH (9 : 1) | 50 |
7 | Pd(OAc)2 | L1 (30) | TDG1 (80) | HFIP/AcOH (9 : 1) | 25 |
8 | Pd(OAc)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 70(68)b |
9 | Pd(OAc)2 | L1 (75) | TDG1 (60) | HFIP/AcOH (9 : 1) | 51 |
10 | Pd(TFA)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 60 |
11 | PdCl2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 52 |
12 | PdBr2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 54 |
13 | Pd(OAc)2 | — | TDG1 (60) | HFIP/AcOH (9 : 1) | 9 |
14 | Pd(OAc)2 | L1 (60) | — | HFIP/AcOH (9 : 1) | 0 |
15c | Pd(OAc)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 55 |
10.
We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cpt affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.C–H activation mediated processes have provided a unique retrosynthetic approach to access a variety of substituted heterocycles.1 One tactic that has received increased attention is the coupling of π-components with heteroatom containing molecules.2 A variety of transition metals are capable of catalyzing this type of transformation, providing access to dozens of heterocyclic motifs.1–3 A challenge for these methods is controlling the regioselectivity of migratory insertion across alkenes and alkynes after the metallacycle forming C–H activation (eqn 1).Steric and electronic effects are understood to control migratory insertion of unsymmetrical alkynes in Rh(iii) catalyzed isoquinolone syntheses (eqn 1). When the substituents are electronically similar, the larger group resides β- to Rh in the metallacycle to avoid unfavorable steric interactions (selectivity is generally >10 : 1).4 When the substituents are electronically different, the more electron-donating group prefers being α- to rhodium in the metallacycle, presumably to stabilize the electron poor metal.5,6 The type of C–H bond being activated also plays an important role in the regioselectivity of migratory insertion; aromatic substrates typically provide synthetically useful regioselectivities when electronically different alkynes are used (>10 : 1) but alkenyl C–H activation leads to products with lower regioselectivities, presumably due to minimal steric interactions during migratory insertion.7,8 We found that sterically bulky di-tert-butylcyclopentadienyl ligand (Cpt) enhances the regioselectivity of the alkyne migratory insertion event in these cases, delivering regioselectivities (>10 : 1) modestly above those achievable by Cp* ligated Rh complexes (<6 : 1). However, when the alkyne migratory insertion was poorly selective with RhCp* (<3 : 1), RhCpt complex was ineffective at providing synthetically useful levels of selectivity. Furthermore, the Cpt ligand was only effective with aryl substituted alkynes, presumably because of strong steric interactions between the ligand and alkyne in the insertion event.
Migratory insertion of alkenes to access heterocycles using C–H activation chemistry is still relatively rare, with seminal studies by Glorius and Fagnou reporting the synthesis of dihydroisoquinolones.9–11 Similar to alkynes, alkenyl electron-donating groups favor the position adjacent to the metal in the metallacycle delivering high regioselectivity. In contrast to alkynes, aliphatic alkenes afford product with poor regioselectivity (2 : 1) (eqn 2).5h,12 We hypothesized competing steric and electronic effects cause the low regioselectivity, with steric effects favoring the formation of a 4-substituted product and electronics favoring the formation of a 3-substituted product.13 As a temporary solution to this problem, our group and others have employed tethering strategies to increase the regioselectivity of the migratory insertion event (eqn 3).14,15 Of course, regioselectivity controlled by the ligand on Rh would be the optimal solution to the selectivity problem (eqn 4).16 Consequently, we focused our attention toward developing an intermolecular variant of this reaction that would provide product with improved regioselectivity.As a model system, we explored the impact ligands have on the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1-decene 2a to provide dihydroisoquinolones 3a and 3a′. When Cp* is used as a ligand, the desired products are isolated in excellent yield but poor selectivity (2.4 : 1 3a : 3a′) (
a
Open in a separate window
aReaction conditions: 1a (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bCpCF3 = 1-trifluoromethyl-2-3,4,5-tetramethylcyclopentadienyl.
cCp‡ = 1,2-di-phenyl-3,4,5-trimethylcyclopentadienyl.
dCpt = 1,3-di-t-butylcyclopentadienyl.To determine the effect that ligand electronics have on product regioselectivity, we employed an electron deficient 1-trifluoromethyl-2,3,4,5-tetramethylcyclopentadienyl ligand originally developed by Gassman (CpCF3)17 and found that this catalyst provides 3a and 3a′ products in good yield but without an increase in selectivity (2.4 : 1) (18,19 Since ligand electronics did not appear to affect product regioselectivity, we tested an electron rich, sterically bulky di-phenyl-tri-methyl Cp ligand (Cp‡) and were pleased to find a remarkable increase in selectivity from 2.4 : 1 to 12 : 1 (3a : 3a′). Pleased by this improvement, we tested the sterically bulky di-tert-butyl Cp ligand Cpt and were surprised to find that RhCpt provides the desired product in 91% yield with exquisite regioselectivity (15 : 1) (
a
Open in a separate window
aReaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bIsolated yield of reaction using [RhCptCl2]2 as a precatalyst.
meta-Substituents also provide exquisite levels of regioselectivity for alkene migratory insertion when Cpt is used (>15 : 1) (
a
Open in a separate window
aReaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M). isolated yield of reaction using [RhCptCl2]2 as a precatalyst.
b67% yield.
c80% yield.
d85% yield.
e79% yield.We next explored the alkene tolerance of the method. Allyl benzene 2b furnishes a 1.6 : 1 ratio of dihydroisoquinolone with RhCp* (
a
Open in a separate window
aReaction conditions: 1a (.2 mmol), alkene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bIsolated yield of reaction using [RhCptCl2]2 as a precatalyst.
cReaction conducted at 0 °C.
dProducts isolated as a 1 : 1 ratio of diastereomers.
eProduct isolated as a 2 : 1 ratio of diastereomers.While it is desirable to achieve high regioselectivity for a single regioisomer, it is even more attractive to use a ligand to access alternate regioisomers. Currently, the only example of Rh(iii)-catalyzed synthesis of 4-substituted dihydroisoquinolones is with potassium vinyltrifluoroborates where electronics are believed to control regioselectivity.20 We found that when vinylcyclohexane was submitted to a reaction with [RhCp*Cl2]2 as the precatalyst, the 3-substituted dihydroisoquinolone 4a was isolated in 90% yield with 11 : 1 regioselectivity (Fig. 1). However, when the same reaction was catalyzed by [RhCptCl2]2 the opposite isomer 4b was isolated in 75% yield and 10 : 1 (4b : 4a) regioselectivity. Given this unexpected discovery, we were interested in gleaning insight into how Cpt influences regioselectivity of alkene migratory insertion. A competition experiment between vinyl cyclohexane 2m and 1-decene 2a run to 10% conversion favored the formation of dihydroisoquinolone 3a in >19 : 1 ratio as determined by 1H NMR. This experiment suggests that enhanced steric interactions between the substrate and ligand slow the rate of migratory insertion.Open in a separate windowFig. 1Impact of ligand on reaction of vinyl cyclohexane.To investigate the steric differences between the RhCp* and RhCpt systems X-ray analysis was conducted on a 5-membered RhCpt metallacycle. While we were unable to obtain a 5-membered rhodacycle from our system, Jones and coworkers previously characterized 5-membered rhodacycle 5a from N-benzylidenemethanamine and [RhCp*Cl2]2.21 We found that a similar metallacycle 5b derived from [RhCptCl2]2 could be obtained in crystalline form under identical conditions and was evaluated by single crystal X-ray diffraction.A comparison of the bond lengths and angles reveals several notable differences between our Cpt rhodacycle and the Cp* rhodacycle reported by Jones (Fig. 2). The Rh–Cp centroid distance in 5b is 0.011 Å longer than 5a which is either the result of increased steric interactions, or an artifact of Cpt being a less electron-donating ligand. While there are subtle differences in many bond lengths and angles, the most striking difference is the angle C3–Rh–Cl, which is 98.03° in 5b while only 90.09° in 5a. The angle increase is likely the result of steric interactions caused by the tert-butyl moiety being situated directly over the Rh–Cl bond. As alkene exchange presumably occurs with Cl, we suggest that steric interactions between the t-butyl of the ligand and the alkene substituent affect both the alkene coordination and 1,2-insertion events.Open in a separate windowFig. 2X-Ray analysis.Based on the X-ray crystal structure and regioselectivity data, we propose the following model for regioselectivity of the 1,2-migratory insertion of alkenes, where steric contributions from the t-butyl groups influence both alkene coordination and insertion events to give high selectivity. With small alkyl alkenes, we propose that steric interactions from one t-butyl of Cpt disfavor alkene coordination (I) and subsequent insertion to give the β-substituted product 3a′ (Fig. 3). Coordination of the alkene with the steric bulk oriented away from the t-butyl group finds minimized steric interactions during coordination (II). Subsequent migratory insertion from II places the alkyl substituent α to Rh in the transition state, which we propose is able to stabilize a buildup of partial positive charge, making the α-substituted product 3a both sterically and electronically favored with Cpt. In the case of the Cp* ligand with small alkyl alkenes, neither steric nor electronic interactions dominate so low selectivity is observed.Open in a separate windowFig. 3Rationale for selectivity.However if the size of the alkene substituent is significantly increased, as in the case of vinyl cyclohexane, then Cpt favors the opposite regioisomer. While certainly a puzzling result, we propose that the selectivity can be explained by Cpt rotation such that the t-butyl groups both occupy the space above the metallacycle. Cpt rotation gears the O-piv toward the alkene coordination site disfavoring alkene coordination to this side (IV) favoring the α-substituted product 3a. At the same time, alkene coordination (III) with the cyclohexyl opposite the O-piv minimizes steric interactions enabling insertion of the large alkene and preferential formation of β-substituted product 3a′. While not conclusive, the observation that cyclohexyl alkene reacts significantly slower than n-octyl alkene suggests that migratory insertion of the cyclohexyl alkene proceeds through a higher energy and potentially highly ordered transition state, such as Cpt rotation. 相似文献
| |||
Entry | Catalyst | Yield (%) | Regioselectivity |
1 | [RhCp*Cl2]2 | 90 | 2.4 : 1 |
2 b | [RhCpCF3Cl2]2 | 85 | 2.4 : 1 |
3 c | [RhCp‡Cl2]2 | 82 | 12 : 1 |
4 d | [RhCptCl2]2 | 92 | 15 : 1 |
| ||||
Entry | Starting material | Yield b (%) | Cp* | Cpt |
1 | X = CF3 (1b) | 50 | 1.5 : 1 | 19 : 1 |
2 | X = Cl (1c) | 76 | 2.2 : 1 | 19 : 1 |
3 | X = OMe (1d) | 70 | 1.9 : 1 | 16 : 1 |
4 | X = Ph (1e) | 75 | 1.7 : 1 | 14 : 1 |
5 | 95 | 1.9 : 1 | 15 : 1 | |
6 | 84 | 2.5 : 1 | 19 : 1 | |
7 | 88 | 1.8 : 1 | 19 : 1 |
| ||||
Entry | Alkene | Yield b (%) | Cp* | Cpt |
1 c | 85 | 1.6 : 1 | 5.1 : 1 | |
2 | 68 | 1.6 : 1 | 9.4 : 1 | |
3 | 70 | 1.3 : 1 | 5.5 : 1 | |
4 | 95 | 2.3 : 1 | 14 : 1 | |
5 | 85 | 1.6 : 1 | 8 : 1 | |
6 d | 92 | 1.2 : 1 | 7.2 : 1 | |
7 | 80 | 1.4 : 1 | 12 : 1 | |
8 e | 93 | 1 : 1 | 11 : 1 | |
9 | 89 | 2 : 1 | 14 : 1 | |
10 | 94 | 3 : 1 | 14 : 1 |
11.
Singlet molecular oxygen, O2(1Σ), is one of the important intermediate species in the atmospheres of Earth, Mars, and Venus. To elucidate the chemistry of this excited molecular oxygen, a series of kinetic measurements have been undertaken using the flow-discharge/optical-emission technique. By monitoring the characteristic emission (762 nm for 1Σ), the quenching rates for several important molecules have been obtained at room temperature. The following table summarizes measurements.
The error limits represent one standard deviation. The systematic error is estimated to be about 15%. For CO2 and O3 molecules, the quenching rate constants were also measured in the temperature range of 245–362 K. In both reactions, negligible temperature dependences (with the activation energy less than 0.6 kcal/mole) were observed. 相似文献
Quencher | Rate Constants (cm3/s) |
---|---|
CH2 | (4.6 ± 0.5) × 10?13 |
H2 | (7.0 ± 0.3) × 10?13 |
N2 | (1.7 ± 0.1) × 10?15 |
Cl2 | (4.5 ± 0.8) × 10?16 |
CO | (4.5 ± 0.5) × 10?15 |
O3 | (2.2 ± 0.3) × 10?11 |
2,3 DBM-2 | (6.0 ± 0.1) × 10?13 |
12.
13.
The gas phase photolysis of CCl4 in the presence of several alkanes has been used to obtain Arrhenius parameters for the abstraction of hydrogen atoms by the CCl3 radical: The following log k4 values were obtained:
The results are compared to those for CH3 and CF3 radicals. 相似文献
RH | log k4 |
---|---|
c-C5H10, | |
n-C6H14 | |
2,3-Dimethylbutane | |
c-C7H14 | |
Methylcyclohexane | |
c-C8H16 |
14.
15.
V. D. Makhaev A. P. Borisov T. P. Karpova É. B. Lobkovskii B. P. Tarasov A. N. Chekhlov 《Russian Chemical Bulletin》1989,38(2):377-382
1. | Reaction of MnCBH4)2(THF)3 with tetrabutylammoniura and tetraphenylphosphonium borohydndes, and with tetraphenylphosphonium chloride, has given the compounds (Bu4N)[Mn(BH4)3], (Ph4P)[Mn(BH4)3], (Ph4P)[Mn(BH4)3(THF)], (Ph4P) [Mn(BH4)3Cl], and (Ph4P) [Mn(BH4)2Cl(THF)], which have been characterized by IR spectroscopy and thermogravimetric studies. |
2. | The crystal and molecular structure of the manganese complex (Ph4P) [Mn(BH4)3–xClx (THF)] (x 0.5) has been found. |
16.
1. | It has been shown by PMR spectroscopy that in a solution of RYbI there exists an equilibrium similar to that established by Schenk for Grignard reagents. |
2. | The compound formed by the action of an equimolar mixture of PhI and LiI on Yb metal in THF differs in reactivity from PhYbI in its reaction with CF2=CF2. |
3. | The reaction of PhSmI with 1,2,2-trifluorostyrene differs from the reactions of PhEuI and PhYbI in that it gives an equimolar mixture of the cis and trans isomers of 5,6-difluoro-4,6-diphenyl-5-hexene-1-ol. |
4. | PHCeI does not react with 1,2,2-trifluorostyrene. However, the organocerium complex formed by the oxidatlve addition of Ce to PhI in the presence of an equivalent quantity of LiI reacts with 1,2,2-trifluorostyrene to form an equimolar mixture of the cis and trans isomers of 5.6-difluoro-4,6-diphenyl-5-hexene-1-ol. |
17.
Wen-Xin Lv Yin Li Yuan-Hong Cai Dong-Hang Tan Zhan Li Ji-Lin Li Qingjiang Li Honggen Wang 《Chemical science》2022,13(10):2981
β-Difluoroalkylborons, featuring functionally important CF2 moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.Organofluorine compounds have been widely applied in medicinal chemistry and materials science.1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,3a,b photoredox difluorination,4 radical difluorination,5 and cross-coupling reactions with suitable CF2 carriers6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.7iOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates8a–c as starting materials.9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).10 While extending the scope of our previous work,9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,10 could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et3N·HF in association with PhI(OAc)2 (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions
Open in a separate windowWith the optimized reaction conditions in hand, we set out to investigate the scope and limitation of this gem-difluorination reaction. The reaction of a series of E-type 1,2-disubstituted alkenyl MIDA boronates were first examined. As shown in Scheme 2, the reaction of substrates with primary alkyl (1b, 1e–g), secondary alkyl (1c, 1d), or benzyl (1h–k) groups proceeded efficiently to give the corresponding gem-difluorinated alkylboronates in moderate to good yields. Halides (1i–k, 1m) and cyano (1l) were well tolerated in this reaction. Of note, cyclic alkene 1n is also a viable substrate, affording an interesting gem-difluorinated cyclohexane product (2n).Open in a separate windowScheme 2Scope of 1,2-H migratory gem-difluorinations. a 4 h. b PIFA was used.To define the scope further, the substrates with Z configuration were also employed under the standard reaction conditions (eqn (1) and (2)). The same type of products were isolated with comparable efficiency, suggesting that the reaction outcome is independent of the substrate configuration and substrates with Z configuration also have a profound aptitude of 1,2-hydrogen migration. Nevertheless, the reaction of t-butyl substituted alkenyl MIDA boronate (1p) delivered a normal 1,2-difluorinated alkylboron product (eqn (3)). The 1,2-hydrogen migration was completely suppressed probably due to unfavorable steric perturbation. With an additional alkyl substituent introduced, a 1,2-alkyl migrated product was formed as expected (eqn (4)).1The gem-difluorination protocol was amenable to gram-scale synthesis of 2a (Scheme 3, 8 mmol scale of 1a, 1.24 g, 50%). To assess the synthetic utility of the resulting β-difluorinated alkylborons, transformations of the C–B bond were carried out (Scheme 3). Ligand exchange of 2a furnished the corresponding pinacol boronic ester 4 without difficulty, which could be ligated with electron-rich aromatics to obtain 5 and 6 in moderate yields. On the other hand, 2a could be oxidized with high efficiency to alcohol 7 using H2O2/NaOH. The hydroxyl group of 7 could then be converted to bromide 8 or triflate 9. Both serve as useful electrophiles that can undergo intermolecular SN2 substitution with diverse nitrogen- (10, 13), oxygen- (14), phosphorus- (11) and sulfur-centered (12) nucleophiles.Open in a separate windowScheme 3Product derivatizations. PMB = p-methoxyphenyl.To gain insight into the reaction mechanism, preliminary mechanistic studies were conducted. The reaction employing deuterated alkenyl MIDA boronate [D]-1a efficiently afforded difluorinated product [D]-2a in 72% isolated yield, clearly demonstrating that 1,2-H migration occurred (Scheme 4a). However, when the MIDA boronate moiety was replaced with a methyl group (15), no difluorinated product (derived from 1,2-migration) was detected at all, suggesting an indispensable role of boron for promoting the 1,2-migration event (Scheme 4b). Also, with a Bpin congener of 1a, the reaction led to large decomposition of the starting material, with no desired product being formed (Scheme 4b).Open in a separate windowScheme 4Mechanistic studies and proposals.Based on the literature precedent and these experiments, a possible reaction mechanism is proposed in Scheme 4c. With linear alkenyl MIDA boronates, the initial coordination of the double bond to an iodium ion triggered a regioselective fluoroiodination to deliver intermediate B. The regioselectivity could arise from an electron-donating inductive effect from boron due to its low electronegativity, consistent with previous observations.13a,b Thereafter, a 1,2-hydrogen shift, rather than the typical direct fluoride substitution of the C–I bond, provides carbon cation C. The formation of a hyperconjugatively stabilized cation is believed to be the driving force for this event.12a–d The trapping of this cation finally forms the product.In conclusion, we demonstrated herein our second generation of β-difluoroalkylboron synthesis via oxidative difluorination of easily accessible linear 1,2-disubstituted alkenyl MIDA boronates. An unexpected 1,2-hydrogen migration was observed, which was found to be triggered by a MIDA boron substitution. Mild reaction conditions, moderate to good yields and excellent regioselectivity were achieved. The applications of these products allowed the facile preparation of a wide range of gem-difluorinated molecules by further transformations of the boryl group. 相似文献
Entry | F− (equiv) | Oxidant | Solvent | Yield (%) |
---|---|---|---|---|
1 | CsF (2.0) | PIDA | DCM | 0 |
2 | AgF (2.0) | PIDA | DCM | 0 |
3 | Et3N·HF (40.0) | PIDA | DCM | 0 |
4 | Py·HF (20.0) | PIDA | DCM | 39 |
5 | Py·HF (40.0) | PIDA | DCM | 61 |
6 | Py·HF (100.0) | PIDA | DCM | 55 |
7 | Py·HF (40.0) | PIFA | DCM | 52 |
8 | Py·HF (40.0) | PhIO | DCM | 26 |
9 | Py·HF (40.0) | PIDA | DCE | 49 |
10 | Py·HF (40.0) | PIDA | Toluene | 46 |
18.
Eun Kee Cho Phong K. Quach Yunfei Zhang Jae Hun Sim Tristan H. Lambert 《Chemical science》2022,13(8):2418
The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).1 For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine2 and eupolauramine3 to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.4 Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.5 Meanwhile, chalcogenoarenes6 such as dinaphthofuran7 and benzodithiophene8 have attracted high interest for both their medicinal properties9 and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).10 These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis15 (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.16 In this case, 5 mol% FeCl3 catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studiesa
Open in a separate windowaConditions: substrate 8 (0.2 mmol) and 5 mol% catalyst in 0.4 mL of solvent (0.5 M) in a 5 mL sealed tube were heated to the temperature indicated for 15 h. Yields were determined by 1H NMR using CH2Br2 as an internal standard.b2 equiv. of TFA was used.c85% isolated yield.Using the optimized conditions, we explored the synthesis of various PHAs (Fig. 2). In addition to benzo[h]isoquinoline (8), products 12 and 13 with fluorine substitution at various positions could be generated in good yields. Similarly, benzoisoquinolines 14 and 15 bearing electron-donating methoxy groups and the dioxole-fused product 16 were also accessed efficiently. Furthermore, a phenolic ether product 17 with a potentially acid-labile N-Boc group was generated in modest yield. We found that an even more electron-donating dimethylamino group was also compatible with this chemistry, allowing for the production of 18 in 68% yield. On the other hand, adduct 19 bearing a strongly electron-withdrawing trifluoromethyl group was isolated in only modest yield. The naphtho-fused isoquinoline 20 could be generated as well; however, 20 mol% catalyst was required to realize a 35% yield. The thiophene-fused product 21 was furnished in much better yield, also with the higher catalyst loading. Although not a heterocyclic system, we found that the reaction to form phenanthrene (22) was well-behaved, providing that compound in 83% yield. In addition, an amino-substituted phenanthrene 23 was also formed in good yield. Other thiophene-containing PAHs such as 24–26 were produced efficiently. On the other hand, adduct 27 was generated only in low yield. Naphthofuran (28), which is known to have antitumor and oestrogenic properties,21 was synthesized in good yield. Finally, pharmaceutically important structures such as benzocarbazole2229 and naphthoimidazole2330 could be accessed in moderate yields with increased catalyst loading.Open in a separate windowFig. 2Substrate scope studies for hydrazine 1-catalyzed RCCOM synthesis of polycyclic heteroaromatics. a Conditions: substrate and catalyst 1·(TFA)2 (5 mol%) in THF (0.5 M) were heated to 100 °C in a 5 mL sealed tube for 15 h. Yields were determined on purified products. b 20 mol% catalyst.We also examined the scope of the olefin substitution pattern ( Entry Substrate Time (h) Yield (%) 1 15 96 2 48 5 3b 48 27 4 48 54 5 48 64
Entry | Catalyst | Solvent | Temp. (°C) | 8 yield (%) |
---|---|---|---|---|
1 | 10 | THF | 80 | 67 |
2 | 11 | THF | 80 | 53 |
3 | FeCl3 | DCE | rt | 0 |
4 | FeCl3 | DCE | 80 | 0 |
5 | TFA | THF | 80 | 0b |
6 | 10 | i-PrOH | 80 | 31 |
7 | 10 | CH3CN | 80 | 28 |
8 | 10 | EtOAc | 80 | 26 |
9 | 10 | Toluene | 80 | 24 |
10 | 10 | THF | 90 | 87 |
11 | 10 | THF | 100 | 96c |