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Triple iron/copper/iminium activation for the efficient redox neutral catalytic enantioselective functionalization of allylic alcohols Mylène Roudier, Thierry Constantieux, Adrien Quintard, and Jean Rodriguez ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01102 • Publication Date (Web): 28 Jun 2016 Downloaded from http://pubs.acs.org on June 30, 2016
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ACS Catalysis
Triple iron/copper/iminium activation for the efficient redox neutral catalytic enantioselective functionalization of allylic alcohols Mylène Roudier,a Thierry Constantieux,a Adrien Quintard,a* Jean Rodrigueza * a
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, 13397, France
ABSTRACT: A detailed study on the enantioselective borrowing hydrogen functionalization of allylic alcohols has allowed the understanding of the reaction parameters affecting both rate and enantiocontrol. This subsequently led to the identification of a triple catalysis combination between iron-, copper- and organocatalysts. By this cooperative action between three distinct activation modes, a wide variety of allylic alcohols have been functionalized in improved typical 90% ee providing a rapid access to crucial synthetic building blocks. KEYWORDS: enantioselective synthesis, triple catalysis, iron catalysis, copper catalysis, organocatalysis, borrowing hydrogen
INTRODUCTION Developing eco-compatible reactions while respecting the principles of redox-, step- and atom- economy is crucial in order to keep the chemical industry at the center of modern society.1 In this context, innovative tools allowing the efficient catalytic construction of valuable enantioenriched chemicals must continuously be developed and improved. To tackle these objectives, metal-catalyzed borrowing hydrogen enables transformations on initially relatively inert substrates via an OFF↔ON process initiated by a reversible hydrogen transfer from the substrates to a metal center. This simple hydrogen activation avoids using multiple redox manipulations and stoichiometric additives and results in drastically limited waste generation. 2 Unfortunately, despite their great potential, borrowing hydrogen transformations face two major challenges: 1) the replacement of expensive and rare noble metal complexes by more abundant metallic catalysts; 3 2) the development of robust enantioselective variants.4 In these directions, combining an iron-catalyzed borrowing hydrogen cycle from allylic alcohols 2 (OFF reactant) to -unsaturated aldehydes (ON reactant) with a chiral iminium activation 5 promotes an efficient enantioselective addition of pronucleophiles such as 1,3-diketones 1, providing functionalized alcohols 3.6a,b Combined with a Claisen fragmentation, synthetically valuable 3-alkylpentanols 4 are obtained in one single otherwise inconceivable cascade (Scheme 1a).6c This integrated double catalytic system constitutes a modern enantioselective approach avoiding classical distinct oxidation/iminium-activation/reduction sequences and the troublesome manipulation of relatively unstable aldehydes.7 However, originally, the enantiocontrol of these transformations remained modest, in the average of
80% ee as in the synthetically relevant compound 4a, despite numerous efforts to solve this major drawback. O
a) Previous work (double catalysis) OH
H2 O R1 1
O R2 OH
+
R3
Fe
Im
Fe
* R3 cascade
O
1
O
2
R 3
b) This work (triple catalysis)
* R3 4 O R1 typically 75% ee (R1 , R2, R3 = Me (4a): 80% ee)
mechanistic study
H2
O OH
O R1 1 R3
O
Im R2 OH
+
R2
O
R2
Fe
Cu
O
R2
R2 Fe
* R3 cascade
O O
2 Fe
iron catalysis
Im
iminium activation
Cu
copper catalysis
3
R1
triple catalysis
O
* R3 4
R1
improved enantiocontrol
Scheme 1. Proposed strategies for the enantioselective functionalization of allylic alcohols To tackle these challenges and given the synthetic interest of the developed double catalytic transformation in the context of green chemistry, we decided to have a closer look at its mechanism whose understanding should also help to develop other related enantioselective transformations. Given the possible intricate connection of the two supposedly distinct metallic and organocatalytic cycles, we notably wondered what are the factors governing the kinetics and the origin of the thermodynamic driving
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force of the reaction. In addition, the nature of the resulting moderate stereocontrol had to be clarified. To our knowledge, such deep analysis has scarcely been done on challenging multiple catalyzed processes and could result in a considerable increase in the understanding of this type of complex transformations. 8 Indeed, the overall reaction pathway should hardly be simplified to the sum of its individual elementary steps, and the relative low concentration of the different ON-intermediates before the final back-hydrogenation should deeply impact the reaction profile. Herein, we report this complete investigation on the ironcatalyzed borrowing hydrogen/iminium activation revealing a complex kinetic profile where initially both hydrogen transfer and Michael addition govern the reaction rate.9 This study also clearly highlights the synergistic implication of the starting allylic alcohol in the C-C bond-forming event that lead us to the development of a new triple catalyzed transformation using copper salt as third co-catalyst. 10 With this newly discovered activation, the functionalization of allylic alcohols is possible with significantly improved enantioselectivity up to 96% ee and successfully extended to other pro-nucleophiles such as keto-sulfones or nitroesters (Scheme 1b).
RESULTS AND DISCUSSION Functional group tolerance of the multicatalysis The functionalization of crotyl alcohol 2a was initially developed using iron complex [Fe] for the borrowing hydrogen,11 trimethylamine N-oxide dihydrate (Me3NO.2H2O) to activate this complex by CO decoordination and cat1 for the iminium activation (Scheme 2).12 TMS O O
O
[Fe] (6.5 mol%) O Ph Me3 NO.2H2O (8 mol%) Ph + Ph 1b OH cat1 (13 mol%) 2a toluene, 30 °C, 24 h + additive (1 eq)
Compatible:
O 4b
Partially compatible:
O
TMS OC Fe CO OC Ph [Fe] Ar Ar N OTMS H cat1 Ar = (3,5-CF 3 )-C6 H3
R 9
OH
R = NO2, SO2 Me, C(=O)NMe2, Cl, CF3, Br
O n-Bu
C9 H19
NH2 n-Bu
N
O
OH n-Pr O
O
n-Pr
N
Ph 1b
O Ph OH
+
2a
O OH
O OMe n-Bu
Mechanistic study of the iron-amine catalysis Mechanistically, given the multicatalytic character of the transformation, we initially confirmed the role of each constituents of the reaction mixture (Scheme 3). When cat1 was removed from the mixture, only trace amount of 4b was observed. This indicated that the Michael addition is extremely slow in the absence of the secondary amine organocatalyst. Similarly, removal of [Fe] or trimethylamine N-oxide completely shut down the reactivity. Interestingly, when Me3NO was replaced by UV (350 nm) to activate the iron complex, reactivity was restored providing the final rearranged product in decreased yield due to other side products formation. 16 This indicates that Me3NO only activates the iron complex (by CO decoordination liberating trimethylamine) and therefore Me3NO as well as the trimethylamine generated do not interfere in the subsequent steps.17 O
CN
N
N H N
n-Pr
10 O
Cl
6
Glorius was first conducted.13 The study was performed at 30 °C focusing exclusively on reactivity issues and the results with a selected range of functional groups are presented in Scheme 2.14 As expected from our previous results,6b,c ketones, esters, ethers and aliphatic alcohols were well tolerated by the system (good conversion to 4b and recovery of the additive). It also revealed that a wide range of aromatics, alkenes, internal alkynes, amides as well as chlorinated alkyl chain were compatible with the reactivity of the multi-catalytic system. Several other heteroaromatics or phosphine-oxide furnished the expected product albeit with decreased yield or with only partial recovery of the additive. Finally, phenol, cyanide, carboxylic acid, primary amine, pyridine or terminal alkyne did not provide compound 4b in acceptable yield. Overall, given the known compatibility of cat1 and of the corresponding Michael addition,15 this functional group tolerance study might reflect mostly the compatibility of the iron catalytic system under the given conditions. Indeed, as soon as a relatively good ligand for the iron is used (cyanide, imidazole, pyridine, phenol, carboxylic acid), the overall reactivity drops. The functional compatibilities shown in Scheme 2 are interesting for future works by providing a reactivity map to orientate future investigations.
Incompatible:
O Ph P Ph Ph
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[Fe] (6.5 mol%) Me3 NO.2H2O (8 mol%) cat1 (13 mol%) toluene, 25 °C, 66 h
O Ph
O 4b
O
Ph
68% yield, 78% ee
Variation from standard: -no cat1 : conv< 10% -no [Fe] : no reaction -no Me3 NO.2H2 O : no reaction -hv (350 nm), 30 °C and no Me3 NO.2H2 O: 51% yield, 70% ee
C6 H13
Scheme 3. Initial control experiments
S
n-Pr n-Pr n-Pr
Scheme 2. Reactivity compatibility of the multicatalysis To better appreciate the potential of the multi-catalytic system in terms of scope, extension to other transformations and anticipate compatibilities issues, a functional group tolerance study based on the work from the group of
With the clarification of the role of the different species, we next checked the kinetic profile of the reaction. 18 From the monitoring of the conversion vs. time, it is apparent that an initial induction period is present (Scheme 4). This induction period might be attributed to the activation time necessary for the Me 3NO to form the active dehydrogenation catalyst. Once the active iron complex is generated, a linear conversion is observed, consistent with a relative absence of catalyst deactivation and a strong
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thermodynamic displacement of the reaction towards product formation. To identify the kinetically significant parameters of the transformation, the kinetic dependence in each component at the initial rate (20 hours) were determined by independently varying their respective concentration (Figure 1). O Ph 1b
O Ph OH
+
2a
[Fe] (6.5 mol%) Me3 NO.2H2O (8 mol%) cat1 (13 mol%) toluene, 25 °C
O Ph
O
Standard conditions: O Ph 1b
O 4b
hydrogen but somehow strongly linked to the organocatalytic cycle. Clearly, this rules out the first hypothesis of a simple Michael addition of the 1,3-diketone to the iminium ion but puts in perspective a more complex pathway.
Ph
O Ph OH
+
2a
Scheme 4. Kinetic profile of the multicatalysis Quite surprisingly and highlighting the complexity of the mechanism, at low concentrations, a positive rate order was observed for all constituents of the reaction. More closely, the concentration of trimethylamine N-oxide influenced the reaction until it reached a plateau corresponding to 8 mol% (Figure 1a). This behavior is more likely due to the fact that Me3NO is directly linked to the concentration of active iron dehydrogenation complex. Until around 8 mol%, each molecule of Me3NO.2H2O activates one molecule of iron complex. After this point, the reaction becomes zero order in Me3NO that subsequently becomes spectator. Interestingly, for the iron complex [Fe], a non-linear behavior is observed (Figure 1b). Varying the concentration of [Fe] while using only 8 mol% of Me3NO.2H2O, results in a positive order ending around 8 mol% from where a zero order is found. We initially believed that this plateau was observed because we only used 8 mol% of Me 3NO.2H2O and that above this ratio, no more active iron catalyst could be formed. However, the non-linear behavior was confirmed using an excess of Me3NO (20 mol%, Figure 1b). A positive order in [Fe] is observed at low concentration and a plateau where the reaction becomes zero order is rapidly reached at a concentration corresponding to 15 mol % in [Fe]. This suggests, that at low concentration, the hydrogen transfer influences the overall kinetics while at higher concentration, a steady state is reached and this hydrogen transfer becomes negligible on the reaction rate.19 On the contrary to the iron complex [Fe], a linear positive rate order is observed for crotyl alcohol 2a, organocatalyst cat1 and diketone 1b (Figures 1c-e). For the cat1 and 1b, the positive order seemed logical and pointed toward the CC bond-formation as rate determining. Control experiments proved that cat1 did not influence the rate of hydrogen transfer (see SI for details). Given the zero-order in [Fe] at high concentration, the positive order in crotyl alcohol is quite surprising since in our first hypothesis, it should only be involved in the hydrogen transfer step. This seems to indicate that, after sufficient enal formation, the rate in crotyl alcohol becomes independent of the borrowing
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[Fe] (6.5 mol%) Me3 NO.2H2O (8 mol%) cat1 (13 mol%) toluene, 25 °C, 20 h
O Ph
O 4b
O
Ph
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Figure 1. Initial rate dependence of the multicatalysis on the concentration of the different components. To better understand the observed reactivity, we subsequently checked the influence of both the iron complex and the crotyl alcohol on the kinetic of the Michael addition between 1b and crotonaldehyde (5) (Figure 2). O Ph 1b
is conceivable because it is known that alcohols favor enol formation from 1,3-diketones.20 Therefore, a more complex synergistic transition state for the C-C bond-formation seems to include the iminium ion, the 1,3-diketone and the crotyl alcohol. This point seemed of utmost importance and if the crotyl alcohol was indeed present in the C-C bond-forming event, it might also influence the enantioselectivity of the reaction. To confirm this last point, we looked at the effect of additives on the stereocontrol of the Michael addition of 1b to 5a catalyzed by cat1 (Table 1). As expected from the kinetic study, crotyl alcohol influenced both the yield (73 vs 44%) and the stereochemical outcome of the reaction confirming the involvement of crotyl alcohol in the Michael addition (89 vs 85% ee) (Table 1 entries 1-2). On the contrary, addition of activated iron complex decreased both the yield and enantiocontrol (entry 3). Table 1. Influence of the multicatalytic reaction constituents on the Michael addition O
O +
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O Ph O
cat1 (13 mol%) toluene, 25 °C, 20 min
5a + additive (x mol%)
Ph
Ph 1b
O
Ph
Ph O
O cat1 (13 mol%)
Ph
5a + additive (x mol%)
O Ph
O 6b
Entry
additive
Yield (%)a
ee (%)
1
none
44
85
2
Crotyl alcohol 2 (400 mol%)
73
89
23
81
3 a
We observed that while the active dehydrogenation iron catalyst slightly limited the reaction possibly through coordination with the 1,3-diketone or the amine catalyst (Figure 2a), the crotyl alcohol considerably increased the reaction rate (Figure 2b). This unexpected kinetic profile is fully consistent with a transition state for the Michael addition involving an association with crotyl alcohol and it
+
toluene, 25 °C, 20 min
O 6b
Figure 2. Initial rate dependence of the Michael addition on the concentration of:
O
[Fe] (6.5 mol%) + Me3NO.2H2O (8 mol%)
Isolated yield after silica gel chromatography.
With a better understanding of the kinetic parameters, we next decided to have a look at the thermodynamic control of the hydrogen transfers that can be crucial especially for the irreversible reduction of the Michael adduct 6 rendering the key aliphatic alcohol intermediate 3.21 This behavior is confirmed by the clean formation of nonanol (8) from nonanal (7) in 18 h at room temperature using crotyl alcohol (2a) as hydrogen donor (Scheme 5a). Oppositely, crotonaldehyde (5) revealed to be a very poor hydrogen acceptor hampering the formation of decanal (10) from decanol (9) (Scheme 5b). Concerning the Michael addition, as already shown in Table 1, it is strongly displaced towards product formation (full conversion after less than 1 hour). This confirms an overall displacement of the multicatalytic reaction by the Michael addition additionally favored by the ultimate aliphatic aldehyde reduction. Overall, all these data point toward a mechanism where after a sufficient concentration in intermediate α,βunsaturated aldehydes is obtained (initial positive order in [Fe]), the Michael addition is the only factor governing the rate of the transformation. A plausible mechanism is suggested in Scheme 6. Initial activation of [Fe] by Me3NO furnishes the active iron dehydrogenation catalyst liberating trimethylamine and CO2 (Scheme 6, step 1). The iron(0) catalyst subsequently abstracts an hydrogen molecule from allylic alcohol 2 (Scheme 6, step 2). This dehydrogenation initiates the overall transformation by forming a catalytic amount of α,β-unsaturated aldehyde 5 corresponding at the
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maximum to the catalytic amount in [Fe]. As a result, the concentration in iron catalyst directly influences the concentration in reactive α,β-unsaturated aldehyde. Once a minimal concentration is reached, subsequent iminium formation (Scheme 6, step 3) is not any more rate determining so that the reaction rate does not any more depend on the α,β-unsaturated aldehyde concentration and consequently on the iron catalyst concentration as well. This is a crucial observation since it indicates that to extend the scope of such borrowing hydrogen-organocatalyzed transformation, one should probably focus on reactions where the rate order in intermediate aldehyde is zero and the following organocatalyzed addition relatively fast. 22 a)
O
forms the crucial aliphatic alcohol intermediate (Scheme 6, step 6) precursor of the final compound 3 by Claisen fragmentation (Scheme 6, step 7-9). This fragmentation occurs spontaneously without any catalytic species involved. Indeed, in the case of acetylacetone 1a, direct NMR analysis after acidic treatment at room temperature, showed a mixture of lactol 12 and rearranged product. Heating up the mixture to 40°C during solvent evaporation rapidly forms 4a indicating that the fragmentation is thermically spontaneous. In the case of 4b, the fragmentation is directly observed even at lower temperatures (25°C). The rapid iminium ion formation is confirmed by starting from either (Z)- or (E)- allylic alcohols 11 (Scheme 7). Indeed, the same absolute configuration is observed on the final adduct 4c from both isomers, indicating that iminium ion formation and (Z)- to (E)- isomerization of the corresponding α,β-unsaturated aldehyde are faster than the Michael addition.
OH
[Fe] (6.5 mol%) Me3NO.2H2 O (8 mol%) OH 7
6
6 8 60% conv
2a, 1eq xylenes, 25 °C, 18 h
b)
OH
[Fe] (6.5 mol%) Me3 NO.2H2O (8 mol%)
9
O 5a, 1eq
7
O
O
7 10 conv ~5%
xylenes, 25 °C, 18 h
O
[Fe] (6.5 mol %) O n-C6H13 O Me3 NO.2H2O (10 mol %) Ph O Ph OH cat1 (13 mol %) + 4c xylenes, 20 °C, 66 h starting from (E)-11 : 78% yield, 77% ee n-C6 H1 3 starting from (Z)-11 : 73% yield, 40% ee (E)-11 or (Z)-11 Ph
Ph
1b
Scheme 5. Thermodynamic control of the borrowing hydrogen
Scheme 7. Influence of allylic alcohol configuration
From the iminiun ion, key Michael addition involving the enol form of the 1,3-diketone in the presence of the allylic alcohol occurs (Scheme 6, step 4). The absolute configuration of the final product is in accordance with a steric repulsion from the organocatalyst substituent on the pyrrolidine backbone even-thought the exact nature of this complex transition state remains unclear.12c,15 Enamine-iminium equilibrium followed by hydrolysis releases back the organocatalyst and the Michael adduct (Scheme 6, step 5). Then a chemoselective and irreversible reduction of the aldehyde function by the iron hydride
Rational optimization of the enantioselectivity With this better view of the mechanism, we next sought at improving both reactivity profile and enantioselectivity by focusing on the transition state of the key Michael addition. For this purpose, we attempted to replace the allylic alcohol as 1,3-diketone activating agent in the C-C bond-formation by another synergistic co-catalyst in order to develop a new enantioselective triple catalytic sequence. First of all, as a model reaction we tested several external alcohols as additives in the addition of acetylacetone (1a) to crotyl alcohol (2a) (Table 2). In the absence of any
OH
R2
positive order
O
2 2) hydrogen abstraction
R
3) iminium formation
R
1) iron catalyst
TMS formation O TMS OC Fe CO OC [Fe]
TMS O
Me3 NO OC Fe OC
CO2 + Me3N
TMS
positive order then 0 order: influences [5]
TMS OC Fe H OC O
6) chemoselective aldehyde reduction
O
R
1
O
R2
H O R2
O
H R2
R1 O 12
H2 O R2 O 5) catalyst liberation R1 6 O
O R
O
R
R
8)fragmentation
R1
2
O R
9) protonation
O
R2 Ar Ar OTMS
O
4
R1
O
Scheme 6: Proposed mechanism of the multicatalysis
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R O
4) Michael addition Turnover
R limiting R1 Displace the equilibrium
O H
H O
O
R R1
7) lactol formation
N
O
R 3
O 1 positive order
Ar Ar OTMS OH N
Ar positive order Ar OTMS
N H
OH
R
fast
OH
OH
R2
5
TMS
Ar Ar OTMS OH
N
R1
H2 O
2
R
positive order
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additives, cascade product 4a was obtained in 66% yield and 80% ee (entry 1). Use of relatively acidic alcohols as additives (CF3CH2OH) or CCl3CH2OH) totally inhibited the reaction (entries 2, 3) while ethanol or tert-amyl alcohol decreased either yield or ee (entries 4, 5). With these disappointing results, we next turned our attention to the use of catalytic Lewis acids. Indeed, Lewis acids such as copper salts are 1) able to easily coordinate to 1,3dicarbonyls catalyzing the corresponding Michael additions;23 2) have been shown to positively influence reaction outcomes in dual iminium-Lewis acid catalysis. 24 Table 2. Influence of additives on the multicatalysis outcome O 1a
O +
[Fe] (6.5 mol%) Me 3NO.2H2 O (8 mol%) OH
2a
O
O 4a
cat1 (13 mol%) additive (x mol%) toluene, 25 °C, 40 h
N H
O Ar Ar OR
R = TMS, Ar = (3,5-CF 3 )-C 6H3: cat1 R = TMS, Ar = Ph: cat2 R = TBDMS, Ar = Ph: cat 3
Entry
additive
Yield (%)a
ee
1
none
66
80
2
CF3CH2OH (4 eq)
