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Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols Xiaobin Mo, and Dennis G Hall J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Aug 2016 Downloaded from http://pubs.acs.org on August 12, 2016
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Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols Xiaobin Mo, Dennis G. Hall* Department of Chemistry, Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2
Supporting Information Placeholder ABSTRACT: A ferrocenium boronic acid salt activates allylic alcohols to generate transient carbocations that react with in situ generated chiral enamines from branched aldehydes. The optimized conditions afford the desired acyclic products embedding a methyl-‐aryl quaternary carbon centre with up to 90 % yield and 97:3 enantioselectivity ratio, with only wa-‐ ter as the by-‐product. This noble metal-‐free method com-‐ plements alternative methods that are incompatible with C– halogen bonds and other sensitive functional groups.
co-‐workers prepared acyclic quaternary carbon centers with a clever combination of palladium, Brønsted acid, and amine 6b catalysis (Figure 1a). Similarly, Carreira and co-‐workers employed dual iridium and amine catalysis as a complemen-‐ tary strategy to obtain the branched products of allylic alkyl-‐ 6d ation in high enantio-‐ and diastereoselectivity (Figure 1b). Previous work (a) List; Pd + amine + chiral acid (ref. 6b)
O Ar
H
R1
Me
The advent of new strategies for the catalytic activation of organic molecules creates new opportunities to design un-‐ conventional bond forming processes. In dual catalysis, two mutually compatible catalysts are combined to independent-‐ ly activate two different substrates and expand the scope of reactions with substrates that are unreactive under tradition-‐ 1 al conditions. In this perspective, the concept of boronic acid catalysis (BAC), which exploits the ability of boronic acids to form reversible covalent bonds with hydroxyl func-‐ tionalities, was examined by our group and others in the 2 catalytic direct activation of carboxylic acids and alcohols. For instance, we recently reported direct boronic acid-‐ catalyzed Friedel-‐Crafts alkylations of neutral arenes with readily available allylic and benzylic alcohols as a way to cir-‐ 3 cumvent the use of toxic organohalide electrophiles. With a view to extend this strategy towards other classes of nucleo-‐ philes such as carbonyl enolates, we envisaged the possibility of merging BAC with chiral amine catalysis to achieve alkyla-‐ tion of enamines with carbocations via dual activation of 4,5 aldehydes and alcohols, respectively. A priori, the com-‐ bined use of Lewis acidic and Brønsted basic catalysts poses challenging issues of chemoselectivity, including the threat of catalysts’ inter-‐annihilation. Moreover, the use of alcohols as precursors of reactive carbocations can lead to side-‐ reactions like homoetherification or alkylation of the amine catalyst. Cozzi and co-‐workers overcame these challenges by employing InBr3 and imidazolidinone catalysts to alkylate linear aldehydes with secondary allylic alcohols in high enan-‐ 4b tioselectivities. Similar approaches to asymmetric allylation of branched aldehydes with allylic alcohols engaging transi-‐ 6 tion metals as co-‐catalysts were reported. In 2011, List and
[Pd] + amine chiral phosphoric acid
R2
HO R1 ,
R2
O
= H, Me, Ph
R2
H Me Ar R1
66-98% yield up to 99.8:0.2 er
linear product
(b) Carreira; Ir + amine + acid (ref. 6d)
O Ar
H
[Ir] + amine chiral ligand acid activator
OH Ar
Me
42-86% yield >99.5:0.5 er, >20:1 dr
O
H Ar
H Me Ar branched product
This work (c) Boronic acid + chiral amine
O
O H
Ar Me
complementary functional group tolerance
HO Ar
Ar
boronic acid + chiral amine
noble-metal free, benign byproduct (H 2O)
54-90% yield up to 97:3 er stereogenic quaternary carbon centers
H
Ar Ar
Me Ar further product transformations, e.g. oxidative cleavage
Figure 1. Methods for dual catalytic asymmetric allylation of branched aldehydes with allylic alcohols As highlighted through these key contributions, the prepara-‐ tion of acyclic quaternary all-‐carbon centers remains an im-‐ 7 portant objective in organic synthesis. For instance, methyl-‐ aryl quaternary carbons are present in a number of bioactive 8 natural products and drug candidates (Figure 2). Although 9 several methods exist based on the use of chiral auxiliaries, there are relatively few strategies available through asymmet-‐ ric catalysis. Furthermore, preparative methods based on palladium catalysis are not orthogonal with functionalities like aryl halides and are often incompatible with nitro or other basic functional groups. Herein, we describe a concep-‐ tually novel, noble metal-‐free methodology based on dual BAC and amine catalysis that is compatible with these func-‐ tional groups and provides methylated quaternary carbon centers in high enantioselectivity (Figure 1c).
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Me
N Ph
Me
OMe H 2N
Me
2TFA
Cl
O N Me
O
O
N F
N
Me
O
N
Cl
Me
LY426965 serotonin antagonist
(+)-cuparene O 2N
Ph H N
N
O
O O S N Me
O N Me
O
NK1/NK3 receptor antagonist
CCR5 antagonist
Figure 2. Examples of biologically active compounds contain-‐ ing stereogenic methylated quaternary carbon centers The initial optimization was performed on the racemic reac-‐ tion and focused on selecting the best boronic acid co-‐ catalyst and allylic alcohol partner with aldehyde 1a and ben-‐ 6d zhydrylamine A1 (see SI). This effort identified the most promising conditions with ferrocenium boronic acid B1 and alcohol 2a in a dichloromethane/hexafluoroisopropanol mix-‐ ture (v:v=10:1) at 40 °C for 48 h, affording product 3a in 88% yield (Table 1, entry 1). The use of HFIP was critical to in-‐ crease the solubility of ferrocenium boronic acid B1 as well as 10 stabilizing the putative carbocation intermediate. Allylic alcohol 2a with para fluorine substituents was employed to best suppress the boronic acid-‐catalyzed 1,3-‐rearrangement of allylic alcohols, a process competing with the desired al-‐ 11 lylation. Even though a limited number of allylic alcohols were suitable (see SI), it is often inconsequential because one of the most compelling synthetic transformation of the diaryl alkene moiety of products like 3a is oxidative cleavage.
Table 1. Chiral Amine Optimization in the Dual Cata-‐ lytic Asymmetric Allylationa O Ph
H
Me
2a: Ar = 4-F-C6H 4
1a
O
B1 (20 mol%) amine (20 mol%)
Ar
HO Ar
Ar Ar
H
DCM:HFIP = 10:1, 40 °C, 48 h, 0.125 M
Me Ph
3a F 3C
CF3 CF3
Fe +
B(OH) 2
NH 2
SbF6
B1
entry
a
Ph
Ph
A1
N NH 2
A2
amine
R
N H
N H
O TMS
O R
CF3
A4-8
A3 b
yield (%)
c
er
1
A1
-‐
88
50:50
2
A2
-‐
86
76.5:23.5
3
A3
-‐
n.r.
n.d.
4
A4
-‐SiMe3
20
87.5:12.5
5
A5
-‐SiEt3
34
83.5:16.5
6
A6
-‐Si(i-‐Pr)3
51
85.5:14.5
7
A7
-‐SiPh3
31
85.5:14.5
8
A8
-‐Si(t-‐Bu)Me2
47
90:10
Reactions conditions: 0.25 mmol of aldehyde and 0.50 mmol of alcohol in a solvent mixture of dichloromethane (2.0 mL) and hexafluoroisopropanol (0.2 mL) under nitrogen at 40 °C b 1 for 48 h. Yields were determined by H NMR analysis of the reaction mixture with 1,4-‐dinitrobenzene as internal stand-‐ c ard. Determined by chiral HPLC analysis of the correspond-‐ ing alcohol product of aldehyde reduction (see SI).
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The enantioselectivity of the allylation was examined by screening over 30 different chiral amines, based on condi-‐ tions of the optimized racemic reaction (see SI). Chiral pri-‐ mary amines were investigated first because they are less 12 sterically hindered for branched aldehydes. Unfortunately, these amines generally provided poor performance, as exem-‐ 13 plified with A2 affording a 76.5:23.5 er (Table 1, entry 2). The more common chiral secondary amines were evaluated even though α-‐functionalization of branched aldehydes catalyzed by secondary amines is generally more challenging and less 14 15 successful. When diphenylprolinol trimethylsilyl ether A3 was employed, the reaction provided no product (Table 1, entry 3). We hypothesized that this failure may be due to the nucleophilic secondary amine center, which could deactivate the ferrocenium boronic acid B1. To our satisfaction, upon using the less nucleophilic diarylprolinol silyl ether A4, the desired product was observed in high enantioselectivity (87.5:12.5 er) albeit with low yield (20%). Encouraged by this result, we eventually identified A8 as the best amine catalyst providing 47% yield and 90:10 er (Table 1, entry 8). With this optimal chiral amine in hand, we turned our attention to the optimization of other reaction parameters. A brief solvent screening identified toluene/HFIP (v:v=10:1), at a concentra-‐ tion of 0.25 M, as the solvent system providing the highest enantioselectivity albeit, in 32% yield (see SI). Additives (wa-‐ 16 ter, acetic acid ) provided no improvement. According to Bräse and co-‐workers, the use of microwave irradiation can 17 accelerate enamine formation for branched aldehydes. By applying the same strategy with a catalyst loading of 30 mol%, the yield of 3a near doubled. Catalysts ratio other than 1:1 B1:A8 led to no improvement (see SI). At this stage, a re-‐ optimization of the allylic alcohol showed that 2b can serve as a cheaper and more effective allylation agent providing a higher yield of 60% while maintaining the enantioselectivity. The remainder of the mass balance consists mostly of unre-‐ acted aldehyde and transposed alcohol. The scope of aldehyde substrate was assessed under the optimal conditions of (Scheme 1). Branched aldehydes with an aryl group bearing electron-‐donating substituents (-‐ OMe, -‐Me) provided products 4b and 4c in slightly lower yield and enantioselectivity compared to 4a. While existing 6b methods also reported high yield and high enantioselectivi-‐ ty for select aldehydes containing simple aryl substituents (-‐ OMe, -‐Me, -‐F), we were delighted to observe a wider func-‐ tional group tolerance with our reaction system, especially for electron withdrawing aryl substituents. Branched alde-‐ hydes with bromo/chloro aryl substituents, which are partic-‐ ularly useful for derivatization by cross-‐coupling chemistry, were well tolerated and gave high yield and high enantiose-‐ 18 lectivity in the preparation of products 4d-‐f. Highly enanti-‐ oselective catalytic α-‐functionalization of aldehydes 1g-‐j has 6f,14d,19 been shown to be challenging with other methods. In contrast, with our system, polar basic functional groups such as -‐CO2Me, -‐NO2, and CF3 fared well affording products 4g-‐ 20 j. An aldehyde with a naphthyl group afforded product 4k in good yield and enantioselectivity. The auspicious applica-‐ bility of this method towards heterocyclic substrates is high-‐ lighted with indolyl product 4l, which despite a lower yield, was obtained in high er. Unfortunately, the α-‐ethyl aldehyde 1m was not readily applicable. The absolute configuration of the allylation products 4a-‐m was assigned as (S) based on the 21 derivatization of 4a into a known compound (see SI).
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Scheme 1. Substrate Scope of Dual Catalytic Asym-‐ metric Allylationa H
F 3C O
CF3
H SbF6 Fe +
R1
1f (1.00 g, 4.95 mmol)
B(OH) 2 N H
1a-k
O TBS
R1 R2
2. NaBH 4 (10.0 equiv) DCM:MeOH = 10:1, 0 °C
Ph HO
Ph Ph
HO
Me
Ph
HO
Ph
Ph
HO
Br
4d 77% (70%) 95.5:4.5 er
Ph Ph
Ph
HO
Me
Me
Me
Me
Ph
Ph HO
Me Cl Cl
Br
4e 73% (68%) 96:4 er
EWG
Ph Ph
Me
Me
4i: EWG = CF3 90% (80%) 96:4 er
Ph Ph
HO
4h: EWG = NO 2 82% (79%) 97:3 ere
4g: EWG = CO 2Me 69% (58%) 95:5 er
4f 87% (82%) 96.5:3.5 er
Ph HO
Ph
HO
4c 62% (57%) 93:7 er
4b 54% (42%) 92.5:7.5 er
Ph Ph
HO Me
Ph
HO Et
CF3 F 3C
4j 70% (70%) 95.5:4.5 er
4k 76% (71%) 96:4 er
N Ts
4l 52% (49%) 94:6 er
Me
4m 24% (19%) 80:20 er
Reactions conditions: 0.25 mmol of aldehyde and 0.50 mmol of alcohol in 1.1 mL of solvent in a microwave reactor under b nitrogen at 60 °C for 12 h. Yield of first step were determined 1 by H NMR analysis of the reaction mixture with 1,4-‐ c dinitrobenzene as internal standard. Isolated yield over two d steps, of the alcohol product of aldehyde reduction. Deter-‐ mined by chiral HPLC analysis of the alcohol products 4 (see e SI). Enantiomeric ratio of 4i was obtained by Mosher’s acid analysis of the reduced alcohol product. a
To demonstrate the practicality of this method, a gram scale reaction with aldehyde 1f was performed (Scheme 2). Even though a lower yield was observed compared to the explora-‐ tory scale of Scheme 1, the enantioselectivity was maintained. Oxidative cleavage of the double bond of product 4f afforded compound 5 as a key building block possessing correctly differentiated side chains for the quaternary carbon fragment 8d of Servier’s NK1/NK3 receptor antagonist, which could not be prepared previously in catalytic asymmetric fashion.
Scheme 2. Application of Dual Catalytic Allylation
H 2N 2TFA
Cl
5 (89%)
Ph
Me
OMe
4a (60%) c 94:6 erd
60%b
2. NaBH 4 (10.0 equiv) DCM:MeOH = 10:1, 0 °C
OH
TBSO
2. i. O3, DCM, -78 °C ii. NaBH 4 (10.0 equiv)
4a-m Ph
Me
2b (9.90 mmol)
1. TBSCl (1.1 equiv), imidazole (2.0 equiv) DCM, rt, 16 h (96%)
Ph
HO
toluene:HFIP = 10:1, 0.250 M, µw 60 °C, 12 h,
2b
Ph
toluene:HFIP = 10:1, 0.250 M, µw 60 °C, 12 h,
Ph
CF3
1. B1 (30 mol%), A8 (30 mol%)
Ph
HO Ph
HO Ph
Cl Me
CF3
R2
Ph
1. B1 (30 mol%), A8 (30 mol%)
Cl
O
Cl
Ph H N O
HO
Ph Me Cl Cl
4f (67%, 96:4 er)
Cl
O N Me
Cl Me
R 2N
NK1/NK3 receptor antagonist (see full structure in Scheme 1)
Mechanistic control experiments were conducted. Ferroceni-‐ um boronic acid B1 was shown to be a superior acid catalyst 4a 4b 5b compared to TFA, InBr3, and p-‐TsOH for the asymmet-‐ ric allylation (Scheme 3, top). Though it provides a signifi-‐ cantly lower yield, the ferrocenium catalyst devoid of a bo-‐ ronyl group, CpFe(III)CpSbF6, is also active (Scheme 3, top). This result indicates that cooperative activation involving both Lewis acidic sites of B1 cannot be ruled out. In the pres-‐ ence of HFIP, with none or trace water, a complex dynamic equilibrium is likely to establish consisting of the free bo-‐ ronic acid, the bis(hexafluoroisopropoxide), the hydroxy (hexafluoroisopropoxide) hemiester, and the corresponding anionic species (Scheme 3). Formation of boronic anhydrides was not detected by mass spectrometry. The possible exist-‐ ence of inter-‐catalyst interactions was examined by NMR spectroscopy in the reaction solvent (10:1 d8-‐toluene:HFIP). 11 In the presence of the amine catalyst, a new B NMR reso-‐ nance appears at ~5 ppm, possibly indicative of reversible catalyst interactions as a tetrahedral amine-‐borate, or, more likely a base-‐promoted formation of the tri(hexafluoroisopropoxy)borate complex observed by MS 11 (see SI). According to B NMR analysis, catalyst B1 appears largely transformed at the end of the reaction. Although a slow destructive interaction between the Fe(III) ion and nu-‐ 22 cleophilic reagents cannot be ruled out, reversible interac-‐ tion of the catalyst with the water by-‐product or unreacted substrates is also possible and would require further studies. Altogether, based on these preliminary experiments and pre-‐ 3b vious work with catalyst B1, an SN1 mechanism is proposed with the dual-‐catalyzed cycles depicted in Scheme 3. Face-‐ selective attack of the in situ formed chiral enamine (H) to the reactive carbocation (E) results in the allylation product. Substitution of boronic acid B1 for a mixture of 2,3,4,5-‐ F4HC6B(OH)2 and Cp2Fe(III)SbF6 provided a lower yield (32%), which lends further support to an ion redistribution mechanism that is possible only with ionic boronic acid B1. In summary, we have disclosed the first application of BAC in asymmetric dual catalysis. This noble metal-‐free method for allylation of branched aldehydes provides moderate to high yields with high enantioselectivity, and it displays broad functional group tolerance. The reliability of this asymmetric allylation was demonstrated on a gram-‐scale for the prepara-‐ tion of a quaternary carbon fragment of Servier’s NK1/NK3 receptor antagonist. A dual catalyzed SN1 mechanistic cycle was proposed. We envision that more dual catalyzed trans-‐ formations of synthetic interest can be developed based on the BAC concept.
Scheme 3. Mechanistic Controls and Proposed Cata-‐ lytic Cycle of Dual Catalytic Asymmetric Allylation
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Control experiments with other acid catalysts O Ph
H
HO Ar
Me
1a
O
Ar
acid catalysts, A8
Ar
H
Ar Me Ph
conditions
2a or 2b
3a or 4a
B1: up to 60%, 94:6 er
InBr 3: up to 21%, 93:7 er
CpFe(III)CpSbF6 : up to 35%, 93:7 er
TFA: up to 18%, 88:12 er
CpFe(III)CpSbF6 + 2,3,4,5-F4HC 6B(OH) 2: up to 32%, 94:6 er
p-TsOH : < 5%, er n.d.
Proposed catalytic cycle
SbF6 Fe +
Ion Exchange
Fe +
B(OR) 3
HO Ph
Ph
Ph
Ph C (tetra-ion)
B(OR) 3 Boronic Acid Cycle
SbF6 Fe +
D (zwitterion)
B(OR) 2
B(OH) 2
SbF6 Fe +
HFIP B1 (R = H or CH(CF3) 2)
B1
Ph SbF6
Ph
O
E (carbocation)
Ph
H R1
N
N
Ar
R2
H
+ H 2O
Me
H R1
Ph Me Ar
R2
H (chiral enamine)
Me
Ar G (imine)
F 3C R1
Chiral Amine Cycle
N H A8
CF3 CF3
R2 N H
O TBS
CF3
A8 H 2O
R2 R1 N OH
O Ar
H F
Me
H
Ar Me
ASSOCIATED CONTENT Supporting Information Experimental details, analytical and spectral reproductions for the prepared compounds. The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION Corresponding Author *E-‐mail:
[email protected] Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT This research was funded by the Natural Science and Engi-‐ neering Research Council of Canada (Discovery Grant to D.G.H.) and the University of Alberta. X.M. thanks Alberta Innovate − Health Solutions for a Graduate Studentship. We thank Dr. Angelina Morales-‐Izquierdo for help with mass spectrometric analyses, and Dr. Tristan Verdelet for sugges-‐ tions on the manuscript.
REFERENCES
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Journal of the American Chemical Society
(20) The racemic background enol allylation did not undermine the 17 enantioselectivity as proposed by Bräse and co-‐workers. (21) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-‐Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2011, 50, 3760. (22) Prins, R.; Korswagen, A. R.; Kortbeek, A. G. T. G. J. Organomet. Chem. 1972, 39, 335.
For Table of Contents Only HO Ph
Boronic Acid Catalysis
Ph
Ar OH B HO OH Ph
O H
Ar Me
Ph
O R1
Me
N
R2
Me
H
Ar
H
Ph Ph up to 90% yield Chiral Amine Catalysis up to 97:3 er Ar
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