Enantioselective preparation of 1,1-diarylethanes: Aldehydes as removable steering groups for asymmetric synthesis

DOI: 10.1002/anie.200702995

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Angewandte Chemie - International Edition p. 9331 - 9334 (2007)

Update date:2022-07-30

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Authors:

Fessard, Thomas C.

Andrews, Stephen P.

Motoyoshi, Hajime

Carreira, Erick M.

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Article abstract of DOI:10.1002/anie.200702995

Cut it out! Convenient procedures have been delineated for the synthesis of optically active, functionalized 1,1-diaryl-ethanes by decarbonylation of β,β-diaryl-propionaldehydes. The process can be conducted as a one-pot 1,4-addition/decarbonylation sequence. Aldehydes are used as removable steering groups in this new strategy for the preparation of optically active building blocks. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200702995

Angewandte

Chemie

DOI: 10.1002/anie.200702995

Asymmetric Catalysis

Enantioselective Preparation of 1,1-Diarylethanes: Aldehydes as

Removable Steering Groups for Asymmetric Synthesis**

Thomas C. Fessard, Stephen P. Andrews, Hajime Motoyoshi, and Erick M. Carreira*

Among the varied contributions that asymmetric synthesis

can make to the drug-discovery process and materials

research, access to collections of novel, diverse chemical

entities is eminent.^[1]This enabling feature facilitates entry

into uncharted chemical and intellectual property (IP) space.

In this context, the demand for optically active building

blocks continues to rapidly expand. Herein, we document the

preparation of optically active 1,1-diarylethanes from b,b-

diarylpropionaldehydes [Eq. (1)]. We describe convenient

procedures for the decarbonylation reaction (RCHO!RH)

the approaches rely on steric or electronic biasing of the

flanking substituents of an olefin to obtain asymmetric

induction. Consequently, it is hardly surprising that enantio-

selective hydrogenation of 1,1-diarylethenes lacks prece-

dence.

We have previously reported the catalytic enantioselec-

tive 1,4-addition of arylboronic acids to cinnamaldehyde

derivatives with rhodium–diene complexes^[8]to generate b,b-

diarylpropionaldehydes 1 in high enantiopurity.^[9]The use of 1

as a building block can be envisioned to involve common

synthetic steps, such as condensations, additions, reductive

aminations, and olefination reactions, all of which enjoy

significant precedence. With a view to expanding the menu of

transformations available to 1, we have examined these

aldehydes as substrates for the catalytic decarbonylation

reaction.

At the outset, it was not obvious whether the decarbon-

ylation reaction of b,b-disubstituted aldehydes 1 could be

successfully implemented as an enantioselective approach to

1,1-diarylethanes (Scheme 1). It was also not clear whether

the reaction itself would be relevant in the formation of the

of substrates incorporating functionalities relevant to the

synthesis of complex molecules. Additionally, an

enantioselective, sequential 1,4-addition/decarbon-

ylation procedure furnishes a one-pot route to 1,1-

diarylethanes. More broadly, the work entails the

implementation of a new strategy for asymmetric

synthesis, involving the use of aldehydes as remov-

able steering groups.^[2]

To date, optically active diarylalkanes can be

prepared through some rather laborious

approaches.^[3]These include asymmetric alkylations

of lithiated diarylmethanes,^[4]and Pd-catalyzed

cross-couplings of benzylsilanes with aryl triflates.^[5]

The former procedure is limited in scope and suffers

from modest yields. The cross-coupling approach

requires the synthesis of benzylsilane precursors in

Scheme 1. Metal-mediated decarbonylation versus dehydroformylation.

optically active form, which is not trivial.^[6]There has been

desired optically active products and whether the formation

of the corresponding unsaturated by-products 3 would lead to

complications. Thus, for example, in preliminary experiments

with Rh, Pd,^[10]and Ir^[11]catalysts, competitive formation of

the 1,1-diarylethene 3 was observed. It is likely that 3 arises

following b-hydride elimination by intermediate 4. The

formation of 3 could have deleterious consequences because

subsequent reduction would lead to erosion in the optical

purity of 2.

significant progress in enantioselective C C reductions,^[7]yet

[*] Dr. T. C. Fessard, Dr. S. P. Andrews, Dr. H. Motoyoshi,

Prof. Dr. E. M. Carreira

Laboratorium für Organische Chemie

ETH Zürich

8093 Zürich (Switzerland)

Fax: (+41)44-632-1328

To examine the use of the decarbonylation of b,b-

disubstituted aldehydes as an approach to 1,1-diarylethanes,

we screened a range of conditions with aldehyde 1a (Ar¹=

Ph, Ar²= p-(MeO)C₆H₄) as a test substrate. The standard

procedure for this reaction prescribes the use of Wilkinsonꢀs

E-mail: carreira@org.chem.ethz.ch

[**] This work was supported by the ETH Zurich (INIT), SNF, and the

Uehara Memorial Foundation (to H.M.)

Supporting information for this article is available on the WWW

under http://www.angewandte.org or from the author.

Angew. Chem. Int. Ed. 2007, 46, 9331 –9334

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

9331

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Communications

complex, [RhCl(PPh₃)₃], in stoichiometric quantities.^[12]This

ꢀ

follows because the intermediate Rh CO species generated

in the course of the reaction is stable (up to 2008C) and

incapable of engaging in further decarbonylations. In the case

of 1a, stoichiometric quantities of Wilkinsonꢀs complex in

toluene at 1108C furnished the corresponding product (2a) in

90% yield along with 4% of the corresponding ethene

derivative.

A number of methods have been devised to regenerate

the active decarbonylating Rh species in situ.^[13]For example,

reactions have been carried out with catalytic amounts of Rh

at ꢁ 2008C to remove CO or with additives such as

diphenylphosphoryl azide (DPPA, typically 1–2 equiv).^[14]

For 1a, the addition of 1.2 equiv DPPA permitted the reaction

to be conducted at 508C with 10 mol% [RhCl(PPh₃)₃],

furnishing 2a in 77% yield. However, we note that rigorous

exclusion of moisture is required as well as slow (syringe

pump) addition of distilled DPPA. Given the potentially

explosive nature of DPPA as well as its hydrolysis product

(HN₃), we sought more practical, catalytic decarbonylation

methods.

In screening of conditions, 1,3-bis(diphenylphosphino)-

propane (dppp) proved effective at facilitating decarbon-

ylations with rhodium species.^[15]When the reaction was

performed with [Rh(dppp)₂Cl] (generated in situ from [{Rh-

(cod)Cl}₂] and dppp; cod = cyclooctadiene) in a sealed tube in

refluxing toluene or m-xylene, no conversion was observed in

the former case and a complex mixture of products in the

latter. However, the use of the higher-boiling solvent, p-

cymene, at 1408C, with a continuous stream of N₂to purge the

reaction mixture of CO, allowed the isolation of 2a in 92%

yield [Eq. (2)].

Table 1: 1,1-Diarylethanes prepared from cinnamaldehydes via b,b-diaryl

propionaldehydes 1 as intermediates.^[a]

Entry

Aldehyde

Diarylalkane

Yield [%] ee [%]^[b]

With this workable decarbonylation protocol in hand

(2 mol% [{Rh(cod)Cl}₂], 8 mol% dppp, p-cymene, 1408C,

continuous N₂stream), we examined the scope of the reaction

(Table 1). The optical purity of the products obtained was

observed unchanged from that of the starting aldehydes.^[16,17]

Numerous functional groups are compatible with the process,

including ethers, halides, esters, and nitro groups (Table 1,

entries 1–6). Of further interest, substrates containing furans,

thiophenes, and indoles are also well tolerated, furnishing

decarbonylation products in high yield (Table 1, entries 7–9).

We subsequently set about developing a one-pot protocol,

allowing direct conversion of the cinnamaldehyde derivatives

into 1,1-diarylethane products without the need to isolate the

intermediate aldehydes. The reaction of trans-cinnamalde-

hyde with 4-methoxyphenylboronic acid was conducted with

[{Rh(C₂H₄)₂Cl}₂] and dolefin ligand according to the liter-

ature procedure.^[9]When the formation of 1a was observed to

be complete, MeOH was removed in vacuo and replaced by p-

cymene.^[18]The decarbonylation step was then performed

with the same rhodium–diene complex at 1408C with N₂

sparging. The desired product was isolated in 33% yield

from the reaction mixture after 40 h. Although this result is

unoptimized, it constitutes, to the best of our knowledge, the

first example of decarbonylation of an aldehyde with a

rhodium–diene complex, in the absence of phosphine ligand.

Additional benefits in yield were observed with added dppp

–

[a] Typical conditions: [{Rh(cod)Cl}₂] (2 mol%), dppp (8 mol%), p-cymene,

1408C, N₂stream. [b] For 2a–d and 2i the enantiopurity was determined by

HPLC and by comparison to authentic racemates. For 2e, 2g, and 2h the

enantiopurity could not be assessed by HPLC and was therefore correlated

to that ofthe starting aldehyde by analogy to 2a–d and 2i. The enantiomers

and slightly increased catalyst loading. In the event, following of 1 f and 2 f could not be separated by HPLC with a chiral phase.

9332

www.angewandte.org ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 9331 –9334

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Angewandte

Chemie

conjugate addition (1.5 mol% [{Rh(dolefin)Cl}₂]), addition of

1.5 mol% [{Rh(cod)Cl}₂] along with 3.3 mol% dppp led to 2a

in 71% yield. Significantly, the optical purity of the diaryl-

alkane product was 93% ee [Eq. (3)].

observed. It may open up new possibilities for the decarbon-

ylation reaction as a preparatively useful procedure.

In conclusion, we have reported an efficient process to

form 1,1-diarylethane compounds in high yield and high

optical purity. We have also conducted the transformation

using a tandem 1,4-addition of boronic acids to cinnamalde-

hydes followed by a Tsuji–Wilkinson decarbonylation. It is

worth noting that this family of compounds is otherwise not

readily accessed enantioselectively by existing methodologies.

An additional salient feature of the work is the identification

of several protocols with which to effect decarbonylation,

including mechanistically intriguing solvent effects. Concep-

tually, the work described provides a useful strategy for

asymmetric synthesis, wherein an aldehyde acts as an

activating/directing group and is subsequently removed or

excised. When this concept has been used previously the

excisable groups have been limited to heteroatom-based

systems, such as sulfones or nitroalkanes. The field of

enantioselective synthesis has recently witnessed some

impressive advances with methods employing unsaturated

aldehydes. In this respect, the decarbonylation strategy we

describe may have additional useful applications.

In the course of our investigations, it became clear that

under the conditions described above the decarbonylation

reaction might prove problematic for small-scale reactions

and/or with more volatile aldehydes. Consequently, we

examined the possibility of coupling the decarbonylation to

a process that consumes CO. This would facilitate turnover

and obviate the need to physically remove CO. The coupled

reaction would need to consist of substrates, intermediates,

and products that do not themselves undergo reaction with

aldehydes or inactivate the decarbonylation catalyst.

We became intrigued by two key reports describing

aldehydes as sources of CO. In the first of these it had been

shown that aldehydes may participate in Pauson–Khand

reactions,^[19]and the second involved the carbonylative

cyclizations of benzylic alcohols.^[20]These results suggested

that coupling of the decarbonylation reaction to either of the

carbonylative cyclizations could prove useful for our own

objectives. Indeed, the decarbonylation reaction of 1a could

be performed neat in a sealed vessel at 1008C in the presence

of 2 equiv [3-(allyloxy)prop-1-ynyl]benzene (Scheme 2) to

furnish 2a in 78% yield. Additionally, the decarbonylation of

1a could be performed with 1 equiv of commercially available

o-bromobenzylalcohol at 1408C in a sealed vessel, affording

2a in 67% yield.

Received: July 5, 2007

Published online: November 6, 2007

Keywords: asymmetric synthesis · cleavage reactions ·

decarbonylation · diarylethanes · synthesis design

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the use of CO-trapping agents. Interestingly, when the

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3.3 mol% dppp in a sealed vessel with CF₃CH₂OH as solvent,

2a was isolated in 79% yield [Eq. (4)]. This unusual solvent

effect has not, to the best of our knowledge, previously been

unfunctionalized C C bonds, see: a) S. Bell, B. Wuestenberg,

Angew. Chem. Int. Ed. 2007, 46, 9331 –9334

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

9333

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Communications

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[17] Signals corresponding to b-elimination products 3 were not

observed in the ¹H NMR spectra of the crude reaction mixtures.

[18] It was found that stringent removal of methanol was necessary to

minimize the oxidative Tishchenko-like coupling of the alcohol

and the intermediate aldehyde 1a, generating methyl ester by-

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[(1R,4R,8R)-5-benzyl-8-methoxy-1,8-dimethyl-2-(2’-methyl-

propyl)-bicyclo[2.2.2]octa-2,5-diene].

[8] The optically active diene ligand, [(1R,4R,8R)-5-benzyl-8-

methoxy-1,8-dimethyl-2-(2’-methylpropyl)bicyclo[2.2.2]octa-

2,5-diene] and its enantiomer are commercially available from

Aldrich under the name “dolefin”.

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[22] The reaction was performed with epi-(ꢀ)-dolefin ligand

[(1S,4S,8R)-5-benzyl-8-methoxy-1,8-dimethyl-2-(2’-methyl-

propyl)-bicyclo[2.2.2]octa-2,5-diene].

[16] The optically active aldehydes 1a, 1b, 1d, and 1g have been

prepared previously. For corresponding ee values and exper-

imental data, see reference [9]. In all other cases, see the

Supporting Information.

9334

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Angew. Chem. Int. Ed. 2007, 46, 9331 –9334

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Article Doi

Enantioselective preparation of 1,1-diarylethanes: Aldehydes as removable steering groups for asymmetric synthesis

DOI: 10.1002/anie.200702995

Source and publish data:

Authors:

Article abstract of DOI:10.1002/anie.200702995

Full text of DOI:10.1002/anie.200702995

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