Pyruvate enolate arylation and alkylation: OBO ester protected pyruvates as useful reagents in organic synthesis

Article abstract of DOI:10.1021/acs.orglett.7b02524

A protected pyruvate equivalent is described that allows arylation and arylation/alkylation reactions to be performed at the methyl group. Utilization of the OBO derivative of the pyruvate ester allowed the application of palladium catalyzed arylation reactions together with subsequent alkylation, under basic conditions. Moreover, the OBO protecting group could be easily removed in one step to provide access to a wide range of substituted pyruvate derivatives.

Full text of DOI:10.1021/acs.orglett.7b02524

Letter
pubs.acs.org/OrgLett
Pyruvate Enolate Arylation and Alkylation: OBO Ester Protected
Pyruvates as Useful Reagents in Organic Synthesis
C. Henrique Alves Esteves,† Christopher J. J. Hall,† Peter D. Smith,‡ and Timothy J. Donohoe*,†
†
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
‡
AstraZeneca, Pharmaceutical Sciences, Silk Road Business Park, Macclesfield SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: A protected pyruvate equivalent is described
that allows arylation and arylation/alkylation reactions to be
performed at the methyl group. Utilization of the OBO
derivative of the pyruvate ester allowed the application of
palladium catalyzed arylation reactions together with sub-
sequent alkylation, under basic conditions. Moreover, the
OBO protecting group could be easily removed in one step to
provide access to a wide range of substituted pyruvate derivatives.
Scheme 1. Synthesis of Arylated Pyruvates
yruvic acids and esters are attractive building blocks in
Porganic synthesis due to their densely situated reactive
centers which can display both nucleophilic and electrophilic
character.1 A variety of reactions have been described in the
literature that utilize pyruvate substrates, such as a nitro-
Mannich reaction,2 Michael addition,3 amination,4 aldol
processes,5 fluorination,6 and [3 + 2] cycloaddition.7 Such
reactions are inherently useful and have been applied in the
synthesis of cyclohexanes,8 dihydrofurans,9 dihydropyridazine-
4-carboxylic acids,10 and 3-deoxy-2-ulosonic acids.11 Despite
this impressive range of applications, pyruvate chemistry still
suffers from the major drawback that strongly basic media are
not well tolerated, often causing decomposition of the pyruvate
starting material (e.g., treatment of ethyl pyruvate with t-
BuONa).
Inspired by this problem, we designed an orthoester-masked
pyruvate equivalent (oxabicyclo[2.2.2]octyl orthoester, OBO)12
robust enough to tolerate basic conditions that could
potentially allow an expansion of the scope of pyruvate
chemistry via Pd-catalyzed α-arylation.13 Moreover, the α-
arylated pyruvates that could be prepared via this trans-
formation would have the potential to serve as important and
versatile synthetic intermediates.14
Until very recently, the main methodologies available to
install aryl groups at the α-keto position of pyruvates relied on
the condensation of aromatic aldehydes with N,N-dimethylgly-
cine methyl ester followed by acidic hydrolysis,15 Cu(II)-
catalyzed aerobic deacylation of acetoacetate esters16 or the
oxidation of β-ketonitriles with PIDA.17 Although very useful,
none of this methodologies delivers α,α-diarylated pyruvates or
α-quaternary centers and each method has its own limitations.
Some impressive work by Johnson and co-workers has
recently accomplished the enolate α-arylation of α-alkyl
pyruvates using a hindered tert-butyl ester moiety and K2CO3
as a mild base, delivering α-aryl-α-alkyl pyruvates in good yields
(Scheme 1a).18 Concomitantly, we have explored an alternative
approach based on the use of an OBO-masked pyruvate
equivalent, which has facilitated the preparation of not only α-
aryl-α-alkyl pyruvates, but also a combination of different mono
and multiply α-functionalized pyruvates (Scheme 1b). Notably,
the variety of functionalities that can be installed at the α-center
considerably expands the range of pyruvates that can be
synthesized and should facilitate their use in future applications.
We began by preparing the OBO-protected pyruvate ketone
4 via a convenient three-step procedure, starting from pyruvic
acid 1 and proceeding via intermediate ester 3 (Scheme 2). The
overall yield for the synthesis was 49%, and the sequence could
be carried out on a multigram scale, requiring only filtration
through a plug of silica and crystallization to purify compound
4.
We then examined the α-arylation of compound 4 using aryl
bromide 5, base, and palladium catalysis, aiming to find general
conditions for the introduction of an aryl group adjacent to the
ketone, Table 1.
Received: August 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02524
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Letter
Scheme 2. Synthesis of OBO-Protected Pyruvate 4
Scheme 3. Scope of the Monoarylation Reaction
Table 1. Optimization of the α-Arylation of Compound 4
a
base
(2.5 equiv)
yield 6a
(%)
entry
catalyst (5 mol %)
solvent
1
2
3
4
5
6
Pd(Amphos)2
THF
THF
THF
THF
THF
THF
THF
toluene
DCE
dioxane
THF
THF
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
LiHMDS
0
40
64
0
Pd(QPhos)(crotyl)Cl
Pd(t-Bu3P)(PhCH2)Cl
Pd(Ph3P)(PhCH2)Cl
Pd(cod)Cl2
52
85
Pd(dtbpf)Cl2
b
c
7
Pd(dtbpf)Cl2
0
8
Pd(dtbpf)Cl2
39
51
44
0
9
Pd(dtbpf)Cl2
10
11
12
Pd(dtbpf)Cl2
Pd(dtbpf)Cl2
Pd(dtbpf)Cl2
Cs2CO3
14
a
b
c
Isolated yields. Temperature = 75 °C. Diarylated material was
isolated. Amphos = di-tert-butyl(4-dimethylaminophenyl)phosphine.
QPhos = 1,2,3,4,5-pentaphenyl-1′-(ditert-butylphosphino)ferrocene.
dtbpf = 1,1′-bis(di-tert-butylphosphino)ferrocene.
Our summary of the screening results, shown in Table 1,
reveals that product 6a could be formed using a variety of
different catalysts, bases, and solvent. However, preformed
Pd(dtbpf)Cl2 performed best as the catalyst, with t-BuONa as
the preferred base in THF (entry 6). Interestingly, an increase
of the reaction temperature to 75 °C (entry 7) did not allow
the isolation of any monoarylated compound 6a, but instead
led to complete formation of the diarylated material (vide
infra).
The optimal conditions were then applied to the arylation of
4 using a wide variety of aryl bromides (Scheme 3a). It can be
seen that electron-rich, electron-deficient, and heteroaromatic
arenes were all compatible with the reaction. Amides, styrenes,
and TBS-protected phenols were also tolerated, proving the
broad applicability of this method. Pleasingly, substitution was
allowed at every position on the phenyl ring. It is also
noteworthy that despite the preference for aryl bromides (see
example 6f), aryl chlorides are also viable starting materials for
this chemistry (Scheme 3b), with compounds 6r−t being
readily preparable in good yield. In order to demonstrate
synthetic utility, a single example (6c) was conducted on a
gram scale using a lower catalyst loading and relying on a single
crystallization as the purification method. Given the crystalline
nature of many of these arylation products, this is an important
feature for the future scale-up of this methodology.
7), we conducted a set of arylations that introduced two
equivalent aryl groups simply by adding 3 equiv of the aryl
bromide and heating the reaction to 80 °C (Scheme 4). In
addition, heterodiarylated products were formed in good yields
when we ran the arylation reaction with 1 equiv of one aryl
halide and then added an excess of another, different, aryl
halide after 8 h.19 Interestingly, the products 7c and 7d formed
in this manner could be made in good yield with the p-
(dimethylamino)bromobenzene used as either the first (7d) or
second (7c) aryl-coupling partner.
The enolate arylation reaction requires at least 2 equiv of
base to achieve clean monoarylation, as the product is more
acidic than the starting material.20 Hence, the initially formed
aryl ketone is deprotonated in situ by the excess base.
Consequently, we found it possible to quench the reaction
directly with an electrophile and so generate doubly function-
alized products in one pot. The results shown in Scheme 5
Building on the observation of double-arylation products
when the reaction temperature was raised (see Table 1, entry
B
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compounds were treated with PTSA (1 equiv) in ethanol
under heating in a sealed vial (Scheme 6). Pleasingly, in each
Scheme 4. Diarylation for Homo- and Heterodiaryl Products
Scheme 6. Removal of the OBO Protecting Group
case, the corresponding ethyl ester 9a−f was formed in good
yields. This method was applicable to mono- and diarylated
substrates as well as compounds containing aryl and alkyl
substituents.
Scheme 5. One-Pot Arylation and Alkylation Sequences
Finally, in order to demonstrate the utility of this chemistry,
we addressed the one-pot arylation/deprotection sequences
shown in Scheme 7. The first three examples illustrate that the
Scheme 7. One-Pot Arylation and Deprotection Sequence
(8a−g) illustrate that several different aryl halides can be
combined with different electrophile traps and thus form a
variety of products as shown. In fact, the addition of excess
electrophile (allyl bromide) and extra base after the arylation
reaction allowed a double-allylation reaction to proceed (see
8h, Scheme 5). Finally, by adding methyl iodide (1 equiv)
followed by allyl bromide and extra base, we were able to
perform a one-pot arylation and then a sequential double
alkylation reaction to form compound 8i in 48% yield.
OBO ketone 4 could be conveniently transformed into various
arylated and further functionalized pyruvate esters in one pot
(punctuated with a solvent change) and in good yield. The
formation of pyruvic acids by OBO deprotection was also
investigated, but we found that the polar products were
extremely difficult to purify. Therefore, we have restricted
ourselves to the one example shown (10) in which the product
was recovered in high purity from aqueous extraction.
However, this single example shows that it is possible to
produce the arylated pyruvic acid directly from compound 4.
Clearly, if this reaction methodology is to prove useful in
organic synthesis it is imperative that we are able to deprotect
the OBO moiety. Therefore, a series of representative
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exploring the properties of 4 in diastereoselective aldol reactions:
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A new method for the enolate arylation of protected pyruvate
esters has been presented. The methodology allows mono- and
diarylation reactions to take place on an easily accessible OBO-
protected starting material. Moreover, the monoarylated
intermediates could be readily alkylated in situ to allow the
formation of a wide range of differently substituted pyruvate
equivalents. Finally, the OBO protecting group could be
removed conveniently using acidic conditions.
(14) (a) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org. Biomol.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02524.
■
S
Full experimental details; spectroscopic data (PDF)
AUTHOR INFORMATION
(15) (a) Horner, L.; Renth, E. O. Liebigs Ann. Chem. 1967, 703, 37.
■
(b) Sivanathan, S.; Korber, F.; Tent, J. A.; Werner, S.; Scherkenbeck, J.
̈
Corresponding Author
*E-mail: timothy.donohoe@chem.ox.ac.uk.
ORCID
J. Org. Chem. 2015, 80, 2554.
(16) Steward, K. M.; Johnson, J. S. Org. Lett. 2011, 13, 2426.
(17) Xie, Y.; Liu, J.; Huang, Y.; Yao, L. Tetrahedron Lett. 2015, 56,
3793.
(18) Zavesky, B. P.; Bartlett, S. L.; Johnson, J. S. Org. Lett. 2017, 19,
2126.
Timothy J. Donohoe: 0000-0001-7088-6626
Notes
(19) (a) Churruca, F.; SanMartin, R.; Carril, M.; Tellitu, I.;
Domínguez, E. Tetrahedron 2004, 60, 2393−2408. (b) Cao, C.;
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Chem. 2011, 2011, 1570−1574.
(20) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
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(c) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank CAPES, Coordenaca
̧
o de Aperfeico
̧
amento de
̃
́
Pessoal de Nivel Superior, Brazil, and AstraZeneca for
supporting this project.
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DOI: 10.1021/acs.orglett.7b02524
Org. Lett. XXXX, XXX, XXX−XXX