Stereospecific Decarboxylative Benzylation of Enolates: Development and Mechanistic Insight

Article abstract of DOI:10.1021/acs.orglett.8b00169

A palladium-catalyzed decarboxylative coupling of enol carbonates with diarylmethyl electrophiles that are derived from secondary benzylic alcohols has been developed. This method allows the generation of a variety of β-diaryl ketones through an efficient and highly stereospecific coupling. In addition, detailed mechanistic insight into the coupling suggests that the reaction is a rare example of an intramolecular decarboxylative coupling that proceeds without crossover between reactants.

Full text of DOI:10.1021/acs.orglett.8b00169

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereospecific Decarboxylative Benzylation of Enolates:
Development and Mechanistic Insight
Tian-Ren Li,†,‡,§,⊥ Mary L. Maliszewski,†,‡,⊥ Wen-Jing Xiao,§ and Jon A. Tunge*,†,‡
†Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
‡The KU Chemical Methodologies and Library Development Center of Excellence, 2034 Becker Drive, Lawrence, Kansas 66047,
United States
§Key Laboratory of Pesticide & Chemical Biology Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed decarboxylative coupling
of enol carbonates with diarylmethyl electrophiles that are
derived from secondary benzylic alcohols has been developed.
This method allows the generation of a variety of β-diaryl
ketones through an efficient and highly stereospecific coupling.
In addition, detailed mechanistic insight into the coupling
suggests that the reaction is a rare example of an intramolecular decarboxylative coupling that proceeds without crossover
between reactants.
Scheme 1. Decarboxylative Benzylation of Enolates
he formation of C−C bonds via palladium-catalyzed
Tdecarboxylative coupling reactions has been proven to be
a powerful tool in organic synthesis.1 Compared to traditional
coupling reactions, the avoidance of toxic organic halides and
sensitive preformed organometallics, in addition to the neutral
coupling conditions, make decarboxylative coupling reactions
increasingly attractive. In the 30 years since Saegusa and Tsuji’s
pioneering work on decarboxylative allylation,2 a large number
of contributions have furthered the utility and scope of such
couplings.3 Among them, α-allylation of enolates has received
significant attention in the past several years due to the
synthetic flexibility of the product ketones.4 A number of
research groups, including ours as well as those of Stoltz and
Trost, have been dedicated to the understanding of the
mechanisms of decarboxylative allylation as well as the
application of these methods toward catalytic asymmetric
reactions and total synthesis.5,6
While there have been significant advances in the develop-
ment and understanding of decarboxylative allylations, the
analogous decarboxylative benzylations have seen much less
progress.7 Although decarboxylative benzylations using primary
benzyl alcohol derivatives have had some success, few examples
using secondary benzyl esters have been reported.8 Moreover,
the development of decarboxylative benzylations that give rise
to enantioenriched products lags far behind related allylation
chemistry.9 Thus, we aimed to develop a decarboxylative
coupling of diarylmethyl electrophiles that would be applicable
to the stereospecific synthesis of enantioenriched tertiary
diarylmethanes (Scheme 1).10 This is particularly challenging
due to the propensity of diarylmethyl electrophiles to
homocouple to form benzyl dimers11 or racemize via formation
of achiral cationic intermediates.9a,12c Nonetheless, such a
stereospecific coupling could address the difficulty of
construction of tertiary stereogenic centers with two aryl
substituents. Although excellent progress has been made in
nickel-catalyzed cross-coupling reactions of secondary benzylic
alcohol derivatives,11b,12 those reactions inevitably require
Received: January 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00169
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Letter
stoichiometric organometallic reagents and they are rarely used
to couple diarylmethyl electrophiles that bear important
heteroaromatics like indole.12c Herein we report the develop-
ment and mechanistic study of a decarboxylative coupling of
secondary benzyl esters with enolates, with a particular focus on
coupling difficult indole-based diarylmethyl electrophiles.
Considering the utility of the products,13 we initially chose
the secondary 3-indolylcarbinol-derived enol carbonate 1a as a
model substrate to test the feasibility of our decarboxylative
coupling, and to optimize reaction conditions (Table 1). Unlike
With the optimized conditions in hand, we first tested the
generality of this method for coupling enolates with indole-
derived diarylmethyl electrophiles.15 These studies showed that
various substituted secondary 3-indolylcarbinols served as
suitable coupling partners (Scheme 2). Substitution with an
Scheme 2. Decarboxylative Functionalization of Different
a b c
, ,
Enolates
a
Table 1. Optimization of Decarboxylative Coupling
concn
(M)
yield
b
entry
Pd source
ligand
none
solvent
(%)
1
Pd(PPh3)4
toluene
toluene
toluene
toluene
toluene
dioxane
DME
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.04
0.04
trace
2
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd(dba)2
P(furyl)3
dppe
trace
N.R.
trace
47
3
4
Xantphos
MePhos
5
6
MePhos
32
7
MePhos
55
8
XPhos
DME
60
9
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
tBu-DavePhos
DME
73
10
11
12
13
14
DME
66
c
Pd(dmdba)2
DME
74
Pd(dmdba)2
Pd(dmdba)2
Pd(dmdba)2
THF
75
THF
76
THF
86 (86)
a
Reactions of enol carbonate (0.1 mmol), Pd/ligand (10/12 mol %),
b
24−48 h. NMR yield using 1,3,5-trimethoxybenzene internal
c
standard (isolated yield in parentheses). dmdba = 3,5,3′,5′-
a
Reactions of enol carbonate (0.2 mmol, 0.04 M), Pd/ligand (10/12
(dimethoxydibenzylidene)acetone.
b
c
mol %) in 25 mL microwave vial. Isolated yields. 1.5 mmol scale
reaction. 140 °C in butyl ether. dr values determined by H NMR
spectroscopy of the crude reaction mixture.
d
e
1
electron-donating group, such as a methoxy group (2b),
provided somewhat higher yields than analogous reactants that
were p-substituted with electron-withdrawing groups, such as F
or CF3 (2c, 2d). The electron-donating methoxy likely
stabilizes the intermediate π-benzyl palladium complex,
allowing more facile oxidative addition. Sterics may also play
a role in the reaction, with the o-F substrate giving a low yield
(2e), and the mesityl substrate failing to undergo any reaction
(2h) (Figure 1).
our previous experience with primary benzyl electrophiles,8b
Pd(PPh3)4 was not an effective catalyst for coupling secondary
benzylic carbonates (entry 1). Other common ligands used in
palladium-catalyzed benzylic coupling reactions, including tri(2-
furyl)phosphine, dppe, and xantphos, were also not suitable for
this decarboxylative coupling (entries 2−4). To our delight,
Buchwald’s bulky monophosphorus ligand MePhos provided
the desired product in moderate yield (entry 5).14 Using DME
as solvent further improved the yield to 55% (entry 7).
Testing other classes of Buchwald ligands showed that XPhos
increased the yield to 60%, and DavePhos further improved the
reaction to give the desired product in a good yield (entry 9,
73%). The use of Pd(dmdba)2 precatalyst in THF under more
dilute conditions also led to a cleaner reaction and slightly
better yields (entry 13). Finally, increasing the steric hindrance
of the ligand by using tBu-DavePhos led to the optimal yield
(entry 14).
Substitution at the 4-position of the indole also completely
inhibited the reaction. Presumably these substrates fail due to
steric destabilization of the intermediate π-benzyl complexes,
Figure 1. Reaction limitations.
B
DOI: 10.1021/acs.orglett.8b00169
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Letter
preventing oxidative addition (Figure 1). Finally, the coupling
does not require both the indole and the phenyl group;
replacing the phenyl group with an alkynyl group also produced
a corresponding homopropargylic ketone (2m), and a
secondary benzylic enol carbonate that lacks the indole motif
was also a good substrate for decarboxylative coupling (2n)
(Scheme 2).
Scheme 3. Stereospecific Coupling
Enol carbonates derived from a variety of ketones were also
compatible reaction partners, giving the corresponding α-
functionalized ketones in good to excellent yields (Scheme 2).
The acetophenone enolate provided the coupling product (2o)
in even higher yield than was achieved with the acetone enolate.
Similarly, other enol carbonates derived from aromatic ketones
underwent decarboxylative coupling in good to high yield
(2p,q,r,t). In addition, secondary nucleophilic coupling
partners, including cyclic enolates, were also suitable for the
process; the reaction efficiency was not affected, even if the
newly formed bond had two tertiary stereogenic centers (2q−t,
83−95%). However, the diastereoselectivities of the coupling
were not high. Interestingly, the geometry of the substituted
enolate is critical for successful reaction. When a 50:50 E/Z
mixture of enol carbonates was subjected to the reaction
conditions, only the E isomer underwent reaction, while the
majority of the Z isomer was isolated unchanged (eq 1). Thus,
attainment of high yields with substituted enolates necessitates
use of the E-enol carbonates.
Next, the constitution and absolute configuration of the
product were definitively determined by X-ray crystallography
((S)-2k, CCDC 1532316). The observed stereochemistry
shows that the decarboxylative benzylation of enolates occurs
with stereochemical retention. Since oxidative addition
generally occurs with inversion of configuration,9c,18 this critical
observation suggests that the C−C bond forming step also
occurs with inversion of stereochemistry.7c,19 Thus, the
coupling is an outer-sphere process, requiring dissociated
enolates; both inner-sphere and outer-sphere reactions are
known for related allylation chemistry,1a,5e,g but this is the first
determination of the mechanism of decarboxylative benzyla-
tion.
To further investigate the mechanistic details of this
transformation, we attempted to divert the π-benzyl palladium
complex by reaction with an external nucleophile (eq 3).
Stereospecific cross-coupling reactions of readily available
secondary alcohols, or their derivatives, has the potential to be a
significant tool for asymmetric synthesis. Thus, developing an
enantiospecific decarboxylative coupling under neutral con-
ditions was highly desired. Since indole-based electrophiles
form relatively stable carbocations, they have an inherent
tendency toward racemization.12c In keeping with this
observation, the N-protecting group proved critical for highly
enantiospecific coupling. For example, an enantioenriched N-
tosyl protected enol carbonate produced a nearly racemic
product, proceeding with only 7% stereochemical fidelity, or
enantiospecificity. However, we were excited to find that the
analogous N-triflyl reactant produced 2a, with high stereo-
specificity (94%, Scheme 3). Several other enol carbonates that
varied the enolate, indole fragment, or aryl group all underwent
similar decarboxylative coupling with high enantiospecificity to
produce products in good yield, which makes this trans-
formation a potentially practical method for asymmetric
synthesis.16,17 Importantly, the use of a triflyl protecting
group destabilizes the free carbocation enough to allow
stereospecific coupling and also allows straightforward depro-
tection to form free indoles using mild conditions that did not
racemize the product (eq 2).
Interestingly, adding 2 equiv of sodium dimethyl malonate
produced a ca. 2:1 mixture of the malonate substitution product
and decarboxylative coupling product. The fact that both
products are formed at similar rates suggests that oxidative
addition is rate-limiting, which is commonly the case for
catalytic benzylic coupling.7c Furthermore, although the
decarboxylative coupling product is the minor product, the
coupling with the acetone enolate must be quite facile given
that the malonate concentration is at least 20 times larger than
that of the enolate.
C
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Letter
Accession Codes
A crossover experiment performed between two different
enol carbonates proved to be even more informative (eq 4).
Treatment of a 50:50 mixture of two equally reactive substrates
under the conditions of catalysis failed to produce either
crossover product when analyzed by mass spectrometry or
NMR spectroscopy.20 This is a very rare example of an
intramolecular decarboxylative coupling; most decarboxylative
allylations give extensive crossover.1a,5g,6a The lack of crossover
suggests that enolate dissociation occurs to form short-lived
solvent-caged ion pairs that undergo C−C bond formation
faster than escape from the solvent cage. Moreover, it is
unlikely that the ion pair A is long-lived, as ion pairs can easily
crossover by ion exchange.
CCDC 1532316 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tunge@ku.edu.
ORCID
Analysis of all of the data suggest that the mechanism occurs
by ionization of the benzyl enol carbonate with inversion of
configuration to form A (Scheme 4). Coordination and
Wen-Jing Xiao: 0000-0002-9318-6021
Jon A. Tunge: 0000-0002-5849-0888
Author Contributions
⊥T.-R.L. and M.L.M. contributed equally.
Scheme 4. Hypothetical Mechanism
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1465172)
and the Kansas Bioscience Authority Rising Star program for
financial support. T.-R.L. (201606770032) acknowledges the
fellowship from the China Scholarship Council (CSC). Support
for the NMR instrumentation was provided by NIH Shared
Instrumentation Grant No. S10RR024664 and NSF Major
Research Instrumentation Award No. 1625923.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00169.
Experimental procedures and complete compound
characterization data (PDF)
D
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