Decarboxylative benzylations of alkynes and ketones

Article abstract of DOI:10.1021/ja1035557

Benzyl esters of propiolic and β-keto acids undergo catalytic decarboxylative coupling when treated with appropriate palladium catalysts. Such decarboxylative couplings allow the benzylation of alkynes without the use of strong bases and/or organometallics. This allows the synthesis of sensitive benzylic alkynes that are prone to undergo isomerizations under basic conditions. Additionally, decarboxylation facilitates the site-specific benzylation of diketones and ketoesters under mild, base-free conditions. Ultimately, the methodology described expands our ability to cross-couple medicinally relevant heterocycles.

Full text of DOI:10.1021/ja1035557

Published on Web 06/21/2010
Decarboxylative Benzylations of Alkynes and Ketones
Robert R. P. Torregrosa, Yamuna Ariyarathna, Kalicharan Chattopadhyay, and Jon A. Tunge*
Department of Chemistry, UniVersity of Kansas, 2010 Malott Hall, 1251 Wescoe Hall DriVe, Lawrence, Kansas 66045
Received April 26, 2010; E-mail: tunge@ku.edu
Abstract: Benzyl esters of propiolic and ꢀ-keto acids undergo
catalytic decarboxylative coupling when treated with appropriate
palladium catalysts. Such decarboxylative couplings allow the
benzylation of alkynes without the use of strong bases and/or
organometallics. This allows the synthesis of sensitive benzylic
alkynes that are prone to undergo isomerizations under basic
conditions. Additionally, decarboxylation facilitates the site-specific
benzylation of diketones and ketoesters under mild, base-free
Having demonstrated a successful decarboxylative benzylation,
we briefly examined the scope of this transformation. Doing so
revealed that a variety of benzylic esters that have extended aromatic
conjugation underwent smooth decarboxylative benzylation (Table
1). Heteroaromatic benzyl esters, including an array of quinolines
conditions. Ultimately, the methodology described expands our
ability to cross-couple medicinally relevant heterocycles.
Utilization of palladium π-benzyl complexes in cross-coupling
reactions is becoming increasingly important in organic synthesis.1
However, methods for benzylic cross-couplings typically rely on
the use of basic reagents or preformed organometallics. For
example, Buchwald reported the cross-coupling of benzyl halides
with alkynes using stoichiometric Cs2CO3; unfortunately, the basic
reaction conditions often induce isomerization of the product
benzylic alkynes to isomeric allenes.2 Negishi reported the benzylic
cross-coupling with acetylides via stoichiometric alkynyl zinc
bromides that must be prepared from ZnBr2.3 Not only do these
methods require stoichiometric bases or organometallics, but they
also utilize benzyl halides that are expensive, hazardous, and more
difficult to handle than related benzyl alcohol derivatives.
Legros, Kuwano, and others have reported catalytic benzylation
of stabilized nucleophiles using activated benzylic alcohol deriva-
tives.4 While benzylations of highly stabilized enolates (pKa ≈
10-13),4a-d phenols (pKa ≈ 10),4e and arene sulfinates (pKa ≈
7)4f have been successful, the reaction of less stabilized nucleophiles
has proven difficult.5 Since we have previously developed decar-
boxylative coupling strategies that allow allylation of nonstabilized
nucleophiles without the use of an external base or organometallic,
we hypothesized that a similar strategy might allow decarboxylative
coupling of benzylic esters with nonstabilized nucleophiles
(eq 1).5-7
and indoles, provide good to excellent yields of the coupled products
(entries 2b-2h). In addition, both 1-naphthyl- and 2-naphthylmethyl
esters are compatible reaction partners (entries 2i-2o). Similarly,
the alkyne can bear an aliphatic or aromatic group with little effect
on the yield of the reaction. This lies in contrast to decarboxylative
Table 1. Decarboxylative Benzylations of Alkynes
To test this hypothesis, several benzyl phenylpropiolates were
synthesized and heated to 110 °C in the presence of catalytic
Pd(PPh3)4 (eq 2). While the simple benzyl phenylpropiolate failed
to undergo reaction under these conditions, it was gratifying to find
that the heterobenzylation to form 2a proceeded in high yield.
Importantly, control reactions showed no conversion in the absence
of the palladium catalyst. The much slower formation of π-benzyl
palladium complexes from benzyl acetate relative to polycyclic
analogs has been previously noted and ascribed to the disruption
of aromaticity.4a,8
a Must be stored cold upon isolation. b 7 h reaction time. c 10 mol %
Pd(PPh3)4.
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9280 J. AM. CHEM. SOC. 2010, 132, 9280–9282
10.1021/ja1035557  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Decarboxylative Benzylations of Substituted Ketones
allylation of alkynes where aromatic propiolates are superior
substrates.6 Lastly, while a terminal alkyne failed to undergo any
reaction, trimethylsilyl-protected alkynes could be used in lieu of
a terminal alkyne (2h, 2j, 2n, Table 1).
Given the success of the benzyl alkynyl coupling, we turned our
attention to developing decarboxylative benzylation of ketones.
Related decarboxylative allylations have allowed allylation of ketone
enolates, but these reactions have not been extended to related
benzylation chemistry.7 To begin, the 1-naphthyl-ꢀ-ketoester 3a
was treated under identical conditions to those used for benzyl
alkynyl coupling (entry 1, Table 2). The reaction proceeded to 53%
conversion, allowing isolation of 4a in just 36% yield. Initial catalyst
screening revealed that combination of a more electron-deficient,
dba-ligated palladium precatalyst with triphenylphosphine was
ineffective (entry 3, Table 2). Reasoning that a more electron-rich
catalyst may facilitate the formation of the putative electron-
deficient π-benzyl palladium complex, several additional Pd
catalysts and ligands were explored (Table 2). While bulky,
electron-rich phosphines failed to promote the reaction (entries
4 and 5), smaller electron-rich ligands provided better conversion
(entries 6-8). In addition, diphenylphosphinoferrocene (dppf)
provided high conversion to product when combined with a
catalyst precursor that is devoid of an electron-withdrawing dba
ligand (entry 10).
Table 2. Catalyst Screening
entry
X
Pd
Y
ligand
conversion (%)a
1
2
3
4
5
6
7
8
9
10
5
10
5
5
5
5
5
2.5
1
Pd(PPh3)4
Pd(PPh3)4
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
-
-
none
none
PPh3
P(t-Bu)3
PCy3
PMe3
PBu3
PBu3
PBu3
dppf
53
70
4
0
0
19
>99
>99
21a
97
a 10 mol % Pd(PPh3)4. b 10 mol % CpPd(allyl), 11 mol % dppf.
10
10
10
10
10
10
5
c reaction performed at 85 °C. d 5 mol % Pd(PPh3)4, 25 °C, MeCN.
difficult, if not impossible, to achieve using standard enolate
alkylation chemistry.
10
CpPd(allyl)
11
a
Determined by H NMR spectroscopy. b 97% conversion after 40 h.
1
Using the optimized conditions with PBu3 as a ligand,9 various
substituted benzyl esters were converted to benzylated ketones in
good to high yields (Table 3). It is noteworthy that the reaction
allows C-C bond formations that give rise to hindered quaternary
carbon centers. While attempted coupling of an unsubstituted benzyl
electrophile failed, a p-methoxybenzyl electrophile was compatible
with the ketone coupling (4g). Presumably the electron-donating
methoxy substituent stabilizes the putative π-benzyl intermediate
enough to facilitate the reaction. The reaction can also be extended
to the formation of less substituted ketones; however Pd(PPh3)4
proved to be the best catalyst for those substrates. Importantly, the
coupling is compatible with a variety of electron-rich benzyl and
heterobenzylic reaction partners that are of significant interest in
medicinal chemistry.
In conclusion, we developed new catalytic decarboxylative
benzylations of alkynes and ketones. Such decarboxylative cou-
plings utilize the loss of CO2 as a driving force in lieu of the use
of external bases and/or organometallics. Furthermore, the coupling
allows the site-specific benzylation of 1,4-ketone analogues to form
products that would be difficult to access via traditional base-
mediated enolate methodology. Ultimately, both ketones and
alkynes can be coupled with a variety of medicinally relevant
heterobenzylic species including quinolines, indoles, and coumarins.
Acknowledgment. We thank the National Science Foundation
(CHE-0548081), the National Institutes of Health, KU Chemical
Methodologies, and Library Development Center of Excellence
(P50 GM069663) for support. We also thank Dr. Shelli Waetzig.
To examine the regiospecificity of benzylation, substrate 3s was
prepared via alkylation of the ketoester with 1-bromobutanone.
Treatment of 3s under our catalytic reaction conditions led to site-
specific benzylation of the enolate to form 4s; no product resulting
from enolate isomerization (4s′) was observed. Thus, decarboxyl-
ative benzylation allows regiospecific benzylation of 1,4-diketone
analogues (4f, 4i-4l, Table 3). Such regioselectivity would be
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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