Pd-catalyzed direct coupling of indoles with carbon monoxide and alkynes: Selective synthesis of linear α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol400722h

A new strategy is described for the direct coupling of indoles with CO and alkynes to generate α,β-unsaturated ketones. This procedure, employing Xantphos and Pd(CH₃CN)₄(BF₄) ₂, is attractive from both environmental and operational points of view and adds value to the method for the carbonylation of alkynes by using carbon nucleophiles and affording linear regioselectivity.

Full text of DOI:10.1021/ol400722h

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2034–2037
Pd-Catalyzed Direct Coupling of Indoles
with Carbon Monoxide and Alkynes:
Selective Synthesis of Linear
r,β-Unsaturated Ketones
Fanlong Zeng and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
howard.alper@uottawa.ca
Received March 18, 2013
ABSTRACT
A new strategy is described for the direct coupling of indoles with CO and alkynes to generate R,β-unsaturated ketones. This procedure,
employing Xantphos and Pd(CH3CN)4(BF4)2, is attractive from both environmental and operational points of view and adds value to the method for
the carbonylation of alkynes by using carbon nucleophiles and affording linear regioselectivity.
The transition-metal catalyzed addition of nucleophiles
and carbon monoxide to alkynes has attracted consider-
able attention, since it provides a straightforward and
atom-economical approach to valuable R,β-unsaturated
carboxylic acid derivatives.1 A number of catalytic systems
based on transition metals, such as Rh,2 Pt,3 Pd,4 and Fe,5
have been used for this reaction. The seminal contributions
by Drent made Pd-catalyzed processes one of the most
useful synthetic routes to methacrylates.4b,c Nonetheless,
several drawbacks still limit this useful protocol: first, strong
acids (e.g., TsOH, CH3SO3H) are needed in most cases to
generate the active palladium hydride species. Second,
systems giving linear regioselectivity are rare.6 Third, the
nucleophiles are mainly restricted to heteroatoms with
active protons, such as alcohols, amines, (thio)phenols,
and water. To our knowledge, an analogous transformation
using carbon nucleophiles to accessR,β-unsaturated ketones
has not been reported. On the other hand, the addition of
(hetero)aromatic CꢀH and CO to alkenes via chelation-
assisted CꢀH activation strategy was well established and
exploited by Moore, Murai, Chatani, and co-workers.7
The ubiquitous presence of the indole nucleus in alka-
loids and synthetic pharmaceuticals has stimulated great
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r
10.1021/ol400722h
Published on Web 03/29/2013
2013 American Chemical Society

interest in functionalizing the indole skeleton. Classical
and widely used methods include FriedelꢀCrafts acyla-
tion, alkylation, allylic alkylation, and conjugate addition,
which are based on the carbon nucleophilicity of indoles.8
Recently, transition metal-catalyzed C(sp2)ꢀH bond acti-
vation has emerged as an alternative strategy. Regioselec-
tive alkylation,9 alkenylation,10 and arylation11 of indoles
at either the C2 or C3 position have been achieved. By
contrast, direct carbonylation of indoles is not well devel-
oped, and only a few catalytic systems for esterification
and amidation of indoles have been reported.12 Herein we
describe a novel protocol for the direct coupling of indoles/
CO/alkynes to afford linear R,β-unsaturated ketones in a
highly regioselective and chemoselective manner.
Initially, we subjected N-methylindole (1a) and methyl
propiolate (2a) to Drent’s alkoxycarbonylation condi-
tions, and the desired R,β-unsaturated ketone 3a was
isolated in 10% yield, as well as 16% of the 1,3-diindolyl
compound3a0 (Table 1, entry 1). Thestrong Brønstedacid,
TsOH, simultaneously promotes the carbonylation of
alkynes and the Michael addition between indole 1a and
the product 3a. Increasing the acid promoter to 20 mol %
selectively furnished the product 3a0 in 46% yield (Table 1,
entry 5). Employing 9,9-dimethyl-4,5-bis(diphenylphosphino)-
xanthene (Xantphos) gave the same tendency but showed
higher activities than other phosphines, such as 2-PyPPh2,
PPh3, dppb, and dppp. Pivalic acid, which is weak and
widely employed in C(sp2)ꢀH bond activation,13 did not
show any activity for this transformation (Table1, entry 8).
Based on the investigation of the mechanism for the
alkoxycarbonylation of alkynes, the cationic palladium
complex, Pd(CH3CN)4(BF4)2, was tested as a surrogate
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
additive (%) PCO (psi) 3ab (%) 3a0b (%)
1
PdCl2/PyPPh2
TsOH(5)
300
300
300
300
300
300
300
300
300
300
300
300
300
200
50
10
16
2c
3c
4c
5c
6c
7c
8c
9c
PdCl2(PPh3)2
TsOH (5)
TsOH (5)
TsOH (10)
TsOH (20)
TsOH (30)
n.d.
14
trace
27
PdCl2(Xantphos)
PdCl2(Xantphos)
PdCl2(Xantphos)
PdCl2(Xantphos)
PdCl2(Xantphos)
PdCl2(Xantphos)
PdCl2(dppb)
8
43
trace
trace
29
46d
44
trace
trace
11
PivOH(30)
TsOH (20)
TsOH (20)
21
10
10c PdCl2(dppp)
trace
70
32
11e Pd2þ/Xantphos
12e Pd2þ/DPEphos
13e Pd2þ/tBuXantphos
14e Pd2þ/Xantphos
15e Pd2þ/Xantphos
16e Pd2þ/Xantphos
17e Pd2þ/Xantphos
18f Pd2þ/Xantphos
4
16
8
trace
33
trace
9
trace
66
trace
3
400
500
300
62
3
34
35
a All reactions were carried out with 1.0 mmol of 1a, 1.5 mmol of 2a,
4 mol % of palladium precursor and ligand, 5 mL of THF, 105 °C, 15 h.
b Isolated yield based on 1a. c Using palladium complexes. d Molecular
structure was determined by HSQC and HMQC spectra. e Pd2þ
=
Pd(CH3CN)4(BF4)2. f 70 °C.
for the mixture of acids and palladium salts. Gratifyingly,
the Xantphos/Pd(CH3CN)4(BF4)2 system gave the antici-
pated product 3a in 70% isolated yield, also along with 4%
of the dimer 3a0 (Table 1, entry 11). Similar phosphines
to Xantphos, e.g., bis(2-diphenylphosphinophenyl) ether
(DPEphos) and 9,9-dimethyl-4,5-bis(di-tert-butylphosphino)-
xanthene (t-BuXantphos), gave unsatisfactory results for
this transformation. It is noteworthy that lowering the
pressure of carbon monoxide proved to be detrimental to
both efficiency and selectivity (Table 1, entries 14 and 15).
The outcome of this procedure also significantly depends on
the nature of solvents, and THF is the best reaction solvent
(for the influence of other parameters, see the full Table 1 in
the Supporting Information).
With the optimized reaction conditions established, the
generality of the reaction was explored using a variety of
indoles (Table 2). Interestingly, the system tolerates the
active NH group and smoothly converts free indole to the
desired product 3b, albeit in moderate yield (54%). The
efficiency of this transformation is highly dependent upon
the electronic properties of R2 groups. When electron-
donating groups, i.e., Bz, nBu, iPr, and tBu, were presented
at the R2 position, the products 3cꢀf were isolated in good
yields (63ꢀ77%; Table 2, entries 3ꢀ6). In contrast, the
strongly electron-withdrawing group, Ac, totally inhibited
the process (Table 2, entry 10). The system is compatible
with the Reppe carbonylation candidate CC double
bond and the weakly coordinating CN group. This
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Org. Lett., Vol. 15, No. 8, 2013
2035

incorporation at the 2 position and 31% D incorporation
at the 3 position. Increasing the amounts of propiolate
2a does not change the percentage of D incorporation in
3a-D, which excludes the possibility of direct H/D ex-
change under the reaction conditions. Moreover, using
methyl 3-D-propiolate (2a-D, 89% D incorporation) afforded
the deuterated 3a-D0 in 63% yield, with 56% D incorporation
at the 3 position and 31% D incorporation at the 2 position.
Table 2. Synthesis of R,β-Unsaturated Ketonesa
Scheme 1
a All reactions were carried out with 1.0 mmol of 1, 1.5 mmol of 2a,
4 mol % of Pd(CH3CN)4(BF4)2 and Xantphos, 5 mL of THF, 300 psi of
CO, 105 °C, 15 h. b Isolated yield based on indoles. c Isolated yield of the
corresponding 1,3-diindolyl compounds in parentheses. d Determined
by NMR. e R3 = Et.
On the basis of the above observations, a possible mecha-
nism for this transformation is outlined in Scheme 2. There
are two parallel pathways to produce the Pdꢀ(σ-vinyl)
intermediate 6 from terminal alkynes and the active palla-
dium hydride species 2, which is in situ generated from the
cationic palladium complex Pd(CH3CN)4(BF4)2.14 In path-
way A, the palladium hydride 2 may be oxidized by terminal
alkynes to the Pd(IV) species 3, followed by the formation of
two isomers 4 and 5. The insertion of the coordinated alkyne
in 4 or 5 into the PdꢀH bond affords the Pdꢀ(σ-vinyl)
intermediate 6. In pathway B, terminal alkynes are directly
captured by the electrophilic cationic palladium complex 2
to give the intermediate 5. The mechanism involving
two competing pathways is believed responsible for the
transformation also tolerates different substituents, such
as Me, MeO, Ph, and Cl, on the phenyl subunit of indoles.
However, it is worth mentioning that the electron-rich R1
(Table 2, entries 11ꢀ14) groups boosted the Michael
addition between the indoles and the products, which gives
the corresponding 1,3-diindolyl compounds as accompa-
nying products. The catalytic system was not useful for
substrates with strong coordination properties, perhaps
because the highly electrophilic cationic palladium species
are prone to be poisoned by a Lewis base (Table 2, entry 18).
This system represents acceptable catalytic activities to pyr-
role derivatives yet expresses poor regioselectivity between R
and β positions in pyrrole rings. For example, free pyrrole
gave the R-carbon carbonylated product in 23% and the
β-carbon carbonylated product in 18%, and N-isopropyl-
pyrrole afforded the two products in 14% and 23% yields,
respectively. N-tert-Butylpyrrole selectively furnished the
β-carbon carbonylated product 3s in 60% yield, owing to
the strong steric hindrance from the bulky tert-butyl group
to the R carbon (Table 2, entry 19).
Scheme 2. Possible Reaction Mechanism
To gain mechanistic insight for the reaction, the follow-
ing experiments were conducted (Scheme 1). Performing
the reaction under nitrogen resulted in 3,3-bis(1-methylin-
dol-3-yl)propionic acid methyl ester (4) in 10% yield.
When 1-methyl-3-D-indole (81% D incorporation) was
subjected to the standard reaction conditions, the deuter-
ated 4-(1-methylindol-3-yl)-4-oxo-(2E)-butenoic acid methyl
ester (3a-D) was obtained in 66% yield, with 38% D
2036
Org. Lett., Vol. 15, No. 8, 2013

deuterium distribution in deuterium-labeling reactions
(Scheme 1, eq 2 and 3). The acylpalladium species 7 is
obtained by CO insertion into the PdꢀC bond, which is
more electrophilic relative to the corresponding intermediate
6 and thus facilitates the nucleophilic attack of indoles to
furnish 8. Rearomatization of 8 generates the Pd(IV)ꢀH
intermediate 9, which is subseqentially reduced to the
Pd(II)ꢀH 2 by forming the product 10. Meanwhile, the
cationic palladium species (either 1 or 2) catalyzes the
addition of indoles to the R,β-unsaturated ketone 10 to
form the accompanying product 11.
indoles/CO/alkynes. This acid-free protocol tolerates a variety
of indoles with weak coordination, electron-donating, and
electron-withdrawing groups and enriches the method for the
carbonylation of alkynes by using carbon nucleophiles and
giving linear selectivity, albeit restricted to active terminal
alkynes.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
support of this research.
In summary, a novel strategy for the synthesis of
R,β-unsaturated ketones was developed for the first time
based on cationic palladium-catalyzed direct coupling of
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
the starting materials and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
€
€
(14) Roesle, P.; Durr, C. J.; Moller, H. M.; Cavallo, L.; Caporaso, L.;
Mecking, S. J. Am. Chem. Soc. 2012, 134, 17696 and references cited
therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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