Palladium-catalyzed nucleophilic substitution of propargylic carbonates and meldrum's acid derivatives

Article abstract of DOI:10.1002/ejoc.201500337

The palladium-catalyzed reaction of propargylic carbonates with Meldrum's acid derivatives proceeds smoothly in the presence of Pd(OAc)₂ and P(2-furyl)₃ in THF at 80 °C to give substitution products. The substitution products can be

Full text of DOI:10.1002/ejoc.201500337

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DOI: 10.1002/ejoc.201500337
Palladium-Catalyzed Nucleophilic Substitution of Propargylic Carbonates and
Meldrum’s Acid Derivatives
Ilaria Ambrogio,[a] Sandro Cacchi,[a] Giancarlo Fabrizi,[a] Antonella Goggiamani,*[a] and
Antonia Iazzetti[a]
Keywords: Homogeneous catalysis / Palladium / Nucleophilic substitution / Alkynes
The palladium-catalyzed reaction of propargylic carbonates
with Meldrum’s acid derivatives proceeds smoothly in the
presence of Pd(OAc)2 and P(2-furyl)3 in THF at 80 °C to
give substitution products. The substitution products can be
useful intermediates for the stereoselective synthesis of func-
tionalized (Z)-γ-alkylidene-γ-butyrolactones.
Introduction
Results and Discussion
During the course of our studies on the development of
new palladium-catalyzed transformations of propargylic
carbonates,[4] we found that propargylic carbonate 2a could
be recovered in almost quantitative yield upon treatment
Propargylic esters are versatile compounds that are
known to undergo several synthetically useful palladium-
catalyzed transformations.[1] With soft carbon nucleophiles
derived from compounds with activated methylene groups,
propargylic carbonates undergo double nucleophilic attack,
with dppe [1,2-bis(diphenylphosphanyl)ethane] usually be-
ing the ligand of choice in this reaction.[1] For example, the
palladium-catalyzed reaction of methyl propargyl carbonate
with 2-methyl-3-oxopentanoate gives adduct 1 in 69% yield
(Scheme 1).[2] This type of reaction is assumed to proceed
through nucleophilic attack of the soft carbon nucleophile
at the central carbon of an initially formed propargyl/allen-
ylpalladium complex,[1,3] followed by a second nucleophilic
attack at one of the allylic termini of the resulting η3-allyl-
palladium complex.[1]
Table 1. Optimization studies.[a]
Entry [Pd]
Ligand
Solvent
Time [h] Yield of 4a [%][b]
[c]
1
2
3
4
5
6
7
8
–
–
THF
THF
THF
THF
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
MeCN
DMF
24
24
24
24
24
–
[c]
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppe[d]
dppf[e]
–
[c]
–
[c]
dppb[f]
–
–
[c]
dppe[d]
P(o-tol)3
PPh3
[g]
24
–
24
64
70
[h]
–
1[i]
24
[c]
9
dppe[d]
PPh3
–
10
11
12
13
14
15
16
17
5[i]
24
65
[c]
ttmpp[j]
P(C6F5)3
P(C6H4-p-Cl)3
P(2-furyl)3
P(2-furyl)3
P(2-furyl)3
P(2-furyl)3
–
[c]
16
24
2[i]
0.5[i]
1[i]
0.5[i]
–
Scheme 1. Palladium-catalyzed double nucleophilic attack of a soft
carbon nucleophile derived from a 1,3-dicarbonyl compound onto
a propargylic carbonate.
[c]
–
80
50
62
70
In this paper, we report that, in contrast to the behavior
described above, the palladium-catalyzed reaction of prop-
argylic carbonates with monosubstituted Meldrum’s acid
derivatives give SN2-like substitution products.
[a] Unless otherwise stated, reactions were carried out on a
0.38 mmol scale at 80 °C in anhydrous solvent (2 mL) using 2a
(1 equiv.), 3a (1.5 equiv.), [Pd] (0.05 equiv.), and monodentate
ligand (0.2 equiv.) or bidentate ligand (0.1 equiv.). [b] Yields are
given for isolated products. [c] 2a was recovered in almost quantita-
tive yield. [d] dppe = 1,2-bis(diphenylphosphanyl)ethane. [e] dppf =
1,1Ј-bis(diphenylphosphanyl)ferrocene. [f] dppb = 1,4-bis(diphenyl-
phosphanyl)butane. [g] 2a was recovered in 58% yield.
[h] 0.05 equiv. [i] The reaction time refers to the disappearance of
2a. [j] ttmpp = tris(2,4,6-trimethoxyphenyl)phosphine.
[a] Dipartimento di Chimica e Tecnologie del Farmaco, La
Sapienza, Università di Roma
P.le A. Moro 5, 00185 Rome, Italy
E-mail: antonella.goggiamani@uniroma1.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500337.
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I. Ambrogio, S. Cacchi, G. Fabrizi, A. Goggiamani, A. Iazzetti
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with Meldrum’s acid derivative 3a in the presence of the scope of the reaction. The propargylic subunit is part
Pd2(dba)3 (dba = dibenzylideneacetone) and dppe in THF of a variety of natural products, synthetic pharmaceuticals,
at 80 °C (Table 1, entry 2). In contrast, the same reaction and fine chemicals,[6] and this may justify efforts to develop
led to the isolation of the propargylic substitution product an efficient synthetic protocol for the preparation of prop-
(i.e., 4a) in 64% yield when PPh3 was used instead of dppe argylic derivatives through a C–C-bond-forming reaction.
(Table 1, entry 7).
A brief optimization study revealed that a satisfactory
Intrigued by this result (the first example of such result could be obtained when 2a was treated with 1.5 equiv.
behavior of propargylic carbonates with soft carbon nucleo- of 3a in the presence of 0.05 equiv. of Pd(OAc)2 and
philes in the presence of palladium catalysts to the best of 0.2 equiv. of P(2-furyl)3 in THF at 80 °C for 2 h: 4a was
our knowledge[5]), we decided to explore the generality and isolated in 80% yield (Table 1, entry 14). Notably, the reac-
Table 2. Palladium-catalyzed substitution of propargylic carbonates with Meldrum’s acid derivatives.[a]
[a] Reactions were carried out on a 0.38 mmol scale at 80 °C in anhydrous THF (2 mL) using 2 (1 equiv.), 3 (1.5 equiv.), Pd(OAc)2
(0.05 equiv.), and P(2-furyl)3 (0.2 equiv.). [b] Yields are given for isolated products. [c] In the presence of 5 mol-% Pd(PPh3)4.
2
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Palladium-Catalyzed Nucleophilic Substitution
tion of Meldrum’s acid with 2a under the same conditions rium[5,8] with η3-allenyl/propargylpalladium complex B and
(18 h) gave a complex mixture that we have not investigated η1-propargylpalladium complex C, is formed through the
further.
anti-SN2Ј-type displacement of the ethyl carbonate group
Using the optimized conditions, we next examined dif- by Pd0. Its reaction with Meldrum’s acid derivative 3 gives
ferent substrates for this new substitution reaction. As D, which is in equilibrium with E and F.
shown in Table 2, a variety of functional groups are
The presence of η1-allenylpalladium complexes D along
tolerated including ester, keto, ether, amido, and chloro sub- the reaction coordinate is supported by the fact that 5a was
stituents. The reaction works well, even with propargylic formed when 2a was treated with 2-methyl-1,3-cyclo-
carbonates bearing a substituent on the propargylic carbon. hexandione under the standard conditions (Scheme 2). In
As shown by the results summarized in Table 1, the fact, according to literature data,[3] its formation may be
course of the reaction is strongly dependent on the nature ascribed to nucleophilic attack at the central carbon of the
of the phosphine ligand. Even the basicity/polarizability of allenylpalladium fragment followed by a second nucleo-
the anion derived from the 1,3-dicarbonyl compound philic attack at the less substituted allylic terminus of the
appears to play a key role. For example, in contrast with resulting η3-allylpalladium complex.
the result obtained with the anion formed from Meldrum’s
The subsequent anti-SN2Ј-type nucleophilic attack of the
acid derivative 3a, the reaction of 2a with the more basic anionic fragment of D onto the cationic η1-allenylpalladium
anion derived from 2-methyl-1,3-cyclohexandione[7] under fragment gives 4 and regenerates the active palladium cata-
the standard conditions gave the usual diaddition deriva- lyst.
tive[1a,1b] in 90% yield as a 50:50 stereoisomeric mixture
A mechanism of this kind, based on an anti-SN2Ј-type
(Scheme 2), and no formation of the substitution product displacement of mesylate by Pd0 followed by an anti-SN2Ј
was observed. However, the specific role of these factors in nucleophilic attack of aromatic amines on the resulting η1-
favoring the different behavior of Meldrum’s acid deriva- allenylpalladium intermediate, has been proposed for the
tives as compared to the typical trend for 1,3-dicarbonyl palladium-catalyzed synthesis of propargylic amines from
compounds in palladium-catalyzed reactions with prop- propargylic mesylates.[9]
argylic carbonates is uncertain at the moment.
The formation of the substitution product (i.e., 4) by di-
rect displacement of palladium from the cationic fragment
of η1-propargylpalladium complex F might also be possible.
Such a mechanism has been suggested to account for the
formation of syn-substitution products in the palladium-
catalyzed reactions of cyclic allylic esters with primary
amines,[10] and of propargylic esters with phenylzinc
chloride.[11]
The alternative pathway involving nucleophilic attack of
the anionic Meldrum’s acid fragment of E onto the terminal
allenyl/propargyl carbon of the cationic η3-allenyl/prop-
argylpalladium fragment appears less likely in view of the
regioselectivity observed with propargylic carbonates sub-
Scheme 2. Palladium-catalyzed reaction of 2a with 2-methyl-1,3-
cyclohexandione under the standard conditions.
A possible reaction mechanism is outlined in Scheme 3. stituted at the propargylic carbon. In these cases, if the reac-
Initially, η1-allenylpalladium intermediate A, in equilib- tion proceeded through nucleophilic attack at one of the
Scheme 3. Proposed reaction mechanism.
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I. Ambrogio, S. Cacchi, G. Fabrizi, A. Goggiamani, A. Iazzetti
FULL PAPER
η3-allenylic/propargylic termini, formation of the C–C
bond would be expected to generate variable amounts of
allenyl and propargyl derivatives as the result of the nucleo-
philic attack at Cc and at the Ca, respectively, in particular
when differences in the electronic and steric effects that
might influence the reactivity are small (see, for example,
Table 2, entries 17 and 18). However, the nucleophilic attack
was found to occur exclusively at Ca. No evidence was ever
obtained of products derived from nucleophilic attack at
Cc.
The synthetic potential of this new reaction is broadened
by the ease with which the substitution products can be
converted into functionalized (Z)-γ-alkylidene-γ-butyro-
lactones through stereoselective cyclization.[12,13] An exam-
ple of this chemistry is shown in Scheme 4.
Experimental Section
Reagents and Methods: All of the reagents, catalysts, bases, solvents,
and eluents are commercially available and were used as purchased
without further purification. Propargylic ethyl carbonates were
prepared in 70–98% overall yield by Sonogashira cross-coupling of
aryl iodides with propargylic alcohols followed by reaction of the
isolated cross-coupling products with ethyl chlorocarbonate. Reac-
tion products were purified on axially compressed columns, packed
with SiO2 25–40 μm, connected to a solvent-delivery system and a
refractive-index detector, eluting with n-hexane/EtOAc mixtures.
1H (400.13 MHz), 13C (100.6 MHz) and 19F (376.5 MHz) NMR
spectra were recorded with a Bruker Avance 400 spectrometer.
Splitting patterns are designated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), or br. s (broad singlet). Mass
spectra were determined with a QP2010 Gas Chromatograph Mass
spectrometer (EI ion source). Infrared spectra were recorded with
a Jasco FTIR-430 spectrophotometer. Melting points were deter-
mined with a Büchi B-545 apparatus.
Typical Procedure for the Sonogashira Cross-coupling of Aryl Iod-
ides with Propargylic Alcohols: Preparation of 3-(m-Tolyl)prop-2-yn-
1-ol: PdCl2(PPh3)2 (0.017 mmol, 12.0 mg) was put into a flask
equipped with a magnetic stirrer bar, and a solution of CuI
(0.017 mmol, 3.2 mg) in diisopropylamine (1.8 mL) and N,N-di-
methylformamide (0.9 mL) was added. The resulting solution was
stirred under nitrogen at room temperature for 10 min, then a
solution of 3-iodotoluene (1.7 mmol, 372.8 mg) in N-ethyl-N-diiso-
propylamine (1.2 mL) was added, followed by 2-propyn-1-ol
(2.05 mmol, 115.0 mg, 119.4 μL). The reaction mixture was stirred
for 3 h at room temperature. After this time, the mixture was di-
luted with Et2O, washed with HCl (2 n), saturated NH4Cl solution,
and brine. The organic layer was separated, dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (n-hexane/EtOAc,
3:1) to give 3-(m-tolyl)prop-2-yn-1-ol (211.0 mg, 85%).
Typical Procedure for the Synthesis of Propargylic Carbonates (2):
Preparation of Ethyl 3-(m-Tolyl)prop-2-ynyl Carbonate: A solution
of 3-(m-tolyl)prop-2-yn-1-ol (1.44 mmol, 210.5 mg) in CH2Cl2
(3 mL) was put into a flask equipped with a magnetic stirrer bar,
and 4-(dimethylamino)pyridine (2.16 mmol, 263.9 mg) was added.
The resulting solution was stirred at –30 °C for 10 min, then ethyl
chloroformate (1.73 mmol, 186.8 mg, 164.6 μL) was added. The re-
action mixture was stirred for 30 min at –30 °C, and then for 1 h
at 0 °C. After this time, the reaction mixture was diluted with Et2O,
and washed with HCl (2 n), and with brine. The organic layer was
separated, dried with Na2SO4, filtered, and concentrated under re-
duced pressure to give 3-(m-tolyl)prop-2-ynyl carbonate (308 mg,
98%).
Scheme 4. The conversion of a substitution product into the corre-
sponding (Z)-γ-alkylidene-γ-butyrolactone.
Conclusions
In conclusion, a new palladium-catalyzed reaction of
propargylic carbonates with Meldrum’s acid derivatives has
been developed. This approach gives substitution products
in good to excellent yields. The new method tolerates a
variety of useful functional groups, including ester, keto,
ether, amido, and chloro substituents. Propargylic carb-
onates bearing a substituent at the propargylic carbon can
also be used successfully. The substitution products can be
valuable synthetic intermediates. For example, they can
easily be converted into (Z)-γ-alkylidene-γ-butyrolactones
through stereoselective gold-catalyzed cyclization. A more
detailed mechanistic evaluation of the factors influencing
the course of the reaction (phosphine ligands, nucleo-
philicity of soft carbon nucleophiles) and a greater evalu-
ation of the scope of the reaction are underway.
Typical Procedure for the Palladium-Catalyzed Reaction of Prop-
argylic Carbonates with Meldrum’s Acid Derivatives: Pd(OAc)2
(4.3 mg, 0.019 mmol), P(2-furyl)3 (17.6 mg, 0.076 mmol), and
anhydrous THF (1 mL) were put into a carousel reaction tube
(Radley Discovery). The resulting solution was stirred under argon
at room temperature for 10 min, and then a solution of ethyl 3-m-
tolylprop-2-ynyl carbonate (83.0 mg, 0.380 mmol) in THF (1 mL)
was added, followed by 2,2,5-trimethyl-1,3-dioxane-4,6-dione
(90.0 mg, 0.570 mmol). The reaction mixture was warmed at 80 °C
and stirred for 5 h. After cooling, the volatile materials were evapo-
rated at reduced pressure, and the residue was purified by
chromatography on silica gel (n-hexane/EtOAc, 85:15) to give 4d
(55.4 mg, 51%).
Supporting Information (see footnote on the first page of this arti-
cle): Typical procedures for the preparation of propargylic carb-
4
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Palladium-Catalyzed Nucleophilic Substitution
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The authors gratefully acknowledge the Ministero dell’Università
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Received: March 12, 2015
Published Online: ᭿
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I. Ambrogio, S. Cacchi, G. Fabrizi, A. Goggiamani, A. Iazzetti
FULL PAPER
Propargylic Substitution
I. Ambrogio, S. Cacchi, G. Fabrizi,
A. Goggiamani,* A. Iazzetti ............. 1–6
Palladium-Catalyzed Nucleophilic Substi-
tution of Propargylic Carbonates and Mel-
drum’s Acid Derivatives
Propargylic carbonates react with Meld-
rum’s acid derivatives in the presence of
Pd(OAc)2 and P(2-furyl)3 in THF at 80 °C
to give propargylic substitution products.
Keywords: Homogeneous catalysis / Pal-
ladium / Nucleophilic substitution / Alk-
ynes
6
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