Palladium NNC Pincer Complex as an Efficient Catalyst for the Cycloisomerization of Alkynoic Acids

Article abstract of DOI:10.1002/adsc.201600492

A two-step (nucleophilic substitution/palladation by oxidative addition) sequence provides a high-yielding access to a non-symmetrical palladium NNC pincer complex. A number of terminal and internal alkynoic acids with different substitution patterns at the α- and β-positions are regio- and diastereoselectively cycloisomerized to the corresponding exocyclic enol lactones in the presence of exceedingly low amounts of the latter palladium complex, so that unprecedented turnover numbers and frequencies ranging from 1,000,000 to 700,000 and from 41,667 to 9722 h^?1, respectively, are achieved. The optimized protocol, based on the use of a catalytic amount of triethylamine as base, allows an easy real-time monitoring of the reaction by NMR spectroscopy. Several pieces of evidence in favor of the direct participation of the above pincer complex as the catalyst of the reaction have been gathered from kinetic and poisoning experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.201600492

UPDATES
DOI: 10.1002/adsc.201600492
Palladium NNC Pincer Complex as an Efficient Catalyst for the
Cycloisomerization of Alkynoic Acids
Nerea Conde,a Raul SanMartin,a,* Marꢀa Teresa Herrero,a
and Esther Domꢀngueza,*
a
Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country (UPV/EHU),
Sarriena auzoa z/g, 48940 Leioa, Spain
Fax : (+34)-94-601-2748; e-mail: raul.sanmartin@ehu.es or esther.dominguez@ehu.es
Received: May 9, 2016; Revised: June 30, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600492.
Abstract: A two-step (nucleophilic substitution/pal-
ladation by oxidative addition) sequence provides
a high-yielding access to a non-symmetrical palladi-
um NNC pincer complex. A number of terminal
and internal alkynoic acids with different substitu-
tion patterns at the a- and b-positions are regio-
and diastereoselectively cycloisomerized to the cor-
responding exocyclic enol lactones in the presence
of exceedingly low amounts of the latter palladium
complex, so that unprecedented turnover numbers
and frequencies ranging from 1,000,000 to 700,000
and from 41,667 to 9722 hÀ1, respectively, are ach-
ieved. The optimized protocol, based on the use of
a catalytic amount of triethylamine as base, allows
an easy real-time monitoring of the reaction by
NMR spectroscopy. Several pieces of evidence in
favor of the direct participation of the above pincer
complex as the catalyst of the reaction have been
gathered from kinetic and poisoning experiments
The cycloisomerization reaction of g-alkynoic acids
is an extremely valuable transformation that provides
an easy and atom-economical entry to enol-lactones.
In recent years, a number of well-designed protocols
based on transition metals such as Rh,[10] Hg,[11] Ru,[12]
Ag,[13] Au,[14] Cu,[15] and Pd[16] have been developed
for the preparation of the g-alkylidenelactone motif.
However, most of these procedures require relatively
high catalyst loadings (10–0.01 mol%), prolonged re-
action times and/or elevated temperatures. The use of
more elaborated catalysts from specially designed li-
gands or complexes,[17,18] and heterogeneous scaf-
folds[19] has overcome the above limitations to some
extent. In this regard, it is worth mentioning the high
activity shown by pincer-type complexes in spite of
the few examples described to date.[18b–e]
Herein, we report the synthesis and characteriza-
tion of a new non-symmetrical palladium pincer NNC
that resulted to be an exceedingly efficient catalyst
for the intramolecular addition of carboxylic acids to
alkynes. In addition to the exceptionally low catalyst
loadings achieved, a number of experiments have
shed light on the role of the above palladacycle in this
advantageous route to diversely structured alkylidene-
lactones.
Keywords: alkynoic acids; cycloisomerization; lac-
tones; palladium; pincer complexes
As displayed in Table 1, complex 1 was synthesized
The enol lactone motif is present in several naturally from commercially available o-bromobenzyl chloride
occurring products, such as cyanobacterin,[1] freelin- 2 and pyrazolylpyridine 3. For the synthesis of the in-
gyne,[2] or eremofargurein A[3] and in a number of termediate ligand 4, a modification of the procedure
biologically active compounds.[4] In addition, the prep- for the alkylation of pyrazoles reported independently
aration of enol lactones continues to be actively pur- by the groups of Mukherjee and Bu[20] was tested,
sued due to the broad use of such heterocyclic struc- thus prolonging the heating of both substrates and
tures as synthetic intermediates,[5] and therefore sever- a phase-transfer catalyst [(n-Bu)4NOH] in a biphasic
al routes[6] towards g- or d-alkylidenelactones, classi- system (H2O/PhMe) for 48 h to provide regioselec-
fied into three main strategies (coupling reactions tively the intermediate bromo-derivative 4 in an ex-
with already formed lactones,[7] condensation reac- cellent yield (95%).
tions,[8] and electrophilic lactonizations, such as halo-
The insertion of palladium was carried out by an
lactonization and cycloisomerization[9]) have been de- oxidative addition process. In the first assays
veloped over the years.
Pd2(dba)3 was used as the palladium source, in tolu-
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Table 1. Synthesis of palladium pincer complex 1. Optimiza-
tion of the oxidative addition step.
Entry
Conditions (ii)
1 [%][a]
1
2
3
4
5
6
Pd2(dba)3, PhMe, 608C, 48 h
Pd2(dba)3, PhMe, r.t., 48 h
Pd(dba)2, THF, 1208C, 8 h
Pd(dba)2, THF, r.t., 48 h
Pd(dba)2, THF, 808C, 8 h
Pd(dba)2, THF, r.t., 5 days
–
–
88
42
65
82
Figure 1. Molecular structure of palladium pincer complex
1 with the atomic numbering scheme. Thermal ellipsoids are
given at the 50% probability level.
The cycloisomerization of 4-pentynoic acid 5a into
5-methylenedihydrofuran-2(3H)-one 6a was then ex-
plored in the presence of palladacycle 1. In order to
[a]
Isolated yields.
ene at room temperature and at 608C during 48 h. In facilitate the observation of target 6a in the reaction
none of the trials was the desired product obtained medium by 1H NMR, deuterated solvents were
(Table 1, entries 1 and 2). Therefore, we decided to chosen, and the initial catalyst loading and reaction
change both the source of Pd(0) and the solvent, thus concentration were set at 10À2 mol% and 0.1M, re-
reacting ortho-bromo derivative 4 with Pd(dba)2 in spectively.
tetrahydrofuran in a similar way as described by Xia
and co-workers for the formation of iminophosphinite ature, in the absence and in the presence of substoi-
palladium complexes.[21]
chiometric amounts of base (5 mol%) (Table 2, en-
The first experiments were assayed at room temper-
Process optimization by adjusting temperature and tries 1–6). Only the use of Et3N in CDCl3 provided
reaction times led to the isolation of target palladacy- enol lactone 6a with 27% yield (entry 4), so the latter
cle 1 in a good yield (entry 3), and although longer re- base and solvent were chosen for further studies.
action times were necessary to obtain similar yields, Temperature and reaction time were increased (en-
oxidative addition/coordination was also attained at tries 7 and 8), and the product was obtained with ex-
room temperature (entry 6). Thus, metal complex cellent yields in both cases. The required loading of
1 was prepared in just two steps with an overall yield Et3N was also investigated, and it was found that an
of 83%.
increase from 5 to 10 mol% caused a decline in the
1H NMR signals, slightly shifted downfield com- yield from 99% to 70%, thus indicating that relatively
À
pared to ligand 4, and the absence of Carom Br in high base concentrations had an inhibitory effect on
13C NMR were indicative of the formation of complex the reaction, while 2 mol% of Et3N was enough to get
1. The structure of palladacycle 1, determined by quantitative yields (entries 7, 8 and 10–12). Encour-
single crystal X-ray diffractometry (Figure 1), showed aged by this excellent result we decided to reduce the
a distortion from square planar geometry, probably catalyst loading (Table 2, entries 13–16). Even when
due to the uncommon combination of 5- and 6-mem- employing 10À4 mol% or 10À5 mol% of complex 1 the
bered rings in the metal coordination sphere.[22a]
desired lactone was obtained in quantitative yield, al-
Whereas the 5-membered ring containing pyridine though at the cost of longer reaction times or higher
and pyrazole heterocyclic moieties and Pd(II) core is temperatures, respectively (entries 14 and 16 vs.
almost flat, the planarity of the adjacent 6-membered entry 12). On account of a balance between the above
À
À
ring is far from ideal, as the meaningful N-3 N-2
factors (catalyst amount, temperature and reaction
À
À
À
À
Pd C-15 and C-9 C-10 C-15 Pd (6.4 and 9.28, re- time), the conditions displayed in Table 2, entry 14
spectively) torsion angles clearly reflect. Such a distor- were determined as optimal. The same result was ob-
tion can be also visualized by observation of bond tained when using CHCl3 as solvent.
À
À
À
À
angles C-15 Pd N-1 and N-2 Pd Br, which instead
It should be mentioned that the cycloisomerization
neither occurred in the absence of the pincer complex
of 1808, are 164.9 and 169.98, respectively.[22b]
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Table 2. Cycloisomerization of 4-pentynoic acid 5a in the presence of complex 1.[a]
Entry
Solvent
1 [mol%]
Base
T [8C]
t [h]
Conversion [%][b]
1
2
3
4
5
6
7
8
CDCl3
CD3COCD3
CDCl3
CDCl3
CD3COCD3
CDCl3
CDCl3
CDCl3
CH2Cl2
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À2
10À3
10À4
10À5
10À5
10À4
–
–
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
50
50
90
90
50
50
50
50
90
50
50
50
2
2
2
2
2
2
12
12
12
12
12
12
24
24
24
12
12
24
24
–
–
–
27
–
K2CO3 (5 mol%)
Et3N (5 mol%)
Et3N (5 mol%)
KO-t-Bu (5 mol%)
Et3N (5 mol%)
Et3N (5 mol%)
Et3N (5 mol%)
Et3N (2 mol%)
Et3N (10 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
Et3N (2 mol%)
–
99
99
11
99
70
99
99
99
83
99
72
–
9
10
11
12
13
14
15
16
17
18
19[c]
10À4
–
[a]
Reaction conditions: 4-pentynoic acid 5a (0.2 mmol), solvent (0.1M).
Conversion rate determined by H NMR spectroscopy.
Pd(OAc)2
[b]
[c]
1
1 nor in the presence of such small amounts of com- omatic 4-alkynoic acids 5h–l was also submitted to
mercially available palladium sources like Pd(OAc)2 the optimized reaction conditions to provide the cor-
(Table 2, entries 17 and 18). Moreover, the reaction responding benzo-, naphtho-, thieno- and pyridofura-
could be carried out in an air atmosphere without the none derivatives 6h–l in good to excellent yields (en-
requirement of inert conditions.
tries 8–12). TON and TOF values ranged from
Subsequently the scope of the reaction was exam- 1,000,000 to 700,000 and from 41,667 to 9722 hÀ1, re-
ined by submitting a series of commercial or readily spectively, the highest achieved so far for any metal
available acetylenic acids 5[23] to the optimized reac- catalyst.
tion conditions. As shown in Table 3, the reaction
With the purpose of gaining new insight into the
proved to be highly regioselective for 4-alkynoic acids catalytic profile observed for pincer complex 1,
5a–e and 5h–l assayed, affording the corresponding 5- a number of poisoning assays and kinetic studies were
exo-dig lactones.
carried out. The procedures reported by Finke and
Our protocol tolerated the presence of different Widegren serve to make a distinction between homo-
substituents at the a-position to the carboxy group geneous and heterogenous catalysis.[24,25] Indeed, het-
(Table 3, entries 2–4), although higher temperatures erogeneous catalysts expose only a fraction of the
were required when a long n-hexyl chain was attached active metal atoms in their surface, so the addition of
at that position (entry 2). A complete regiocontrol certain additives in substoichiometric amounts is
was also achieved from intrinsically challenging sub- enough to poison (partially or totally) the catalyst. In
strates such as internal alkynes, 3-alkynoic and 5-alky- contrast, homogeneous catalysts are unaffected by
noic acids (Table 3, entries 5–7). For lactones 6f–6g an such amounts.[24] In this context, it is also known that
increase of the temperature was required (908C) to mercury metal has an ability to poison metal(0) parti-
get full conversion to 5-endo-dig and 6-exo-dig prod- cles, both by amalgamating the metal or adsorbing on
ucts, respectively. We should also mention the com- the metal surface.[25] As shown in Table 4 (entry 1),
plete diastereoselectivity in the transformation of 5- when a drop of mercury was added to the reaction
phenylpent-4-ynoic acid 5e into (Z)-benzylidenedihy- mixture, the desired product 6a was still obtained in
drofuranone 6e. A set of rigid aromatic and heteroar- excellent yield (negative mercury drop test). With
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Table 3. Cycloisomerization of alkynoic acids 5 in the presence of palladium complex 1.[a]
[a]
Reaction conditions: alkynoic acid 5 (0.2 mmol),palladium complex 1 (10À4 mol%), Et3N (2 mol%),
CDCl3 (2 mL).
Isolated yields.
[b]
[c]
1
Determined by H NMR spectroscopy. 3,4,5-Trichloropyridine was used as internal standard.
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Table 4. Summary of poisoning experiments.
The shape of the observed kinetic curve, with no in-
duction period,[27] also indicated the participation of
homogeneous catalytic species other than colloidal
palladium clusters or nanoparticles formed by decom-
position of the organometallic complex.
Finally, the reaction was carried out with a high cat-
alyst loading (1 mol%) in order to verify that the cat-
alyst 1 did not disintegrate or undergo degradation
during the cycloisomerization process. After 3 h the
reaction was stopped and the crude mixture was
evaporated under vacuum. The residue was analyzed
Entry
Poisoning additive
6a [%][a]
1
2
3
4
Hg (one drop)
99
99
97
99
99
98
99
99
CS2 (0.5 equiv. per metal atom)
CS2 (2.0 equiv. per metal atom)
PPh3 (0.03 equiv. per metal atom)
PPh3 (0. 3 equiv. per metal atom)
PPh3 (4.0 equiv. per metal atom)
Py (150 equiv. per metal atom)
PVPy (300 equiv. per metal atom)
1
by H NMR, showing that the pincer complex 1 re-
mained intact. This fact, in addition to providing
more proof of the role of 1 as a true catalyst, opens
further possibilities for a potential recycling protocol.
To sum up, an extremely efficient procedure for the
cycloisomerization of acetylenic acids to the corre-
sponding enol lactones under relatively mild reaction
conditions has been developed, using infinitesimal
amounts of a new non-symmetrical palladium pincer
complex as the catalyst and a catalytic loading of trie-
thylamine as base. This method tolerates the presence
5
6
7[b]
8[c]
[a]
Determined by 1H NMR. 3,4,5-Trichloropyridine was
used as internal standard.
Py=pyridine.
[b]
[c]
PVPy=polyvinylpyridine.
regard to the addition of other poisoning additives in of different substitution patterns on both a- and b-po-
sub- and overstoichiometric amounts, the yields for sitions of the alkynoic acid. Furthermore, the reac-
the cycloisomerization in the presence of CS2 and tions were found to be highly regioselective, resulting
PPh3 were unchanged regardless of the amount of ad- in selective formation of the exo-dig products and, for
ditive added, as displayed in Table 4, entries 2–6.
internal g-alkynes, the Z-alkene was steroselectively
These results provide evidence for the participation obtained. The direct participation of the readily avail-
of homogeneous catalytic species, a proposal support- able NNC palladium complex as the catalyst is evi-
ed by the behavior observed in the presence of pyri- denced by several kinetic and poisoning experiments
dine and polyvinylpyridine (PVPy). Once again no and NMR monitoring techniques.
changes were observed in the reaction after adding
overstoichiometric amounts of these additives (en-
tries 7 and 8), known for their application to detect
participation of Pd(0) colloids and soluble Pd species
Experimental Section
prone to temporarily coordinate with pyridine and
General Information
therefore to get trapped in the insoluble anchored
PVPy.[26]
Commercially available reagents were used throughout
without purification unless otherwise stated. 1H and
On account of the extremely low amount of the cat-
13C NMR spectra were recorded on a Bruker AC-300 instru-
alyst employed, a convenient NMR monitoring of the
1
ment (300 MHz for H and 75.4 MHz for 13C) at 208C.
reaction was also possible by recording 1H NMR spec-
Chemical shifts (d) are given in ppm downfield from
tra at regular intervals for 24 h (represented as
Me4Si and are referenced as internal standard to the residu-
a stacked plot, Figure 2). The transformation of 4-
1
al solvent (unless indicated) CDCl3 (d=7.26 for H and d=
77.00 for 13C). Coupling constants, J, are reported in hertz
(Hz). Melting points were determined in a capillary tube
and are uncorrected. TLC was carried out on SiO2 (silica gel
pentynoic acid 5a into 5-methylenedihydrofuran-
2(3H)-one 6a can be easily monitored by observing
the decrease of the signal corresponding to the acety-
lenic proton and the rise of the signals belonging to 60 F254, Merck), and the spots were located with UV light.
Flash chromatography was carried out on SiO2 (silica gel 60,
Merck, 230–400 mesh ASTM). IR spectra were recorded on
Perkin–Elmer 1600 FT and JASCO FTIR-4100 infrared
spectrophotometers as thin films, and only noteworthy ab-
sorptions are reported in cmÀ1. Drying of organic extracts
during work-up of reactions was performed over anhydrous
Na2SO4. Evaporation of solvents was accomplished with
a Bꢃchi rotatory evaporator. Mass spectra were recorded on
an Agilent 5975 mass spectrometer under electronic impact
(EI) conditions. HR-mass spectra were recorded using
a Waters GCT mass spectrometer. Intensity data were col-
the alkene moiety. No intermediates or other species
were detected, and as shown in Figure 2, the reaction
was almost finished in 6 h.
1
Furthermore, integration of the above H NMR sig-
nals at different reaction times allowed a very easy
conversion rate vs. time plot (Figure 3). According to
the latter data, the reported cycloisomerization is
a first-order reaction in pentynoic acid, with a rate
constant k=9.3ꢂ10À3 sÀ1.
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1
Figure 2. Stacked plot of the time-dependent H NMR spectra for the cycloisomerization of 4-pentynoic acid 5a in the pres-
ence of non-symmetrical pincer complex 1.
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tered through a plug of celite. The filtrate was evaporated
under reduced pressure and the crude was purified by flash
chromatography with a gradient starting at hexanes:EtOAc
(1:1) and ending at 100% EtOAc. Complex 1 was obtained
as an orange powder; yield: 191 mg (88%); mp 142–1448C
1
(hexanes:EtOAc). H NMR (CDCl3): d=9.1 (d, J=5.3 Hz,
1H), 8.41 (d, J=2.8 Hz, 1H), 7.83 (td, J=9.3, 1.6 Hz, 1H),
7.65 (d, J=5.1 Hz, 2H), 7.32 ( m, 1H), 7.00–6.89 (m, 3H),
6.71 (d, J=5.3 Hz, 1H), 5.31 (s, 2H); 13C NMR (CDCl3): d=
151.2, 150.8, 149.2, 143.1, 138.9, 135.6, 132.4, 131.5, 127.3,
127.0, 124.6, 124.5, 120.4, 104.9, 60.6; HR-MS: m/z=
340.00613 [M]+, calcd. for C15H12N3Pd: 340.00665.
General Procedure for the Cycloisomerization of
Alkynoic Acids 5 in the Presence of Complex 1
Figure 3. Conversion rate (%) of 4-pentynoic acid 5a vs.
time.
The alkynoic acid 5 (0.2 mmol), triethylamine (25 mL of
a 0.16M solution in CHCl3, 4ꢂ10À3 mmol), palladacycle
1 (50 mL of a 4ꢂ10À6 M solution in CHCl3, 2ꢂ10À7 mmol)
and CDCl3 (2 mL) were placed in a screw-capped tube and
heated in an oil bath at the indicated temperature for an ap-
propriate time. The reaction mixture was subsequently fil-
tered through a short plug of silica gel to remove triethyl-
lected on an Agilent Technologies Super-Nova diffractome-
ter, which was equipped with monochromatic Cu ka radia-
tion (l=1.54184 ꢄ) and Atlas CCD detector. Measurement
was carried out at 100(2) K with the help of an Oxford
Cryostream 700 PLUS temperature device. Data frames
were processed (united cell determination, analytical ab-
sorption correction with face indexing, intensity data inte-
gration and correction for Lorentz and polarization effects)
using the Crysalis software package. The structure was
solved using Olex22 and refined by full-matrix least-squares
with SHELXL-97.3 Final geometrical calculations were car-
ried out with Mercury4. and PLATON5 as integrated in
WinGX.
AHCTUNGTREGaNNUN mine, thus providing pure lactone 6, or alternatively, puri-
fied by flash column chromatography using hexanes:EtOAc
(7:3) in the referred cases. The progress of the reaction was
1
monitored by H NMR.
5-Methylenedihydrofuran-2(3H)-one (6a):[19a] The general
procedure for cycloisomerization was followed, and the re-
action mixture was heated at 508C for 24 h. Due to the vola-
tility of the product, initial NMR yields (using 3,4,5-
trichloroACTHNUTRGENUGpN yridine was as internal standard) were determined
from the crude. Special care was taken for the vacuum evap-
Synthesis of the Palladium Pincer NNC
oration of the solvent. Compound 6a was obtained as a col-
1
2-[1-(2-Bromobenzyl)-1H-pyrazol-3-yl]pyridine
a round-bottom flask 2-bromobenzyl chloride 2 (0.29 mL,
2.28 mmol), 2-(1H-pyrazol-3-yl)pyridine (333 mg,
(4):
In
orless oil; yield: 19.1 mg (94%). H NMR (CDCl3): d=4.75
(dd, J=4.2, 2.0 Hz, 1H), 4.31 (dd, J=4.2, 2.0 Hz, 1H), 2.93–
2.83 (m, 2H), 2.72–2.63 (m, 2H); 13C NMR (CDCl3): d=
175.0, 155.6, 88.7, 28.0, 25.1.
3
2.23 mmol), 3.5 mL of a 40% aqueous solution of NaOH,
and 165 mL of a 40% aqueous solution of (n-Bu)4OH were
dissolved in toluene (27 mL) at room temperature under an
argon atmosphere. The mixture was heated to 1208C for
48 h. After cooling the reaction mixture was washed with
H2O (3ꢂ5 mL) and the aqueous layer was extracted with di-
ethyl ether (3ꢂ5 mL). The organic layers were combined
and dried over anhydrous Na2SO4 and the solvent was re-
moved under reduced pressure. The crude oil was purified
by flash column chromatography using hexanes:EtOAc
(6:4) as eluent to afford pure product 4 as a yellow powder;
yield: 682 mg (95%); mp 62–658C (hexanes/EtOAc).
1H NMR (CDCl3): d=8.61 (d, J=4.7 Hz, 1H), 7.93 (d, J=
7.9 Hz, 1H), 7.66 (td, J=7.8, 1.7 Hz, 1H), 7.55 (d, J=
7.8 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H, H-8), 7.28–7.06 (m,
3H), 6.93 (d, J=2.4 Hz, 2H), 5.46 (s, 2H); 13C NMR
(CDCl3): d=151.9, 151.8, 149.2, 136.3, 135.8, 132.5, 131.3,
129.2, 129.0, 127.6, 122.4, 122.0, 119.8, 104.6, 55.7; HR-MS
(m/z): m/z=313.0209 [M]+, calcd. for C15H12N3Br: 131.0215.
(2-{1-[(Phenyl-kC2)-methyl]-1H-pyrazol-3-yl-kN2]-pyri-
dine-kN-palladium(II) bromide (1): In a round-bottom flask
pyrazole 1 (200 mg, 0.63 mmol) was dissolved in 15 mL of
THF under an argon atmosphere and then added to previ-
ously dried Pd(dba)2 (400 mg, 0.69 mmol). The reaction mix-
ture was heated to 1208C for 8 h. After cooling it was fil-
4-Hexyl-5-methylenedihydrofuran-2(3H)-one (6b):[19a] The
general procedure for cycloisomerization was followed, and
the reaction mixture was heated at 708C for 24 h. Com-
pound 6b was obtained as a colorless oil; yield: 32.1 mg
1
(88%). H NMR (CDCl3): d=4.71 (dd, J=3.9, 2.0 Hz, 1H),
4.30 (dd, J=3.9, 2.0 Hz, 1H), 2.99 (dd, J=15.9, 9.6 Hz, 1H),
2.74 (ddd, J=14.1, 8.7, 4.9 Hz, 1H), 2.54 (ddt, J=15.9, 7.7,
2.1 Hz, 1H), 1.94–1.77 (m, 1H), 1.59–1.44 (m, 1H), 1.43–
1.21 (m, 8H), 0.88 (t, J=6.6 Hz, 3H); 13C NMR (CDCl3):
d=177.2, 154.5, 88.6, 39.9, 31.6, 31.5, 30.9, 28.9, 26.9, 22.5,
14.0.
3-Methylene-2-oxaspiro[4.5]decan-1-one (6c):[28] The gen-
eral procedure for cycloisomerization was followed, and the
reaction mixture was heated at 508C for 24 h. Compound 6c
was obtained as a colorless oil; yield: 32.4 mg (97%).
1H NMR (CDCl3): d=4.72 (dd, J=4.1, 2.0 Hz, 1H), 4.31
(dd, J=4.1, 2.0 Hz, 1H), 2.73 (t, J=1.7 Hz, 2H), 1.83–1.68
(m, 4H), 1.68–1.50 (m, 3H), 1.43–1.20 (m, 3H); 13C NMR
(CDCl3): d=179.7, 153.8, 88.9, 44.7, 37.2, 32.8, 25.1, 22.0.
Methyl 5-methylene-2-oxotetrahydrofuran-3-carboxylate
(6d):[19a] The general procedure for cycloisomerization was
followed, and the reaction mixture was heated at 508C for
24 h. Compound 6d was obtained as a colorless oil; yield:
26.0 mg (85%). 1H NMR (300 MHz, CDCl3): d=4.82 (dd,
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J=4.5, 2.3 Hz, 1H), 4.41 (dd, J=4.4, 1.8 Hz), 3.83 (s, 3H),
3.76 (dd, J=10.4, 7.6 Hz, 1H), 3.31 (ddt, J=16.6, 7.6,
2.1 Hz, 1H), 3.09 (ddt, J=16.6, 10.4, 1.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=169.5, 167.3, 153.1, 89.9, 53.4, 46.2,
29.3.
4.9 Hz, 1H), 7.25 (d, J=4.9 Hz, 1H), 5.17 (d, J=3.1 Hz,
1H), 5.00 (d, J=3.1 Hz, 1H); 13C NMR (CDCl3): d=161.2,
153.2, 149.1, 140.6, 130.2, 118.9, 92.60; IR (ATR): nmax
=
;
3091, 2951, 2922, 2915, 1763, 1662, 1289, 991, 941, 776 cmÀ1
HR-MS: m/z=153.0004 [M+H]+, calcd. for C7H5O2S:
153.0010.
(Z)-5-Benzylidenedihydrofuran-2(3H)-one (6e):[19a] The
general procedure for cycloisomerization was followed, and
the reaction mixture was heated at 508C for 72 h. Com-
pound 6e was obtained as a white powder after purification
by flash chromatography; yield: 24.4 mg (70%); mp 88–
3-Methylenefuro[3,4-c]pyridin-1(3H)-o (6k): The general
procedure for cycloisomerization was followed, and the re-
action mixture was heated at 508C for 24 h. Compound 6k
was obtained as a white powder; yield: 27.9 mg (95%); mp
1
1
918C (CHCl3)(Lit.[29] 91–938C). H NMR (CDCl3): d=7.55
99–1028C (CHCl3). H NMR (CDCl3): d=9.17 (s, 1H), 8.89
(d, J=5.0 Hz, 1H), 7.80 (d, J=5.0 Hz, 1H), 5.41 (s, 2H);
13C NMR (CDCl3): d=165.2, 150.7, 149.8, 143.8, 133.2,
130.0, 118.2, 93.9; IR (ATR): nmax =3105, 3001, 2930, 2847,
1788, 1432, 1285, 1001, 951, 682 cmÀ1; HR-MS: m/z=
148.0389 [M+H]+, calcd. for C8H6NO2: 148.0399.
5-Methylenefuro[3,4-b]pyridin-7(5H)-one (6l): The gener-
al procedure for cycloisomerization was followed, and the
reaction mixture was heated at 508C for 24 h. Compound 6l
was obtained as a white powder; 27.4 mg (93%); mp 129–
1328C (CHCl3). 1H NMR (CDCl3): d=8.93 (dd, J=4.7,
1.3 Hz, 1H), 8.09 (dd, J=8.0, 1.3 Hz, 1H), 7.63 (dd, J=8.0,
4.7 Hz, 1H), 5.44–5.36 (m, 1H), 5.36–5.27 (m, 1H);
13C NMR (CDCl3): d=164.3, 153.5, 149.2, 143.7, 133.5,
129.0, 127.7, 94.2; IR (ATR): nmax =2962, 2919, 2875, 2851,
1784, 1257, 1095, 1009, 811, 689 cmÀ1; HR-MS: m/z=
148.0391 [M+H]+, calcd. for C8H6NO2: 148.0396.
(d, J=7.4 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.21 (t, J=
7.3 Hz, 1H), 5.55 (s, 1H), 3.12–2.93 (m, 2H), 2.81–2.62 (m,
2H); 13C NMR (CDCl3): d=174.9, 148.1, 133.9, 128.5, 128.3,
126.7, 104.9, 27.0, 26.3;.
5-Methylfuran-2(3H)-one (6f):[18b] The general procedure
for cycloisomerization was followed, and the reaction mix-
ture was heated at 908C for 24 h. Due to the volatility of
the product, initial NMR yields (using 3,4,5-trichloropyri-
dine was as internal standard) were determined from the
crude. Special care was taken for the vacuum evaporation of
the solvent. Compound 6f was obtained as a colorless oil;
1
yield: 19.3 mg (93%). H NMR (CDCl3): d=5.11 (td, J=3.3,
2.0 Hz, 1H,), 3.20–3.09 (m, 2H,), 1.99 (d, J=2.0, 3H);
13C NMR (CDCl3): d=176.9, 153.3, 99.0, 34.1, 14.0.
6-Methylenetetrahydro-2H-pyran-2-one (6g):[19a] The gen-
eral procedure for cycloisomerization was followed, and the
reaction mixture was heated at 908C for 24 h. Due to the
volatility of the product, initial NMR yields (using 3,4,5-tri-
chloropyridine was as internal standard) were determined
from the crude. Special care was taken for the vacuum evap-
oration of the solvent. Compound 6g was obtained as a col-
Acknowledgements
1
This research was supported by the Basque Government (IT-
774-13), the Spanish Ministry of Economy and Competitive-
ness (CTQ2013-46970-P) and the University of the Basque
Country (UFI QOSYC 11/12). N.C. thanks the Basque Gov-
ernment for a predoctoral scholarship. The authors also
thank Petronor, S.A. for generous donation of hexane. Final-
ly, technical and human support provided by SGIker of
UPV/EHU is gratefully acknowledged.
orless oil; yield: 23.9 mg (95%). H NMR (CDCl3): d=4.64
(s, 1H), 4.29 (s, 1H), 2.63 (t, J=6.8 Hz, 2H), 2.48 (t, J=
6.5 Hz, 2H), 1.93–1.81 (m, 2H); 13C NMR (CDCl3): d=
168.1, 155.3, 93.7, 30.3, 26.7, 18.6.
3-Methyleneisobenzofuran-1(3H)-one (6h):[18b] The gener-
al procedure for cycloisomerization was followed, and the
reaction mixture was heated at 508C for 24 h. Compound 6h
was obtained as a white powder; yield: 30 mg (94%); mp
1
50–538C (CHCl3)(Lit.[30] 55–578C). H NMR (CD3OD): d=
7.90 (t, J=7.5 Hz, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.79 (td, J=
7.5, 1.1 Hz, 1H), 7.64 (td, J=7.4, 1.0 Hz, 1H), 5.40 (d, J=
3.0 Hz, 1H), 5.22 (d, J=3.0 Hz, 1H); 13C NMR (CD3OD):
d=166.9, 152.0, 138.9, 134.6, 130.4, 124.6, 124.5, 120.7, 90.4.
1-Methylenenaphtho[1,2-c]furan-3(1H)-one (6i): The gen-
eral procedure for cycloisomerization was followed, and the
reaction mixture was heated at 508C for 24 h. Compound 6i
was obtained as a white powder after purification by flash
chromatography; yield: 29.8 mg (76%); mp 90–938C
(CHCl3). 1H NMR (CDCl3): d=8.37–8.25 (m, 1H), 8.06–
7.94 (m, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.78–7.65 (m, 2H),
5.71 (d, J=3.3 Hz, 1H), 5.57 (d, J=3.3 Hz, 1H); 13C NMR
(CDCl3): d=167.1, 152.5, 136.6, 136.0, 132.2, 129.9, 128.9,
128.8, 126.9, 124.7, 124.1, 120.0, 96.7; IR (ATR): nmax =3619,
2965, 2926, 2857, 1759, 1289, 1063, 991, 962, 754 cmÀ1; HR-
MS: m/z=197.0596 [M+H]+, calcd. for C13H9O2: 197.0603.
4-Methylenethieno[2,3-c]furan-6(4H)-one (6j): The gener-
al procedure for cycloisomerization was followed, and the
reaction mixture was heated at 908C for 24 h. Compound 6j
was obtained as an orange powder; yield: 30 mg (98%);
m.p. 85–888C (CHCl3). 1H NMR (CDCl3): d=7.48 (d, J=
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Palladium NNC Pincer Complex as an Efficient Catalyst for
the Cycloisomerization of Alkynoic Acids
11
Adv. Synth. Catal. 2016, 358, 1 – 11
Nerea Conde, Raul SanMartin,* Marꢀa Teresa Herrero,
Esther Domꢀnguez*
Adv. Synth. Catal. 0000, 000, 0 – 0
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