Efficient Synthesis of Unsaturated δ- and ε-Lactones/Lactams by Catalytic Cycloisomerization: When Pt Outperforms Pd

Article abstract of DOI:10.1002/adsc.201600382

Platinum pincer complexes featuring an SCS indenediide backbone have been prepared and evaluated in the catalytic cycloisomerization of alkynoic acids and N-tosyl alkynylamides. One of the platinum complexes significantly outperforms its palladium analogue for the formation of 6- and 7-membered rings. The catalytic system takes advantage of the alkynophilicity of Pt and of the non-innocent character of the indenediide framework. Like for Pd, the catalytic performance is significantly improved by using an H-bond donor additive such as pyrogallol. For the first time, a large variety of ω-unsaturated δ- and ε-lactones/lactams could be prepared with high selectivities and in very good yields. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600382

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DOI: 10.1002/adsc.201600382
Efficient Synthesis of Unsaturated d- and e-Lactones/Lactams by
Catalytic Cycloisomerization: When Pt Outperforms Pd
Diandian Ke,a,b Noel ꢀngel Espinosa,a,b Sonia Mallet-Ladeira,c Julien Monot,a,b
Blanca Martin-Vaca,a,b,* and Didier Bourissoua,b,*
a
Universitꢁ de Toulouse, UPS, 118 route de Narbonne, F-31062 Toulouse, France and CNRS, LHFA UMR5069, F-31062
Toulouse, France
E-mail: bmv@chimie.ups-tlse.fr or dbouriss@chimie.ups-tlse.fr
CNRS, LHFA UMR5069, F-31062 Toulouse, France
Universitꢁ de Toulouse, UPS, Institut de Chimie de Toulouse, FR2599, 118 Route de Narbonne, F-31062 Toulouse, France
b
c
Received: April 15, 2016; Revised: May 12, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600382.
Abstract: Platinum pincer complexes featuring an the catalytic performance is significantly improved
SCS indenediide backbone have been prepared and by using an H-bond donor additive such as pyrogal-
evaluated in the catalytic cycloisomerization of alky- lol. For the first time, a large variety of w-unsaturat-
noic acids and N-tosyl alkynylamides. One of the ed d- and e-lactones/lactams could be prepared with
platinum complexes significantly outperforms its pal- high selectivities and in very good yields.
ladium analogue for the formation of 6- and 7-mem-
bered rings. The catalytic system takes advantage of
the alkynophilicity of Pt and of the non-innocent Keywords: cyclization; lactams; lactones; pincer
character of the indenediide framework. Like for Pd, complexes; platinum
Introduction
bered rings is even more difficult and examples of e-
lactone/lactam preparations are extremely scarce.[7]
As part of our ongoing research on 1,3-bis(thio-
Lactones and lactams are widespread motifs in natu-
ral and pharmaceutical products as well as useful phosphinoyl)indenediide (SCS indenediide) pincer
building blocks for synthesis.[1,2] Their preparation is complexes,[9] we discovered recently that Pd com-
thus an important challenge and over the last decades, plexes thereof are good cycloisomerization catalysts
numerous studies have been performed in this direc- (Figure 1).[10] Thanks to metal-ligand cooperation, g-
tion, making use of electrophilic reagents,[3] organic lactones and lactams were prepared under mild condi-
acids/bases[4] or transition metals.[5–8] Among the syn- tions with high functional group tolerance and with-
thetic routes to lactones and lactams, the cyclization out the need of an external base. In addition, 6- and
of alkynoic acids and alkynylamides is very appealing. even 7-membered rings could be isolated in moderate
It is fully atom-economic and gives straightforward
access to w-unsaturated products which are interest-
ing in their own right and can be readily derivatized.
Such cycloisomerization reactions have been exten-
sively studied and catalysts based on Pd, Rh, Ru, Au
etc. have been shown to be very powerful for the syn-
thesis of 5-membered rings, namely g-lactones and
lactams.[5] However, no general and efficient method
is known so far for the preparation of 6 and 7-mem-
bered rings. A few d-lactones/lactams have been pre-
pared by cycloisomerization, but the scope is rather
limited and the Thorpe–Ingold effect is generally
Figure 1. General structure of Pd indenediide complexes;
cycloisomerization of alkynoic acids and N-tosylalkynyl-
used to favour cyclization.[6] The formation of 7-mem-
AHCTUNGTERGaNNUN mides (exo and endo products).
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to good yields (~50–90%) using high temperatures
(90–1208C) and prolonged reaction times (10–120 h).
Later on, thanks to a detailed experimental-computa-
tional mechanistic study, the catalytic efficiency of the
Pd indenediide complexes was greatly enhanced by
the use of catechols as additives.[11] The impact of
these H-bond donors was particularly prominent on
challenging substrates bearing internal alkynes. The
catalytic activity was increased by up to 60-fold and 6-
endo was favoured over 5-exo cyclization.
Despite these advances, the formation of 6-mem-
bered rings from internal alkynes and the preparation
of 7-membered rings remain very challenging. Im-
provements are also highly desirable on exo/endo se-
lectivity. To these ends, we became interested in re-
placing Pd for Pt. So far, platinum has scarcely been
used to catalyze the cyclization of alkynoic acids and
related amides.[12] But its ability to activate carbon-
carbon multiple bonds (alkynes, alkenes and allenes)
is well-known[13] and, in particular, PtCl2 proved very
efficient in the skeletal rearrangement of enynes.[14,15]
In this work, SCS indenediide Pt complexes were pre-
pared and applied to the cycloisomerization of chal-
lenging alkynoic acids and related N-tosylamides. Ac-
cordingly, for the first time, a large variety of d and e-
lactones/lactams could be prepared with high selectiv-
ities and in very good yields.
Scheme 1. Synthesis of Pt indenediide complexes III–IV.
Results and Discussion
The targeted platinum indenediide complexes were
synthesized in two steps starting from the bis(thio-
phosphinoyle) pro-ligands Ia, b (Scheme 1). The in-
À
denyl complexes IIa, b were first formed by C H acti-
vation and then deprotonated. Using sodium acetate
in toluene at 908C, the neutral dimeric/trimeric com-
plexes IIIa, b were obtained in pure form and good
yield (IIIa: 78% and IIIb: 87%). Furthermore, the
chloro platinate complexes IVa, b were prepared
using polystyrene-supported DIEA (diisopropylethyl-
amine) in the presence of tetrabutylammonium chlo-
ride (IVa: 88% and IVb: 84%).
The structures of all complexes were unambiguous-
1
ly ascertained by 31P, H and 13C NMR spectrosco-
py.[16] Most diagnostic are the 13C NMR signals for the
central carbon atom of the SCS pincer which appear
slightly upfield compared to those of the related Pd
complexes (by ~10 ppm) with the expected multiplici-
Figure 2. Ellipsoid drawing (50% probability level) of the
molecular structure of IVa. For the sake of clarity, lattice
solvent molecules, hydrogen atoms, and the tetrabutylam-
monium counter-cation were omitted; the phenyl groups at
phosphorus were also simplified. Selected bond lengths [ꢃ]:
À
ty (t or dd due to P C coupling). In addition, com-
À
À
À
À
C2 Pt 1.977(7), S1 Pt 2.308(2), S2 Pt 2.310(2), Pt Cl
plexes IIb, IIIa and IVa were characterized by X-ray
diffraction (see Figure 2 for an ellipsoid drawing of
IVa).[16,17] In all cases, the SCS ligand forms a quasi-
À
À
2.402(2), C1 C2 1.428(10), C2 C3 1.395(10).
perfect square-planar pincer complex (SPtS=174– of Pt and Pd (covalent radii of 1.36 and 1.39 ꢃ, re-
1788) and the Pt center deviates only marginally from spectively),[18] the geometric features of the Pt com-
the indenyl/indenediide plane (by less than 0.5 ꢃ, in- plexes are quasi-identical to those of the correspond-
plane coordination). In line with the very similar sizes ing Pd complexes.
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A rapid evaluation of the catalytic performances sought to reduce the catalytic loading. Using 1, or
was first based on the cycloisomerization of 5-hexyno- even only 0.2 mol% of Pt, the cycloisomerization
ic acid 1a to discriminate between the four complexes went to completion in 3 and 18 h, respectively (en-
III–IV (Suppoprting Information, Table S4).[16] The tries 6 and 7), demonstrating the robustness of the Pt
best results were obtained with the platinum dimer complex. The same study was carried out for the con-
IIIb. Complete conversion was achieved within 3 h at version of 1a into 2a. The catalytic loading was pro-
508C in chloroform at 1 mol% Pt loading (Table 1), gressively lowered down to 500 ppm of Pt and the re-
which represents a significant improvement over the action temperature was increased from 50 to 908C,
related Pd dimer V (10 h at 908C and 5 mol% Pd without a detrimental effect on the performance:
were required in this case).[10b] Complex IIIb was se- complete conversion within 12 h, corresponding to
lected for the rest of the study. The very good result turnover number (TON) and turnover frequency
obtained with 5-hexynoic acid 1a encouraged us to (TOF) of 2000 and 167 hÀ1, respectively (entry 3).
test the cyclization of the related N-tosylamide 1b
To substantiate the contribution of the indenediide
which is notoriously more challenging. A slight in- ligand, the catalytic activity of IIIb was compared to
crease of the reaction temperature (from 50 to 908C) those of its precursors.[16] In the presence of
enabled us to achieve complete conversion within [PtCl2(ethylene)2], the alkylidene lactone 2a forms
25 min with IIIb (5 mol% of Pt, entry 5). The forma- but rapidly degrades into a mixture of unidentified
tion of the alkylidene lactam 2b is much faster (~30 products. In the case of the alkynylamide 1b, no reac-
times) with IIIb than with the Pd complex V (which tion occurred after heating for 24 h at 908C (Support-
required 12 h of reaction under the same conditions, ing Information, Table S5).[16] As for the indenyl com-
entry 4).[10b] Given the very high activity of IIIb, we plex IIb, very low conversions of 1a and 1b (traces)
were observed even after prolonged reaction times
(24 h). The cyclizations of 1a, b catalyzed by IIIb
were monitored by 31P NMR: a clean indenyl species
Table 1. Evaluation of the catalytic properties of the indene-
is observed during the transformation and the indene-
diide complex IIIb is regenerated at the end of the re-
action (Supporting Information, Figures S1 and S2).[16]
Altogether, these results support an active participa-
tion of the indenediide ligand and metal-ligand coop-
erativity (activation of the acid/amide pronucleophile
diide Pt complex IIIb in the cyclization of 1a–d.
ꢀ
by deprotonation, activation of the C C triple bond
by side-on coordination to Pt), in line with what we
reported previously for Pd species.[10,11]
The influence of the ring size was then studied. In
contrast with what was observed for the d-lactone and
lactam 2a, b, Pt does not outperform Pd for the for-
mation of 5-membered rings. The cyclization of penty-
noic acid 1c proceeds equally well with IIIb as with V
(30 min at 258C, Table 1, entries 8 and 9), but com-
plete conversion of the corresponding N-tosylamide is
much slower with IIIb than with V (1 h vs. 10 min at
608C, entries 10 and 11). On the other side, the Pt
dimer IIIb proved much more active than its Pd ana-
logue V for the formation of 7-membered rings
(Table 2). The first tests were performed with the sim-
plest substrates 1e and 1f, whose flexible unsubstitut-
ed backbones make the cyclization all the more chal-
lenging. Using IIIb (1 mol% of Pt), 6-heptynoic acid
1e was completely consumed after only 21 h at 908C.
The corresponding alkylidene e-lactone 2e was ob-
tained in pure form and very good yield (84%) after
distillation.[19] This outcome represents a significant
improvement of the result we recently reported with
the Pd complex V (51% isolated yield after 22 h at
1208C using 5 mol% of Pd),[10b] which was at that
time the most efficient system to cyclize 1e into
2e.[6b,e,7a,d] The Pt complex IIIb also gave excellent re-
Entry Sub. Cat. (mol% [M]) T [8C] t [h] Conv. [%][b]
1
2
3
4
5
6
7
8
1a
V (5)
90
50
90
90
90
90
90
25
25
60
60
10
3
12
12
0.4
3
18
0.5
0.5
>99
97
IIIb (1)
IIIb (0.05)
V (5)
IIIb (5)
IIIb (1)
IIIb (0.2)
V (5)
IIIb (5)
V (5)
IIIb (5)
>99[c]
>99 (98)
>99
1b
>99[c]
>99[d]
>99
1c
9
10
11
>99
1d
0.16 >99 (98)
>99 (88)
1
[a]
Catalytic reactions performed under argon atmosphere
using 0.1 mmol of substrate (0.14M in CDCl3).
Conversions were determined by H NMR analysis. Iso-
[b]
1
lated yields are given in brackets.
Substrate concentration of 2M.
Substrate concentration of 0.83M.
[c]
[d]
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Table 2. Scope of the cycloisomerization of alkynoic acids and N-tosylalkynylamides 1e–l by indenediide Pt IIIb.
[a]
Catalytic reactions performed under argon atmosphere using 0.1 mmol of substrate (0.14M in CDCl3) and catalyst load-
ing of 1 and 5 mol% for the alkynoic acids and the N-tosylalkynylamides, respectively.
Conversions were determined by H NMR analysis with mesitylene as internal standard. Isolated yields are given in
[b]
1
brackets.
Substrate concentration of 0.5M.
Intermolecular addition products were detected by H NMR in the crude reaction mixture.
Unidentified products (19%) were detected by H NMR in the crude reaction mixture.
Substrate concentration of 1M.
Phthalic anhydride (57%) was detected by H NMR in the crude reaction mixture.
[c]
[d]
[e]
[f]
1
1
[g]
1
sults in the cycloisomerization of the N-tosylamide 1f. cyclization of 1i with the Pd indenediide complex V
Full conversion was achieved in 22 h at 908C using required 9.5 h to reach 95% conversion.[10b] Using IIIb
5 mol% of Pt (entry 2). Previously, 2f was obtained in as catalyst, the e-lactones and lactams 2g–j were read-
moderate yield (53%) after 130 h at 908C with the Pd ily formed and isolated in good to excellent yield (57–
complex V.[10b] Replacing Pd for Pt, the reaction time 92%). X-Ray diffraction studies were performed on
is considerably shortened (by ~6 times) and pure al- 2h and 2j, unambiguously confirming the mode of
kylidene e-lactam 2f was isolated in excellent yield cyclization (7-exo vs. 6-endo and N vs. O attack).[20]
(93%).
The very good results obtained with 7-membered
To illustrate the generality of the Pt complex IIIb, rings prompted us to envision then the formation of
the formation of other 7-membered rings was then ex- 8-membered lactones and lactams.[21] Unfortunately,
plored. The a-substituted substrates 1g, h were effi- intermolecular reactions leading to a mixture of oligo-
ciently cyclized (entries 3 and 4), demonstrating the mers were observed with 7-octynoic acid,[22] and the
compatibility with ester groups. Note that only 7 h corresponding alkynylamide remained unaffected
were necessary to convert 1h into 2h. This is a signifi- after 24 h. To favour cyclization, the rigid substrates
cant speed up, when compared with the parent sub- 1k, l deriving from phthalic anhydride were selected.
strate 1f (which required 22 h of reaction), which may Gratifyingly, the 8-membered lactone 2k could be
be attributed to the Thorpe–Ingold effect and acidifi- prepared in 43% isolated yield (21 h of reaction at
cation of the N-tosylamide. Very facile and rapid re- 608C, entry 7), although 1k concomitantly converts
actions were also observed with the o-benzoic sub- back into phthalic anhydride (retro-acylation) under
strates 1i, j (entry 5 and 6). Their cyclization is com- these conditions. The corresponding N-tosylamide 1l
plete within only 1–2 h at 908C. For comparison, the was also converted by IIIb. But instead of the target-
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ed 8-membered lactam, two novel spiro compounds we were eager to evaluate its behaviour towards sub-
were obtained (86% yield, 86:14 ratio, entry 8). The strates raising issues of 5-exo/6-endo and 6-exo/7-endo
molecular structures of 2l-N-spiro and 2l-O-spiro selectivity (Table 3). Accordingly compounds 1m, n
were established by X-ray diffraction studies.[16] Their were cyclized at 908C using 5 mol% of Pt (entries I
formation apparently results from intramolecular cas- and II). In both cases, the use of IIIb spectacularly
cade cyclizations.[23] Although very efficient for e-lac- shortened the reaction time (by up to 28 times) com-
tones and lactams, the Pt complex IIIb thus shows pared with V.[10b,11] An impressive speed up is also ob-
limitations towards 8-membered rings and side-reac- served with the a-substituted substrates 1o, p (by up
tions prevail.
to 18 times, entries III and IV). Complete conversion
Carboxylic acids and N-tosylamides bearing inter- of the acid requires only 5 min with IIIb (vs. 1.5 h
nal alkynes are particularly challenging substrates for with V).[10b]
cycloisomerization reactions, in terms of activity as
Besides remarkable rate enhancement, replacing
well as exo/endo selectivity. Given the efficiency of Pd for Pt influences the exo/endo selectivity. As
the Pt complex IIIb (and superiority over the Pd com- glimpsed previously upon cyclization of hexynoic and
plex V) in the formation of 6- and 7-membered rings, pentynoic substrates 1a–d, the Pt complex IIIb dis-
Table 3. Cycloisomerization of alkynoic acids and N-tosylamides 1m–r bearing internal alkynes catalyzed by the in-
denediide Pt complex IIIb without or with additive (pyrogallol).
[a]
Catalytic reactions performed under argon atmosphere using 0.1 mmol of substrate (0.14M in CDCl3), 5 mol%
of Pt and 0/30 mol% of pyrogallol at 908C.
Yields were determined by H NMR analysis with mesitylene as internal standard. Isolated yields are given in
brackets.
[b]
[c]
1
15% of ethyl ketone side-product (5-oxoheptynoic acid).
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plays a noticeable preference over its Pd analogue V tosylamide 1r is even more striking. For the first time,
for the formation of 6-membered rings. Accordingly, this substrate can be efficiently cyclized. Conversion
the 6-endo cyclization of 1m was slightly predominant is complete within 18 h at 908C and a 2.1/1 mixture of
with Pt (exo/endo 1:1.6) while the 5-exo cyclization the 6-exo/7-endo products (both unambiguously au-
was favoured with Pd (exo/endo 1.5:1). An increase in thenticated by X-ray diffraction)[16] is obtained (entry
6-endo vs. 5-exo selectivity is also observed with the VI).
a-substituted acid 1o (from 1.2 with V,[10b] to 4.9 with
IIIb, entry III). The corresponding N-tosylamides 1n,
p undergo exclusively 6-endo cyclization. The ensuing Conclusions
alkylidene d-lactams 2n, p are obtained in pure form
and very high yield (entries II and IV).
In summary, the Pt pincer complex IIIb was found to
The ability of IIIb to form efficiently 6- as well as complete and outperform the related Pd complex V
7-membered rings is unique and raises the issue of 6- in the catalytic cycloisomerization of alkynoic acids
exo/7-endo selectivity. To try to answer this question, and N-tosylalkynylamides. In particular, Pt is very ef-
we studied the cyclization of two types of very chal- ficient for the formation of 6- and 7-membered rings.
lenging substrates: internal 5-alkynoic acids, that have The reaction rate and the selectivity for 6-endo (vs. 5-
been very rarely engaged in cycloisomerization so exo) as well as 6-exo (vs. 7-endo) cyclizations is signif-
far,[24] and their related N-tosylamides, whose cycliza- icantly improved by using pyrogallol as H-bond donor
tion is unprecedented. Accordingly, prolonged heating additive. For the first time, a large variety of d- and e-
of 5-heptynoic acid 1q in the presence of IIIb induced lactones/lactams could be prepared with high selectiv-
cyclization, although the conversion remained modest ities and in very good yields.
(38% after 36 h at 908C, no reaction at all was detect-
These results emphasize the unique properties of
ed with the Pd complex V). The reaction is highly se- SCS indenediide pincer complexes and extend further
lective for 6-exo cyclization and the d-lactone 2qexo their catalytic applications. Future work will seek to
was formed in 24:1 ratio with respect to the corre- take advantage of the associated metal/ligand cooper-
sponding e-lactone 2qendo (entry V). A similar test was ation in tandem catalytic transformations combining
performed with the corresponding N-tosylamide 1r the fixation of small molecules (such as CO2) with the
(entry VI). The Pt complex IIIb showed some activity intramolecular hydrofunctionalization process.
but the conversion of 1r was too low (6% after 18 h
at 908C) to characterize the cyclization products and
evaluate their ratio.
Experimental Section
Our mechanistic investigations of the cycloisomeri-
zation reactions catalyzed by indenediide Pd com- General Procedure for the Pt-Catalyzed Cycloiso-
plexes have pointed out the importance of proton merization of Alkynoic Acids and N-Tosylalkynyl-
shuttling. H-bond donor additives, in particular cate- amides
chol derivatives, were shown to significantly increase
In an NMR pressure tube, the dried substrate (0.1 mmol)
and complex IIIb (1–5 mol% [Pt]) were dissolved in CDCl3
activity and selectivity.[11] To try to improve further
the scope and efficiency of the Pt complex IIIb, the
influence of pyrogallol (1,2,3-benzenetriol, chosen as
the best comprise in terms of activity and solubility)
was studied on the cyclization of internal substrates
(Table 3). Accordingly, the addition of 30 mol% of
pyrogallol was found to significantly speed up the cyc-
lization of 1m–p (by up to 12 times, entries I–IV).
(0.7 mL) and heated at the corresponding temperature
under argon atmosphere. The progress of the reaction was
monitored by 1H NMR and 31P NMR. After evaporation,
the residue was purified by flash column chromatography to
afford the corresponding lactone/lactam in pure form.
The corresponding d-lactones and lactams are ob- Acknowledgements
tained in high, often improved selectivities with 5-exo/
6-endo ratios ranging from 1:3 to >1:99. The H-bond
Financial support from the Centre National de la Recherche
Scientifique, the Universitꢀ de Toulouse, and the Agence Na-
tionale de la Recherche (ANR CE6-CYCLOOP) is acknowl-
edged. N. A. E.-J. thanks the Consejo Nacional de Cienca y
tecnologꢁa (CONACYT) for a Postdoctoral fellowship. D. K.
thanks the Chinese Scholarship Council (CSC) for a PhD fel-
lowship. We thank Isabelle Fabing for technical assistance
with the Waters Autopurification system provided by the In-
stitut de Chimie of Toulouse (ICT-FR2599).
donor additive also proved very beneficial to the cy-
ACHTUNGTRENNUNGclization of 5-alkynoic derivatives. The carboxylic acid
1q was fully converted in 6 h (entry V) and the d-lac-
tone Z-2qexo was obtained with excellent selectivity
(6-exo/7-endo 32:1, only the Z isomer is detected).
Once again, Pt is remarkably more active than Pd,
IIIb achieving full conversion 10 times faster than V.
In addition, cyclization is cleaner with IIIb (15% of
ethyl ketone side-product is formed, vs. 30% with
V).[11] The result obtained with the corresponding N-
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1
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[16] See the Supporting Information for details.
[17] Crystallographic data (excluding structure factors) have
been deposited to the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC
[23] See the Supporting Information for plausible mecha-
nisms.
[24] Pale et al. reported the cycloisomerization of 5-decyno-
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lactones were isolated in 60 and 97% yield, respective-
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of 5-decynoic acid.
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FULL PAPERS
Efficient Synthesis of Unsaturated d- and e-Lactones/
Lactams by Catalytic Cycloisomerization: When Pt
Outperforms Pd
9
Adv. Synth. Catal. 2016, 358, 1 – 9
Diandian Ke, Noel ꢀngel Espinosa, Sonia Mallet-Ladeira,
Julien Monot, Blanca Martin-Vaca,* Didier Bourissou*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!