Cyclobutene formation in PtCl2-catalyzed cycloisomerizations of heteroatom-tethered 1,6-enynes

Article abstract of DOI:10.1002/chem.201403643

Aza(oxa)bicyclo[3.2.0]heptenes are accessed through the PtCl ₂-catalyzed cycloisomerizations of heteroatom-tethered 1,6-enynes featuring a terminal alkyne and amide as the solvent. It is shown that the weak coordinating properties of the solven

Full text of DOI:10.1002/chem.201403643

DOI: 10.1002/chem.201403643
Communication
&
Synthetic Methods
Cyclobutene Formation in PtCl2-Catalyzed Cycloisomerizations of
Heteroatom-Tethered 1,6-Enynes
Zhenjie Ni, Laurent Giordano, and Alphonse Tenaglia*[a]
Abstract: Aza(oxa)bicyclo[3.2.0]heptenes are accessed
through the PtCl2-catalyzed cycloisomerizations of heter-
oatom-tethered 1,6-enynes featuring a terminal alkyne
and amide as the solvent. It is shown that the weak coor-
dinating properties of the solvent and alkyl substituent(s)
at the propargylic carbon atom favor the formation of cy-
clobutenes instead of other possible cycloisomerization
products such as 1,3-diene derivatives or cyclopropane-
fused heterocycles.
Transition-metal-catalyzed cyclization reactions of enynes
Scheme 1. Gold- and platinum-catalyzed cycloisomerizations of heteroatom-
tethered 1,6-enynes.
based on p-alkynophilic metal complexes have become one of
the fastest growing areas in modern organic chemistry,[1] with
many interesting applications to the syntheses of natural prod-
ucts.[2] Mechanistic investigations using theoretical calculations
at the propargylic position took place with 1,2-alkyl migration
to form cyclopropanated heterocycles.[7] With the knowledge
have been conducted to gain a more detailed understanding
of the intimate processes involved in the reactions.[3] According
that structural patterns of enynes can influence the outcome
to the nature of the catalyst and the structural patterns of
enynes, the cycloisomerizations of heteroatom-tethered 1,6-
enynes give rise to various (bi)cyclic compounds. Simple allyl-
propargyl ethers or amines can be converted into cyclopropa-
nated heterocycles with platinum or gold catalysts.[4] However,
cyclobutene formation with these enynes remains unusual.
Kang and Chung reported that cationic gold catalysts are able
to convert electronically biased enynes such as allyl alkynoates
(or alkynamides) into cyclobutene-fused lactones (or lactams)
(Scheme 1, a), whereas platinum(II) catalysts are totally ineffec-
tive.[5] One important feature of these reactions involves the
use of enynes bearing an aryl substituent at the terminus sp
carbon atom to stabilize ionic intermediates. Examples of cy-
clobutene adducts from nitrogen-tethered enynes substituted
with a TMS group at the alkyne moiety were reported, but the
reactions suffer from a lack of selectivity, giving TMS-contain-
ing adducts along with protodesilylated and over-reduced
compounds (Scheme 1, b).[6] It is worth noting that, to the best
of our knowledge, no cyclobutene formation has been report-
ed with heteroatom-tethered 1,6-enynes having terminal al-
kynes. Our group and others showed that cycloisomerizations
of heteroatom-tethered enynes with gem-dialkyl substitution
of the reactions, we examined the behavior of substrates with
structural modifications on the alkyne. Herein, we report plati-
num-catalyzed cyclobutene formation from nitrogen and
oxygen-tethered enynes with terminal alkynes and propargyl
substituents through the use of amides as weakly coordinating
solvents.
We initiated our studies with enyne 1a bearing gem-substi-
tution at the propargylic carbon atom and conducted a solvent
screening investigation (Table 1). Alongside the typical cyclo-
isomer products 2a and 3,[8] compound 1a could also undergo
a competitive [1,2]-alkyl shift, leading to ring-extended cyclo-
isomer 5.[7] A typical nonpolar solvent such as toluene was
competent only when the reaction was carried out under a CO
atmosphere[10] to give diene 3 through single bond carbon–
carbon cleavage (entries 1 and 2). The reaction in MeOH af-
forded only the CÀN bond-cleavage product 4 (entry 3). The
cycloisomer 5 was not observed with the solvents screened in
Table 1. Finally, we were pleased to find that amide and even
imide solvents were uniquely able to produce cyclobutene
2a[9] in satisfactory yields (entries 4–7), with DMA proving to
be the best solvent (entry 7). The beneficial effect of DMA was
still observed when it was used in catalytic amounts (20 mol%
with respect to 1a) in toluene, however, the yield of 2a dra-
matically decreased (entry 10). Consequently, the reactions of
various N,N-allylpropargylamines were conducted in DMA to
give the expected cyclobutenes in fair to excellent yields
(Table 2). Minor amounts of other compounds were detected
[a] Z. Ni, Dr. L. Giordano, Dr. A. Tenaglia
Aix-Marseille Universitꢀ, Centrale Marseille, CNRS
ISm2, UMR 7313, 13397 Marseille (France)
E-mail: alphonse.tenaglia@univ-amu.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403643.
1
(1–5%) in the H NMR spectra of the crude reaction mixtures.
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patible with the reaction conditions, giving cyclobutene 2d,
with the TMS group retained.[11] Enynes monosubstituted at
the propargylic position, which are prone to undergo [1,2]-H
shift to give the cyclopropane-fused azacycles, were examined
to evaluate the feasibility of the [2+2] cycloaddition pathway.
In these cases, cyclobutenes 2j–m were obtained as single dia-
stereoisomers. The structure of 2m and its relative stereo-
chemistry was secured by a single-crystal X-ray diffraction anal-
ysis.[12] The diastereochemical outcome of the reaction enabled
access to chiral azabicyclic alkenes. Subjecting chiral enyne (R)-
1l (96%ee) to the cycloisomerization conditions afforded
(1S,2R,5R)-2l in 62% yield and 98%ee after purification by
chromatography. Variation of substituents at the nitrogen
atom was briefly examined. Whereas the reactivity of N-meth-
ylsulfonyl enyne was similar to that of p-tolylsulfonamide 1a,
thus forming 2n (96%), the N-benzoyl enyne reacted in a less
satisfactory way to give 2o in only
Table 1. Solvent screening for the reaction of enyne 1 with PtCl2.[a]
Entry
Solvent[b]
Product
Yield [%][c]
[d]
1
2
3
4
5
6
7
8
9
toluene
toluene
MeOH
DMF
DMPU
NMP
DMA
DMA/toluene (1:1)
DMA/toluene (1:9)
DMA(20 mol%)/toluene
–
3
4
2a
2a
2a
2a
2a
2a
2a
–
65[d,e]
74[f]
63
88
87
98
78[g]
75[g]
63[d]
10
[a] Reaction conditions: c=0.2m, PtCl2 (5 mol%), 1058C, 24 h. [b] Ts=tol-
uene-4-sulfonyl, DMF=N,N-dimethylformamide, DMPU=1,3-dimethyl-
32% yield. Unexpectedly, enyne 6,
3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
NMP=N-methyl-2-pyrrolidone,
substituted with a phenyl group at
DMA=dimethylacetamide. [c] Isolated yield. [d] Complex mixture of
products. [e] Reaction carried out under CO atmosphere. [f] Reaction car-
ried out at 708C. [g] Diene 3 (<5%) was detected by 1H NMR of the
crude reaction mixture.
the terminal carbon of alkyne
(Scheme 2), was reluctant to un-
dergo cycloisomerization.
Scheme 2. Unreactive enyne
6.
Since the structural patterns of
the enyne play an important role
on the outcome of cycloisomeriza-
Azabicycloheptenes 2a–c, featuring the spirocyclohexane
ring and bearing a substituent at C-6, were observed in higher
yields with respect to 2 f–h, exhibiting gem-dimethyl substitu-
tion. An enyne derivative with an allylsilane group was com-
tions, the reactivity of unsubstituted enyne 1p was evaluated.
Under the developed conditions, cyclobutene 2p was still
formed in 17% yield alongside known cyclopropane 7[11b] as
the major cycloisomer (76%) (Scheme 3). It is noteworthy that
cyclobutene 2p was not observed when the reaction was per-
formed in toluene.[11b] Thus, the [1,2]-H migration remains the
preponderant path when no substituent is present at the
propargylic carbon atom.
Table 2. Cycloisomerization of nitrogen-tethered enynes.[a]
Scheme 3. Cycloisomerization of enyne 1p.
These results suggested that, upon coordination of the
alkyne to platinum, the propargylic substituent(s) induce a sig-
nificant relative stabilization of the developing positive charge
at the internal sp carbon through hyperconjugation. However,
although this condition is necessary, it is not sufficient: DMA as
the coordinating solvent plays a decisive role in the evolution
of the ionic species to the cyclobutene. Nevertheless, the exact
role of amide ligands in favoring the formation of cyclobutenes
remains to be established.[13]
Oxygen-tethered enynes participate equally in the cycloiso-
merization to give the expected bicyclic ethers, although these
products were more sensitive than the parent nitrogen com-
pounds and were prone to decomposition (Table 3).[4b] To this
end, the reactions of allylpropargyl ethers were performed
with additional trimethylallylsilane to trap the adventitious
acidic species responsible for decomposition. Cyclobutenes 9a
[a] Reactions conditions: PtCl2 (5 mol%), DMA (0.2m), 858C, 16 h, isolated
yields. [b] The remaining mass balance (65% yield) was composed of an
inseparable mixture of products.
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Table 3. Cycloisomerization of oxygen-tethered enynes.[a]
Scheme 4. Reactions of enyne 11.
Scheme 5. Proposed reaction mechanism.
[a] Reactions conditions: PtCl2 (5 mol%), allyltrimethylsilane (3 equiv),
DMA (0.2m), 808C, 8 h, isolated yields. [b] Reaction performed at 1058C
without allyltrimethylsilane.
secutive [1,2]-H shifts through intermediates C and D followed
by demetalation complete the formation of cyclobutene. This
mechanism could explain the inertness of aryl-substituted
enynes 6 and 10 and is reminiscent of the mechanism pro-
posed for the isomerization of methylenecyclopropanes to cy-
clobutenes.[10c]
and 9b were formed in higher yield than 9c and 9d, which
contain an acid-sensitive protecting group. For instance, reac-
tion of an enyne bearing a 1,3-dioxolane protecting group car-
ried out without trimethylallylsilane afforded a mixture of 9b
and 9d. Cyclobutene 9e, which exhibits similar substitution
patterns to those of 2m, was formed in only 32% yield.
This proposal was probed with deuterium labeling experi-
ments (Scheme 6). Cyclization of [D]-1a (> 99% D) gave cyclo-
butene [D]-2a with deuterium incorporation at C-1, C-6, and C-
7 (Scheme 6, a). The depletion of deuterium to a significant
extent was attributed to the presence of residual water. To this
end, deuterium to proton exchange on terminal alkyne [D]-12
(98% D) in the presence of H2O was established (Scheme 6, b).
This should presumably occur prior to the cyclization. The in-
corporation of deuterium at the sp2 carbon atoms of [D]-2a is
not so clear.[16] Heating cyclobutene 2a with D2O in the pres-
In this system, DMA can be regarded as a ligand (Table 1,
entry 10), therefore the well-defined complex [PtCl2(DMA)2][14]
was prepared and used as catalyst (5 mol%) in toluene at
1058C. Under these conditions, enyne 1a was converted into
cyclobutene 2a in 56% yield along with diene 3 (11%) and N-
prenyl-p-tolylsulfonamide 4 (9%). Considering the weak coordi-
nating properties of DMA,[14] we presumed that [PtCl2(DMA)2] is
in equilibrium with [PtCl2(DMA)], and is thus able to activate
alkyne coordination and to trigger the [2+2] cycloaddition.
[PtCl2(DMA)], in turn, dissociates from DMA to form PtCl2,
which is believed to be responsible for side-product formation.
To maintain a high concentration of the putative [PtCl2(DMA)],
the reaction was performed with additional DMA (107 equiv
with respect to Pt). These conditions suppressed the CÀN
bond cleavage path and afforded 2a in increased yield (76%),
along with 3 in only 5% yield. The coordinative properties of
the amide (MÀO bond) and the CO (MÀC bond) are totally dif-
ferent and change the catalytic behaviour of the platinum
center as highlighted by the controlled experiments described
in Scheme 4. Fꢁrstner showed that treatment of 10 with PtCl2
in toluene under a CO atmosphere gave cyclobutene 11 in
84% yield.[10a] When the reaction was performed under our
conditions (DMA, 1058C), compound 10 was recovered un-
changed.
Considering the peculiar structural patterns that favor the
formal [2+2] cycloaddition, a mechanism based on cationic in-
termediates is proposed (Scheme 5). Activation of the alkyne
by platinum(II) initiates cyclization of the enyne through A to
generate a cyclobutyl cation B. Nonbonding interactions with
substituent(s) at the propargylic carbon atom mean that the
platinum cannot be located at the ring junction.[10a,15] Two con-
Scheme 6. Deuterium labeling experiments.
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through the cycloisomerization of heteroatom-tethered 1,6-
enynes catalyzed with platinum(II) dichloride. This study shows
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Acknowledgements
We gratefully acknowledge the CNRS and MRES for financial
support. Z.N. gratefully acknowledges the China Scholarship
Council (CSC) for a doctoral scholarship. We thank Dr. Michel
Giorgi (Aix-Marseille Universitꢂ) for X-ray crystallography analy-
ses and Dr. Innocenzo DeRiggi (Ecole Centale Marseille) for
help with the NMR spectra analysis.
Keywords: cyclobutenes
platinum · small ring systems · solvent effects
· cycloisomerization · enynes ·
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Received: May 22, 2014
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Published online on August 5, 2014
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