Bi-directional alkyne tandem isomerization via Pd(0)/carboxylic acid joint catalysis: expedient access to 1,3-dienes

Article abstract of DOI:10.1039/c8cc08561g

An in situ formed palladium hydride catalyst enables the sequential dual isomerization of propargylamide derivatives to 1-amido-1,3-dienes with high chemo- and regioselectivity. The reaction shows ample functional group tolerance, delivering a valuable class of products, including highly deuterated ones, from readily available reagents. The reaction occurs through a complex mechanism studied by DFT modelling.

Full text of DOI:10.1039/c8cc08561g

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Bi-directional alkyne tandem isomerization via
Pd(0)/carboxylic acid joint catalysis: expedient
access to 1,3-dienes†
Cite this: Chem. Commun., 2018,
54, 14021
Received 25th October 2018,
Accepted 23rd November 2018
a
Gianpiero Cera,‡a Matteo Lanzi,‡a Franca Bigi,a Raimondo Maggi,
Max Malacriab
a
and Giovanni Maestri
*
DOI: 10.1039/c8cc08561g
rsc.li/chemcomm
An in situ formed palladium hydride catalyst enables the sequential
dual isomerization of propargylamide derivatives to 1-amido-1,3-
dienes with high chemo- and regioselectivity. The reaction shows
ample functional group tolerance, delivering a valuable class of
products, including highly deuterated ones, from readily available
reagents. The reaction occurs through a complex mechanism
studied by DFT modelling.
Conjugated 1,3-dienes are an important class of building blocks
in organic chemistry, commonly employed to design synthetic
transformations to complex targets.1 In this context, 1-amido-1,3-
dienes are a stabilized N-delivering structural motif whose use in
intra- and inter-molecular Diels–Alder (DA) cyclizations is already
well-documented.2 However, the synthetic potential of these
molecules has not been fully grasped yet, mainly because of the
lack of simple and robust synthetic methods to access them.
Metal-catalyzed C–C or C–N cross-couplings suffer from the
inherent limitations connected with the synthesis of halodienes
or vinyl halides. This is coupled with issues in the stereochemical
control of both reagents and products.3 An alternative, atom-
economical approach relies on metal-catalyzed alkyne isomeriza-
tions (Scheme 1a).4 However, palladium catalysis requires the
use of acylalkynes and related substrates with strongly electron-
withdrawing (EWG) groups. Rare examples based on either
rhodium or gold catalysis display a larger scope, although this
comes at the cost of elaborate ligands to afford desired dienes.
Scheme 1 State of the art of metal-catalyzed diene syntheses.
During our studies on palladium-catalyzed cascades of alkyne isomerization of propargylamides A to form 1,3-dienes with high
derivatives,5 we serendipitously disclosed that combination of regiocontrol, on which we report herein.
palladium(0) with cheap benzoic acid6,7 can promote a tandem
This catalytic system promoted an unprecedented bi-
directional p-walk involving the two a-C(sp3) of a 2-butynyl
fragment to form diene B (Scheme 1b). This is in sharp contrast
with well-established isomerizations, in which the electron
density of the p-system extends in a single direction instead.8
This unique tandem isomerization strategy is therefore com-
plementary to existing routes and, furthermore, it benefits from the
most straightforward substrate preparation. At the outset of our
studies, we submitted substrate 1a to different ligands in the
presence of 5 mol% Pd(PPh3)4 and 30 mol% benzoic acid (Table 1).
a
`
Universita di Parma, Dipartimento di Scienze Chimiche, della Vita e della
`
Sostenibilita Ambientale, 17/A Parco Area delle Scienze, 43124 Parma, Italy.
E-mail: giovanni.maestri@unipr.it
b
´
UPMC Sorbonne Universite, IPCM (UMR CNRS 8232), 4 place Jussieu, C. 229,
75005 Paris, France
† Electronic supplementary information (ESI) available: Experimental details,
modeling and characterization data, copies of NMR spectra, XYZ coordinates.
See DOI: 10.1039/c8cc08561g
‡ GC and ML contributed equally.
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Table 1 Optimization of reaction conditions
(entry 6). Different carboxylic acid derivatives were then tested
(entries 7–11); beside weaker pivalic acid (44%, entry 7), we did
not note however a marked electronic effect (entries 8–11)
compared to user-friendly benzoic acid, which seemed therefore
the most convenient hydride source for the reaction. Finally, a
catalyst loading as low as 3% led to the isolation of 2a in 85%
yield, further showing the high efficiency of the optimized
catalytic system (entry 12). Subsequently, we studied the scope
of the reaction submitting a family of propargyl amides 1 to the
Pd-catalyzed tandem isomerization reaction (Fig. 1, see ESI† for
scope limitation). The methodology was found broadly applic-
able in the presence of different N-protected sulphonamides as
well as benzamide derivatives 2b–f (73–78%), with the corres-
ponding N-arylated diene 2d isolated in somehow diminished
yields (34%). Oxazolidinone 2g was delivered with high compe-
tence (82%). The robustness of the methodology was reflected by
a 3 mmol scale dienamide synthesis (2h, 76%), which was
isolated with a comparable yield in respect to the model reaction
conducted on a 0.2 mmol scale. Noteworthy, the protocol
prevents any racemization, allowing for the synthesis of the
enantiomerically enriched amido-diene (R)-2i in 74% yield.
Differently substituted benzylamine derivatives, including fluori-
nated and chlorinated ones, were found to be tolerated with
Entry
Pd source
Ligand
Acid
Yield [%]
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
PPh3
—
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PivCO2H
MesCO2H
MesCO2H
2-FurylCO2H
4-FC6H4CO2H
PhCO2H
78a
71b
66b
56b
59b
87
PPh3
dppe
Davephos
PCy3
PPh3
PPh3
PCy3
PCy3
PCy3
PCy3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
44b
83b
85
9
10
11
12
80b
84
85c
a
Conditions: 1a (0.20 mmol), [Pd] (0.01 mmol), ligand (0.02 mmol),
ArCO2H (0.06 mmol), toluene (0.1 M, 2.0 ml), 100 1C, 16 h, isolated
yields. b 1H-NMR yields determined with 1,4-dimethoxybenzene as
c
internal standard. [Pd] (0.06 mmol, 3.0 mol%), PCy3 (0.012 mmol,
6.0 mol%). PMB = pMe-benzyl.
Monodentate phosphine performed better with respect to the amido-dienes 2j–m isolated in very good yields (65–86%).
their bidentate analogues, promoting the formation of the Different heterocycles such as halogenated tryptamines and
corresponding diene (E)-2a in moderate to good yields and high triazole-based propargyl amide derivatives were converted in to
stereocontrol (420: 1, entries 1–5). Electron-rich PCy3 showed the corresponding products 2n–p in synthetically useful yields by
improved competence providing the amidodiene 2a in 87% yield using PPh3 as ligand in the catalytic protocol (51–61%).
Fig. 1 Scope of the dual isomerization.
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The chemoselectivity of the method was highlighted by the
Communication
functional group tolerance with respect to the highly reactive
geranyl fragment, with the synthesis of tetraene 2q accom-
plished in good yields (60%) and without any trace of cyclo-
isomerization product.9 Noteworthy, the bi-directional nature
of the isomerization was reflected when employing 2-pentyne
and 2-octyne fragments. Indeed, the synthesis of amido-dienes
2r–s occurred with complete chemoselectivity and good levels
of regioselectivity (E/Z up to 4 : 1). The absence of 2r0 and 2s0
confirms that present method is orthogonal to existing strate-
gies (Scheme 1). Finally, conjugated trienes can be accessed,
such as 2t (66%, E/Z up to 6.6 : 1). Nonworking substrates
include various enynes and diynes, as well as butynyl ethers
and maleimides (Fig. S3 in ESI†).
Scheme 3 Isomerization of propargylamides 1u–w and allenamide 1h0.
Amidodiene 2a can smoothly undergo DA cycloaddition in situ formation of palladium hydride II, ligand exchange with
with maleic anhydride, delivering bicycle 4aa in good yields a molecule of 1 delivers complex III, which is less stable than the
and high diastereocontrol (64%, dr 4 20 : 1). Hence, a one-pot/ entry channel by +16.8 kcal molꢀ1 in DG. Product 2 can then form
two-step strategy from 1a was possible, delivering 4aa with good through two competing pathways, depending on the regioselectivity
efficacy (57%, Scheme 2a).
of the first insertion on complex III. Each manifold involves twice a
Present route involves a protic acid in contrast to existing sequential hydride-transfer/b-elimination. Barriers for the former
isomerization methods.4 This can in turn enable deuterium transition states (values between +3 and +8 kcal molꢀ1) are lower
labelling of products, and of their subsequent polycyclic deri- than those of the latter in all these four sub-sequences (barriers
vatives such as 4aa, offering a convenient handle for biological between +18 and +29 kcal molꢀ1). In particular, b-eliminations
applications. To our delight, the use of labelled acetic acid from vinylpalladium complexes are the most demanding (DDG
afforded highly enriched dienamide 2h-d5, in which all protons +29.4 and +27.0 kcal molꢀ1 for TS(IV-V) and TS(IV–V)*, respec-
of its chain can be scrambled, up to excellent levels in the tively), followed by the b-elimination involving the terminal methyl
terminal vinyl group (Scheme 2b, details in ESI†).
group (+23.8 kcal molꢀ1 for TS(VI–VII)). The relatively most favour-
Reasoning that the formation of 1,3-dienes would have able b-elimination involves the methylene alpha to nitrogen
involved an allene intermediate, we prepared 1u to form (+17.8 kcal molꢀ1 for TS(VI-VII)*). These computational results
allenamide 5u. However, we disappointingly got no conversion are thus consistent with the results observed with 1r and 1s
(Scheme 3a). We thus prepared 1v, aiming to trap the kineti- (Fig. 1). These reagents afforded the corresponding dienamide
cally favoured allene 6v instead. Surprisingly, this reagent too only, leaving their terminal methyl group untouched and showing
followed suit. On the contrary, allenamide 1h0 gave desired therefore that present bi-directional p-rearrangement is orthogonal
products 2h in 75% yield (Scheme 3b). Moreover, 1w, which to literature examples. All s-complex are more stable than the
bears a tertiary carbon alpha to nitrogen, led surprisingly to entry channel (IV, IV*, VI* and VI**, by ꢀ1 to 13 kcal molꢀ1). This
diene 2w0 (Scheme 3c, 55%). To rationalize these results, which suggests that these intermediates are the least reactive ones
suggested that steric demands could dictate the directionality and could even represent catalytic dead-ends. On the contrary,
of the dual isomerization, we used DFT to check the multiple all p-complex are less stable than the combination of the
competing reaction pathways.
starting catalyst and 1 (III, V, V*, V**, VII and VII*, by +2 to
We analysed the complete sequences leading to model diene 25 kcal molꢀ1). Among these, the two final intermediates VII and
2 (Fig. 2, details in ESI†) at the M06/Def2-svp(d)10 level using VII* are the relatively more stable ones, followed by the initial
toluene as implicit solvent. This model was able to rationalize complex III (+7.7, +1.6 and +16.8 kcal molꢀ1 respectively).
the behaviour of elaborate palladium species.11 Upon reversible Reagent 1 is more stable than both allenamide 5 and allene 6.
This fits with the experimental failure to synthesize them using
reagents 1u–v that could not evolve into 1,3-dienes. Dienamide
2 is the sole thermodynamically favoured isomer of 1 (by
ꢀ10.6 kcal molꢀ1), ultimately ensuring the catalytic turnover
by dictating the driving force of the dual isomerization.
This trend is confirmed by the modelling of 1z, which has a
2-pentyne chain. Its allene isomers parallel the outcome of their
peers and dienes 2z and 2z0 are the sole thermodynamically
favourable isomers. The dienamide 2z is the most stable one
(by 7.2 kcal molꢀ1 in DG), in perfect agreement with the
complete absence of 2r0 observed experimentally (Fig. 1).
We reported a simple method to convert easily-available
Scheme 2 Synthetic applications of the catalytic method.
alkynes to the corresponding 1,3-dienamides, including highly
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We thank support from UniPr and MIUR (Grant AROMA-TriP
and Departments of Excellence framework). Modeling facilities
ware provided by ICSN-CNRS (UPR2301, Gif s/Yvette, France).
We gratefully acknowledge Prof. Marco Bandini (UniBo) for
experimental support.
Conflicts of interest
There are no conflicts to declare.
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14024 | Chem. Commun., 2018, 54, 14021--14024
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