Auto-Tandem Catalysis: PdII-Catalysed Dehydrogenation/Oxidative Heck Reaction of Cyclopentane-1,3-diones

Article abstract of DOI:10.1002/chem.201704442

A Pd^II catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one-pot procedure: dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and the subsequent oxidative Heck coupling. This auto-tand

Full text of DOI:10.1002/chem.201704442

A Journal of
Accepted Article
Title: Auto-Tandem Catalysis: Pd(II)-Catalysed Dehydrogenation/
Oxidative Heck of Cyclopentane-1,3-diones
Authors: Claire J C Lamb, Bryan G Nderitu, Gemma McMurdo, John M
Tobin, Filipe Vilela, and Ai-Lan Lee
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To be cited as: Chem. Eur. J. 10.1002/chem.201704442
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10.1002/chem.201704442
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Auto-Tandem Catalysis: Pd(II)-Catalysed Dehydrogenation/
Oxidative Heck of Cyclopentane-1,3-diones
Claire J. C. Lamb, Bryan G. Nderitu, Gemma McMurdo, John M. Tobin, Filipe Vilela* and Ai-Lan Lee*[a]
Abstract: A Pd(II) catalyst system has been used to successfully
catalyse two mechanistically distinct reactions in a one-pot procedure:
dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and
the subsequent oxidative Heck coupling. This auto-tandem catalytic
reaction is applicable to both batch and continuous flow processes,
via stoichiometric oxidation by CuBr2 or CuCl2 (Scheme 1B).[16]
Such a procedure necessarily produces stoichiometric amounts
of halogenated waste. Meanwhile, Stahl and co-workers have
developed a Pd(II)-catalysed aerobic dehydrogenation of cyclic
ketones 5 and chromanones 6 to enones 7 and chromones 8
respectively (Scheme 1C).[17],[18] Although Stahl’s conditions are
very different to the oxidative Heck conditions in Scheme 1A, and
has only been applied to ketones such as 5/6 rather than 1,4-
diketone motifs (e.g. 4), we were intrigued by the possibility of
utilising the same Pd(II) catalyst to carry out both the
dehydrogenation of 4→1 and the oxidative Heck coupling 1→2 in
a one-pot reaction (Scheme 1D). Such an auto-tandem catalytic
reaction,[19] if successful, will clearly maximise the efficiency of the
desymmetrisation strategy towards 1: by reducing the number of
discrete steps, maximising the efficiency of the Pd(II) catalyst by
enabling it to catalyse two mechanistically distinct reactions, and
avoiding the use of stoichiometric copper salts and thereby its
corresponding stoichiometric halogenated waste.
with the latter being the first example of
a tandem aerobic
dehydrogenation/oxidative Heck in flow. In addition, a telescoped
reaction involving enantioselective desymmetrisation of the all-C
quaternary centre was successfully achieved.
Introduction
Efficient methods to synthesise the 2,2-disubstituted
cyclopentene-1,3-dione core is widely sought after, as this motif
is present in a several biologically active compounds[1] and natural
[3]
products such as madindolines A and B,[2] ochroleucin A1 and
similin A,[4] as well as metabolites such as involutone[5] and
preussidone[6] (e.g. Fig. 1). Towards this end, we have recently
developed a Pd(II)-catalysed oxidative Heck[7],[8] strategy to
desymmetrise the achiral precursor 1, thereby providing an
expedient way of enantioselectively desymmetrising the all-
carbon quaternary centre[9] (1→2, Scheme 1A).[10],[11] Alternative
approaches include elegant organocatalytic methods by
Mukherjee and Enders,[12] Cu- or Rh-catalysed conjugate
additions to 1 by Mikami[13] and Hayashi[14] respectively, and
silver-catalysed desymmetrisations by Singh and Wang.[15]
(A) Previous work: oxidative Heck desymmetrisation[10]
O
O
O
Ar
Pd(OAc)2 (cat.)
Ligand (cat.)
R
R
B
O
B
O
B
+
DMA or DMF, O2,
50-70 oC
Ar
R'
R'
Ar
Ar
O
3
O
1
2
40-95 h
-up to quant. yield
-up to 94:6 e.r.
-all-C quat centre
(B) Typical synthesis of precursor 1:[16]
O
O
O
OH
CuBr2 (2.2 equiv.)
R
R
HO
-stoichiometric oxidant
-extra step
-halogenated waste
R'
MeOH, reflux
2-18 h
R'
O
O
O
O
OH
O
O
N
H
CHO
Ar'
4
1
Me
OH
O
Me
O
O
(C) Aerobic dehydrogenation by Stahl:[17]
Ar'
O
R
R
O
X
O
Pd(TFA)2 (5 mol%)
DMSO (10 mol%)
OMe
OH
Preussidone
O
Ar' =
R'
R
HO
O
OH
(+)-Madindoline A:
R=Me, R'=nBu
R =
Ochroleucin A1
AcOH, O2,
80 oC
X
(+)-Madindoline B:
Involutone
R=nBu, R'=Me
X=CH2/CHR 5
X=CH2/CHR 7
X=O 6a, X=NR 6b
X=O 8a, X=NR 8b
Figure 1. Examples of natural products containing the 2,2-disubstituted
cyclopentene-1.3-dione core.
(D) This work: one-pot auto-tandem catalysis
O
O
O
O
Pd(II) cat., ligand, O2
Ar
R
R
R
9
Bpin ( )
In all of the aforementioned methods, however, the achiral
R'
R'
precursor 1, is generally accessed from cyclopentane-1,3-dione 4
R'
oxidative
Heck
Ar
dehydrogenation
O
O
4
1
2
[a]
C. J. C. Lamb, B. G. Nderitu, G. McMurdo, John M. Tobin, Dr F.
Vilela,* Dr A.-L. Lee*
auto-tandem catalysis: batch and continuous flow
Pd catalyses two different reactions
Institute of Chemical Sciences, Heriot-Watt University
Edinburgh EH14 4AS, United Kingdom.
E-mail: A.Lee@hw.ac.uk
telescoped synthesis for enantioselective desymmetrisation
Scheme 1. (A) Previous oxidative Heck desymmetrisation; (B) stoichiometric
oxidant method towards 1; (C) Stahl’s aerobic oxidation; (D) this work.
Supporting information for this article is given via a link at the end of
the document.
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In related work, Kim and co-workers recently demonstrated
a Pd(II)-catalysed one-pot procedure towards flavones from
chromanones 6a,[20] and Hong and co-workers synthesised
functionalised cyclic enaminones and enolones from
dihydroquinolinones 6b and chromanones 6a respectively.[21],[22]
Nevertheless, we envisioned that the one-pot process 4→2 that
we have set out to develop would be challenging: while the one-
pot procedures mentioned above[20-21] utilise dehydrogenation
6→8 previously demonstrated by Stahl,[17] the Pd(II)-catalysed
aerobic dehydrogenation of molecules with 1,4-diketone motifs
such as 4 is unprecedented. Furthermore, the one-pot Pd-
catalysed dehydrogenation/oxidative Heck process 4→2 has the
potential to be rendered enantioselective, which is once again
unprecedented.
We herein disclose the successful development of the one-
pot dehydrogenation/oxidative Heck reaction of 2,2-disubstituted
cyclopentane-1,3-diones 4 and its corresponding substrate scope.
Furthermore, the methodology can be successfully adapted for
use in a continuous flow reactor, which constitutes the first
example of an auto tandem catalytic aerobic dehydrogenation
/oxidative Heck in flow. Finally, we demonstrate that the reaction
can also be adapted for the enantioselective desymmetrisation of
the all-carbon quaternary centre in 4, through a telescoped
reaction.
Table 1. Selected optimisation of the Pd(II)-catalysed aerobic
dehydrogenation step.
Entry[a]
Ligand
10
x
Temp (°C)
100
Time (h)
72
Conv. (%)[b]
1
2
3
4
5
5
50
11
5
100
72
18
12
5
100
72
74
10
5
120
72
72
10
10
120
48
100 (85)[c]
[a] Anhydrous conditions used. [b] Conversions by 1H NMR analysis. [c] Isolated
yield.
With these optimised conditions in hand for the first
oxidation step 4→1, we proceeded to investigate the one-pot
procedure by carrying out the oxidation reaction at 120 °C for
approximately 30 h, followed by addition of arylboroxine 3a
(prepared by dehydrating the corresponding arylboronic acid),
and allowing the oxidative Heck reaction to proceed at 70 °C (this
is the optimal temperature for the separate oxidative Heck step)[10]
for 43-93 h (Scheme 2). Following extensive optimisation (see
Supporting Information), the oxidative Heck product 2a was
successfully formed in up to 60% yield. Frustratingly, however,
the one-pot procedure under these conditions produced very
inconsistent results, with yields ranging from 23-60% (see
Supporting Information).
Results and Discussion
We initiated our studies by investigating the Pd(II)-catalysed
aerobic dehydrogenation of 4→1, since this reaction has not
previously been studied and would therefore require separate
optimisation before the one-pot procedure 4→2 could be
attempted.
Rather
than
Stahl’s
original
conditions
[(DMSO)2Pd(TFA)2 in AcOH, Scheme 1C], we chose to
investigate the use of 1,10-phenanthroline type ligands in DMF
(Table 1). The reasons for this are twofold: 1,10-phenanthroline
10 was shown to be optimal for the following oxidative Heck
reaction, and would also be more suitable for adaptation to
enantioselective catalysis for the following oxidative Heck step
1→2.
Ar
O
Ar
B
B
Firstly, the use of
5
mol% Pd(OAc)2 with 1,10-
Pd(OAc)2
(10-15 mol%)
(10-15 mol%)
O
O
O
O
O
O
O
3a
B
phenanthroline 10 as ligand successfully produced the desired
oxidation product 1, albeit in modest conversion (50%) after 72 h
(Entry 1, Table 1). Adopting 5-nitro-1,10-phenanthroline 11 as the
ligand resulted in an even worse conversion (18%) under the
same conditions (Entry 2). Pleasingly, dmphen 12 turned out to
be a good ligand for this oxidation step (Entry 3), however, its use
as a ligand in the subsequent oxidative Heck step 1→2 results in
poor conversion. Ligand 12 is therefore unsuitable for the one-
pot reaction despite being the best ligand for dehydrogenation
4→1. We therefore proceeded to optimise the oxidation step
using 1,10-phenanthroline 10 as ligand (Entries 4-5). Increasing
the reaction temperature to 120 °C provided a decent conversion
of 72% in 72 h (Entry 4). Finally, increasing the catalyst and ligand
loading to 10 mol% at 120 °C resulted in full conversion within 48
h, and an 85% isolated yield of 1 (Entry 5).
Me
Bn
Me
Bn
Me
Bn
2.5 equiv.
10
Ar
Ar=p-MeOC6H4
70 o
O2, DMF
Ar
120 o
C
C
O
2aa
23-60%
inconsistent results
4a
1a
Scheme 2. Initial attempts at the one-pot reaction led to inconsistent results.
Whenever the yield of desired product 2aa was lower than
expected, unreacted starting material 4a and intermediate 1a was
usually present in varying amounts (see Supporting Information).
At this point, we therefore surmised that first the oxidation step 4a
to 1a was the cause of the inconsistent results. If the conversion
of 4a to 1a is incomplete before the addition of 3a and cooling of
the reaction to 70 °C, then no further oxidation of 4a to 1a can
take place at the lower temperature. Fortunately, a quick
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investigation of the oxidative Heck step showed that the reaction
is equally effective at higher temperatures of 100 or 120 °C (Table
2). Therefore, we proceeded to re-investigate the full one-pot
reaction at 120 °C, in the hope that the first oxidation step will be
less inconsistent at this higher temperature (Table 3).
Unfortunately, this still did not lead to higher yields of desired 2aa.
Another possible reason for the inconsistent oxidation step
4→1 was thought to be the stability of the active Pd(II) catalyst at
this high temperature of 120 °C: palladium black formation was
occasionally observed when equal amounts of Pd(OAc)2 and
ligand 10 were used (10 mol% respectively). This problem was
successfully circumvented by addition of excess ligand (vs. Pd).
Pleasingly, the addition of 20 mol% ligand 10, while maintaining
the Pd(OAc)2 loading at 10 mol%, resulted not only in
reproducible and reliable oxidation of 4 to 2, but also a much
faster reaction time of 18 h (Scheme 3).
Table 2. Effect of temperature on the oxidative Heck reaction.
O
O
O
Ar
O
Ar
Pd(OAc)2 (10 mol%)
Me
Bn
Me
Bn
B
B
10 (10 mol%)
O
O
B
Ar
Table 4. One-pot reaction with increased ligand loading.
O2, DMF
O
Ar
3a
1a
2aa
2.5 equiv.
Entry[a]
Temp (°C)
70
Time (h)
48
Conv. (%)[b]
Yield (%)[c]
1
2
3
100
100
95
n.d.
82
100
30
Entry[a]
X (°C)
t1+t2 (h)
y (equiv.)
2aa
(%)[b]
1a
(%)[b]
120
24
75
2+1.5[c]
2+1.5[d]
2+1.5[e]
2+1.5[f][g]
41
37
40
28
21
35
41
40
[a] Anhydrous conditions used. [b] Conversions by 1H NMR analysis. [c]
Isolated yield. n.d.=not determined.
1
2
3
4
100
120
70
29+46
22+73
17+69
20+68
120
Table 3. Increasing temperature of the second step does not improve yield.
[a] Anhydrous conditions used. [b] Determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as internal standard. No unreacted 4a observed in all
reactions. [c] 2nd portion added 17 h later. [d] 7 h later. [e] 20 h later. [f] 28 h later.
[g] p-Benzoquinone (1 equiv. added).
With much more consistent oxidation conditions in hand, the
one-pot procedure was investigated once again using the
increased ligand loading (Table 4). While the oxidation of 4 to 1
was now consistently proceeding to completion (as evidenced by
the absence of recovered starting material 4a), the oxidative Heck
reaction 4 to 2 now proved problematic. Although the oxidative
Heck reaction goes to completion when carried out as a separate
step, it struggles to go to completion under superficially similar
conditions in the one-pot reaction. Various attempts at portion-
wise addition of boroxine at a range of temperatures failed to
improve the yield of 2aa (Entries 1-4, Table 4). Significant
amounts of side products resulting from the boroxine 9, such as
homocoupling and phenol formation, is usually observed in the
one-pot procedure.[23] Stahl proposes that the first Pd(II)-
catalysed aerobic dehydrogenation produces hydrogen peroxide
as the by-product,[17] and it is therefore likely that the presence of
peroxide is facilitating the unwanted side-product formation in the
one-pot reaction.[23]
Entry[a]
Temp (°C)
100
2aa (%)[b]
1a (%)[b]
4a (%)[b]
1
2
44
44
-
-
25
-
120
[a] Anhydrous conditions used. [b] Determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as internal standard.
O
O
O
Pd(OAc)2 (10mol%)
10
Me
Bn
Me
Bn
(20 mol%)
O2, DMF, 120 oC
18 h
O
1a
4a
In order to overcome this problem, the boron coupling
partner was changed from arylboroxine 3 to the less reactive
arylboronic esters ArBpin 9. Pleasingly, this modification finally
provided consistent and reproducible results (Scheme 4A). The
desired product 2ab can now be formed from 4a in a one-pot
100% conv.
Scheme 3. Increasing ligand:Pd ratio significantly improves reproducibility of
oxidation step.
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procedure and consistent 65-67% yields over the two steps
(increases to 72% under non-anhydrous conditions, see later).
Another advantage of using ArBpin 9 is that it allows for a more
practical procedure, as it can be added to the reaction from the
outset. This is in contrast to arylboroxine 3, which had to be added
only after oxidation of 4 to 1 was complete; yields were otherwise
low due to more side-product formation from the arylboroxine 3.
in one-pot still renders the reaction more efficient than the
separate two-step procedure, which would require 10 mol% of
Pd(OAc)2 catalyst in each distinct step to go to completion under
a similar timescale.
Finally, carbonyl containing substituents on the aryl ring
results in low to moderate yields (47% 2al and 18% 2am)
regardless of catalyst loading. Interestingly, these functional
groups were tolerated well under the separate oxidative Heck
conditions.[10] These results imply that the amide and ester
functionality is sensitive to the first dehydrogenation step, rather
than the oxidative Heck coupling itself. Once again, it is possible
that the hydrogen peroxide generated in the first step[17] may be
responsible for the lower yields of 2al and 2am.
O
O
Pd(OAc)2 (10mol%)
10
O
O
Me
Bn
Me
Bn
B
(20 mol%)
+
O2, DMF, 120 oC
Ph
O
O
72 h
one-pot
2ab
4a
9b
anhydrous conditions: 65-67% (A)
non-anhydrous conditions: 72% (B)
Table 5. Aryl pinacol boronic ester scope in the one-pot reaction.
Scheme 4. Optimised one-pot dehydrogenation/oxidative Heck reaction.
With reproducible and optimal one-pot conditions in hand,
we set out to investigate the substrate scope of the reaction.
Firstly, the aryl pinacol boronic ester scope 9 was investigated
using model dione substrate 4a (Table 5). Unfortunately, the
optimal conditions for PhBpin 9b shown in Scheme 4A proved not
to be general, and much lower yields were frustratingly observed
when 9a and 9c were used (43% and 34% of 2aa and 2ac
respectively, Table 5). Increasing the catalyst and ligand loading
to 15 and 30 mol% led to no significant improvement (45% and
35% of 2aa and 2ac respectively).
At this point, our reasoning for this setback was that aryl
pinacol boronic esters 9 are a less reactive coupling source than
our original arylboroxine or arylboronic acid coupling partners.[23-
24] Under strictly anhydrous conditions, it was thought that the aryl
pinacol boronic esters 9 struggle to transmetallate in the absence
of base, thereby resulting in low yields of 2aa and 2ac. This
prompted us to attempt the reaction under “wet conditions”: non-
anhydrous solvents and non-dried glassware, in the hope that
residual water in the solvent will be sufficient to help promote
transmetallation.[23-25],[26] Pleasingly, these “wet” conditions
resulted in significant improvement in yields: 45% to 77% in the
case of 3aa and 35% to 68% in the case of 2ac (Table 5). These
non-anhydrous conditions were thus applied to the subsequent
substrate scope studies (Tables 5 and 6).
[a] Non-anhydrous solvent and non-dried glassware used (“wet conditions”)
unless otherwise stated. Isolated yields unless otherwise stated. [b] Extra
Pd(OAc)2 (5 mol%) added after 72 h and reaction left for a further 20 h. [c]
Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal
standard.
Results in Table 5 demonstrate that the one-pot reaction
works well for Ph- and naphthyl-pinacol boronic esters (72% 2ab
and 61% 2ad). Para- and meta-substitution are tolerated well
(70% 2ae and 68% 2af), but a drop in yield to 44% is observed
for the ortho-substituted tolyl 2ag, presumably due to steric
factors. Both electron-donating (2ae-ag, 2aa, 2aj, 2al) and
electron-withdrawing 2ac, 2ah-ai, 2ak) substituents are tolerated.
For a selection of these pinacol boronic esters, however, the
yields were fairly moderate using the standard conditions A (e.g.
2ac 32%). The use of a higher catalyst loading (15 mol%,
conditions B) significantly improved the yields (e.g. 2ac 68%) and
conditions B were thus adopted for the less reactive coupling
partners. Although this is admittedly a relatively high catalyst
loading, the fact that it is used to carry out two distinct reactions
Next, the 2,2-disubstituted cyclopentane-1,3-dione (4)
scope was investigated using aryl pinacol boronic esters 9h as
the model coupling partner (Table 6). Replacing the Ph ring in 4a
with a bulkier napthyl ring in 4b still produced the desired product
2bh in a good 79% yield. Replacing the benzyl substituent in 4a
with aromatic rings (4c-e) is also tolerated, with 2ch, 2dh and 2eh
formed in 75%, 77% and 71% yields respectively. An aryl/benzyl
substituent on the cyclopentane-1,3-dione 4 is not necessary for
good reactivity, as demonstrated by the formation of 2fh in a good
80% yield. An ester group is tolerated (2gh, 67%) as is the benzyl
protected alcohol (2hh, 54%). Finally, the spirocyclic 4i reacted
smoothly to form 2ih in 68% yield.
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conditions also results in full conversion, furnishing 2ah in 55%
yield after 3 days.
Table 6. 2,2-Disubstituted cyclopentane-1,3-dione scope in the one-pot
reaction.
Scheme 5: Tandem dehydrogenation/oxidative Heck under continuous flow
conditions.
Finally, we aimed to extend the one-pot procedure to the
t
enantioselective version (Scheme 6). Bu-PyOx ligand 13 was
previously used to successfully desymmetrise 1e via oxidative
Heck coupling to produce 2ea in 90:10 e.r.[10] We therefore
initiated our studies by investigating whether the less reactive
Pd(OAc)2/ligand 13 catalyst combination could oxidise 1e→4e.
The oxidation did indeed proceed to completion at 120 °C, but
required 72 h using 13 as ligand (see Supporting Information)
compared to 18 h using phenanthroline 10 as ligand (Scheme 3).
Nevertheless, this was deemed promising enough to employ in
the full on-pot procedure (Scheme 6).
A) One-Pot Reaction:
[a] Non-anhydrous solvent and non-dried glassware used (“wet conditions”).
Isolated yields.
i)
O
N
F3C
tBu
N
Following the successful development of the one-pot
procedure in batch, we proceeded to investigate the reaction
under continuous flow. Continuous flow chemistry is an attractive
alternative to traditional batch chemistry as it allows for strict
regulation of specific parameters (i.e. temperature, pressure, flow
rate) to control reactions which are otherwise too reactive,
exothermic or hazardous for conventional use.[27] The increased
surface to volume ratio is especially useful for facilitated scale-up
of gas-liquid reactions where a segmented flow can be beneficial
for improving interface mixing.[27a] In our case, it should allow for
more efficient O2 facilitated catalyst turn over. Furthermore, the
scaled-up reaction can be carried out more safely and practically
under flow conditions compared to batch, especially when a
flammable gaseous reagent such as oxygen is employed.[28] We
therefore sought to demonstrate this by carrying out the first auto-
tandem catalytic dehydrogenation/oxidative Heck under flow
conditions.[29]
O
13 (20 mol%)
O
O
Pd(OAc)2 (10 mol%)
DMA, 120 °C, O2, 72 h
Ar
ii) 3a (3.0 equiv.)
Pd(OAc)2 (10 mol%)
13 (11 mol%)
O
4e
2ea 60%
74:26 e.r.
DMA, 50 °C, O2, 94 h
B) Telescoped Reaction:
O
1. Pd(OAc)2 (10 mol%)
13 (20 mol%)
DMA, 120 °C, O2, 72 h
filtration through silica
O
Ar
O
2. 3a (3.0 equiv.)
Pd(OAc)2 (10 mol%)
13 (11 mol%)
O
2ea 70%
88:12 e.r.
4e
DMA, 50 °C, O2, 94 h
Scheme 6: Enantioselective dehydrogenation/oxidative Heck reactions.
The continuous flow reaction was initially investigated on
0.15 mmol of substrate 4 before it was scaled up to 1.0 mmol of
substrate (Scheme 5). Initial optimisation was carried out by
varying the flow rate of both the reaction mixture (pump A) and
oxygen (pump B, see Supporting Information). A flow rate of 0.4
mL min-1 and a reactor temperature of 120 °C was found to be
optimal for achieving full conversion to product 2ah in 3 days.
Pleasingly, scaling the reaction up to 1.0 mmol under the same
In addition to the longer reaction times, a few further
modifications were required compared to the racemic procedure.
Primarily, the second oxidative Heck step needs to be carried out
at a lower temperature of 50 °C for optimal enantioselectivity,
whereas the first dehydrogenation step requires 120 °C to
proceed. Secondly, in contrast to the phenanthroline 10 ligand
system used in the racemic protocol (Tables 5 & 6), switching to
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A solution of 2-benzyl-2-methylcyclopentane-1,3-dione 4a (20.3 mg, 0.100
mmol, 1.0 equiv.), 1,10-phenanthroline 10 (3.6 mg, 20.0 μmol, 0.2 equiv.),
Pd(OAc)2 (2.2 mg, 9.8 μmol, 0.1 equiv.) and 4,4,5,5-tetramethyl-2-phenyl-
1,3,2-dioxaborolane 9a (60.4 mg, 0.296 mmol, 3.0 equiv.) in DMF (1 mL)
was allowed to stir at room temperature for 20 minutes before being heated
to 120 °C under an O2 atmosphere (balloon) for 71 h. Upon completion of
the reaction, 2:1 Et2O:EtOAc (30 mL) was added and the resulting mixture
washed with H2O (2×10 mL) and brine (10 mL). The combined organic
layers were dried over MgSO4 and solvent was removed under reduced
pressure. The resulting crude product was purified by silica gel column
chromatography (25:1 → 20:1 petroleum ether:EtOAc) to yield 2-benzyl-2-
methyl-4- phenylcyclopent-4-ene-1,3-dione 2aa (19.8 mg, 0.072 mmol,
72%) as a yellow crystalline solid.
PyOx ligand 13 results in noticeable Pd-black formation after
dehydrogenation (i, Scheme 6A). Therefore, a second portion of
Pd/ligand 13 was added together with the coupling partner 3a
during the one-pot procedure (Scheme 1A). Thirdly, the less
ligating solvent dimethylacetamide (DMA) was used in order to
avoid issues with competitive ligation from DMF.[30][31]
Although the one-pot reaction proceeded to a satisfactory
yield of 60%, the enantioselectivity was moderate at 74:26 e.r. (vs.
90:10 e.r. when the oxidative Heck step is carried out
separately).[10] The moderate enantioselectivity was attributed to
the presence of unligated Pd formed during the aerobic
dehydrogenation step in the one-pot reaction. As a result, we
proceeded to investigate the telescoped reaction instead,
whereby the reaction mixture is filtered through a short plug of
silica to remove any unligated Pd prior to addition of the coupling
partner 3a (Scheme 6B). To our delight, the telescoped reaction
provided a good 70% yield of 2ea over two steps, in 88:12 e.r.,
which is comparable to the 90:10 e.r. achieved in the separate
oxidative Heck procedure.[10]
Full experimental procedures, characterisation for all new compounds and
copies of 1H and 13C NMR spectra are provided in the Supporting
Information.
Acknowledgements
We would like to thank the Engineering and Physical Sciences
Research Council and CRITICAT Centre for Doctoral Training for
financial support [Ph.D. studentship to CJCL; Grant code:
EP/L016419/1], Heriot-Watt University for ICS Undergraduate
Bursary (GMcM). Mass spectrometry data was acquired at the
EPSRC UK National Mass Spectrometry Facility at Swansea
University. Vapourtec is acknowledged for their technical support.
Conclusions
In conclusion, a Pd(II) catalyst system has been used to
successfully and efficiently catalyse two mechanistically distinct
reactions: dehydrogenation of 2,2-disubstituted cyclopentane-
1,3-diones (4→1) and the subsequent oxidative Heck coupling
(1→2) in a one-pot procedure. Such auto-tandem catalytic
reactions maximise efficiency and cut down on time, cost and
waste. The development of the optimal one-pot conditions was
initially a challenging prospect, as the optimal conditions for the
dehydrogenation step was not suitable for the oxidative Heck step
and vice versa. Initial optimisation studies were dogged with
reproducibility issues, which was thought to derive from partial
decomposition of the active Pd(II) catalyst. This problem was
solved by increasing the ligand loading (vs. Pd). Secondly, the
use of arylboroxine as a coupling partner was no longer optimal
in the one-pot protocol as it was susceptible to side-product
formation, thought to be facilitated by hydrogen peroxide
formation from the aerobic oxidation step. Changing from
arylboroxine 3 to the less reactive ArBpin 9 coupling partner
solved these issues and allowed for consistent and reproducible
one-pot dehydrogenation/oxidative Heck reactions.
Keywords: palladium • one-pot • oxidative Heck • aerobic
oxidation • auto-tandem catalysis
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Entry for the Table of Contents
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Claire J. C. Lamb, Bryan G. Nderitu,
Gemma McMurdo, John M. Tobin, Dr.
Filipe Vilela* and Dr. Ai-Lan Lee*
Page No. – Page No.
Auto-Tandem Catalysis: Pd(II)-
Catalysed Dehydrogenation/Oxidative
Heck of Cyclopentane-1,3-diones
A Pd(II) catalyst system has been used to successfully catalyse two mechanistically
distinct reactions: dehydrogenation of cyclopentane-1,3-diones and the subsequent
oxidative Heck coupling in a one-pot procedure. This auto-tandem catalytic reaction
is applicable to both batch and continuous flow processes. In addition, a telescoped
reaction involving enantioselective desymmetrisation of the all-C quaternary centre
was successfully achieved.
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