Dual Oxidation State Tandem Catalysis in the Palladium-Catalyzed Isomerization of Alkynyl Epoxides to Furans

Article abstract of DOI:10.1021/acscatal.8b02248

A two-catalyst system consisting of different oxidation states of palladium is described, which mediates the isomerization of alkynyl epoxides to furans. In a process termed dual oxidation state tandem catalysis , a multistep isomerization pathway is delineated in which the different metal oxidation states and ligands play independent mechanistic roles, but which, in combination, enable the use of milder reaction conditions and lower catalyst loadings than a single catalyst in isolation. In the present context, this rare example of a homobimetallic catalytic transformation provides a mild, scalable, and atom-efficient route for furan synthesis.

Full text of DOI:10.1021/acscatal.8b02248

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Letter
Dual oxidation state tandem catalysis in the palladium-
catalyzed isomerization of alkynyl epoxides to furans
Carlos Arroniz, Guilhem Chaubet, and Edward A. Anderson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02248 • Publication Date (Web): 03 Aug 2018
Downloaded from http://pubs.acs.org on August 4, 2018
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ACS Catalysis
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Dual oxidation state tandem catalysis in the palladium-catalyzed
isomerization of alkynyl epoxides to furans
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Carlos Arroniz, Guilhem Chaubet and Edward A. Anderson*
Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
ABSTRACT: A two-catalyst system comprising different oxidation states of palladium is described, which mediates the isomeriza-
tion of alkynyl epoxides to furans. In a process termed 'dual oxidation state tandem catalysis', a multistep isomerization pathway is
delineated in which the different metal oxidation states and ligands play independent mechanistic roles, but which in combination
enable the use of milder reaction conditions and lower catalyst loadings than a single catalyst in isolation. In the present context, this
rare example of a homobimetallic catalytic transformation provides a mild, scalable and atom-efficient route for furan synthesis.
KEYWORDS: Tandem catalysis, oxidation state, palladium, cyclization, oxygen heterocycles.
a
The integration of multiple catalysts in a single reaction to
mediate sequential chemical transformations, known as or-
thogonal tandem catalysis, has become widely recognised as a
powerful synthetic tool. In the field of transition metal cataly-
catA
catB
Substrate
Intermediate
Product
1
Previous work:
Orthogonal tandem catalysis
This work:
Dual oxidation state tandem catalysis
sis, such processes typically use two different metals, and there-
fore require careful control of reaction conditions to ensure
catA = Transition metal 1
catB = Transition metal 2
catA = Transition metal oxidation state 1
catB = Transition metal oxidation state 2
2
compatibility of the two catalyst systems. Here we describe a
rare example of an orthogonal tandem catalytic process in
which two different oxidation states of the same metal are em-
ployed, where a single catalyst is markedly less effective (Figure
O
H
b
CO2H
HO
HO
OH
OH
O
plakorsin D (cytotoxic)
3
1a). While distinct metal oxidation states are commonly in-
O
MeHN
voked as part of a single catalytic cycle (e.g. Pd(0)/Pd(II) spe-
cies), we show that co-existing Pd(0) and Pd(II) catalysts work
synergistically by displaying divergent affinity for consecutive
NO2
crassifogenin A (pneumonitis)
N
H
N
S
O
ranitidine (peptic ulcer disease)
N
N
O
4
substrates in a sequential reaction pathway. In the context of
O
NH
X
O
dantrolene
this work, this 'dual oxidation state tandem catalysis' enables a
mild isomerization of readily available alkynyl epoxides to fu-
N
N
O2N
O
X = NO2 (muscle relaxant)
azumolene
X = Br (malignant hyperthermia)
O
5
O
furazolidone (leishmaniasis)
rans, heterocycles that are important building blocks in organ-
ic chemistry, and present in many natural products and phar-
6
maceutical agents (Figure 1b).
Figure 1. a) Orthogonal tandem catalysis, and 'dual oxidation
state' tandem catalysis. b) Furan-containing pharmaceuticals and
bioactive natural products.
Our interest in alkynyl epoxides arose from earlier work on
palladium-catalyzed cyclizations of propargylic carbonates to
alkynylated heterocycles, via allenylpalladium intermediates.
7
oxidation of Pd(0) to Pd(II), with only the latter being capable
of effecting the conversion of 4b to 2b. To test this, the reac-
tion was again run under an inert atmosphere, but now with
both a Pd(0) and Pd(II) source present from the outset
(Pd(dba)2 and Pd(OAc)2, Entry 12). To our delight, smooth
conversion to the furan was observed, indicating a beneficial
effect of this dual oxidation state catalyst combination. Further
optimization enabled reduction of the reaction temperature (to
40 °C) and the loadings of both catalysts (to 1.25 mol%), since
the consumption of Pd(0) to produce Pd(II) was no longer re-
quired; under these optimized conditions (Entry 13), 2b was
isolated in 93% yield.
On extending this chemistry to epoxide electrophiles, reaction
of 1a (Table 1, Entry 1) afforded furan 2a, rather than the an-
ticipated tetrahydrofuran 3. With palladium catalysis of this
8
method for furan synthesis being almost unknown, epoxide
1b was selected for optimization of the reaction conditions.
Interestingly, both Pd(0) and Pd(II) catalysts were able to pro-
mote moderate yielding isomerizations of 1b to 2b, albeit high
temperatures were required (Table 1, Entries 2, 3). Mindful of
7,9
ligand effects in allenylpalladium chemistry, screening of
several bidentate phosphine ligands (Entries 4-6) and acidic
additives (Entries 7-9) resulted in improved reactivity, with the
combination
of
Pd(dba)2,
Xantphos,
and
2-
The benefit of using the dual oxidation state system was
confirmed through control experiments. Conducting the reac-
tion without Pd(II) (Entries 14-15) led only to formation of
small amounts of allene 4b at 1.25 mol% loading of Pd(dba)2,
and poor conversion to furan with 2.5 mol%, which may sug-
gest oxidation of non-ligated Pd(0) to generate sufficient Pd(II)
(trifluoromethyl)benzoic acid affording 2b in good yield at 70
°C (Entry 10). However, when this Pd(0)-catalyzed reaction
was carried out under an inert atmosphere, no furan was
formed (Entry 11), with allenyl ketone 4b instead observed by
H NMR spectroscopy, which then converted to furan 2b on
exposure of the reaction mixture to air. This suggested an
1
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Table 1. Optimization of the dual catalytic isomeri- Scheme 1. Reaction scope.
Page 2 of 7
a
a
1
2
3
4
5
6
7
8
zation.
Pd(OAc)2 (1.25 mol%)
Pd(dba)2 (1.25 mol%)
O
R2
HO
Conditions
(see Table)
O
R1
R2
R
Et
Xantphos (1.25 mol%)
o-CF3BzOH (5 mol%)
PhMe, 40 °C, 16 h
O
R1
Ph
R
Ph
O
1
2
O
Ph
O
Ph
3
1a: R = CH2CH2OH
1b: R = Et
2a: R = CH2CH2OH
2b: R = Et
4b
Ph
Et
Ph
Bn
Ph
Ph
Et
O
O
O
O
En-
try
T
tim Yieldb
(2, %)
Pd cat. (mol%)
additives (mol%)
Me
2b 93%b
91%c
2c 81%
2d 89%
2e 83%
(°C) (h)
9
1c
2
3
4
5
6
7
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(OAc)2 (10)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
dppf (10)
dppf (5)
-
100 16 24
100 16 40
110 16 39
OMe
10
11
12
13
14
15
16
17
18
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Et
Bn
Bn
Bn
Bn
Bn
Bn
O
O
O
MeO
PhO
Ph
2f 80%
2i 72%
2g 85%
2h 89%
dppm (5)
dppp (5)
dppe (5)
105
105
105
105
2
2
2
2
38
32
47
61
Bn
Et
O
O
O
F3CO
F
2j 85%
2k 82%
Cl
Cl
dppe (5)
Bn
Bn
O
O
O
o-ClBzOH (5)
F3C
2l 60%d
2m 65%d
2n 77%
8
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (6)
105
105
70
2
2
2
2
6
63
67
76
n.r.
76
dppe (5)
o-CF3BzOH (5)
Bn
Bn
9
Xantphos (5)
o-CF3BzOH (5)
O
O
O
MeO
2o 92%
2p 82%b
2q 91%b
10
11d
12d
13e
14e
15e
16e
17e
Xantphos (5)
o-CF3BzOH (5)
Bn
Bn
O
O
O
70
Xantphos (6)
o-CF3BzOH (6)
2r 75%
2s 88%
2t 82%
aReaction conditions: 0.2 mmol of 1 in degassed toluene (0.4 M)
under an Ar atmosphere. Yields are isolated yields. Reaction run
neat. Reaction run neat using 1 g (5.8 mmol) of 1b, with 0.5
mol% of each Pd catalyst. dReaction run for 24 h using double the
amount of catalysts / additives.
50
Pd(dba)2 (6)
Pd(OAc)2 (1)
Xantphos (6)
o-CF3BzOH (6)
b
c
40
40
16 93
16 0f
Pd(dba)2 (1.25)
Pd(OAc)2 (1.25)
Xantphos (1.25)
o-CF3BzOH (5)
Pd(dba)2 (1.25)
Pd(dba)2 (2.5)
Pd(OAc)2 (1.25)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Xantphos (1.25)
o-CF3BzOH (5)
to mediate allene-to-furan isomerization in the latter case.
Similarly, reactions run in the absence of Pd(0) (Entries 16-17)
also showed poor conversion to the furan, albeit Pd(0) could in
these cases be generated through Xantphos-mediated reduc-
40
16 30g
16 15
16 41
16 n.r.
Xantphos (1.25)
o-CF3BzOH (5)
10
tion. This is supported by the equivalent reaction in the ab-
40
Xantphos (1.25)
o-CF3BzOH (5)
sence of the phosphine ligand, which showed no reactivity (En-
try 18). These observations were reinforced by further experi-
ments at room temperature (with higher catalyst loadings, En-
tries 19-21), where only the binary system resulted in any suc-
cessful transformation (Entry 19); no reaction was observed at
room temperature with either Pd(0) or Pd(II) catalysis alone.
The potential for inhibition of isomerization by the dibenzyli-
dene acetone ligand under solely Pd(0) catalysis was also tested
using Pd(Pt-Bu3)2 as an alternative Pd(0) source (Entry 22).
However, no conversion was observed, other than a trace
quantity of allene 4b. Finally, the need for palladium catalyst
(in either oxidation state) was unequivocally demonstrated by
attempted metal-free reactions in the presence of Xantphos,
benzoic acid additive, or both (Entries 23-25). No reaction was
observed in any of these cases.
The scope of the reaction was studied through the synthesis
of 2,5-disubstituted furans featuring a variety of substituents
(Scheme 1). The formation of aryl/aliphatic and aryl/aryl di-
substituted furans proceeded in good to excellent yields in all
cases, with the arenes tolerating both electron-donating (2e-i)
and electron-withdrawing (2j-m) groups. Naphthyl derivatives
also underwent high-yielding cyclizations to give furans 2n
and 2o. Aliphatic sidechains containing linear, branched or
40
Xantphos (1.25)
o-CF3BzOH (5)
18e
o-CF3BzOH (5) 40
19e
25
9
80
Pd(dba)2 (6)
Pd(OAc)2 (5)
Xantphos (6)
o-CF3BzOH (6)
20e
21e
Pd(OAc)2 (10)
Pd(dba)2 (10)
-
25
25
62 n.r.
62 n.r.
Xantphos (10)
o-CF3BzOH (10)
22e
Pd(Pt-Bu3)2 (1.25)
40
16 0h
Xantphos (1.25)
o-CF3BzOH (5)
23e
24e
25e
–
–
–
Xantphos (1.25) 40
16 n.r.
16 n.r.
16 n.r.
o-CF3BzOH (5) 40
40
Xantphos (1.25)
o-CF3BzOH (5)
aReaction conditions: 0.2 mmol of 1b in toluene (0.2 M). I-
b
c
solated yields. Reaction of 1a (0.2 mmol) to form 2a in 1,4-
d
e
dioxane (0.1 M). Under Ar atmosphere. Under Ar in degassed
toluene (0.4 M). 25% yield of 4b. gDetermined by 1H NMR with
f
mesitylene as internal standard. h4% yield of 4b. n.r.=no reaction.
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Pd0(dba)2
and / or
Pd(0) or Pd(II) (1.25 mol%)
Bn
Bn
O
Pr
Bn
Pr
Bn
Bn
Pr
Pr
Bn
1
2
Xantphos (0 or 1.25 mol%)
o-CF3BzOH (5 mol%)
d8-toluene, 40 °C
O
O
Pr
O
Pr
Bn
PdII(OAc)2
(1.25 mol% each)
O
O
O
Pr
4p
5p
2p
1p
2p
4p
5p
1:1 ratio
3
4
5
6
7
8
9
Pd(dba)2 (1.25 mol%)
Xantphos (1.25 mol%)
Pd(OAc)2 (1.25 mol%)
Xantphos (1.25 mol%)
a
b
100
75
50
25
0
a
Pd(dba)2 (1.25 mol%)
Pd(OAc)2 (1.25 mol%)
60
60
50
40
30
20
10
0
50
40
30
20
10
0
1p (epoxide)
4p (allene)
5p (alkyne)
2p (furan)
4p (allene)
5p (alkyne)
2p (furan)
Time (h)
12
0
2
4
6
8
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
0
2
4
6
8
10
0
2
4
6
8
10
Time (h)
Time (h)
100
100
b
c
Pd(dba)2
(1.25 mol%)
Pd(OAc)2
(1.25 mol%)
Pd(OAc)2 (1.25 mol%)
100
75
50
25
0
c
100
75
50
25
0
100
75
50
25
0
0
0
0
0.5
0
0.5
0
2
4
6
8
10
Time (h)
0
2
4
Time (h)
6
8
10
12
0
2
4
6
8
10
1
Time (h)
Figure 3. H NMR spectroscopic profiles of reaction of a 1:1
mixture of allenyl ketone 4p and alkynyl ketone 5p under: a)
Pd(0) / Xantphos catalysis; b) Pd(II) / Xantphos catalysis; c)
Pd(II) catalysis (no Xantphos).
1
Figure 2. H NMR spectroscopic profiles of reaction of epoxide
1p under: a) Pd(0)/Pd(II) catalysis; b) Pd(0) catalysis; c) Pd(II)
catalysis. All reactions run using Xantphos (1.25 mol%) and o-
CF3BzOH (5 mol%) in degassed d8-toluene (0.4 M) at 40 °C.
catalyzed reaction profile (Figure 2b), a lag in the formation of
alkyne and allene was observed (~10 min, see insets), and also
in the consequent production of furan (~40 min). This sup-
ports the notion that a Pd(0) species is required to promote
epoxide ring-opening, and that Pd(OAc)2 in isolation is first
cyclic substituents were similarly accommodated, leading to
furans 2p-2t in excellent yields. On larger scales, the reaction
could be run under solvent-free conditions and the catalyst
loading further reduced, with 1 g (5.8 mmol) of 1b affording
2b in 91% yield using just 0.5 mol% of each pre-catalyst.
The unusual use of two different oxidation states of a single
metal in a tandem catalytic process is intriguing from a mech-
anistic perspective. In our optimization studies we had ob-
served the formation, and subsequent consumption, of allenyl
ketone 4b – suggesting that the reaction passes through this
intermediate. To probe this, the cycloisomerization of 1p un-
10
reduced to a Pd(0) complex to initiate the reaction.
To investigate cyclization of the two acyclic intermediates to
the furan, allenyl ketone 4p and alkynyl ketone 5p were isolat-
ed, and submitted to timecourse experiments in a 1:1 ratio
under solely Pd(0) or Pd(II) catalysis (Figures 3a and 3b respec-
tively). In both cases, a direct correlation was observed be-
tween the consumption of allene 4p and the formation of fu-
ran 2p, while alkyne 5p was barely consumed. Interestingly,
while Pd(OAc)2 proved an active catalyst from the outset of the
experiment, Pd(dba)2 was inactive for the first hour, suggesting
11
1
der the optimized conditions was monitored by H NMR spec-
troscopy (1.25 mol% of each precatalyst, Figure 2a). To our
surprise, allenyl ketone 4p was observed only briefly at the be-
ginning of this reaction, with β,γ-alkynyl ketone 5p instead
being rapidly formed over the first hour of the reaction, and
then consumed at a rate equivalent to the production of 2p.
The detection of this additional compound thus revealed the
involvement of two distinct intermediates (4p and 5p) in the
isomerization of 1p to 2p.
To provide insight on the specific contribution of each cata-
lyst and intermediate, the reaction was next monitored under
solely Pd(0) or Pd(II) catalysis. Using Pd(dba)2 (1.25 mol%,
Figure 2b), both allene 4p and alkyne 5p were formed rapidly
at the onset of the reaction; when the consumption of epoxide
ceased (~2 hours), the concentration of 5p began to decrease
while 4p continued to increase, implying that the alkyne is
formed directly from the epoxide, but then consumed / con-
verted to allene 4p. In sharp contrast to the two-catalyst sys-
tem (Figure 2a), only a trace of furan 2p was observed. The
profile of the reaction catalyzed by Pd(OAc)2 (1.25 mol%, Fig-
ure 2c) also showed accumulation of alkyne 5p, but markedly
less allene 4p; in this instance, 4p appears to be converted to
product 2p as the reaction proceeds. Compared to the Pd(0)-
12
that Pd(dba)2 must be oxidized to a Pd(II) species to trigger
allene cyclization. We further questioned whether Xantphos
was beneficial for the Pd(II)-catalyzed conversion of the alkyne
or allene to the ketone. In fact, the opposite was found to be
the case: the reaction profile in the absence of this ligand (Fig-
ure 3c) showed rapid consumption of both intermediates, with
this reaction reaching completion in <2 h, which contrasts
markedly with the reaction profile in Figure 3b. Paradoxically,
Xantphos seems to be required for the initial ring-opening of
the epoxide, but inhibits the later isomerization steps, presum-
ably by sequestering Pd(II), or by mediating reduction of Pd(II)
10
to Pd(0).
These experiments seemed to suggest a reaction sequence
involving initial Pd(0)-catalyzed epoxide ring opening, followed
by Pd(II)-catalyzed cyclization of an allene intermediate. To
further probe the relative rates of the different isomerization
processes, a 1:1:1 mixture of 1p, 4p and 5p was subjected to
the optimal dual catalysis conditions (Figure 4). Allene 4p was
consumed rapidly to produce 2p (<10 min, Figure 4b), indi-
cating that the cyclization of the allene to the furan is a fast
reaction step. Over a longer period (~45 min), epoxide 1p was
13
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ACS Catalysis
Scheme 2. Possible mechanistic pathway.
Page 4 of 7
O
Bn
Bn
Bn
1p
4p
5p
1
2
3
4
5
6
Pr
Pr
Bn
Pd(OAc)2 (1.25 mol%)
Pd(dba)2 (1.25 mol%)
1p
O
Pr
Pr
Bn
O
Xantphos (1.25 mol%)
o-CF3BzOH (5 mol%)
d8-toluene, 40 °C
O
O
2p
LnPd0
Bn
Pr
O
Pr
7
8
9
a
b
80
60
40
20
0
60
Bn
Pr
LnPdII
50
40
30
20
10
0
HO
O
H
Pd(0)
[Pd0(Xantphos)]
6
1p (epoxide)
4p (allene)
5p (alkyne)
2p (furan)
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
9
LnPd0
Bn
OH
Pr
0
2
4
6
8
10
00
0.1255
03.500
04.755
Time (h)
Time (min)
Bn
Bn
OH
Bn
Pr
Figure 4. 1H NMR spectroscopic profiles of reaction of a 1:1:1
mixture of alkynyl epoxide 1p, allenyl ketone 4p and alkynyl
ketone 5p under dual Pd(0)/Pd(II) catalysis. Graph a shows the
reaction profile for 9 hours. Graph b shows the reaction profile
for the first 45 minutes.
Pr
O
Pr
O
5p
7
4p
LnPdII
Pr
Bn
O
converted equally to furan 2p and alkyne 5p, the latter accu-
mulating until 1p is consumed. Finally, 5p is transformed into
furan 2p, presumably via (relatively slow) conversion to the
allene.
These experiments lead to a mechanistic proposal (Scheme
2) in which oxidative addition of Pd(0) into the alkynyl epoxide
generates allenylpalladium(II) species 6. Formal reductive
elimination via (intra- or intermolecular) deprotonation leads
to enol 7, which can tautomerize to alkynyl ketone 5p – a
LnPdII
Pr
[PdII(Xantphos)]
PdIILn
Pd(II)
Bn
O
LnPdII
Pr
Bn
O
8
2p
Pr
Bn
O
14
temporary resting state in the transformation. Further tau-
tomerization to the allenyl ketone 4p precedes Pd(II)-activated
cyclization, giving furanylpalladium complex 8; proto-
depalladation under the mildly acidic reaction conditions
would then afford furan 2p. That the furan appears to be
formed more rapidly while epoxide 1p is still being consumed,
compared to in its absence, may suggest an alternative path-
way exists for immediate conversion of the alkyne to the furan,
for example via a palladium complex of alkyne 5p formed by
enol-keto tautomerization of 9 before decomplexation of the
ACKNOWLEDGMENT
We thank the EPSRC for funding (CA, EAA) (EP/M019195/1),
and the Marie Skłodowska-Curie actions for an Individual Fellow-
ship (GC, GA N° 656012).
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15
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In conclusion, we have demonstrated an unusual tandem or-
thogonal catalysis process that benefits from the use of two ox-
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of alkynyl epoxides to furans. Such 'dual oxidation state' catal-
ysis is relatively unexplored and offers new possibilities in the
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, char-
acterization data and copies of NMR spectra.
AUTHOR INFORMATION
A
Combined High-Throughput Screening and Reaction Profiling
Approach toward Development of a Tandem Catalytic Hydrogenation for
the Synthesis of Salbutamol. Org. Proc. Res. Dev. 2017, 21, 1806-1814.
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Dimroth, J.; Weck, M. Compartmentalization of Incompatible Catalytic
Transformations for Tandem Catalysis. J. Am. Chem. Soc. 2015, 137,
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Assembled Molecular Containers for Catalyst Isolation Enabling Two-
Step Cascade Reactions. J. Am. Chem. Soc. 2017, 139, 6090-6093.
Corresponding Author
* E-mail: edward.anderson@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
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(14) We do not rule out other pathways, such as a 1,2-hydride shift from
the hydroxyl to directly generate the alkyne 5p.
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Furans via Palladium-Catalyzed Annulation of Alkyl 3-Oxo-6-
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((Trimethylsilyl)ethynyl)phenyl Acetates, and o-Alkynylphenols with
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SYNOPSIS TOC: The isomerization of alkynyl epoxides to furans using a two-catalyst system consisting of different oxida-
tion states of palladium, termed 'dual oxidation state tandem catalysis', is described. A multistep isomerization pathway is de-
lineated in which the different metal oxidation states and ligands play independent mechanistic roles. This is a rare example
of an orthogonal tandem catalytic transformation in which two oxidation states of the same metal show benefits over a single
catalyst system.
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