Palladium(II)-catalyzed oxidative carbocyclizations represent an important class of
reactions, which have provided powerful and atom-economical approaches to carbo- and
heterocycles.1–5 In particular, oxidative carbocyclization strategies have been efficiently
applied to total synthesis.3 As a continuation of our research on the palladium-catalyzed
oxidative carbocyclizations of dienallenes4 and enallenes,5 we recently developed
palladium-catalyzed arylating or borylating oxidative carbocyclizations of allenynes6
by using the corresponding arylboronic acid or B2pin2.7
In connection with our previous studies on acetoxylation(hydroxylation)/carbocyclizations
of dienallenes (Scheme 1 a),4 we envisioned an oxidative acetoxylation/carbocyclization
of allenynes 1 in the presence of HOAc/LiOAc, with a simple PdII salt as the catalyst
(Scheme 1 b). Based on the previously proposed mechanism,4, 5 the reaction was expected
to be initiated by allene attack on PdII through allylic C–H bond cleavage followed
by alkyne insertion to give acetoxylated triene product 2. However, the reaction took
an unexpected path, and herein we report on a palladium-catalyzed oxidative acyloxylation/carbocyclization
of allenynes 1 to give acyloxylated vinylallenes 3 (Scheme 1 b). An aerobic version
of this transformation was also realized by using catalytic amounts of p-benzoquinone
together with cobalt salophen.
Scheme 1
Palladium-catalyzed oxidative acetoxylation/carbocyclization of dienallenes and allenynes
(E=CO2Me).
In our preliminary study, we chose allenyne 1 a with a pentyl group on the triple
bond as the model substrate to study the oxidative carbocyclization in the presence
of HOAc/LiOAc. To our surprise, treatment of 1 a with Pd(OAc)2 (5 mol %), LiOAc⋅2
H2O (2 equiv), and p-benzoquinone (BQ; 1.2 equiv) at 60 °C in HOAc gave an acetoxylated
vinylallene product 3 aa in 61 % yield along with dimer 4 a in 10 % yield (Table 1,
entry 1). The reaction in the absence of LiOAc⋅2 H2O also proceeded smoothly to give
3 aa in 63 % yield and 4 a in 10 % yield (Table 1, entry 2, defined as method A),
whereas the replacement of acetic acid with acetone as the solvent resulted in a complicated
mixture (entry 3). In a solvent study, acetone was found to work as solvent in the
presence of acetic acid (5 equiv) for this transformation (Table 1, entry 4, defined
as method B). Compared with 60 °C, room temperature or a higher temperature (e.g.
80 °C) were found to give inferior yields of 3 aa (compare entries 2, 5 and 6 in Table
1). When Pd(OAc)2 was replaced with Pd(OOCCF3)2 or [Pd(acac)2], the yield of carbocyclized
product 3 aa decreased (Table 1, entries 7 and 8). No conversion was observed with
PdCl2 or [PdCl2(MeCN)2] as the catalyst, and all the starting material 1 a was recovered
in these cases (Table 1, entries 9 and 10). A control experiment without palladium
under otherwise the same reaction conditions showed no conversion of 1 a according
to 1H NMR spectroscopy. The effect of palladium catalyst loading was also investigated.
A lower loading (2 mol %) of Pd(OAc)2 gave only 86 % conversion of 1 a with a yield
of 3 aa of only 50 % (Table 1, entry 11). A higher catalyst loading (10 mol %) also
resulted in a lower yield of 3 aa (Table 1, entry 12).
Table 1
Screening of reaction conditions in the palladium-catalyzed oxidative carbocyclization
of allenyne 1 a with acetic acid.
Entry
PdII
Solvent
T [°C]
Yield of 3 aa [%]a
Yield of 4 a [%]a
1b
Pd(OAc)2
HOAc
60
61
10
2
Pd(OAc)2
HOAc
60
63(63c)
10
3b
Pd(OAc)2
acetone
60
0
0
4d
Pd(OAc)2
acetone
60
62(60c)
6
5
Pd(OAc)2
HOAc
25
<4
0
6
Pd(OAc)2
HOAc
80
42
10
7
Pd(OOCCF3)2
HOAc
60
52
14
8
[Pd(acac)2]
HOAc
60
46
8
9
PdCl2
HOAc
60
0
0
10
[PdCl2(MeCN)2]
HOAc
60
0
0
11e,f
Pd(OAc)2
HOAc
60
50
9
12g
Pd(OAc)2
HOAc
60
38
10
a
Yield determined by NMR spectroscopy with anisole as the internal standard.
b
LiOAc⋅2H2O (2 equiv) was added.
c
Yield of isolated product.
d
HOAc (5 equiv) was added.
e
2 mol % Pd(OAc)2 was used.
f
14 % of 1 a was recovered.
g
10 mol % Pd(OAc)2 was used.
With the optimized conditions in hand, we investigated the scope of allenynes in the
presence of acetic acid (Table 2). When both methyl groups on the terminal carbon
atom of the allene moiety of 1 a were replaced by pentamethylene (forming the cyclohexylidene
group) (1 b), the reaction with acetic acid gave the cyclized vinylallene product
3 ba in 66 % yield with method A. By altering one methyl group on the allene to an
ethyl group, the unsymmetrical allenyne 1 c displayed a similar reactivity. The reaction
of allenyne having an ethyl group (1 d) on the triple bond also reacted smoothly to
afford product 3 da in 52 % yield by employing method B. Methyl-substituted allenyne
1 e gave terminal allene product 3 ea in 39 % yield. Moreover, the reactions of allenynes
bearing two hydroxy or ether groups (1 g and 1 h) instead of the carbomethoxy groups
provided the corresponding products 3 ga and 3 ha in good yields. Even the allenynes
(1 i and 1 j) with the ether as the tether group also worked well and afforded six-membered
ring products 3 ia and 3 ja in moderate yields, respectively.
Table 2
Allenyne scope.a
Entry
Allenyne
Product
Yield [%]
1
63 (method A) 60 (method B) 62 (method C)
2
66 (method A) 67 (method C)
3
66 (method A) 51 (method C)
4
52 (method B)
5b
39 (method A)
6
60 (method B)
7
70 (method B)
8c
51 (method A)
9c
52 (method A)
a
Reaction method A: Pd(OAc)2 (5 mol %), BQ (1.2 equiv), allenyne (1.0 equiv), HOAc,
60 °C, 17 h; method B: Pd(OAc)2 (5 mol %), BQ (1.2 equiv), HOAc (5.0 equiv), allenyne
(1.0 equiv), acetone, 60 °C, 17 h; method C: Pd(OAc)2 (5 mol %), [Co(salophen)] (5
mol %), BQ (20 mol %), HOAc (5.0 equiv), allenyne (1.0 equiv), acetone, 1 atm O2,
60 °C, 18 h.
b
Reaction time: 23 h.
c
Reaction time: 5 h. E=CO2Me.
In addition, the reaction of allenyne (1 f) with a phenyl substitution on the alkyne
gave no acetoxylation product, but afforded cycloisomerization product 5 f (8 %),6
dimerization products 6 f (4 %) and 7 f (29 %); the reaction may be initiated by an
allylic C–H bond cleavage on the allene side (Scheme 2).
Scheme 2
The reaction of phenyl-substituted allenyne 1 f.
Furthermore, the scope of the reaction with respect to the carboxylic acid coupling
partner was also studied by using allenyne 1 b (Scheme 3). In addition to acetic acid,
aliphatic carboxylic acids such as propionic acid or butyric acid reacted smoothly
by employing method A to give the cyclized vinylallene products 3 bb (65 %) and 3
bc (74 %), respectively. Moreover, benzoic acid and other functionalized aromatic
carboxylic acids bearing methoxy, fluorine, or chlorine groups were also tolerated
under the oxidative procedure giving the corresponding carbocyclization products in
good yields (64–84 %). Interestingly, only trace amounts (<1 %) of dimerization product
4 b (formed by dimerization of 1 b through the mechanism shown in Scheme 6) were observed
in the reactions in Scheme 3.
Scheme 3
Carboxylic acid scope. [a] Method A was used.
Oxidation processes utilizing molecular oxygen have attracted considerable attention
in recent years,8 and therefore the oxidative carbocyclization in Table 2 and Scheme
3 was studied under various aerobic conditions. It was found that the combination
of cocatalyst [Co(salophen)]9 with molecular oxygen (balloon) in the presence of catalytic
amounts of BQ (20 mol %) permits the efficient reoxidation of Pd0 to PdII and makes
it possible to use O2 as the oxidant in the acetoxylation/carbocyclization of allenynes
(Table 2, entries 1–3 with method C. For details, please see Scheme S1 in the Supporting
Information).
The synthetic potential of the acyloxylated allene products was demonstrated by a
few transformations of the representative product 3 aa. Acetoxyallene 3 aa was first
converted to 3,4-allenol 8 through hydrolysis10 (Scheme 4). Under different cyclization
conditions,11 the prepared 3,4-allenol 8 was subsequently cyclized to various dihydropyran-fused
bicyclic skeletons such as 9 (81 %),11a
10 (82 %),11b and 11 (85 %),11c respectively.
Scheme 4
Application of the acyloxylated allene product 3 aa.
To gain some insight into the reaction mechanism, the deuterium kinetic isotope effect
(KIE) was determined from the experiment where a 1:1 mixture of 1 a and [D2]-1 a was
allowed to react in acetic acid under the reaction conditions used in Table 2 [Eq.
(1)]. The product ratio 3 aa/[D1]-3 aa at 13 % yield (ca. 35 % conv.) was 4.8:1, and
from this ratio the KIE was determined to k
H/k
D=5.5.12 Furthermore, the intrinsic KIE from intramolecular competition was determined
by the use of [D1]-1 a as the allenyne substrate. In this case k
H/k
D=6.1 [Eq. (2)]. Parallel kinetic experiments using 1 a and [D2]-1 a provided an intermolecular
KIE (k
H/k
D, from initial rate) value of 5.1 [Eqs. (3) and (4)]. These results indicate that
the propargylic C–H bond cleavage is the rate-determining step in the reaction.13
Two control experiments with the deuterium-labeled allenynes [D6]-1 a and [D2]-1 a
were carried out under the standard conditions. Allenyne [D6]-1 a gave an increased
yield (80 %) of acetoxylated vinylallene ([D6]-3 aa) compared to the undeuterated
allene, whereas the yield of the corresponding dimer products decreased to 2 % (Scheme
5 a). In contrast, the allenyne [D2]-1 a gave only 20 % yield of acetoxylated vinylallene
along with an increased yield (16 %) of the corresponding dimers (Scheme 5 b).
Scheme 5
The control reactions of allenynes [D6]-1 a (a) and [D2]-1 a (b).
A control experiment replacing the allenyne by an enyne, dimethyl-2-(3′-methylbut-2′-enyl)-2-(pent-2′-ynyl)malonate,
was also carried out under the standard conditions of Table 2 using method A. No formation
of the corresponding cyclized allene products was observed, which shows that the allene
moiety in the substrate is crucial for the oxidative transformation (Scheme S2 in
the Supporting Information).
On the basis of these experimental findings, we propose the mechanism shown in Scheme
6. π-Complex formation of 1 with Pd(OAc)2 to give chelate A and subsequent rearrangement
involving a propargylic C–H bond cleavage would produce vinylpalladium intermediate
B. Intramolecular vinylpalladation of the allene moiety would generate (π-allyl)palladium
intermediate D, which is attacked by an acetate nucleophile (coordinated or external)14
to give 3. Competing allene attack in A through allylic C–H bond cleavage4d and subsequent
alkyne insertion would generate intermediate E. Reaction of E with another molecule
of allenyne 1 through insertion of the vinyl–Pd bond of E into the allene moiety of
1 would give the π-allyl species F, which would yield dimers (4, 6, and 7; for details,
see the Supporting Information). Also, a mechanism involving a pallada(IV)cyclopentene7
intermediate C could be possible, which would generate intermediates D and E through
β-H elimination and subsequent loss of HOAc leading to product 3 and dimeric by-products,
respectively. Although β-H elimination in electron-deficient PdIV intermediates is
considered to be less likely,15 β-H elimination from less electron-deficient PdIV
intermediate C may occur.
Scheme 6
Plausible mechanisms for the palladium-catalyzed oxidative acetoxylation/carbocyclization
of allenyne 1.
One could also consider a mechanism through acetoxypalladation of the terminal C=C
double bond of the allene, followed by insertion of the alkyne into the newly generated
vinyl–Pd bond and subsequent β-H elimination to give acetoxyallene 3 (for a detailed
mechanism, see the Supporting Information). However, with this mechanism one would
not obtain any significant change of the ratio between vinylallene 3 and dimers with
dideuterated species [D2]-1 a compared to nondeuterated 1 a, since with this mechanism
the ratio between the competing pathways leading to 3 and dimers would be determined
in the first step without any possible isotope effect (see the Supporting Information).
The low ratio of 1.3:1 between [D1]-3 aa and dimers from [D2]-1 a (Scheme 5 b) therefore
rules out this mechanism. In contrast, the two mechanisms proposed in Scheme 6 (via
intermediates B and C, respectively) are in agreement with the results observed in
Equations (1)–(4) and Scheme 5.
In summary, we have developed a novel palladium-catalyzed oxidative carbocyclization
of allenynes in the presence of various carboxylic acids, providing access to potentially
synthetically useful acyloxylated vinylallenes. During this carbocyclization a new
C–C bond, a new C–O bond, and a new allene structure are formed. Furthermore, an aerobic
version of this transformation using a catalytic amount of BQ was developed to enhance
the utility of this method. According to the results of deuterium labeling experiments,
we propose that the reaction of the allenynes proceeds through competing propargylic
and allylic C–H bond cleavage pathways or via a pallada(IV)cyclopentene intermediate
with competing β-eliminations. Further studies on the mechanism and synthetic application
of this reaction are ongoing.
Experimental Section
Typical experimental procedure for palladium-catalyzed oxidative acyloxylation/carbocyclization
of allenyne 1: To a mixture of BQ (26.2 mg, 0.24 mmol) and Pd(OAc)2 (2.4 mg, 0.01
mmol) were added 1 b (69.5 mg, 0.20 mmol) and HOAc (0.4 mL) at room temperature. The
reaction was stirred at 60 °C for 17 h. After full consumption of starting material
1 b, as monitored by TLC, the reaction was cooled to room temperature, diluted with
Et2O (20 mL), and quenched with H2O (5 mL). The organic phase was separated and the
aqueous phase was extracted with Et2O (2×20 mL). The combined organic layers were
washed with H2O and dried over anhydrous Na2SO4. Evaporation and column chromatography
on silica gel (pentane/ethyl acetate=10:1) afforded 3 ba (53.3 mg, 66 %) as a liquid;
1H NMR (400 MHz, CDCl3): δ=5.74 (d, J=1.2 Hz, 1 H), 5.34–5.24 (m, 1 H), 3.73 (s, 3
H), 3.72 (s, 3 H), 3.18 (d, J=3.6 Hz, 2 H), 2.46–2.38 (m, 1 H), 2.36–2.24 (m, 1 H),
2.08–1.98 (m, 2 H), 1.97 (s, 3 H), 1.66–1.46 (m, 7 H), 1.45–1.18 (m, 5 H), 0.89 ppm
(t, J=7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ=198.1, 170.8, 170.7, 169.1, 149.4,
125.3, 104.2, 95.0, 79.7, 63.5, 52.9, 52.8, 36.6, 34.8, 33.6, 31.2, 29.2, 25.4, 22.1,
21.6, 21.52, 21.50, 13.9 ppm; HRMS (ESI): calc. for C23H32NaO6 [M+Na]+: 427.2091;
found: 427.2091.