Palladium-catalyzed carbene migratory insertion using conjugated ene-yne-ketones as carbene precursors

Article abstract of DOI:10.1021/ja4058844

Palladium-catalyzed cross-coupling reactions between benzyl, aryl, or allyl bromides and conjugated ene-yne-ketones lead to the formation of 2-alkenyl-substituted furans. This novel coupling reaction involves oxidative addition, alkyne activation-cyclization, palladium carbene migratory insertion, β-hydride elimination, and catalyst regeneration. Palladium (2-furyl)carbene is proposed as the key intermediate, which is supported by DFT calculations. The palladium carbene character of the key intermediate is validated by three aspects, including bond lengths, Wiberg bond order indices, and molecular orbitals, by comparison to those reported for stable palladium carbene species. Computational studies also revealed that the rate-limiting step is ene-yne-ketone cyclization, which leads to the formation of the palladium (2-furyl)carbene, while the subsequent carbene migratory insertion is a facile process with a low energy barrier (<5 kcal/mol).

Full text of DOI:10.1021/ja4058844

Article
pubs.acs.org/JACS
Palladium-Catalyzed Carbene Migratory Insertion Using Conjugated
Ene−Yne−Ketones as Carbene Precursors
Ying Xia,†,§ Shuanglin Qu,‡,§ Qing Xiao,†,§ Zhi-Xiang Wang,*,‡ Peiyuan Qu,† Li Chen,† Zhen Liu,†
Leiming Tian,† Zhongxing Huang,† Yan Zhang,† and Jianbo Wang*,†
†Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of the Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
‡School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Palladium-catalyzed cross-coupling reactions
between benzyl, aryl, or allyl bromides and conjugated ene−yne−
ketones lead to the formation of 2-alkenyl-substituted furans.
This novel coupling reaction involves oxidative addition, al-
kyne activation−cyclization, palladium carbene migratory in-
sertion, β-hydride elimination, and catalyst regeneration.
Palladium (2-furyl)carbene is proposed as the key intermedi-
ate, which is supported by DFT calculations. The palladium
carbene character of the key intermediate is validated by three
aspects, including bond lengths, Wiberg bond order indices, and molecular orbitals, by comparison to those reported for stable
palladium carbene species. Computational studies also revealed that the rate-limiting step is ene−yne−ketone cyclization, which
leads to the formation of the palladium (2-furyl)carbene, while the subsequent carbene migratory insertion is a facile process with
a low energy barrier (<5 kcal/mol).
received considerable attention in past years.8 For example, the
INTRODUCTION
■
transition-metal-catalyzed cycloisomerization of ene−yne−
Transition-metal-catalyzed cross-coupling reactions involving
diazo compounds or N-tosylhydrazones as coupling partners
ketones has been explored by Uemura and Ohe9 and more
recently by Vicent and Lop
́
ez10 and others.11 In those trans-
have emerged as a practical synthetic method for C−C and
CC bond formation.1,2 In particular, with palladium catalysts,
diazo compounds or N-tosylhydrazones can be coupled with ben-
zyl halides,3a,b aryl halides,3c,d allyl halides,3e and other electro-
philes.3f−i Under oxidative conditions, they can also be coupled
with nucleophiles such as arylboronic acids4a−c and terminal al-
kynes.4d In these transformations, formation of the palladium
carbene and the subsequent migratory insertion is proposed to
play the key role in amalgamating the classical cross-coupling and
carbene chemistry (eq 1).5,6
formations, the alkyne moiety is activated by a transition metal,
which is then attacked by the carbonyl oxygen through 5-exo-dig
cyclization to form zwitterionic intermediate A or its resonance
structure, metal (2-furyl)carbene complex B (eq 2). Complex B
can subsequently participate in various transformations, such as
cyclopropanation, ylide formation, X−H insertion, and other
related reactions.9−12 For example, Ohe, Uemura, and co-
workers reported the polymerization of ene−yne−ketones
through Rh(II) (2-furyl)carbene [B with M = Rh(II)].9e Vicente,
Diazo compounds, either used directly or generated in situ
from N-tosylhydrazones, have served as the common precursors
in various catalytic carbene transfer reactions.7 This has also been
the case for the newly developed cross-coupling reactions
involving palladium carbenes, as shown in eq 1. The obvious
drawback of diazo compounds is their explosive and toxic nature.
It is thus highly desirable to search for alternative precursors for
metal carbenes. In this context, the activation of alkynes with
transition metals to generate carbenoid species, which can serve
as safe and effective alternatives to diazo decomposition, has
́
Lopez, and co-workers demonstrated that Zn(II) (2-furyl)-
carbenes [B with M = Zn(II)] obtained from ene−yne−ketones
undergo cyclopropanation and X−H (X = O, Si) insertions.10
More recently, Jiang and co-workers reported the oxidation of
Cu(I) (2-furyl)carbenes [B with M = Cu(I)] from ene−yne−
ketones.11b These studies demonstrate that metal(2-furyl)carbene
Received: June 12, 2013
© XXXX American Chemical Society
A
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formation from ene−yne−ketones is general and that these
carbenes may undergo various transformations.
Table 1. Optimization Experiments for the Reaction of
Ene−Yne−Ketone 1a and 4-Methylbenzyl Bromide (2a)
a
In connection with our interest in cross-coupling reactions
involving palladium carbenes, we conceived the possibility of
developing precursors other than diazo compounds for palladium
carbene generation. In this way, analogous palladium-catalyzed
cross-coupling reactions between electrophiles and various
metal carbene precursors (eq 1) should be realized, thus
significantly expanding the scope of such coupling reactions. To
verify this conjecture, we chose the ene−yne−ketone system to
generate palladium (2-furyl)carbenes [B, M = Pd-R]. We
expected similar palladium carbene migratory insertion to
occur from the palladium (2-furyl)carbenes generated in this
way. Herein we report the palladium-catalyzed cross-coupling
reaction between ene−yne−ketones and benzyl, aryl, or allyl
bromides. The reaction is efficient and tolerates various func-
tional groups, affording 2-alkenyl-substituted furans in moderate
to good yields. Density functional theory (DFT) calculations
revealed the details of the reaction mechanism, which includes
oxidative addition, alkyne activation−cyclization, palladium
carbene migratory insertion, β-hydride elimination, and catalyst
regeneration. The DFT calculations support the involvement of
palladium (2-furyl)carbene as the reactive intermediate and also
indicate that the migratory insertion is a facile process with a low
energy barrier (<5 kcal/mol).
Pd (mol %)/
yield
b
entry
1
ligand (mol %)
base
solvent
MeCN
(%)
Pd2(dba)3 (2.5)/P(2-
furyl)3 (20)
Cs2CO3
33
2
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Cs2CO3
K2CO3
LiOtBu
iPr2NEt
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
dioxane
DCE
40
3
43
4
trace
62
5
6
trace
51
7
iPr2NH
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
−
8
22
9
25
10
11
12
13
34
THF
1:1 iPr2NEt/MeCN
28
46
iPr2NEt
iPr2NEt
DMF
79
49
c
14
Pd2(dba)3 (2.5)/
XPhos (15)
DMF
a
The reaction was carried out with 1a (0.24 mmol) and 2a
RESULTS
b
■
(0.20 mmol) in 2.0 mL of solvent at 90 °C for 2 h. Yields of products
isolated by column chromatography. The reaction time was 12 h.
c
The ene−yne−ketone substrates 1a−o were easily prepared via
Knoevenagel condensation of conjugated yne−aldehydes with
1,3-dicarbonyl compounds.13 With these substrates in hand,
we first studied their coupling reactions with benzyl bromides.
At the outset of this investigation, ene−yne−ketone 1a and
4-methylbenzyl bromide (2a) were employed as the substrates
(Table 1). We were delighted to find that in the presence of
2.5 mol % Pd2(dba)3, 20 mol % P(2-furyl)3, and 3 equiv of
Cs2CO3, the expected 2-alkenyl-substituted furan 3a was ob-
tained in 33% yield (entry 1). By screening the palladium catalyst,
we found that simple Pd(PPh3)4 could afford a higher yield
(entry 2). A series of bases were then tested with Pd(PPh3)4
as the catalyst (entries 3−7).14 We found that the organic
Scheme 1. Scope of Ene−Yne−Ketones in the Pd-Catalyzed
a
Coupling Reaction
i
base Pr2NEt gave the best result, improving the yield to 62%
(entry 5). Through further inspection of the solvent, we found
that N,N-dimethylformamide (DMF) was more suitable for this
transformation (entries 8−13). Interestingly, the bulky and
electron-rich XPhos ligand made this transformation sluggish,
and only a moderate yield was obtained when the reaction time
was extended to 12 h (entry 14). Thus, the optimal reaction
conditions were found to be Pd(PPh3)4 as the catalyst, iPr2NEt as
the base, and DMF as the solvent (entry 13). It is noteworthy
that only one stereoisomer was obtained in this reaction. The
configuration of the formed double bond of 3a was confirmed to
be Z through nuclear Overhauser effect spectroscopy (NOESY)
experiments. The excellent Z stereoselectivity can be rationalized
by the transition state of the β-hydride elimination of the
palladium intermediate, in which a strong interaction between
the arene and the tert-butyl group is avoided.
The scope of this transformation was first explored by using
various ene−yne−ketones 1a−j and 2a (Scheme 1). The influ-
ence of the R4 group, which is adjacent to the alkyne moiety, was
explored first (3a−d). When the tert-butyl group was changed
to the less hindered trimethylsilyl (TMS) group, the product 3b
was obtained in slightly improved yield, albeit with decreased
selectivity. The bulky triisopropylsilyl (TIPS) group made this
a
Unless otherwise noted, the reactions were carried out with 1a−j
(0.24 mmol), 2a (0.2 mmol), Pd(PPh3)4 (5 mol %), and iPr2NEt (0.6
mmol) in DMF (2.0 mL) at 90 °C for 2 h. Yields of products isolated
by column chromatography are shown. E/Z ratios were determined
b
c
d
by GC−MS. The number in parentheses is the reaction time.
B
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Scheme 2. Scope of Benzyl Bromides in the Pd-Catalyzed
Coupling Reaction
Scheme 3. Pd-Catalyzed Couplings of Ene−Yne−Ketones and
a
a b
,
Aryl Halides
a
Reactions were carried out with 1a (0.24 mmol) and 2 (0.2 mmol),
i
Pd(PPh3)4 (5 mol %), and Pr2NEt (0.6 mmol) in DMF (2.0 mL) at
90 °C for 2 h. Yields of products isolated by column chromatography
are shown.
b
Table 2. Optimization Experiments for the Reaction of Ene−
a
Yne−Ketone 1a and 4-Bromotoluene (4a) or 4-Iodotoluene (4b)
a
Reactions were carried out with 1 (0.26 mmol), 4 (0.2 mmol),
b
entry
Pd (mol %)/ligand (mol %)
Pd(PPh3)(5)
solvent
yield (%)
Pd(OAc)2 (5 mol %), XPhos (15 mol %), and iPr2NEt (0.6 mmol) in
MeCN (2.0 mL) at 90 °C for 2 h. Isolated yields are shown. The
yield in parentheses was obtained by using Pd2(dba)3 (2.5 mol %) in
place of Pd(OAc)2 (5 mol %).
b
c
1
2
3
4
5
6
DMF
25
40
19
65
29
31
trace
42
23
34
68
72
75
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/XPhos(15)
Pd2(dba)3(2.5)/PCy3(15)
Pd2(dba)3(2.5)/2-PhC6H4PCy2(15)
Pd(OAc)2(5)/XPhos(15)
Pd(OAc)2(5)/XPhos(15)
Pd(OAc)2(5)/XPhos(15)
DMF
dioxane
MeCN
toluene
DCE
transformation sluggish. The reaction was completed in 30 h,
affording 3c in 66% yield. Compared with 1b, the slow reaction of
1c may result from the difficulty of activation of the triple bond
by the palladium complex due to the greater steric hindrance of
the TIPS group compared with the TMS group. However, the
bulky TIPS group afforded complete control of the stereo-
selectivity. For R4 = phenyl, the corresponding product 3d was
also obtained in moderate yield, but the selectivity was poor
because of the similar steric bulk of the phenyl and furyl moieties.
The influence of the nucleophilic carbonyl oxygen was also
explored (3f, 3g). In the preparation of ene−yne−ketones 1f
and 1g via Knoevenagel condensation of the conjugated yne−
aldehyde with unsymmetrical 1,3-dicarbonyl compounds, a
c
7
d
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8
9
10
11
e
12
ef
,
13
a
The reaction was carried out with 4a (0.20 mmol), 1k (0.24 mmol)
and iPr2NEt (0.6 mmol) in 2.0 mL of solvent, unless otherwise noted.
b
c
i
Isolated yields. Cs2CO3 was used as the base instead of Pr2NEt.
d
e
iPr2NH was used as the base instead of Pr2NEt. 0.26 mmol of 1k
i
f
was used. The reaction was carried out using 4b.
C
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moiety, while the ester carbonyl oxygen cannot undergo the
similar process because of its lower nucleophilicity.11b,c Besides,
in view of the reaction times, the reaction of 1g was slower than
those of 1a and 1f, and benzoyl-type ene−yne−ketone 1e
showed a much slower reaction. These results indicate that the
reactivity of the carbonyl oxygens in this transformation are
ordered as follows: acetyl > propionyl > benzoyl ≫ ester.11b,c
Finally, we found that other types of ene−yne−ketones could
also undergo similar reactions, although the yields were
diminished (3h−j). The low yields in these cases are attributed
to the instability of both the substrates and the products under
the reaction conditions.
Scheme 4. Pd-Catalyzed Coupling Reaction of Ene−Yne−
a
Ketones and Allyl Bromides
For R4 = methyl (1l), three isomers (3-la, 3-lb, and 3-lc) can
be obtained depending on the selectivity of the β-hydride
elimination (eq 3). The ratio of the three isomers was 78:4:18,
indicating that the benzyl hydride elimination afforded the major
product with excellent E stereoselectivity.13
a
Reactions were carried out with 1 (0.24 mmol), 6 (0.2 mmol),
i
Pd(PPh3)4 (5 mol %), and Pr2NEt (0.6 mmol) in DMF (2.0 mL) at
b
c
90 °C for indicated times. Isolated yields are shown. Although a
single product was isolated, the configuration of the newly formed
double bond could not be confirmed by NMR analysis.
Scheme 5. Proposed Catalytic Cycle
We then investigated the scope of benzyl bromides in this
palladium-catalyzed transformation (Scheme 2). The coupling of
ene−yne−ketone 1a with benzyl bromide (2b) produced the
target product 3k in good yield. This reaction was used as the
model reaction for the computational studies. It was found
that the coupling is not significantly affected by the substituents
on the aromatic ring of the benzyl bromide. Both electron-rich
(3q, 3r, 3t) and electron-deficient (3m−p, 3s) benzyl bromides
afforded the corresponding furan products in good yields.
Remarkably, ester, nitro, chloro, cyano, and alkoxyl groups all were
well-tolerated under the standard reaction conditions. Interestingly,
the aryl bromides were less active than the corresponding benzyl
bromides under the optimized reaction conditions, and the bromo
substituent did not interfere the reaction in the case of 3s.
Next, we investigated a similar reaction between ene−yne−
ketones and aryl halides 4. In these reactions, in order to meet the
requirement of β-hydride elimination of the palladium species in
the final step of the catalytic cycle, the substituent adjacent to the
terminal alkyne moiety of the ene−yne−ketone should have
hydrogen. Consequently, we employed ene−yne−ketone 1k,
in which n-C5H11 is the substituent of the alkyne moiety, along
with 4-bromotoluene (4a) to optimize the reaction conditions
(Table 2). When the standard reaction conditions for the
corresponding coupling reaction of benzyl bromides and ene−
yne−ketones were employed, only a 25% yield of the expected
coupling product could be obtained (entry 1). The yield
improved to 40% when the bulky and electron-rich XPhos ligand
was used (entry 2). The solvent and base were then screened. It
was found that MeCN showed superior results compared with
DMF. When iPr2NEt was used as the base, the best results were
obtained in this coupling reaction (entries 3−8). At this point,
the yield was optimized to 65% (entry 4). Changing XPhos to the
less bulky ligand PCy3 or 2-PhC6H4PCy2 resulted in poor yields
(entries 9 and 10), indicating that the isopropyl groups on XPhos
Table 3. Highest Free Energy Barriers (in kcal/mol) for the
Steps Involved in the Catalytic Cycle
reaction
step 1
step 2
step 3
step 4
step 5
eq 4
eq 5
13.1
3.0
22.4
26.1
4.6
3.6
15.7
15.0
7.2
17.4
mixture of E- and Z-isomeric products was obtained in about a
1:1 ratio, and they were difficult to separate. However, to our
delight, the mixture of (E)- and (Z)-ene−yne−ketones 1f and 1j
smoothly afforded the corresponding 2-alkenyl-substituted
furans 3f and 3j, respectively, as single products. This indicates
that isomerization of the double bonds in 1f and 1j occurs easily
during the course of the reaction.15 Moreover, it is noted that
only the ketone carbonyl oxygen attacks the activated alkyne
D
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Figure 1. (A) Free energy profile for steps 2 and 3 in the reaction shown in eq 4. (B) Optimized structures of key stationary points together with key
bond lengths (in Å). The values in parentheses in Pd-carbene are bond lengths reported in its X-ray structure.21e Trivial H atoms have been omitted.
are essential. With the combination of XPhos and Pd(OAc)2 as
the catalyst, the yield of the reaction could be improved slightly
(entry 11). During optimization of this reaction, we found
that the major side product was 5a′, which might be generated from
β-hydride elimination/reductive elimination sequences or a direct
1,2-hydride shift of the palladium carbene intermediate.8g,11c,16 By
slightly increasing the ratio of the ene−yne−ketone 1k, we finally
obtained 2-alkenyl-substituted furan 5a in 72% yield (entry 12). In
this reaction, 4-iodotoluene (4b) also gave the target product 5a in a
similar yield (entry 13). In all cases, the product was obtained as a
1:1 mixture of the E and Z isomers according to 1H NMR analysis of
the isolated product. Again, this is attributed to the similar size of
the phenyl and furyl groups, which show little difference in the
β-hydride elimination of the palladium intermediate.
Next, we explored the scope of this reaction using the series
of aryl bromides or iodides 4a−n and ene−yne−ketones 1k−o
under the optimized reaction conditions (Scheme 3). The cou-
pling of ene−yne−ketone 1l (R1 = Me, R2 = R3 = H) with
bromobenzene (4c) afforded 1,1-disubstituted alkene 5b in 62%
yield. When Pd2(dba)3 was used in place of Pd(OAc)2, a similar
yield was obtained. This reaction was used as the model reaction
for the computational studies. The reaction of 4-iodotoluene
with 1l also gave the corresponding product in good yield
(5c). When R2 and R3 were not hydrogen, tetrasubstituted
olefins were obtained in moderate to good yields (5d−n). It is
noteworthy that both electron-rich (5f−i, 5n) and electron-
deficient (5e, 5j−m) aryl halides underwent this transformation
smoothly. In addition, bromonaphthalene and bromophenanthrene
E
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Figure 2. (A) Pathways for the β-hydride elimination step in the reaction shown in eq 4 along with relative free energies. (B) Key optimized structures
with selected bond lengths (in Å). Trivial hydrogen atoms have been omitted for clarity.
were also suitable substrates in this reaction (5g, 5n). Finally, we
found that the reaction conditions could also tolerate heteroaryl
bromides, giving olefins bearing two heteroaryl substituents in
good yields (5l, 5m).
using Gaussian 09.17,18 Both phenyl and benzyl bromides can
couple with ene−yne−ketones, so we chose two experimental
reactions (i.e., eqs 4 and 5) as representatives for mechanistic
investigation. It has been reported that the catalytically active
species in palladium-catalyzed C−C couplings are often mono-
phosphine palladium complexes (i.e., LPd)19,20 when bulky phos-
phine ligands such as PPh3,19b PtBu3,19d and XPhos20 are applied.
We thus employed PPh3Pd and XPhosPd as the active catalysts
in the computations, where the actual ligands (PPh3 and XPhos)
were used without any simplification. Nevertheless, we also used
the bisphosphine palladium complex (PPh3)2Pd as an active
catalyst to validate the reasonability of using PPh3Pd, and we
found (PPh3)2Pd to be energetically less favorable than PPh3Pd
(vide infra).
Finally, we investigated the reaction between ene−yne−
ketones and allyl bromides (Scheme 4). Considering the sim-
ilarity between allyl bromide and benzyl bromide, we applied the
reaction conditions used for the reaction with benzyl bromide to
the similar reaction with allyl bromide. However, we found that
the reaction was sluggish for the latter case. For the coupling of
ene−yne−ketone 1a with allyl bromide 6a, 2 h was not enough
for complete conversion; the reaction time was extended to 12 h,
but compound 7a was obtained in only moderate yield. Further
optimization failed to improve the yield of the reaction, probably
because of the bulky tert-butyl group, which hinders the cyclization
process in the transformation. When the substrate bearing the less
bulky pentyl substituent was used, the reaction was significantly
improved and could be finished in 2 h, albeit with moderate yield
(7b). Other ene−yne−ketones and allyl bromides could also be
applied to the reaction, affording the corresponding furyl-
containing 1,3-butadiene derivatives 7c−f in acceptable yields.
MECHANISTIC CONSIDERATIONS
■
To gain insight into the reaction mechanism, in particular to
corroborate the involvement of palladium carbene intermediates
in these transformations, we performed a DFT mechanistic study
F
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Figure 3. (A) Free energy profile for steps 2 and 3 in the reaction shown in eq 5. (B) Optimized structures of key stationary points together with key
bond lengths (in Å). Trivial H atoms have been omitted.
Scheme 5 illustrates our proposed catalytic cycle, which can be
characterized by five steps, namely, oxidative addition (step 1),
alkyne activation−cyclization (step 2), palladium carbene migra-
tory insertion (step 3), β-hydride elimination (step 4), and
catalyst regeneration (step 5). Among the five steps, steps 1, 4,
and 5 are similar to those in classical Heck reactions.19f
IMA4, which is followed by cyclization via TSA4 to give IMA5.
The palladium intermediate IMA5 features metal carbene
character, as validated by comparison with well-characterized
palladium carbenes whose crystal structures have been reported
previously.21 As an example, we specifically compared IMA5 with
the cationic Pd-carbene in Figure 1B21e because they have sim-
ilar coordination environments. The formal PdC double bond
in IMA5 (1.975 Å) is shorter than those in the X-ray (2.005 Å)
and computed (2.021 Å) structures of Pd-carbene, and the
Wiberg bond index22 of the bond in the former (0.699) is larger
than that in the latter (0.587). Furthermore, as compared in
Figure S4 in the Supporting Information, they have very similar
σ and π orbitals involved in the formal PdC bonds. However,
the palladium carbene species (IMA5) is not stable; the benzyl
group can easily migrate to the C1 atom by striding a low barrier
of 4.6 kcal/mol (TSA5), leading to intermediate IMA6, which is
much more stable than IMA5 (by 23.7 kcal/mol). Overall, the
process from IMA3 + 1a to IMA6 overcomes a barrier of 22.4
kcal/mol and is exergonic by 23.7 kcal/mol, indicating that the
process can proceed feasibly.
Table 3 presents the highest free energy barrier (the free
energy difference between the highest transition state and the
lowest intermediate in each step) of each step, and the data show
that step 2 is the rate-determining step for both reactions. The
detailed energetic and geometric results for steps 1 and 5 are
given in the Supporting Information, and hereafter we focus on
the key steps 2−4: steps 2 and 3 involve palladium carbene
intermediates, and step 4 determines the stereoselectivity.
The free energy profile for steps 2 and 3 in the reaction shown
in eq 4 is given in Figure 1, together with the optimized struc-
tures of the key stationary points. The oxidative addition affords
π complex IMA3, as reflected by the two short Pd−C bond
distances (2.504 and 2.309 Å). The subsequent coordination of
1a to IMA3 breaks the π coordination by overcoming a barrier of
16.0 kcal/mol (TSA3) to form alkyne-coordinated π complex
G
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Figure 4. Free energy profile for the β-hydride elimination step in the reaction shown in eq 5. The barrier for the rotation around the P−C2 bond in
going from IMB9 to IMB10 was estimated to be about 12.0 kcal/mol through PES scanning (Figure S9 in the Supporting Information).
Subsequent to the migratory insertion to form IMA6, the
β-hydride elimination takes place. Along the black pathway
in Figure 2, the β-hydride elimination climbs a barrier of 15.7
kcal/mol (TSA6), giving π complex IMA7. In the gas phase,
IMA7 is 0.5 kcal/mol lower than TSA6, but it is 0.6 kcal/mol
higher than TSA6 after thermal and solvent corrections. The
entropy driving force then dissociates IMA7 into IMA8
(LPd(H)(Br)) and 3k (the product). The step from IMA6 to
IMA8 + 3k is endergonic by 5.0 kcal/mol but can be driven by
the subsequent catalyst regeneration, which is thermodynami-
cally favorable (Figure S2 in the Supporting Information). The
trans isomer of IMA8, IMA8′, is 20.3 kcal/mol above IMA8
because of the strong trans influence between the hydride and
the PPh3 ligand. Alternatively, the β-hydride elimination could
proceed along the blue pathway in Figure 2, leading to 3k′. How-
ever, because of the large steric effect between the tBu and phenyl
groups, as reflected by the structures of TSA6 and TSA6′, the
formation of 3k′ is much less favorable than that of 3k in terms of
both kinetics and thermodynamics, explaining our observed anti
stereoselectivity (Table 1 and Scheme 2).
Previously, it has been shown that the pathway involving the
monophosphine is energetically more favorable than the pathway
involving the bisphosphine in palladium-catalyzed C−C
coupling reactions.19b We also used the monophosphine palla-
dium complex (PPh3Pd) as the active catalyst in our mechanistic
computations. To confirm the reasonability of using PPh3Pd, as
mentioned above, we further used (PPh3)2Pd as the active
catalyst to calculate the pathways for the oxidative addition and
cyclization steps (steps 1 and 2). The results (Figure S3 in the
Supporting Information) show that the pathway with (PPh3)2Pd
as the active catalyst is kinetically and thermodynamically
less favorable than that with PPh3Pd as the active catalyst.
Therefore, the active catalyst in the present reaction should also
be monophosphine palladium complex PPh3Pd, verifying the
rationality of using PPh3 as the active catalyst to investigate the
mechanism of the reaction shown in eq 4.
the palladium center in IMB2 is encompassed, leaving no site
available for 1l coordination. Previously, Buchwald and co-
workers revealed that the triisopropylbiphenyl substituent of
XPhos needs to rotate around P−C2 bond to expose the
palladium center for catalysis and reported that it was difficult
to locate the rotation transition state.20 We also were not able
to find the transition state. Similar to the approach used in
Buchwald’s study, we scanned the potential energy surface (PES)
using the dihedral angle (∠C1C2PPd) as the scanning coordinate
(Figure S8 in the Supporting Information). On the basis of the
PES, we estimate the enthalpy barrier to be about 19.0 kcal/mol
relative to IMB2, and therefore, the rotation to transform IMB2
into IMB2′ is feasible. Subsequently, IMB2′ adjusts to give IMB3
via TSB2′, resulting in a structure suitable for coordination of 1l.
The pathway from IMB3 to IMB6 in Figure 3 is similar to that
from IMA3 to IMA6 in Figure 1 except for the energetic differ-
ences. Again, a palladium carbene species (IMB5) is involved. Be-
cause of the trans influence of the phosphine ligand,23 the PdC
bond (1.986 Å) in IMB5 is slightly longer than the one in IMA5
(1.975 Å; Figure 1), and the Wiberg bond index (0.631) in IMB5
is slightly less than that in IMA5 (0.699). Nevertheless, the
palladium species IMB5 also has σ and π orbitals involved in the
formal PdC double bond, similar to those in IMA5 (Figure S7
in the Supporting Information). The palladium carbene IMB5
then undergoes migratory insertion via a barrier of 3.6 kcal/mol,
forming IMB6. Overall, the process from IMB2 + 1l to IMB6
overcomes a barrier of 26.1 kcal/mol and is exergonic by 32.8
kcal/mol.
The pathway for the β-hydride elimination in the reaction in
eq 5 is shown in Figure 4. Unlike the corresponding step in the
reaction in eq 4, which has two possible pathways (Figure 2), the
β-hydride elimination from IMB6 can lead to only one product,
5b, because the hydride transfer takes places on the CH3 group
rather than CH2Ph group in eq 4. To undergo β-hydride elim-
ination, IMB6 first needs to isomerize to IMB7, in which Hβ
interacts with the Pd center via an agostic interaction. The
isomerization breaks the π coordination between the phenyl
group and the Pd center, resulting in an energy increase by 9.5
kcal/mol in going from IMB6 to IMB7. Subsequently, the β-
hydride elimination proceeds via TSB7, leading to π complex
Figure 3 presents the energetic and geometric results for steps
2 and 3 in the reaction shown in eq 5. Unlike the reaction in eq 4,
the substrate ene−yne−ketone 1l cannot directly coordinate to
the oxidation product IMB2, because, as shown by its structure,
H
dx.doi.org/10.1021/ja4058844 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(g) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012,
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IMB8, which is 7.2 kcal/mol lower than TSB7 in the gas phase
but 1.7 kcal/mol higher than TSB7 after thermal and solvent
corrections. Finally, the product 5b is released from IMB8. The
resulting species IMB9 can facilely isomerize to a more stable
complex, IMB10, which then enters the catalyst recovery
step (Figure S6 in the Supporting Information). Similar to the
β-hydride elimination in the reaction in eq 4, the step is endergonic
by 3.5 kcal/mol and needs the thermodynamic driving force from
the catalyst recovery step.
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CONCLUSION
■
We have developed a palladium-catalyzed cross-coupling
reaction between ene−yne−ketones and benzyl, aryl, or allyl
bromides. These transformations represent a novel synthetic
method to produce various 2-alkenyl-substituted furans in
moderate to good yields. Moreover, computational studies
support our hypothesis that palladium carbene formation and
subsequent migratory insertion are the key steps in the catalytic
cycle. The implication of this study is that palladium carbene
migratory insertion can be considered as a general and facile
process that occurs under suitable conditions regardless of the
carbene precursors. This may open up new possibilities for
developing novel transformations based on palladium carbene
migratory insertions.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, copies of 1H and
13C NMR spectra, and details and complete results of the DFT
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
́
anier, V. E; Fillion, E. Organometallics 2007, 26,
7430−7431. (g) Trep
30−32.
(6) For studies of stable palladium carbene species, see: (a) Alben
C.; Espinet, P.; Manrique, R.; Perez-Mateo, A. Angew. Chem., Int. Ed.
2002, 41, 2363−2366. (b) Danopoulos, A. A.; Tsoureas, N.; Green, J.
C.; Hursthouse, M. B. Chem. Commun. 2003, 756−757. (c) Broring, M.;
́
iz, A.
AUTHOR INFORMATION
Corresponding Authors
zxwang@ucas.ac.cn
■
́
̈
Brandt, C. D.; Stellwag, S. Chem. Commun. 2003, 2344−2345. (d) Sole,
́
wangjb@pku.edu.cn
D.; Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. Organo-
́
Author Contributions
metallics 2004, 23, 1438−1447. (e) Alben
Manrique, R.; Per
ez-Mateo, A. Chem.Eur. J. 2005, 11, 1565−1573.
(f) Albeniz, A. C.; Espinet, P.; Perez-Mateo, A.; Nova, A.; Ujaque, G.
Organometallics 2006, 25, 1293−1297. (g) Lopez-Alberca, M. P.;
Mancheno, M. J.; Fernandez, I.; Gomez-Gallego, M.; Sierra, M. A.;
Torres, R. Org. Lett. 2007, 9, 1757−1759. (h) Meana, I.; Albeniz, A. C.;
Espinet, P. Organometallics 2012, 31, 5494−5499.
́
iz, A. C.; Espinet, P.;
§Y.X., S.Q., and Q.X. contributed equally.
́
Notes
́
́
The authors declare no competing financial interest.
́
́
́
̃
ACKNOWLEDGMENTS
́
■
This project was supported by the National Natural Science
Foundation of China (Grant 21272010 and 21332002) and the
National Basic Research Program of China (973 Program,
2012CB821600).
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Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861−2903. (d) Zhang, Z.;
Wang, J. Tetrahedron 2008, 64, 6577−6605.
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