Ruthenium-Catalyzed Formal Dehydrative [4 + 2] Cycloaddition of Enamides and Alkynes for the Synthesis of Highly Substituted Pyridines: Reaction Development and Mechanistic Study

Article abstract of DOI:10.1021/jacs.5b06400

Reported herein is a ruthenium-catalyzed formal dehydrative [4 + 2] cycloaddition of enamides and alkynes, representing a mild and economic protocol for the construction of highly substituted pyridines. Notably, the features of broad substrate scope, high

Full text of DOI:10.1021/jacs.5b06400

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Article
Ruthenium-Catalyzed Formal Dehydrative [4 + 2] Cycloaddition
of Enamides and Alkynes for the Synthesis of Highly Substituted
Pyridines: Reaction Development and Mechanistic Study
Jicheng Wu, Wenbo Xu, Zhi-Xiang Yu, and Jian Wang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Jul 2015
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Jicheng Wu,†,§ Wenbo Xu,‡,§ Zhi-Xiang Yu,‡,* and Jian Wang†,*
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† Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084,
China
‡ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
College of Chemistry, Peking University, Beijing 100871, China
ABSTRACT: Reported herein is a ruthenium-catalyzed formal dehydrative [4+2] cycloaddition of enamides and alkynes, repre-
senting a mild and economic protocol for the construction of highly substituted pyridines. Notably, the features of broad substrate
scope, high efficiency, good functional group tolerance, and excellent regioselectivities were observed for this reaction. Density
functional theory (DFT) calculations and experiments have been carried out to understand the mechanism and regiochemistry. DFT
calculations suggested that this formal dehydrative [4+2] reaction starts with a concerted metallation deprotonation (CMD) of the
enamide by the acetate group in the Ru catalyst, which generates a six-membered ruthenacycle intermediate. Then alkyne inserts
into the Ru-C bond of the six-membered ruthenacycle, giving rise to an eight-membered ruthenacycle intermediate. The carbonyl
group (which comes originally from the enamide substrate and is coordinated to the Ru center in the eight-membered ruthenacycle
intermediate) then inserts into the Ru-C bond to give an intermediate, which produces the final pyridine product through further
dehydration. Alkyne insertion step is the regio-determining step and prefers to have the aryl groups of the used alkynes stay away
from the catalyst in order to avoid repulsion of aryl group with the enamide moiety in the six-membered ruthenacycle, and to keep
the conjugation between the aryl group and the triple C-C bond of the alkynes. Consequently, the aryl groups of the used alkynes
are in the -position of the final pyridines and the present reaction has high regioselectivity.

INTRODUCTION
with internal alkynes, producing highly substituted pyrroles. In
2013, Ackermann13 and Wang14 groups independently found
that Ru catalyst can mediate an oxidative coupling of en-
amides with
Scheme 1. Two different metal-catalyzed reactions of en-
amides and alkynes for the synthesis of pyrroles and pyri-
dines.
Of the N-heterocycles, pyridines are among the most prevalent
scaffolds found in natural products and pharmaceuticals.1 In
the last few decades, a wealth of research has focused on the
construction of these heterocycles.2 Nonetheless, access to
pyridines with desirable substitution patterns often remains a
challenge when traditional multicomponent approaches ap-
plied.3 Though classic condensation protocols are available for
pyridine core construction, substituent patterns of these pyri-
dines are largely dictated by the activating groups required for
reactivity.4 Recently, intermolecular [2+2+2] cycloadditions of
nitriles and alkynes have received much attention because of
broad availability of the starting materials.5 However, this
synthetic method often leads to the generation of regioisomers.
6
Novel complementary approaches to diversely substituted
pyridines are still highly desirable, and several impressive
reports highlight the recent advances in this field.7
Enamides are highly valuable building blocks in organic
synthesis.8 The importance of enamide chemistry has been
highlighted by transition-metal-catalyzed coupling reactions9
and Lewis acid catalyzed nucleophilic addition.10 As outlined
in Scheme 1a, Glorius11 and Fagnou12 groups independently
revealed the Rh-catalyzed oxidative coupling of enamides
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Entry
1
2
3
4
5
6
7
8
Cat.
Nonec
Pd(OAc)2
[Cp*RhCl2]2
Additive
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
t-BuOK
NaOAc
KOAc
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
Dioxane
DCE
Yieldb
n.r.d
n.d.l
8%
k
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
76%j
Trace
Trace
65%j
81%j
79%j
84%j
70%j
86%j
81%j
76%j
51%j
41%j
58%j
61%j
9
CsOAc
Na2CO3
Cs2CO3
10
11
12
13e
14f
15g
16
17
18
19i
20
h
h
h
h
h
h
h
h
h
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
KOAc/Na2CO3
internal alkynes to generate pyrroles in a high efficient man-
ner. In addition, examples of Pd, Ag or Cu catalyzed or pro-
moted cross-coupling of enamides with internal alkynes have
also been reported, but still focused on pyrrole synthesis.15 To
the best of our knowledge, a metal-catalyzed formal dehydra-
tive [4+2] cycloaddition of enamides with alkynes to directly
construct pyridines has remained elusive until now.16 In 2007,
Movassaghi et al. reported a noncatalytic method to make
pyridines by using acetylenes and enamides.17 However, a
stoichiometric amount of Tf2O and 2-chloropyridine were
requested to achieve satisfied yields. We report herein a for-
mal dehydrative [4+2] cycloadditions of enamides and alkynes,
a new complementary process towards highly substituted pyr-
idines, featured with excellent chemo- and regio-selectivities,
broad scope, and functional group tolerance (Scheme 1b).
Meanwhile, experiments and DFT calculations have been car-
ried out to understand the reaction mechanism and regiochem-
istry.
tAmylOH 43%j
DMF
45%j
a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (0.45 mmol, 1.5 equiv),
cat. (5 mol%), additive (2.0 equiv), and toluene (2 mL) at 100 oC under
argon atmosphere for 36 h. Yield of isolated product. c No catalyst. No
b
d
reaction. 80 oC. 120 oC. Air atomosphere. KOAc (1.0 equiv) and
e
f
g
h
i
j
Na2CO3 (1.0 equiv).
t-AmylOH
=
2-Methyl-2-butanol.
Ratio of
Dichlo-
k
regioisomer (r.r.)
> 20:1, determined by crude NMR.
ro(pentamethylcyclopentadienyl)- rhodium(III) dimer. l Not detected.
Substrate Scope. With the optimized reaction conditions in
hand, a series of enamides 1b-u were examined (Table 2). 1b-g
(R2 = phenyl group) reacted with 2a to yield pyridines 3b-g in
moderate to excellent yields. For the syntheses of 3b-e from
1b-e, we found that these substrates were prone to
decomposition. Therefore, 4Å molecular sieves were added to
suppress the enamide hydrolysis and the target reactions under
these new reaction conditions took place smoothly with
reasonable to good yields. Substrates 1h-k (R2 = heterocycles)
were also good substrates and gave the corresponding pyridines
3h-k in yields. Enamides with alkenyl group on R2 position (1l
and 1m) can also be used to afford their corresponding pyridine
products 3l and 3m in good chemical yields. Additionally,
enamides (1n, 1p-s) bearing alkyl groups on R2 position also
underwent cycloaddition to provide pyridines 3n and 3p-s,
respectively. When 1o (R2 = PhCO) and multi-substituted
substrates 1t-u (R2 = Ar and R1 = -(CH2)(1-2)-) were subjected to
the optimal reaction conditions, the desired pyridines 3o and
3t-u were obtained in useful synthetic yields. Notably, the
generated pyridines 3 in all these reactions were formed with
complete regioselectivity (all r.r. > 20:1). Furthermore, we
tested whether acetanilides (e.g. N-phenylacetamide and N-(p-
tolyl)acetamide) can also give pyridine products under the
optimal conditions. Unfortunately, no desired pyridines
products were generated for these tested acetanilides, indicating
the activation of Csp2-H of aromatic compounds in acetanilides
is difficult under current reaction conditions.

RESULTS AND DISCUSSION
Optimization Studies. Key results of reaction condition opti-
mization are summarized in Table 1. Model reaction of N-
vinyl amide 1a and alkyne 2a was used to evaluate reaction
parameters (Table 1). After testing several commonly used
metal catalysts (entries 2-4), [(p-cymene)RuCl2]2 was chosen
to be the best due to its high catalysis efficiency (Table 1, en-
try 4, 76%). Encouragingly, we found that an enhanced chem-
ical yield could be achieved by using a combination of KOAc
and Na2CO3 (entry 12, 86%). Solvent screening disclosed that
toluene was the most efficient medium for this reaction (en-
tries 16-20). In addition, we found that the reaction tempera-
ture did not have a significant impact on the reaction yields, as
demonstrated by the observations that slightly decreased or
increased temperature had very close reaction yields (entries
13 and 14, 80 oC, 81%; 120 oC, 76%). Therefore, we chose the
reaction conditions in entry 12 as the optimal reaction condi-
tions (5 mol% [(p-cymene)RuCl2]2 as catalyst, toluene as the
solvent, and the reaction temperature of 100 oC).
Table 1: Optimization of the reaction conditions.a
Table 2: Scope of enamides.a
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76% yield. When R2 and R3 were both phenyl groups, a
moderate yield (51%) of 5j was achieved by using an excess
amount of alkyne 2a (3.0 equiv). Lastly, N-methyl protected
enamide 1a was synthesized to verify the necessity of the NH
group in the substrate. No desired pyridine 3a was detected
under the standard conditions, proving that the NH group is
essential to the present dehydrative annulation reaction.
To further demonstrate the generality and practicability of
this formal dehydrative [4+2] cycloaddition, we tested an
array of alkynes 2. Symmetric diarylalkynes showed good to
high reactivities (Table 4, 6a, 6e-g). Symmetric dimethyl
acetylenedicarboxylate afforded substituted pyridines 6d and
6p (87% and 55%, respectively). Symmetric dialkyl alkyne
(2q) was also verified to be an active partner for this catalytic
process (6q, 68%). To further understand the regioselectivity
of the present reaction, a number of unsymmetric internal
alkynes were investigated (Table 4). To our surprise, all
unsymmetric internal alkynes underwent cyclization reaction
with enamides 1 to give a single regioisomer in good yields
(6b-c, 6h-o). In addition, pentasubstituted pyridine derivatives
(6r and 6s) were also obtained in 37% and 32%, respectively.
The configuration of these pyridine analogues were assigned
by comparing the NMR spectra of pyridines 3c and 5j with
reference18 and analysis of their 2D NMR spectra (See Sup-
porting Information).
Table 4: Scope of alkynes.a,d
a Reaction conditions: 1b-u (0.3 mmol, 1.0 equiv), 2a (1.5-2.0 equiv), [(p-
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cymene)RuCl2]2 (5 mol%), Na2CO3 (1.0 equiv), KOAc (1.0 equiv), and
o
b
toluene (2 mL) at 100 C under argon atmosphere for 24-48 h. 2a (3.0
c
equiv), Na2CO3 (2.0 equiv), and 4Å MS (100 mg) were used. Yield
based on recovery of 1.
Table 3: Scope of other enamides.a
a Reaction conditions: 4a-j (0.3 mmol, 1.0 equiv), 2a (1.5-2.0 equiv), [(p-
cymene)RuCl2]2 (5 mol%), Na2CO3 (1.0 equiv), KOAc (1.0 equiv), and
o
b
toluene (2 mL) at 100 C under argon atmosphere for 24-48 h. 2a (3.0
a
equiv), Na2CO3 (2.0 equiv), and 4Å MS (100 mg) were used.
Reaction conditions: 1 (0.3 mmol, 1.0 equiv), 2 (1.5-2.0 equiv), [(p-
cymene)RuCl2]2 (5 mol%), Na2CO3 (1.0 equiv), KOAc (1.0 equiv), and
toluene (2 mL) at 100 C under argon atmosphere for 24-48 h. 8 mol%
[(p-cymene)RuCl2]2 was used. Yield based on recovery of 1. Ad =
adamantyl.
o
b
Further investigation of the scope of enamides was
conducted (Table 3). For enamides with R3 = alkyl group,
reactions proceeded well to afford the corresponding products
in good chemical yields (5a-f, 5i). For enamide 4g with R3 =
alkenyl group, the catalytic process smoothly provided
tetrasubstituted 5g in 64% yield. Pleasingly, for enamide 4h
with R3 = difluoromethyl group, pyridine 5h was obtained in
c
d
Synthesis of Bipyridines. It is important to note that this
methodology can be successfully utilized to generate highly
substituted bipyridines in a facile one-pot process when diynes
were used, even though a higher catalyst loading (8 mol%)
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and elongated reaction time (56 h) were required (Table 5). It
was expected that two types of regioisomers can be generated
from the dehydrative [4+2] reaction using diynes. Here only
one type of regioisomers (6t and 6u) was generated. This can
be explained by steric reason for the formations of the second
pyridines, which prefers to have the bulky t-Bu and Ad groups
to stay away from the first-step formed pyridines, as those
shown in 6t and 6u.

MECHANISTIC STUDIES
Table 5: Synthesis of bipyridines.a
Plausible Mechanism. The proposed reaction mechanism for
the present formal dehydrative [4+2] cyclization is given in
Scheme 5. Firstly, catalytic specie I (Ru(p-cymene)(OAc)2) is
in situ formed.19 Then metallation and deprotonation of I to
the enamide substrate generate a six-membered ruthenacycle
intermediate II.20 Intermediate III is then formed after
insertion of 2a into Ru-C bond in II. Carbonly group in III is
then inserts into the Ru-C bond intramolecularly, giving
intermediate IV (pathway A). Finally, through further
dehydration process, intermediate IV in pathway A is
converted to the pyridine product with the concomitant
generation of the catalytic species I. The present reaction has a
competing pathway related to the generation of pyrrole, even
though we did not observe such product in our reaction system.
This competing reaction starts from intermediate III, which
undergoes decarboxylation to give intermediate V (rather than
the C=O insertion into the Ru-C bond to give intermediate IV
in the pyridine formation (pathway A). Intermediate V then
undergoes reductive elimination and oxidation to give the final
pyrrole product (Pathway B). Mechanistic study through ex-
periments and DFT calculations presented below support that
pathway A (leading to the formation of pyridine) is the pre-
ferred one.
a
1
(0.6 mmol), 1,4-diphenylbuta-1,3-diyne (0.2 mmol), [(p-
cymene)RuCl2]2 (8 mol%), Na2CO3 (2.0 equiv.), KOAc (2.0 equiv.),
o
4Å MS (200 mg), and toluene (2 mL) at 100 C under argon atmos-
phere for 56 h.
Late-stage modification was considered as a valuable
method for drug optimization in medicinal chemistry. As indi-
cated in Scheme 2, when we subjected steroid 7 to the dehy-
drative cycloaddition reaction conditions, pyridine 6v was
synthesized in 88% yield.
Scheme 2. Late-stage modification.
Scheme 5. Postulated mechanism of the formal dehydra-
tive [4+2] cycloaddition.
With the aim of evaluating the practicality of this catalytic
process, a gram-scale experiment was performed with 1v (0.88
g) and 2a (0.70 g), yielding the corresponding product 6h in
82% (Scheme 3, 1.04 g)
Scheme 3. Gram-scale synthesis of 6h.
To understand how substituents in the used alkynes affect
the reaction outcome, a competing dehydrative cyclization
experiment using two alkynes 2a and 2b with different elec-
tronic effects to react with 1a had been performed (Scheme 4).
This investigation demonstrated that the dehydrative cycliza-
tion of enamides with alkynes is not sensitive to the electronic
effect of the alkynes (because very close reaction yields of 3a
and 6a were obtained).
Experimental study of the reaction mechanism. To gain
some mechanistic insights into the current protocol, a number
of control experiments were performed, including an intermo-
lecular kinetic isotope effect experiment and several deuteri-
um-labeling experiments (Scheme 6). Notably, a small kinetic
isotope effect was observed in the intermolecular
Scheme 4. Intermolecular competition between alkynes.
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Scheme 6. Experimental studies of mechanism (R=1-
Naphthyl).
DFT Studies of the formal dehydrative [4+2] cycloaddition.
The above mechanism was further scrutinized by DFT calcu-
lations using the M06//B3LYP calculations (geometry optimi-
zations using B3LYP and single-point energy calculations
using M06. For details, see the Supporting Information).21
Here we use relative Gibbs free energies in the gas phase to
discuss the reaction mechanism).22 Figure 1 gives the potential
energy surface of the catalytic cycle together with the compet-
ing processes related to the regiochemistry and side reaction of
pyrrole formation. Figure 2 gives several key transition struc-
tures.
Figure 1a shows that the catalytic cycle begins with coor-
dination of the enamide to the Ru center of the catalyst, giving
complexes IN1 and IN2. Complexes IN1 with carbonyl coor-
dination to Ru atom is more stable than IN2 with alkene coor-
dination to Ru atom. Complexes IN1 and IN2 are in equilibri-
um and IN2 is the reacting conformer for the followed reac-
tion steps of the catalytic cycle.
A concerted metallation deprotonation (CMD) process by
the coordinated acetate converts IN2 to IN3. The computed
activation free energy of the CMD process is 20.4 kcal/mol.
IN3 then releases HOAC molecule to give six-membered
ruthenacycle intermediate IN4. Intermediate IN4 is an 18-e
complex with the coordination of carbonyl group of the en-
amide moiety. The incoming alkyne can replace this carbonyl
group for coordination to form IN5 and IN5a, both of which
are also 18-e complexes (see Figures 1a and 1b). IN5 and
IN5a differ from each other by the relative orientation of the
alkyne with respect to the Ru-enamide bond. The alkyne coor-
dination to the metal center prefers to have the alkyne, its two
substituents, and the Ru atom in the same plane. In IN5, the
Ph group, which points away from the catalyst and experienc-
es no steric hindrance, is in plane with the alkyne moiety to
keep good conjugation. In contrast, in IN5a, the Ph group
experiences repulsion from the amide moiety and has to distort
to a position that does not enjoy conjugation between the Ph
group and the alkyne moiety. Consequently, IN5a is less sta-
ble than IN5 by 1.3 kcal/mol in terms of Gibbs energy in the
gas phase.
(kH/kD = 2.2) competition experiment [eq (a)]. Under the stand-
ard conditions and the addition of 10.0 equiv. of D2O, we
found that approximately 31% deuterium was incorporated
into the recovered 1a and 8% deuterium was incorporated into
product 3a [eq (b)]. Performing this reaction in the absence of
alkynes 2a, about 75% deuterium was found in the recovered
1a [eq (c)]. However, no deuterated 1a was identified when
this substrate was simply mixed with D2O [eq (d)]. Several
conclusions drawn from these experiments include: the C-H
metallation-deprotonation step (1a and I to II, Scheme 5) is
reversible; this step is not involved in the rate-determining
step. These were further supported by DFT calculations (see
below). In the absence of base (e.g. Na2CO3, KOAc), no 3a
could be generated for the dehydrative cyclization reaction,
suggesting that base is very critical to the success of the target
reaction [eq (e)]. The reason why different base influences the
reaction outcomes is not clear at current stage. Notably, addi-
tion of Cu(OAc)2 provided a competing pathway and afforded
undesirable pyrrole 3a’ [eq (f)]. We think that the added oxi-
dant here could significantly alter the reaction pathway shown
in Scheme 5. We also investigated whether the present dehy-
drative cyclization reaction can occur in the presence of Lewis
acids such as Sc(OTf)3, Mg(OTf)2 or Zn(OTf)2. The negative
answer suggests that adding Lewis acid is detrimental for the
pyridine formation reaction [eq (g)].
The disrupted conjugation found in IN5a is also kept in the
alkyne insertion transition state TS2a, but this is still absent in
TS2. Therefore, TS2 is favored than TS2a by 4.4 kcal/mol
and the alkyne insertion has an exclusive preference to give
IN6 via TS2 (see later discussion for this again).
DFT calculations indicated that alkyne insertion into the
Ru-C bond via TS2 requires an activation free energy of 14.9
kcal/mol. The carbonyl group in IN6 is a free ligand but it
then coordinates to the Ru center, giving the eight-membered
ruthenacycle intermediate IN7, which is set up for the fol-
lowed C=O insertion into the Ru-C bond. The carbonyl inser-
tion step, leading to IN8 (and then more stable IN9 with ace-
tate as a bidentate ligand, not a monodentate ligand), needs an
activation free energy of 29.0 kcal/mol and is exergonic by 5.9
kcal/mol. Protonation of IN9 with the assistance of AcOH
furnishes IN10 and regenerates the catalytic species for the
next catalytic cycle: The ligand exchange reaction (IN9 + en-
amide + HOAC → IN10 + IN1) for completing the catalytic
cycle is exergonic by 5.3 kcal/mol. Finally, dehydration of
IN10 gives rise to the polysubstituted pyridine.
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TS2 and TS3 are very close in energy, suggesting that the
computed activation free energy of 35.9 kcal/mol (IN12 can
alkyne insertion is reversible. But TS2a is higher than both
TS2 and TS3 by more than 4 kcal/mol, indicating that the
alkyne insertion is regio-determining step and the exclusive
formation of product pyridine P, which has the Ph group in its
-position. This is consistent with the experiment observed
regiochemistry.
In the pyridine formation pathway, IN3 can be converted
back to IN1 through protonation by AcOH, which is easy and
requires an activation free energy of 12.2 kcal/mol in the gas
phase. This suggests that enamides’ C-H metallation-
deprotonation step is reversible and that is the reason for the
observation of deuterium incorporated enamides in eq (b) of
Scheme 6.
The present reaction has a competing process leading to
the formation of pyrrole (Figure 1c and the pathway B in
Scheme 5). IN6 can be converted to IN11 by switching
carbonyl coordination to amide’s nitrogen coordination to the
Ru atom. Then a concerted deprotonation of nitrogen atom
converts IN11 to IN12 via TS4, requiring an activation free
energy of 15.7 kcal/mol. IN12 loses HOAc and uses its
carbonyl group to coordinate Ru, giving IN13. Reductive
elimination of IN13 to give pyrrole is difficult, with a
directly give pyrrole, but this is difficult and requires an
activation free energy of 31.7 kcal/mol). This implies that
pyrrole cannot be formed in the present reaction system, which
agrees with the experiments. In previous experiments (together
with the present investigated control experiment eq (f) in
Scheme 6), the added oxidants could alter the whole reaction
process to give pyrrole,13-14 but the reasons for this change are
not known at this moment.
Since IN13 can be easily generated from IN6, the pyridine
formation process shown in Figure 1a can have this specie as
the intermediate. IN13 is lower in energy than IN6, suggesting
that the most difficult step in the pyridine formation is from
IN13 to IN6 and then to TS3. Therefore, the formal dehydra-
tive [4+2] reaction requires an overall activation free energy of
32.3 kcal/mol in the gas phase (from IN13 to TS3). The over-
all activation free energy of the present reaction is 32.6
kcal/mol in solution.23
Figure 1. a) DFT computed energy surface, b) disfavored alkyne insertion intermediate and transition state, and c) disfa-
vored pathway to pyrrole.
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Figure 2. DFT computed key transition structure (distanc-
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

CONCLUSIONS
W.J. thanks Tsinghua University and the “Thousand Plan” Youth
program of China for financial support. The Natural Science
Foundation of China is highly appreciated by Z.-X. Y. for finan-
cial support (Project 21232001, Mechanistic Studies of Several
Important Organic Reactions)
In summary, we have developed a new and efficient Ru-
catalyzed formal dehydrative [4+2] cycloaddition of enamides
and alkynes for synthesis of highly substituted pyridines. The
generality of such an intermolecular annulation is demonstrat-
ed by a wide scope with respect to both enamides and alkynes.
The mechanism and regioselectivity of this reaction have been
scrutinized by experiments and DFT calculations. DFT calcu-
lation results indicated that the reaction starts from a concerted
metallation deprotonation process of enamides by the acetate
group in the catalyst, generating a six-membered ruthenacycle
intermediate. Then alkyne insertion into Ru-C bond of the six-
membered ruthenacycle intermediate gives an eight-membered
ruthenacycle intermediate, which undergoes carbonyl insertion
and dehydration to give the final pyridines (Figure 1a). The
high regiochemistry of the present formal dehydrative [4+2]
cycloaddition is determined by the alkyne insertion step,
which prefers to avoid steric repulsion of aryl group with the
enamide moiety in the six-membered ruthenacycle and to have
a good conjugation between the aryl group and the triple bond
of the alkyne substrates, in the alkyne insertion transition state.
Consequently, the aryl group of the used alkynes is in the -
position of the final pyridine products.

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2)
3)
4)

Supporting Information.
Experimental procedures, characterization data, NMR spectra of
the products, and DFT data. This material is available free of
charge via the Internet at http://pubs.acs.org.

*wangjian2012@tsinghua.edu.cn
*yuzx@pku.edu.cn
5)
6)
§J.W. and W.X. contributed equally.
For reviews of pyridine syntheses by [2 + 2 + 2] cycloaddition,
see: (a) Varela, J. A.; Saꢁ, C. Chem. Rev. 2003, 103, 3787. (b)
The authors declare no competing financial interest.
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16) In 2012, Guan group reported an example of Cu(I) catalyzed
coupling of enamides with alkynes for the synthesis of pyri-
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o
high temperature (140 C). For details, see: Zhao, M.-N.; Ren,
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19) The catalytic species here is proposed to be C6H6-Ru(OAc)2, as
supported by the experiment that C6H6-RuCl2 can also catalyze
the target reaction with a yield of 76%. We found that cationic
Ru generated by [(p-cymene)RuCl2]2 and KPF6 can also give
the target product, but with inferior efficiency. DFT calcula-
tions using this cationic species as the real catalyst show similar
reaction mechanism and regiochemistry (for more discussion,
see the Supporting Information).
20) For references of mechanism discussions, see: (a) Li, J.; John,
M.; Ackermann, L. Chem.─Eur.
J 2014, 20, 5403; (b)
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8)
For recent reviews of enamides, see: (a) Gopalaiah, K.; Kagan,
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Low, M. T.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701;
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Commun. 2009, 3472; (d) Zhou, H.; Xu, Y.-H.; Chung, W.-J.;
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21) Gaussian09, RevisionA.02, Frisch, M. J. et al. Gaussion,
Inc.,Wallingford CT, 2009, see the Supporting Information for
detail.
22) The reported values are relative free energies (△Ggas in the gas
phase, △Gsol in toluene) and enthalpies (△Hgas in the gas phase).
23) The computed activation free energies here in solution are
higher than the expected value of the experiment, considering
o
9)
that the reaction was carried out at 100 C. One of the sources
for the overestimation of the reaction activation free energy is
the entropy overestimation in solution: we used the gas phase
computed entropies as the estimated entropies in solution, and
this approximation introduces entropy overestimation for the
present two-molecule to one-molecule process, which converts
two molecules (IN13 and HOAc) to one molecule (IN6).
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