Palladium-Catalyzed [3+2] and [2+2+2] Annulations of 4-Iodo-2-quinolones with Activated Alkynes through Selective C?H Activation

Article abstract of DOI:10.1002/chem.201904558

The palladium-catalyzed reaction of 4-iodo-2-quinolones with activated alkynes was investigated. Cyclopenta[de]quinoline-2(1 H)-ones and/or phenanthridine-6(5 H)-ones were obtained through [3+2] annulation involving aromatic C?H activation or [2+2+2] annulation involving vinylic C?H activation, respectively. Reasonable mechanisms for the formation of these annulation products have been proposed based on density functional theory calculations.

Full text of DOI:10.1002/chem.201904558

A Journal of
Accepted Article
Title: Palladium-Catalyzed [3+2] and [2+2+2] Annulations of 4-Iodo-2-
quinolones with Activated Alkynes via Selective C–H Activation
Authors: Yoshihiko Yamamoto, Jiang Jiyue, and Takeshi Yasui
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To be cited as: Chem. Eur. J. 10.1002/chem.201904558
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Palladium-Catalyzed [3+2] and [2+2+2] Annulations of 4-Iodo-2-
quinolones with Activated Alkynes via Selective C–H Activation
Yoshihiko Yamamoto,*[a] Jiyue Jiang,[a] and Takeshi Yasui[a]
Abstract: The palladium-catalyzed reaction of 4-iodo-2-quinolones
with activated alkynes was investigated. Cyclopenta[de]quinoline-
(a) Our previous work: Catellani-type annulation
R3 R4
2(1H)-ones and/or phenanthridine-6(5H)-ones were obtained via
[3+2] annulation involving aromatic C–H activation or [2+2+2]
annulation involving vinylic C–H activation, respectively. Reasonable
mechanisms for the formation of these annulation products have
been proposed based on density functional theory calculations.
Hb
I
cat. [Pd(OAc)2]
nbe (1 equiv)
R3 R4
HO
Hb
O
R1
Ha
+
R1
R2
K2CO3, DMF
105 °C
N
O
Br
Bn
R2
N
O
Bn
O
CMD
I
PdII
PdII
HO
I
K
H
O
Introduction
K
O
N
Me
O
O
N
Me
O
N
O
Me
TScmd
Int-A
benzosimuline
2(1H)-Quinolone (2-quinolone) is
a
privileged nitrogen-
containing heterocyclic motif, which is found in natural products
and pharmaceutical agents.[1] Therefore, various synthetic
methods have been reported for the synthesis of 2-quinolone
derivatives.[2] However, the discovery of an unprecedented
synthetic route is still important toward the identification of novel
bioactive 2-quinolones. In this regard, we have reported the
modular assembly of 3,4-fused 2-quinolones and 4-aryl-2-
(b) Annulation of 1-iodonaphthalene with diethyl acetylenedicarboxylate (DEAD)
E
E
E
5 mol% [Pd(OAc)2]
15 mol% P(2-furyl)3
Hb
I
E
E
Ha
+
DEAD (4 equiv)
Ag2CO3, DMF
100 °C, 8 h
E
E = CO2Et
37%
Miura et al. [ref. 9]
17%
(c) This study: annulation using alkynes
quinolones
using
suitably
protected
(ortho-
R
R
aminophenyl)propiolates as building blocks.[3] Moreover, we
have investigated the Catellani-type annulation of 4-iodo-2-
R
path B
path A
Hb
I
R
R
R
Hb
cat. Pd
cat. Pd
Ha
Ha
quinolones,
hydroiodination/lactamization
which
are
prepared
via
(ortho-
R
R
R
R
N
O
N
O
of
Bn
C–Hb fission
C–Ha fission
N
O
Bn
Bn
phenanthridine-6(5H)-one
aminophenyl)propiolates.[4] We found that the Pd(0)/norbornene-
mediated reaction occurred preferentially at the vinylic C–Ha
bond over the aromatic C–Hb bond, affording analogs of the
natural product, benzosimuline (Scheme 1a). Based on the
mechanism reported for the Catellani reaction[5] and our own
density functional theory (DFT) calculations, we proposed that a
concerted metalation-deprotonation (CMD) step occurred via
TScmd to produce five-membered palladacycle intermediate Int-
A.[6] Therefore, we further envisaged that the palladium-
catalyzed reaction of 4-iodo-2-quinolones with alkynes would
afford the [2+2+2] annulation products, phenanthridine-6(5H)-
ones, via activation of the vinylic C–Ha bond (path A, Scheme
1c). Alternatively, previously unknown cyclopenta[de]quinoline-
2(1H)-ones can be obtained upon activation of the aromatic C–
Hb bond (path B, Scheme 1c).
R = Ewg
cyclopenta[de]quinoline-2(1H)-one
Scheme 1. (a) Pd/norbornene-mediated Catellani-type annulation of 4-iodo-2-
quinolones, (b) Pd-catalyzed annulation of 1-iodonaphthalene with DEAD, and
(c) Pd-catalyzed annulation of 4-iodo-2-quinolone with alkynes.
Prototypical annulations of iodoarenes with diphenylacetylene
were pioneered by Heck and Grigg. The Heck group performed
the reaction of iodobenzene using [Pd(OAc)2]/2PPh3 and Et3N
as
a
catalyst and
tetraphenylnaphthalene in 47% yield through
a
base, respectively, to obtain
[2+2+2]
a
annulation via activation of the ortho C–H bond.[7] In contrast,
Grigg and coworkers disclosed that the reaction of 1-
iodonaphthalene with diphenylacetylene using TlOAc as a base
afforded the acenaphthylene derivative in 45% yield through a
[3+2] annulation via C–H activation at the 8-position.[8] Later,
Miura and coworkers reported the palladium-catalyzed reaction
of 1-iodonaphthalene with diethyl acetylenedicarboxylate
(DEAD) in the presence of Ag2CO3 as a base (Scheme 1b).[9] In
this case, both the [3+2] and [2+2+2] annulation products were
obtained with the former as the major product. Moreover, Dyker
and the Larock group separately discovered unusual annulations
of iodobenzene with diphenylacetylene, which produced
phenanthrene or benzylidenefluorene derivatives via multiple C–
H activation steps.[10,11] Thus, these precedents exemplify the
divergent C–H activation reactivity of iodoarenes, which is
[a]
Prof. Dr. Y. Yamamoto, J. Jiang, Dr. T. Yasui
Department of Basic Medicinal Sciences
Graduate School of Pharmaceutical Sciences, Nagoya University
Chikusa, Nagoya 464-8601
E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904558
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dependent on the reaction conditions and/or substrate used.
Nevertheless, carboannulation of iodinated heterocycles
involving C–H activation has been underdeveloped, despite the
importance of heteropolycycles as drug lead compounds.[12,13]
Herein, we report our study on the palladium-catalyzed
annulation of 4-iodo-2-quinolones with alkynes via C–H
activation.
reaction time (20 h) was required (entry 3). The selectivity
toward product 3aa over 4aa slightly increased at a lower
temperature. The use of toluene as the solvent instead of DMF
at 80 °C resulted in the recovery of 1a (70% yield) and the
annulation products were not detected. The use of P(2-furyl)3 as
the ligand (3 mol%) did not improve the outcome of the reaction
(entry 4). Using AgOAc (2 equiv) as the base instead of Ag2CO3
resulted in an incomplete reaction (75% conversion of 1a) even
upon heating at 100 °C for 4 h and lower product selectivity
(entry 5). The observed annulation of 4-iodo-2-quinolone 1a with
DMAD is remarkable because 4-iodoquinoline (Figure 1) failed
to afford the corresponding annulation products, and produced
an intractable product mixture under the same reaction
conditions.
Results and Discussion
Reaction of 4-iodo-2-quinolone with non-activated internal
alkynes. At the outset of this study, the reaction of 4-iodo-2-
quinolone 1a with 4-octyne (4 equiv) as an internal alkyne under
conditions similar to the previously reported Catellani-type
annulation was investigated (Scheme 2). As a result, 4-
allenylated product 2 was obtained in 45% yield, instead of the
expected annulation product. As previously suggested for similar
allenylation reactions of iodobenzenes,[14] allene 2 was formed
via b-hydride elimination of an alkenylpalladium(II) intermediate,
indicating that the desired alkyne insertion took place.
Accordingly, internal alkynes bearing no propargylic hydrogens
should be used to realize the desired annulation.
Table 1. Reaction of 1a with DMAD.
E
E
E
Hb
I
E
E
E
Hb
5 mol% [Pd(OAc)2]
Ha
Ha
+
DMAD (4 equiv)
Ag2CO3 (1 equiv)
DMF, heat
N
O
N
O
Bn
N
O
Bn
Bn
1a
3aa
E = CO2Me
4aa
Entry
1[a]
2
Temp. [°C]
120
Time [h]
3aa, 4aa, HMM [%]
ND
3aa/4aa ratio
nPr
nPr
Et
24
4
ND
2.8
4.1
2.5
1.4
•
I
nPr
[PdII]
5 mol% [Pd(OAc)2]
100
42, 15, 6
4-octyne (4 equiv)
K2CO3 (2.5 equiv)
DMF, 105 °C, 2 h
N
O
N
O
Bn
3
80
20
20
4
53, 13, 12
32, 13, 8
N
O
Bn
2 45%
Bn
1a
4[b]
5[c]
80
Scheme 2. Formation of 4-allenyl-2-quinolone 2 from 1a and 4-octyne.
100
41, 30, 8
[a] K2CO3 was used as the base. [b] P(2-furyl)3 (3 mol%) was added. [c]
AgOAc (2 equiv) was used instead of Ag2CO3.
Reaction of 4-iodo-2-quinolones with activated internal
alkynes. Subsequently, the reactivity of dimethyl
acetylenedicarboxylate (DMAD) as an activated internal alkyne
was investigated because Miura and coworkers have previously
reported that acetylenedicarboxylates are efficient alkyne
components for the palladium-catalyzed annulation of
iodoarenes (Table 1).[9] The reaction of 1a with DMAD (4 equiv)
was performed under the same reaction conditions to those
outlined in Scheme 2, which resulted in no reaction. Thus, the
reaction was conducted at a higher temperature (120 °C), but
only an intractable mixture was obtained (entry 1). Ag2CO3 was
used as the base instead of K2CO3 according to the report of
Miura and coworkers.[9] 4-Iodo-2-quinolone 1a was consumed
within 4 h and two new products were formed along with
hexamethyl mellitate (HMM), which was formed via the
cyclotrimerization of DMAD (entry 2). Purification by silica gel
chromatography afforded cyclopenta[de]quinoline-2(1H)-one
3aa as the major product in 42% yield. The expected product,
phenanthridinone 4aa, was also obtained in 15% yield as an
inseparable mixture with small amounts of HMM (6% yield). This
result shows that the aromatic hydrogen (Hb) was preferably
activated over the vinylic hydrogen (Ha). The reaction also
proceeded at a lower temperature (80 °C), although a longer
I
Ph
Ph
HO
OH
N
Figure 1. Unsuccessful reactants.
Plausible pathways for the formation of 3aa and 4aa are outlined
in Scheme 3. Initially, oxidative addition (OA) of 1a is followed by
the insertion of DMAD to generate alkenylpalladium intermediate
int-B, which is the bifurcation point to 3aa and 4aa. The major
product 3aa is produced via six-membered palladacycle
intermediate int-C, which is generated from int-B via CMD of the
aromatic hydrogen (path A). On the other hand, CMD of the
vinylic hydrogen converts int-B into five-membered palladacycle
intermediate int-D (path B), which undergoes insertion of a
second DMAD molecule. Finally, reductive elimination occurs
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10.1002/chem.201904558
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from the resulting seven-membered palladacycle intermediate
int-F to afford minor product 4aa. Alternatively, the insertion of
DMAD occurs from int-B to generate dienylpalladium
intermediate int-E (path C), which can be converted into 4aa.
lower temperature (80 °C) and 4ca was isolated in 54% yield.
Notably, CF3-analog 1d exclusively afforded the corresponding
product 4da in 65% yield.[15] These results suggest that the
substituent at the 6-position hinders the aromatic C–H activation
step. In striking contrast, 6-fluoro-substituted substrate 1e
selectively afforded [3+2] annulation product 3ea in 68% yield
using the slow addition method, showing that a small fluorine
atom at the 6-position was well tolerated (Scheme 4a). When 4-
iodo-2-quinolone 1i bearing no proton at the 5-position was used
as the substrate, the desired phenanthridinone 4ia was
exclusively obtained in 76% yield (Scheme 4b).
E
PdILn
PdLn
E
[Pd]
1a
3aa
OA
path A
RE
N
O
Bn
N
O
Ag2CO3 – AgI
[Pd]
Ag2CO3
E
Bn
int-C
CMD
E
E
E
[Pd]
DMAD
Ag2CO3
[Pd]
E
(a)
E
E
E
E
E
I
5 mol% [Pd(OAc)2]
DMAD (2 equiv)
CMD
N
O
Bn
N
O
N
O
path B
Bn
Bn
+
int-B
int-D
[Pd] = Pd(CO3–]Ln
E = CO2Me
Ag2CO3 (1 equiv)
DMF, 100 °C, 4 h
method A
N
O
DMAD
E
DMAD
E
N
O
N
O
path C
Bn
Bn
Bn
4aa <7%a
E
E
1a
(slow addition, 3 h)
3aa 73%
E
E
E
i
iPrO2C
E
CO2Et
EtO2C
COPh
CO2 Pr PhOC
[Pd]
4aa
[Pd]
RE
variation of
activated
alkynes
N
O
N
O
Bn
Bn
int-E
int-F
N
O
E
N
O
E
N
O
Bn
Bn
Bn
3ab 75%
3ac 87%
3ad 25 h, 78%
w/o slow addition
Scheme 3. Plausible pathways for the formation of 3aa and 4aa.
E
E
E
E
F
variation
of
substituents
Accordingly, minor product 4aa can be produced via two
pathways (path B and path C). The selectivity toward path A vs.
7
N
O
Me
N
O
Cl
N
O
Bn
Bn
Bn
3ea 68%
(4ea <6%)[a]
3ga 62%
(4ga <11%)[a]
3fa 76%
(4fa <8%)[a]
path
B can be determined by the relative rate of the
intramolecular C–H activation step, while the rate of path C
should be influenced by the concentration of DMAD. Thus, to
improve the selectivity of 3aa over 4aa, we next conducted the
reaction of 1a with the slow addition of DMAD (2 equiv) in DMF
for 3 h using a syringe pump (method A, Scheme 4a). As a
result, the formation of 4aa was effectively suppressed (<7%)
and 3aa was obtained in 73% yield. Similarly, the use of bulkier
diethyl and diisopropyl esters instead of DMAD predominantly
afforded 3ab and 3ac in 75% and 87% yields, respectively. In
addition to acetylenedicarboxylates, dibenzoylacetylene can be
used as the activated alkyne component. Notably, the reaction
of 1a with dibenzoylacetylene resulted in the predominant
formation of [3+2] annulation product 3ad in 78% yield without
recourse to the slow-addition technique. In striking contrast, the
use of diphenylacetylene and 2,5-dimethylhex-3-yne-2,5-diol
(Figure 1) instead of DMAD resulted in no reaction. Thus, the
activating groups play a dispensable role in the reaction.
E
(b)
Cl
E
E
E
E
E
I
10 mol% [Pd(OAc)2]
DMAD (4 equiv)
Cl
Cl
6
+
Ag2CO3 (1 equiv)
DMF, 100 °C, 3 h
method B
N
O
N
O
N
O
Bn
Bn
3ba <16%[a]
Bn
1b
4ba 48%
(w/o slow addition)
E
E
E
E
E
E
E
E
E
E
MeO
Me
F3C
E
MeO
MeO
E
N
O
N
O
N
O
Bn
Bn
Bn
4ca 54%[b] (3ca <9%)[a,b]
4ia 76%[c]
4da 65%
E
(c)
E
E
E
E
I
5 mol% [Pd(OAc)2]
DMAD
+
E
conditions
F
N
O
F
N
O
F
N
O
Bn
Bn
Bn
Next, 4-iodo-2-quinolones 1b–d, bearing a substituent at the 6-
position, were examined as substrates (Scheme 4b). The
reaction of 6-chloro derivative 1b was conducted without the
slow addition of DMAD (method B) to preferably afford
phenanthridinone 4ba (48% yield) over [3+2] annulation product
3ba (<16% yield). Similar selectivity was observed for the
1h
3ha
4ha
method A/B: 36%/34%
22%/47%
Scheme 4. Substrate scope of the palladium-catalyzed annulation of 4-iodo-2-
quinolones (E = CO2Me). [a] These minor products include non-negligible
impurities. [b] 80°C, 20 h. [c] 2 h.
1
reaction of 6-methyl analog 1c; H NMR analysis of the crude
product showed that 3ca and 4ca were formed in 17% and 65%
yields, respectively. However, the purification of these products
was rather difficult due to the formation of inseparable
byproducts. Thus, the reaction of 1c was again conducted at a
Subsequently, the effect of the substituents at the 7-position on
the chemoselectivity was investigated using 7-chloro-, 7-methyl-,
and 7-fluoro-substituted substrates 1f–h under slow-addition
conditions (method A). While the reactions of 1f and 1g
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selectively afforded the expected [3+2] annulation products 3fa
and 3ga in 76% and 62% yields, respectively (Scheme 4a), the
chemoselectivity almost disappeared for fluoro-analog 1h,
affording 3ha and 4ha in 36% and 22% yields, respectively
(Scheme 4c). Furthermore, the [2+2+2] annulation was favored
over [3+2] annulation when the reaction was repeated using
method B and the yield of 4ha was significantly increased (47%
yield). Although the details are unclear at this stage, the fluorine
substituent at the 7-position has a significant electronic impact
on the selectivity of the C–H activation step.
The reaction of 1a with an unsymmetrical alkyne is rather
formidable probably due to the lack of regioselectivity in the
alkyne insertion step (Scheme 5). The use of alkynyl esters 5a
and 5b, or ketone 5c without slow addition at 80–100 °C
afforded a complex mixture of products. Nevertheless, the
reaction of 1a with alkynyl ester 5d bearing a bulky trityl ether
moiety under slow-addition conditions (method A) produced the
expected annulation products 3af and 4af in 30% and 26%
yields, respectively. Notably, these products were obtained as
single regioisomers. Although the regioselectivities are unknown
at this stage, we considered that insertion occurred in such a
way that the Pd center is placed on the less congested carbon a
to the ester group.
although small amounts of unidentifiable byproducts were
obtained. In a similar manner, 4-iodocoumarin (8) predominantly
afforded [3+2] annulation product 9 in 41% yield without
recourse to the slow addition technique. The reaction of 4-iodo-
1-isoquinolone (10) resulted in a complex mixture of products.
Nevertheless, cyclopenta[de]isoquinolin-1(2H)-one 11 was
isolated, albeit in a low yield (27%). The corresponding [2+2+2]
annulation product was not detected. In striking contrast, 3-iodo-
4-quinolone (12) failed to afford the expected [2+2+2] annulation
product along with 12 recovered in 60% yield, as indicated by 1H
NMR analysis of a crude reaction mixture. These results
demonstrate that 4-iodo-2-quinolones 1 are much superior as
the substrates to iodinated heterocycles 6, 8, 10, and 12, and
the product selectivity varies depending on the heterocyclic
framework.
E
I
5 mol% [Pd(OAc)2]
DMAD (4 equiv)
E
E
E
Ag2CO3 (1 equiv)
DMF, 100 °C, 6.5 h
method B
N
N
O
Bn
N
N
O
Bn
6
7 46%
E
E
5 mol% [Pd(OAc)2]
DMAD (4 equiv)
I
E = CO2Me
E
Ag2CO3 (1 equiv)
DMF, 100 °C, 4 h
method B
R
E
R
R
E
I
5 mol% [Pd(OAc)2]
O
O
O
9 41%
E
O
5d (2 equiv)
8
+
Ag2CO3 (1 equiv)
DMF, 100 °C, 4 h
method A
(slow addition, 3 h)
E
N
O
N
O
I
N
O
O
N
Bn
5 mol% [Pd(OAc)2]
DMAD (4 equiv)
Bn
Bn
I
1a
3af 30%
4af 26%
NBn
Ag2CO3 (1 equiv)
DMF, 100 °C, 3 h
method B
NBn
E
R
Bn
R
E
12
R
E
O
[PdII]
vs.
[PdII]
O
10
5a R = Ph, E = CO2Et
11 27%
5b R = n-pentyl, E = CO2Me
5c R = CH2OMe, E = COPh
5d R = CH2OTr, E = CO2Me
N
O
N
O
Scheme 6. Palladium-catalyzed reactions of 4-iodinated heterocycles with
DMAD.
Bn
Bn
insertion regioselectivity
Scheme 5. Reaction of 1a with unsymmetrical alkynes.
Mechanistic considerations. To obtain insights into the
reaction mechanism, DFT calculations [SMD (DMF)
B3LYP(GD3BJ)/SDD–6-31++G(d,p)//B3LYP(GD3BJ)/LanL2DZ–
6-31G(d)] were carried out with a particular focus on each
individual step. For computational efficiency, N-methyl 2-
quinolones were analyzed instead of the N-benzyl derivatives
used in this study (for details, see Supporting Information). The
present reaction requires Ag2CO3 as the base, in striking
contrast to our previous Catellani-type annulation; the use of
K2CO3 instead of Ag2CO3 led to an intractable mixture of
products (Table 1, entry 1). These observations suggest that the
Ag+ ion plays a significant role. Thus, Ag+ was included in the
model complexes. Because there are many examples of the
related palladium-catalyzed annulations of iodoarenes,[7-11] it is
reasonable to propose that the present palladium-catalyzed
annulation starts with the oxidative addition of 4-iodo-2-
quinolone to an active Pd(0) species (Scheme 3).[16] After
oxidative addition, the resultant vinyl palladium iodide is
assumed to undergo facile ligand exchange in the presence of
Reactivity of related iodinated heterocycles. As described
above, the palladium-catalyzed reaction of 4-iodo-2-quinolones
with
DMAD
afforded
cyclopenta[de]quinolone
and/or
phenanthridinone derivatives depending on the substrate
structure and reaction conditions used. In contrast, 4-
iodoquinoline failed to afford the corresponding annulation
products. These results demonstrate the distinct reactivity of 4-
iodo-2-quinolones toward the palladium-catalyzed annulations
with activated alkynes. Thus, we investigated the reactions of
related iodinated heterocycles, such as 4-iodo-1,8-naphthyridin-
2(1H)-one (6), 4-iodocoumarin (8), 4-iodo-1-isoquinolone (10),
and 3-iodo-4-quinolone (12) to compare their reactivity with that
of 4-iodo-2-quinolone (1a) (Scheme 6).
The reaction of 4-iodo-1,8-naphthyridin-2(1H)-one (6) with
DMAD was conducted for 6.5 h using method B to selectively
afford [2+2+2] annulation product
7 in 46% yield. The
corresponding [3+2] annulation product was not detected,
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Ag2CO3 and DMAD to produce vinyl palladium carbonate
complexes s0 and sI with a h2-alkyne ligand (Figure S2 in
Supporting Information). Alkyne complex sI bearing a k1-
OCO2Ag ligand associated with additional Ag2CO3 was located
12.8 kcal/mol lower in energy than s0 bearing only k2-OCO2Ag.
Subsequent insertion of the coordinated DMAD was found to be
facile as it proceeds from sI via TSsI-sII with a small activation
barrier of DG‡ = +10.8 kcal/mol, resulting in the highly exergonic
(–38.1 kcal/mol) formation of dienyl palladium intermediate sII.
In contrast, the second insertion step was found to be less
efficient as its activation barrier was estimated to be 9.4 kcal/mol
higher (DG‡ = +20.2 kcal/mol) than that for the first insertion step
and the formation of trienyl palladium sIV is less exergonic (–
29.1 kcal/mol) when compared to the first insertion step (Figure
S3 in Supporting Information).
enough to be overcome under the experimental conditions and
an excess amount of DMAD hampers the CMD step by
capturing intermediates Ia and Ib (Figure 3c). In fact, the slow
addition of DMAD (method A) decreased the formation of the
[2+2+2] annulation products. Accordingly, paths A and B are
favored over path C with the lower DMAD concentration, while
path
C
becomes competitive with the higher DMAD
concentration (Scheme 3).
(a) O
O
Ag
O
Ag
E
O
O
O
Ag
O
O
Ag
Pd
Ag
O
E
O
E
O
Ag
O
O
Ag
E
Pd
O
Pd
O
E
E
H
O
Ag
O
O
Ag
H
H
N
O
N
O
N
O
Me
Me
TSIa-II (+12.4)
Me
Next, the C–H activation step was investigated. Previously, on
the basis of their DFT study, Schaefer and coworkers suggested
Ia (+2.6)
II (–19.2)
Ag
that
a Pd–Ag heterobimetallic complex intermediate with
bridging acetate ligands plays a critical role in the CMD step of
the directed ortho C–H functionalization of benzamides.[17] In
contrast, we couldn't locate any heterobimetallic intermediate
bearing a carbonate bridge. Instead, we found vinyl Pd(k2-
CO3)Ag•Ag2CO3 complexes Ia and Ib as precursors to the CMD
step (Figure 2a). The latter is slightly more stable than the
former. From these intermediates, the CMD step proceeds via
TSIa-II and TSIb-III with activation barriers of DG‡ = +9.8 and +12.8
kcal/mol, respectively. The formation of six-membered
palladacycle II from Ia was found to be more exergonic (–21.8
kcal/mol) than that of five-membered palladacycle III from Ib (–
12.9 kcal/mol).
Pd
Ag
O O
Ag
E
Ag
E
E
Ag
O
E
E
E
OO
O
Ag
O
Ag
O
O
O
Pd
O
Pd
O
Pd
O
O
H
O
H
O
O
O
Ag
Ag
H
Ag
N
O
N
O
N
O
Me
Me
Me
III (–12.9)
Ib (0.0)
TSIb-III (+12.8)
Figure 3a outlines the energy profile for the transformation from
sI to II and III via DMAD insertion/CMD or from sI to V via a
double DMAD insertion/CMD. The first DMAD insertion (sI →
sII) is facile, characterized by a small activation barrier and high
exergonicity. The subsequent CMD of the aromatic proton
proceeds from intermediate Ia, which is slightly less stable than
initially formed isomer sII. The energetic span[18] between sII and
TSIa-II for this process is +10.5 kcal/mol. On the other hand,
intermediate Ib, which undergoes the competitive CMD of the
vinylic proton, is slightly more stable than sII and thus, the
energetic span for this process is identical with its activation
barrier (+12.8 kcal/mol). Accordingly, the aromatic CMD is
kinetically favored over the vinylic CMD, as the energetic span is
smaller. In addition, the resultant six-membered palladacycle II
is more stable than five-membered palladacycle III. Thus, it is
reasonable to assume that the aromatic CMD leading to
thermodynamically more stable palladacycle II is favored over
the vinylic CMD leading to less stable palladacycle III. In fact,
TSIa-II is less strained and earlier than TSIb-III as indicated by the
C–Hb and O–Hb distances in TSIa-II are shorter and longer than
those of C–Ha and O–Ha in TSIb-III, respectively (Figure 3b).
The association of one DMAD molecule with sII produces h2-
alkyne complex sIII, which is more stable than sII, Ia, and Ib.
The activation barrier for the second DMAD insertion is higher
than those of the CMDs. Therefore, the second insertion is less
feasible than the CMDs. However, it is assumed that the second
insertion is non-negligible because the activation barrier is small
(b)
E
E
E
E
E
E
E
Ag
Ag
E
E
E
E
E
O
O
O
O
Ag
O
O
Pd
H
Pd
Ag
Pd
Ag
O
O
O
O
O
H
O
O
O
O
Ag
Ag
Ag
O
N
O
N
O
Ag
N
O
HO
Me
Me
O
Me
TSIV-V (+14.4)
IV (0.0)
V (–5.9)
Figure 2. Calculated model quinolones (E = CO2Me) related to the CMD step.
The relative Gibbs free energies (298 K, 1 atm) are given in the parentheses
(kcal/mol).
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Previously, Glorius and coworkers proposed that
AgOAc oxidizes the Pd(II) center in the key
palladacycle intermediate and thereby, the resultant
Pd(IV) palladacycle undergoes facile reductive
elimination.[19,20] Thus, reductive elimination from
TSsI-sII
+10.8
(a)
blue: CMD for [3+2] annulation (path A)
red: CMD for [2+2+2] annulation (path B)
orange: DMAD insertion/CMD for [2+2+2] annulation (path C)
0.0
sI
TSsIII-sIV
–22.6
+10.5
TSIb-III
–27.2
Ia
palladacycle VIc containing
a
Pd(IV) center
ligand was also
with Glorius’
–37.4
sIII
–42.8
2–
k2-CO3
–27.6
TSIa-II
coordinated by
investigated. In
a
+20.2
–38.1
sII
–40.0
accordance
ΔG (kcal/mol)
TSIV-V
–61.1
Ib
–52.9
III
suggestion, the activation barrier was significantly
reduced (DG‡ = +5.6 kcal/mol) and the formation of
VIIc with a Pd(II) fragment was found to be highly
exergonic (–40.2 kcal/mol). Accordingly, oxidation
of the palladacycle intermediate dramatically
enhances the reductive elimination step. However,
+12.8
–59.2
+14.4
II
–71.9
–75.5
IV
sIV
O
(b)
O
–81.4
V
Ag+ are omitted for clarity.
O
O
E
E
O
Pd
E
OO
O
E
O
O
Hb
Pd
O
O
the involvement of
a highly unstable Pd(IV)
Ha
TSIa-II
TSIb-III
oxidation state is less likely since Ag2CO3 is a weak
oxidant.
C–Hb = 1.315 Å
O–Hb = 1.386 Å
C–Ha = 1.400 Å
O–Ha = 1.267 Å
N
O
N
O
Me
Me
(c)
DMAD
sIII
Ib
conformational isomers
sII
Ia
Figure 3. Energy profile for the transformation from model quinolone complex
sI to intermediates II, III, and V. The relative Gibbs free energies (298 K, 1
atm) are given in the parentheses (kcal/mol).
E
Pd0(dmf)
E
E
E
E
L
E
PdII
(dmad)
Pd0
L
PdII
E
E
N
O
N
O
Double insertion product sIV is considered to be an intermediate
for the [2+2+2] annulation via the seven-membered palladacycle.
Thus, we next analyzed the CMD step from sIV. DFT
calculations identified IV, which is the isomer of sIV, as the
precursor for the CMD step (Figure 2b). The former was located
slightly lower in energy than the latter. CMD occurs via TSIV-V
with an activation barrier of DG‡ = +14.4 kcal/mol. This value is
reasonably low enough for the CMD step to occur at ambient
temperature, but higher than the activation barriers of the CMD
steps from Ia and Ib. The formation of seven-membered
palladacycle V from IV is only slightly exergonic (–5.9 kcal/mol).
Accordingly, the CMD of IV is less favorable than those of Ia and
Ib (Figure 3a).
N
O
Me
Me
N
O
Me
TSVIa-VIIa (+21.6)[a]
TSVIb-VIIb (+13.4)[b]
VIIb (–25.0)
Me
VIa (0.0)[a]
VIb (0.0)[b]
VIIa (–15.7)
E
O
E
E
E
O
O
PdIV
E
PdIV
O
PdII
O
O
O
O
O
O
O
N
O
N
O
N
O
Me
VIc (0.0)
Me
TSVIc-VIIc (+5.6)
Me
VIIc (–40.2)
Figure 4. Calculated model quinolones (E = CO2Me) related to the reductive
elimination step. The relative Gibbs free energies (298 K, 1 atm) are given in
the parentheses (kcal/mol; [a] L = DMF and [b] L = DMAD).
The reductive elimination step from the model six-membered
palladacycles was next investigated using DFT calculations
(Figure 4 and Figure S4 in Supporting Information). Because the
Formation of the [2+2+2] annulation product was analyzed
(Scheme 7 and Figure S5 in Supporting Information). Alkyne
insertion into the C(vinyl)–Pd bond of five-membered
palladacycle VIII occurs via TSVIII-IX with a relatively higher
activation barrier of DG‡ = +28.4 kcal/mol, resulting in the highly
exergonic (–29.6 kcal/mol) formation of seven-membered
palladacycle IX with an open coordination site. Subsequently,
coordination of DMF on the Pd(II) center results in the formation
of tub-shaped palladacycle X, in which the a carbons are placed
in close proximity to each other. From X, facile reductive
elimination proceeds via TSX-XI with a small activation barrier of
DG‡ = +7.0 kcal/mol, resulting in the highly exergonic (–63.6
kcal/mol) formation of arene complex XI. Accordingly, the DMAD
insertion step from five-membered palladacycle VIII is the most
difficult step in the [2+2+2] annulation pathway.
–
anion AgCO3 ligand on the palladium center was replaced by
the aryl ligand after the CMD step, reductive elimination of
palladacycle VI bearing the Pd(II) center with one neutral ligand
was analyzed. It was found that when the neutral ligand is DMF,
the reductive elimination proceeds via TSVIa-VIIa with
reasonable activation barrier of DG‡ = +21.6 kcal/mol and the
formation of [3+2] annulation product VIIa containing
a
a
[Pd(0)(dmf)] fragment is exergonic by –15.7 kcal/mol. Thus, this
process is both kinetically and thermodynamically favorable
under the experimental conditions. The replacement of DMF
with electron-withdrawing DMAD reduces the activation barrier
to DG‡ = +13.4 kcal/mol and increases the exergonicity to –25.0
kcal/mol. These results imply that electron-withdrawing alkynes
facilitate the reductive elimination step by reducing the electron
density of the Pd(II) center in palladacycle VIb.
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TSVIII-IX
+28.4
E
Therefore, the formation of palladacycle sIX is assumed to be a
dead end of the reaction of DPA.
E
E
E
ΔG (kcal/mol)
Pd
E
N
O
E
Conclusions
Me
E
0.0
VIII
E
E
E
dmf
In summary, we have successfully developed the palladium-
catalyzed annulation of 4-iodo-2-quinolones with activated
internal alkynes involving C–H activation. 4-Iodoquinolones were
treated with activated alkynes such as DMAD in the presence of
Pd(OAc)2 and Ag2CO3 in DMF at 100 °C to produce the [3+2]
annulation products (cyclopenta[de]quinoline-2(1H)-ones) via
aromatic C–H activation along with the [2+2+2] annulation
products (phenanthridine-6(5H)-ones) via vinylic C–H activation.
The product selectivity ([3+2] vs. [2+2+2]) varied depending on
the substituents on the benzene ring of the quinolone substrate,
activated alkyne, and reaction conditions. It was found that 4-
iodo-2-quinolone is an exceptional substrate for the present
palladium-catalyzed annulation; 4-iodoquinoline and 3-iodo-4-
quinolone all failed to undergo the annulation, and 4-iodo-1,8-
Pd
E
N
O
TSX-XI
–29.9
Me
Pd
E
E
+7.0
–29.6
IX
N
O
–36.9
E
E
Me
X
E
E
E
E
E
E
E
Pd
O
E
E
Pd(dmf)
O
N
N
Pd
dmf
Me
Me
–63.6
XI
N
O
Me
Scheme 7. The energy surface for the transformation of model quinolone
complex VIII to arene complex XI (E = CO2Me). The relative Gibbs free
energies (298 K, 1 atm) are given in the parentheses (kcal/mol).
naphthyridin-2(1H)-one,
4-iodocoumarin,
and
4-iodo-1-
isoquinolone exhibited diminished reactivity. We also
investigated the individual steps in the catalytic cycle using DFT
calculations on model 4-iodo-2-quinolones. Notably, it was
suggested that the Ag+ ions and ester moieties of DMAD play
significant roles in the CMD steps; the coordination network,
consisting of the Ag+ ion, ester moieties, and carbonate ligand
on the Pd center, effectively places the carbonate base in close
proximity to the proton abstracted.
Finally, the reaction of diphenylacetylene (DPA) was analyzed
for comparison with that of DMAD. The initial DPA insertion from
h2-alkyne complex sV and subsequent aromatic CMD were
investigated (Figures S6, Supporting Information). It was found
that the DPA insertion occurs via TSsV-sVI with an activation
barrier of DG‡ = +18.3 kcal/mol, which is larger than that for the
DMAD insertion from sI (DG‡ = +10.8 kcal/mol). This inefficiency
can be ascribed to the larger geometrical change from sV to
TSsV-sVI than that for the corresponding DMAD complexes (sI →
TSsI-sII) as evidenced by the significant decrease in the C1–C2
distance for the DPA complexes (Figure S7). The aromatic CMD
of sVIIa proceeds via TSsVIIa-sVIII with an activation barrier of DG‡
= +14.6 kcal/mol, which is ca. 5 kcal/mol larger than that for
DMAD-derived intermediate Ia (DG‡ = +9.8 kcal/mol). Due to the
coordination of the ester carbonyl group to the Ag+ counter ion,
the carbonate base is placed in closer proximity to the
abstracted H atom in the DMAD-derived vinyl Pd complex Ia (the
H–O distance = 2.239 Å) than in sVIIa (the H–O distance =
2.475 Å, Figure S8). NBO analyses also indicate that the
electron donation from the carbonate oxygen lone pairs to the
Csp2–H antibonding orbital is stronger in Ia than in sVIIa.
Therefore, proton abstraction is more facile for Ia.
In contrast, the lactam carbonyl moiety plays a role of the
directing group for Ag2CO3, facilitating the vinylic CMD.
Accordingly, the CMD of DPA-derived complex sVIIb proceeds
via TSsVIIb-sIX with an activation barrier of DG‡ = +13.1 kcal/mol
(Figure S6), which is comparable with that of DMAD-derived
complex Ib (DG‡ = +12.8 kcal/mol, Figure 2). Moreover, sVIIb
was located ca. 5 kcal/mol lower than sVIIa. Thus, the five-
membered palladacycle sIX is expected to be produced
predominantly (Figure S9). However, the subsequent insertion of
DPA into the Pd–C bond of palladacycle sX was found to be
difficult as the activation barrier is too high to overcome under
the experimental conditions (DG‡ = +33.8 kcal/mol, Figure s10).
Experimental Section
Reaction of iodinated heterocycles with activated alkynes
Representative procedure A: A solution of 4-iodo-2-quinolone 1a (71.7
mg, 0.199 mmol), [Pd(OAc)2] (2.4 mg, 0.0107 mmol), and Ag2CO3 (56.8
mg, 0.206 mmol) in dry DMF (2.0 mL) was degassed at –90 °C. To this
solution was added a solution of DMAD (49 µL, 0.400 mmol) in dry
degassed DMF (2.0 mL) via syringe pump (0.01 mL/min) under an argon
atmosphere at 100 °C. The reaction mixture was stirred at 100 °C for an
additional 1 h. After cooling to room temperature, insoluble materials
were removed by filtration. To the filtrate was added H2O (20 mL) and the
obtained mixture was extracted with EtOAc/hexane (1:1, 3 × 20 mL). The
combined organic layer was washed with H2O (2 × 40 mL) and brine (40
mL), and dried over Na2SO4. After concentration in vacuo, the crude
material was purified by flash column chromatography on silica gel
(hexane/EtOAc = 10:1~1:1) to afford 3aa (54.4 mg, 73%) as an orange
solid (mp. 151.9–153.7 °C) and then 4aa (6.7 mg, 7%) as a yellow solid
(mp 191.2–193.5 °C).
Representative procedure B: A solution of 4-iodo-2-quinolone 1b (78.5
mg, 0.198 mmol), [Pd(OAc)2] (4.7 mg, 0.0209 mmol), Ag2CO3 (56.0 mg,
0.203 mmol), and DMAD (100 µL, 0.816 mmol) in dry DMF (4.0 mL) was
degassed at –90 °C. The reaction mixture was stirred under an argon
atmosphere at 100 °C for 3 h. After cooling to room temperature,
insoluble materials were removed by filtration. To the filtrate was added
H2O (20 mL) and the obtained mixture was extracted with EtOAc/hexane
(1:1, 3 × 20 mL). The combined organic layer was washed with H2O (2 ×
40 mL) and brine (40 mL), and dried over Na2SO4. After concentration in
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vacuo, the crude material was purified by flash column chromatography
on silica gel (hexane/EtOAc = 10:1~1:1) to afford 3ba (12.8 mg, 16%;
including minor impurity) as a yellow solid (mp 163.1–169.1 °C) and then
4ba (52.9 mg, 48%) as a yellow solid (mp 102.2–106.3 °C).
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Acknowledgements
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This research is partially supported by the Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS) from AMED under Grant Number
JP19am0101099) and JSPS KAKENHI (Grand Number JP
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Keywords: palladium • quinolone • alkyne • C-H activation •
DFT calculation
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Entry for the Table of Contents (Please choose one layout)
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Y. Yamamoto,* J. Jiyue, T. Yasui
Hb
I
E
E
E
Ha
O
E
E
E
Hb
[Pd(OAc)2]
Ag2CO3
[Pd(OAc)2]
Ag2CO3
[2+2+2]
C–Ha
fission
[3+2]
C–Hb
fission
Page No. – Page No.
Ha
O
N
Palladium-Catalyzed [3+2] and
[2+2+2] Annulations of 4-Iodo-2-
quinolones with Activated Alkynes
via Selective C–H Activation
Bn
N
+
N
O
Bn
E
E
Bn
The palladium-catalyzed reaction of 4-iodo-2-quinolones with activated
alkynesaforded cyclopenta[de]quinoline-2(1H)-ones and/or phenanthridine-6(5H)-
ones via [3+2] annulation involving aromatic C–H activation or [2+2+2] annulation
involving vinylic C–H activation, respectively. Reasonable mechanisms for the
formation of these annulation products have been proposed based on density
functional theory calculations.
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