Rhodium-Catalyzed Copper-Assisted Intermolecular Domino C?H Annulation of 1,3-Diynes with Picolinamides: Access to Pentacyclic π-Extended Systems

Article abstract of DOI:10.1002/chem.201900162

A new mode of reactivity of 1,3-diynes in rhodium-catalyzed oxidative annulation reactions has enabled the rapid assembly of extended π systems from readily available picolinamide derivatives. The process involves a double C?H bond activation and the iterative annulation of two 1,3-diyne units, with each alkyne moiety engaged in an orchestrated insertion sequence with high regiocontrol, leading to the formation of five new C?C bonds and the construction of four fused rings in a single operation. Either isoquinoline-1-carboxamides or fused polycyclic systems can be accessed by a switch in the regioselectivity of the second diyne insertion depending on the reaction conditions. DFT theoretical calculations have elucidated that the cooperative participation of both rhodium and copper in substrate activation, favored in the presence of excess of the copper(II) salt, is key to such a reversal of regioselectivity and subsequent multiple cyclization leading to fused polycyclic products. The role of copper was found to be essential in assisting both multiple insertion and rhodium-walking sequences, with the implication of intermediates with a Rh?Cu bond (2.60 ?).

Full text of DOI:10.1002/chem.201900162

A Journal of
Accepted Article
Title: Rhodium-Catalyzed Copper-Assisted Intermolecular Domino
C–H Annulation of 1,3-Diynes with Picolinamides: Access to
Pentacyclic π-Extended Systems
Authors: Ángel Manu Martínez, Inés Alonso, Nuria Rodríguez, Ramon
Gomez-Arrayas, and Juan C. Carretero
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201900162
Link to VoR: http://dx.doi.org/10.1002/chem.201900162
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Rhodium-Catalyzed Copper-Assisted Intermolecular Domino C–H
Annulation of 1,3-Diynes with Picolinamides: Access to
Pentacyclic -Extended Systems
Ángel Manu Martínez,[a] Inés Alonso,*[a],[b] Nuria Rodríguez,* [a],[b] Ramón Gómez Arrayás,* [a],[b] and Juan
C. Carretero[a],[b]
Abstract: A new reactivity mode of 1,3-diynes in Rh-catalyzed
oxidative annulation enables the rapid assembly of extended -
systems from readily available picolinamide derivatives. The process
involves a double C–H bond activation and iterative annulation of two
units of 1,3-diyne, each alkyne moiety of which is engaged in an
orchestrated insertion sequence with high regiocontrol, leading to the
formation of five new C–C bonds and construction of four fused rings
in a single operation. Either isoquinoline 1-carboxamides or fused-
polycyclic systems can be accessed by a switch in regioselectivity
for the second diyne insertion depending on the reaction conditions.
DFT theoretical calculations have elucidated that the cooperative
participation of both Rh and Cu in substrate activation, favored under
excess of copper(II) salt, is key for such a reversal of the
regioselectivity and subsequent multiple cyclization leading to fused
polycyclic products. The role of Cu was found to be essential in
assisting both multiple insertion and Rh walking sequences, with the
implication of intermediates showing a RhCu bond (2.60 Å).
even though this class of compounds is of prime importance as
functional materials.[5] For example, although the [Cp*RhIII]-
catalyzed oxidative alkyne annulation of arenes is one of the
most versatile methods to access heterocyclic compounds,[6,7]
only a handful of approaches have been reported on multiple C–
H annulation involving two or more alkyne units to afford fused
polyaromatic systems (Scheme 1). Most of these methods rely
on: (i) di-ortho- alkenylation/annulation at both sides of a
bidentate directing group (Scheme 1a),[8] (ii) the use of a
directing group that leaves a N-functionality proximal to the aryl
substituent of the newly incorporated alkyne, whose coordination
to RhIII promotes a new C–H annulation with another molecule
of alkyne (Scheme 1b),[9] and (iii) a directed [2+2+2]-type
benzannulation via two-fold cyclorhodation-alkyne insertion,
pioneered by Satoh and Miura (Scheme 1c).[10] Despite this
success, the development of conceptually different tactics in
domino C–H annulation toward expanding the scope of
conjugated -scaffolds is an important goal.
Alkynes in Rh-catalyzed cascade CH annulation
Introduction
Ar
Ar
R
X
Z
Ar
H
Ar
R
X
NR
Ar
The high level of precision and predictability achieved in C–H
activation[1] has enabled recent research to target more difficult
challenges such as iterative C–H functionalizations for a rapid
buildup of molecular complexity.[2,3] However, the application of
such strategy for the synthesis of polycyclic (hetero)aromatic
systems with extended -conjugation remains underdeveloped[4]
N
Y
N
R
Y
N
(a)
H
Z
Ar
R
Ar
Ar
Ar
Ar
Ar
Ar
Ar
X
Ar
Ar
X
Ar
X
[Rh]
NH2
Ar
Ar
(b)
(c)
H
N
N
H
Ar
Ar
Ar
Ar
[a]
Mr. A. M. Martínez, Dr. I. Alonso, Dr. N. Rodríguez, Dr. R. Gómez
Arrayás, Prof. Dr. Juan C. Carretero
[DG]
Ar [DG] Ar
H
Ar
Ar
Ar
Ar
Departamento de Química Orgánica, Facultad de Ciencias
Universidad Autónoma de Madrid (UAM)
Cantoblanco, 28049 Madrid (Spain)
E-mail: ines.alonso@uam.es; n.rodriguez@uam.es;
ramon.gomez@uam.es;
H
Ar
Ar
Ar
Ar
1,3-Diynes in Rh-catalyzed intermolecular CH annulation
[b]
Dr. I. Alonso, Dr. N. Rodríguez, Dr. R. Gómez Arrayás, Prof. Dr.
Juan C. Carretero
O
O
R
OPiv
NH
R
N
H
Institute for Advanced Research in Chemical Sciences (IAdChem)
UAM, 28049 Madrid, Spain
(d)
H
HN
O
R
R
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Cascade Rh-catalyzed multiple C–H annulation of arenes with
alkynes leading to -extended systems.
Scheme 2. Catalytic domino benzannulation of 1,3-diynes toward polycyclic
aromatic -extended systems.
1,3-Diynes have the potential to provide further complexity;
however, the limited number of methods exploiting 1,3-diynes in
CH annulation highlights the challenges of regiocontrol in the
insertion and mono-/diannulation selectivity.[11-13] In a pioneering
example, Glorius demonstrated the RhIII-catalyzed diannulation
of benzamides with 1,3-diynes, thus leading to bisheterocycles
(Scheme 1d).[11] This approach has later been extended to
cobalt-catalysis.[12]
Herein we present a method for the Rh-catalyzed oxidative
intermolecular annulation of picolinamides with two molecules of
diaryl-1,3-diyne in which the four alkyne units do participate in
annulation, thereby enabling the assembly of up to four fused
rings with extended -conjugation in a single step through a
double C–H bond activation and construction of five C–C bonds.
Interestingly, by appropriate choice of the reaction conditions,
either isoquinoline 1-carboxamides or fused-polycyclic systems
can be obtained selectively through a switch in regioselectivity
for the second diyne insertion. Computational studies have
unveiled that the cooperative action of copper in substrate
activation, favored under an excess amount of copper(II) salt, is
key for a reversal of the regioselectivity in the insertion of the
second 1,3-diyne unit. Furthermore, the role of the copper ion
seems to be essential in assisting orchestrated alkyne insertion
processes and metal walking sequences enabling distant
activation and multiple cyclization towards construction of fused
polycyclic products.
While in these transformations each -system of the diyne
undergoes migratory insertion independently of the other, we
questioned whether an alternative mechanism would be possible
in which the 1,3-diyne could engage both alkyne motifs in an
orchestrated sequence of insertion events, thereby enabling the
access to new polycyclic aromatic architectures. During the final
stages of our investigations, Chalifoux and co-workers reported
the first realization of this goal, namely the domino
benzannulation reaction of 1,3-diynes.[14] In their elegant protocol,
-expansion is achieved by an intramolecular double 6-endo-dig
cyclization of properly designed diaryl-1,3-butadiynes in the
presence of InCl3-AgNTf2 as catalyst (Scheme 2A). We
envisaged that an intermolecular cascade CH benzannulation
of 1,3-diynes would be feasible under [Cp*RhIII]-catalysis if, upon
initial alkyne benzannulation, the other alkyne motif of the diyne
is primed for a subsequent benzannulation with the aryl
substituent of the 1,3-diyne component (Scheme 2B). Such a
sequence of bond-forming events has, to our knowledge, never
been described, yet it could greatly expand the repertoire of
cascade annulation. Although we were aware that controlling
regioselectivity in each of the four alkyne migratory insertions
would present an immediate significant challenge, previous
success on regioselectivity control in 1,3-diyne diannulation by
Glorius and others offered hope that these obstacles would not
be insurmountable.[11,12]
Results and Discussion
1. Optimization studies: single benzannulation to afford
isoquinoline-1-carboxamides bearing alkyne handles
(isoquinoline products, IQ)
With these considerations in mind, we chose to explore the
annulation reaction of diphenylbuta-1,3-diyne with N-benzyl-2-
picolinamide (1).[15-17] Interestingly, under similar conditions to
those optimized in our previous Rh-catalyzed benzannulation
with alkynes[10e,15b] the model reaction of diphenylbuta-1,3-diyne
with 1[16] led to clean conversion to the isoquinoline 1-
carboxamide 2 in nearly quantitative yield (98%) with complete
regiocontrol (Scheme 3). The alternate arrangement of the aryl
and alkynyl substituents in the newly formed aryl ring was found
to be opposite to that previously found in RhIII-catalyzed
benzannulation of arenes with unsymmetrically substituted alkyl
aryl alkynes, which favors an orientation of the aromatic
substituents at vicinal 2,3-position.[10a,b,18] The regioselectivity for
the first 1,3-diyne insertion is in complete agreement with the
previous observations by Glorius, suggesting that the
regioselectivity of the migratory insertion is highly affected by the
hybridization of the carbon atom, with the order of preference
being alkynyl > aryl for the group that remains distal to the target
aryl CH bond.[11] However, in this case, the migratory insertion
of the second 1,3-diyne component takes place with opposite
regioselectivity to afford products featuring an alternate
arrangement of the aryl and alkynyl substituents. The X-ray
structure of 2 unambiguously establishes the regioselectivity of
this reaction.[19]
New reactivity mode of 1,3-diynes
: both alkynes are engaged in an orchestrated manner
A. Intramolecular (Chalifoux)
R
R
R
InCl3
AgNTf2
Ar
Ar
Ar
cat.
B. Intermolecular (this work)
Ar
Ar
H
H
Ar
Ar
Ar
R2
[Cp*RhIII
cat.
]
Ar
O
H
N
[Rh]
Ar
R2
NHR
Ar
RN
OC
NHR
N
N
Ar
2
O
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Ar
Ar
Ar
H
Ar
Ph
Ph
[RhCp*Cl2]2 (5 mol %)
AgSbF6 (20 mol %)
[RhCp*Cl2]2 (5 mol %)
AgSbF6 (20 mol %)
Cu(OAc)2 (2.0 equiv)
H
R
R
R1
O
N
NHR2
O
Cu(OAc)2 (2.0 equiv)
DCE, 120 °C, 12 h
Ar
Ph
O
N
R1
O
DCE, 120 °C, 12 h
98%
HN
N
1, 3-10
N
NHR2
11-23
Ar
Ar
Ar
(3.0 equiv)
Ar
Ph
(3.0 equiv)
Ph
NHBn
Ph), 98%
1
Ar
Ar
Ar
Ar
Ar
Ar
2
(R =
Scheme 3. RhIII-catalyzed CH annulation of 1 with diphenylbuta-1,3-diyne
and ORTEP view of compound 2.
Ar
Ar
Ar
O
O
O
R1
N
NHBn
N
N
NHR2
(Ar = p-Tol)
18, R2 = Et,
19, R2 = Ph,
NHBn
11, Ar = p-Me-C6H4, 95%
12, Ar = p-tBu-C6H4, 87%
13, Ar = p-MeO-C6H4,73%
(Ar = p-Tol)
16, R1 = Me,75%
17, R1 = Cl, 75%
The prevalence of isoquinoline skeleton in pharmaceuticals
motivated us to explore the scope of this process (Scheme 4).
Both electron-donating and electron-withdrawing groups at
either the diaryl 1,3-diyne (11-15, 73-98%)[20] or the pyridine unit
(16-17, 75%) were tolerated. It is also remarkable the good
tolerance towards a sensitive Ar-Cl substituent (17). Aryl or alkyl
substituents (other than a benzyl group) on the amide nitrogen
were found to be compatible (18-20, 86-90%); however, a
primary amide group failed (R2 = H, not shown).
90%
86%
20, R2 = (CH2)2Ph,88%
14, Ar = p-F-C6H4,
15, Ar = p-CF3-C6H4, 98%
98%
R
Ar
Ar
O
Ar
Ar
R'
CF3
BnN
N
N
N
S
Bn
S
Bn
O
21
21a, R = p-Tol, R' =
21b, R =
p-Tol, R' = p-Tol, 33%
O
p-Tol, 42%
22 (Ar = p-Tol), 98%
23 (Ar = p-Tol), 98%
Interestingly, the presence of a CF3 group at the C5 position
of the pyridine ring interrupted the aromatic homologation and
led exclusively to the 1,7-naphthyridin-8(7H)-one skeleton with
no regiocontrol (21a and 21b, 42% and 33%, respectively). The
lack of regiocontrol in this case could be related to the ability of
this group to get involved in hydrogen bond formation (vide infra).
Similar interrupted pathway featuring only one alkyne insertion
was observed with thiophene- or benzo[b]thiophene-2-
carboxamide substrates (22 and 23, 98%), which suggests that
the second alkyne C–H insertion is sensitive to steric effects.
Therefore, the presence of a substituent in the pyridyl-ortho-
position to the reactive CH site may impose a significant steric
demand, thereby bypassing the normal reactivity outcome (the
second alkyne C–H insertion) and favoring instead the
competitive trapping of the plausible alkenyl rhodium
intermediate by the amidic NH.
Scheme 4. Benzannulation of picolinamides and interrupted C–H/N–H
annulation. Isolated yields after chromatography.
2. Access to complex pentacyclic systems with extended -
conjugation (products PCS)
During the evaluation of the scope, we observed in some
crude mixtures trace amounts of a side product showing intense
fluorescence under UV irradiation on the TLC plate. This
observation led to the postulation of a polyaromatic nature for
this byproduct, which sparked our interest to find a way for its
selective formation. We decided to re-optimize the catalyst
system in the model annulation of 1 with 1,4-di-p-tolylbuta-1,3-
diyne (Table 1, see SI for details). Gratifyingly, the selectivity
towards 24 improved dramatically by increasing the loading of
Rh-catalyst to 20 mol% in the presence of 2.2 equiv of diyne (at
130 °C in DCE for 3 h), providing product 24 in 45% isolated
yield (entry 1). Higher loadings of Cu(OAc)2 (4.0 equiv) improved
the reactivity to complete conversion, although with a slight
decrease in selectivity (52% yield for 24, entry 2). Pleasingly,
switching the solvent to 1,4-dioxane, improved the yield in favor
of 24 (60%, entry 3). This effect of the solvent on selectivity can
be ascribed to the higher solubility of the Cu salt in 1,4-dioxane
compared to DCE. Finally, the amount of silver salt can be
reduced to 40 mol% without altering the outcome (entry 4).
Table 1. Optimization studies toward fused pentacyclic structures
(PCS).
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Ar
was again confirmed by X-ray diffraction analysis.19
Incorporation of a methyl substituent at C6 of the picolinamide is
also compatible (36, 60%), whereas a Cl atom at C6 did not
survive, leading only to the protodechlorination product 24 in
52% yield (not shown). This side-reaction is likely due to the
excess of Cu present in the reaction medium.
H
p-Tol
p-Tol
H
R
R
Ar
[Rh]-cat. / [AgSbF6]
Ar
Cu(OAc)2
O
H
N
p-Tol
OC
[Rh]
RN
Solvent, T (ºC),
3 h, Ar
HN
N
p-Tol
Ph
N
NHBn
1
O
p-Tol)
11
, (R =
I
p-Tol
Ar
Ar
[RhCp*Cl2]2 (20 mol %)
AgSbF6 (40 mol %)
p-Tol
p-Tol
Ar
Ar
O
N
NHR2
R1
Cu(OAc)2 (4.0 equiv)
DCE, 130 °C, 3 h
Ar
R1
1, 5, 7, 25-26
Ar
OC
NHR2
N
Me
N
OC
(2.2 equiv)
27 36
-
NHBn
24
24
ORTEP view of
Tol
Tol
Ar
Ar
Ar
Tol
Entry[a]
Rh-cat
(mol%)
Cu(OAc)2
(equiv)
Solvent
11
24
(%)[b]
(%)[b]
Me
OC
NHEt
N
R
OC
NHBn
Ar = Ph (R = H),
N
1
20
20
20
20
2.0
4.0
4.0
4.0
DCE
30
46
39
38
45
52
60
62
2
DCE
27,
32
, 44%
43%
52%
28, Ar = p-tBu-C6H4 (R = tBu),
32
ORTEP view of
3
4[c]
dioxane
dioxane
29, Ar = p-MeO-C6H4 (R = OMe),60%
(H atoms omitted for clarity)
30
, Ar = p-F-C6H4 (R = F),
49%
Tol
31
, Ar = p-CF3-C6H4 (R = CF3), 45%
Tol
Tol
Tol
Tol
Tol
Tol
[a] Reaction conditions: 1 (0.15 mmol), 1,3-diyne (0.33 mmol, 2.20 equiv),
[Cp*RhCl2]2 (x mol %), AgSbF6 (4x mol %), Cu(OAc)2, solvent (0.1 M), 130 ºC,
under Ar atmosphere. [b] Isolated yields. [c] AgSbF6 (40 mol%).
Tol
Tol
Me
OC
HN
N
Me
N
OC
Me
Ar
Me
33, 39%
OC
HN
N
NHBn
34
35
, Ar = p-CF3-C6H4, 8%
, Ar = p-Me-C6H4, 66%
Ph
36
, 60%
The examination of the diyne scope showed tolerance to both
electron-rich and electron-deficient p-substituted aromatic
groups (Scheme 5, 27-31 43-60%). Interestingly, the nature of
the N-substituent showed a remarkable influence on the
selectivity towards the fused polycyclic product, a N-benzyl
group providing better results than N-ethyl (32, 44%) or N-
phenethyl (33, 39%). This observation suggested that a potential
interaction of the metal with the aromatic ring of the benzyl unit
could play an essential role in enhancing selectivity. In line with
this proposal, the substrate with an electron-poor p-(CF3)benzyl
substituent provided a very poor yield of 34 (8%), whereas the
more electron-donating 4-methylbenzyl group restored the
selectivity (35, 66%). The fused-pentacyclic ring structure of 32
Scheme 5. Scope of Rh-catalyzed annulation with 1,3-diynes. The
corresponding isoquinoline 1-carboxamides were also isolated (typically 22-
42% yield, see SI).
Although the selectivity is not complete towards formation of
products PCS, a single fused polycyclic structure was observed
in all cases despite multiple competing cyclization pathways are
possible. This distinct feature suggests that the core pentacyclic
framework is constructed sequentially through
a highly
orchestrated process involving multiple domino-type alkyne
insertion and metal walking sequences.
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N
O
N
O
Ph
Ph
N
O
N
N
Rh
Rh
Ph
Ph
Ph
Cp*
Ph
N
Cp*
Ph
N
O
N
Cp*
N
H
Rh
O
O
N
O
O
Ph
Cp*
N
Ph
TS(IV'-V')
Ph
Ph
Rh
N
Ph
37.9
36.0
Rh
H
Me
H
N
Rh
TS(IV-V)
Cp*
Ph
N
O
TS(II-III)
O
N
Ph
O
O
Cp*
33.4
16.0
Ph
13.7
Ph
TSC-N
Ph
Me
II
23.5
H
III
24.2
Ph
H
N
N
Ph
O
N
O
Rh
IV
22.3
Rh
O
O
25.7
Ph
Cp*
Me
Cp*
IV'21.9
O
O
HO
N
Me
O
N
I
N
Ph
Me
HOAc
Ph
Rh
17.7
O
Ph
Ph
Ph
G
TS(VII-VIII)
Ph
N
Rh
VI
6.9
Cp*
H
OH
Rh
N
8.7
N
V
4.9
Cp*
O
Ph
VIII
-0.1
mod 1
Cp*
N
O
Me
Cp*
O
HOAc
0
Ph
Ph
Ph
-4.6
-4.9
IXB
IXA
Me
O
N
Rh
N
VII
-7.7
Ph
Ph
HOAc
Ph
H
O
Rh
Ph
Ph
Ph
O
Ph
Ph
B
N
N
D
H
O
Cp*
N
Ph
C
Rh
H
Ph
N
O
H
O
N
N
Rh
Cp*
Ph
N
Cp*
O
Ph
BCD = 155.9
Cp*
O
Cp*
Me
Ph
Ph
Ph
H
Rh
Rh
D
Ph
O
O
C

B
Ph
BCD = 157.2
Ph
Me
Ph
ligand
exchange
ligand
exchange
1st CH bond cleavage
1st diyne insertion
2nd CH bond cleavage
Figure 1. Energy profile for the C–H annulation of
1
with diphenylbuta-1,3-diyne from RhIII complexes in the gas phase (M06/6-
311++G(d,p)(C,H,N,O),LANL2TZ(f)(Rh)//B3LYP/6-31G(d)(C,H,N,O), LANL2DZ(Rh). Relative G values in kcal·mol1 at 298 K). Intermediates I-III, indicated in blue,
had been previously studied[10e] [M06/6-311+G(d,p)(C,H,N,O),SDD(Rh)//6-31G(d)(C,H,N,O), LANL2DZ(Rh), being 35.2 the free energy value for TS(II-III)].
3. Mechanistic insights
products arising from the opposite regioselectivity have been
experimentally observed in this step.
For a deeper insight into the reaction pathway and the origin
of the selectivity for these complex cyclization processes, we
performed a study of each reaction step by DFT calculations
(see SI for details).
Single benzannulation to afford the isoquinoline-1-
carboxamide (products IQ). On the basis of our previous
studies,10e a RhIII-complex derived from 1 (mod1) would evolve
through an acetate-assisted CMD process to afford intermediate
III that could exchange the AcOH ligand for a diyne unit
(Figure 1). As a result, the two regioisomeric intermediates IV
and IV’ could form, being both similar in energy. However, from
this point onwards, the formation of V is favored due to the lower-
energy barrier via TS(IV-V) than through TS(IV’-V’) (13.7 and
16.0 kcal·mol1, respectively).[21] The higher stability of TS(IV-V)
compared to TS(IV’-V’) could be related to the degree in which
the diyne moiety loses its linear conjugation (Figure 2).[18] The
diyne moiety remains with a smaller deformation of the bond and
dihedral angles in TS(IV-V) in comparison to TS(IV’-V’). Thus,
the delocalization of charge is stronger in TS(IV-V) than in
TS(IV’-V’), resulting into an increase of the negative charge
values located on the Ph ending groups.
0.067
0.082
-0.047
-0.051
-0.061
C
B
-0.041
D
B
-0.113
A
-0.092
-0.105
0.103
C
0.081
0.126
D
-0.083
A
-0.031
0.095
-0.161
TSIV'-V'
ABCD = -28.6
BCD = 138.3
TSIV-V
ABCD = -24.1
BCD = 146.8


Figure 2. Structure of TS(IV’-V’) and TS(IV-V). Natural charges (qi, in a.u.) of
Rh and C atoms involved in the C–C and C–Rh bond formation, charge
delocalization and relevant bond and dihedral angles (
are indicated.
ͦ ) of the diyne moiety
From this point, instead of evolving through reductive elimination
leading to a naphthyridinone skeleton (TSC-N), intermediate V would
rather follow an alternative pathway. Protonation of the amide N with
AcOH (VI) would allow the Rh-atom to coordinate the C4–H bond of
the pyridine (VII) leading to intermediate VIII through a second CMD
(TS(VII-VIII)).[22] After displacement of AcOH by the second unit of
diyne, two similarly stable regioisomeric complexes might form: IXA
It is interesting to note that according to the energy profile, the
1,2-migratory insertion of the first diyne unit should selectively
occur leading the alkynyl group distal to the functionalized CH
bond. This is in complete agreement with the observation that no
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and IXB. On one side, intermediate IXA would afford the isoquinoline
derivatives featuring an alternate arrangement of aryl and alkynyl
substituents (products IQ). On the other side, IXB could progress to
the isoquinoline derivatives with the alkynyl substituents at vicinal
positions that would further evolve to the fused polycyclic skeleton
(PCS) products. Therefore, from here, the regioselectivity achieved
in the insertion of the second unit of diyne would be the key to define
the selectivity of the process.
supporting the selectivity initially observed for the synthesis of
isoquinoline 1-carboxamide products (IQ).
For the second insertion step, there could be two distinct reaction
pathways to consider for each regioisomeric complex (Figure 3). The
route named as “a” implies that the second insertion step takes place
into the alkeneRh bond. The pathway “b” considers the insertion to
occur into the C4(Py)Rh bond. In the case of model A, the “path a”
through TS(IX-X)Aa would be favored with an energy barrier of
12 kcal·mol1 approximately, either in the gas phase or considering
solvation effects of DCE or 1,4-dioxane.[23] In contrast, “path b”
seems to be preferred for model B, proceeding via TS(IX-X)Bb with
an energy barrier about 13 kcal·mol1. However, in any case, the
energy barrier found for model A would be lower than for model B,
Figure 3. Possible transition states for the insertion step of the second unit of
the diyne. The relative G values in kcal·mol1 at 298 K are indicated respect to
mod 1 (Figure 1) in the gas phase (in black). Single point solvation energy
corrections (SMD model) in DCE (blue) and 1,4-dioxane (red) are also
provided.
Ph
Ph
H
N
H
N
N
N
O
O
Cp*
Ph
Ph
N
Cp*
Ph
H
Ph
Cl
Cu
O
O
N
Cl
O
O
Rh
Rh
Cu
Ph
O
Cp*
Ph
Ph
Ph
Ph
Ph
O
O
Rh
Cl
Ph
TS(IX-X)BCua
TS(IX-X)ACub
Cu
Ph
H
N
Ph
2.0, 5.8
B
D
0.8, 5.5
N
C
BCD = 151.1
IXB
O
Ph
0.3, 4.1
TS(IX-X)BCub
-4.6, -2.8
Ph
-0.5, 4.6
TS(IX-X)ACua
Cp*
Ph
Ph
H
N
IXBCu
O
Cl
N
-4.9, -3.0
IXA
Rh
O
-12.1 -7.2
Cu
Ph
G
O
Cp*
Ph
Cp*
Ph
Cl Cu OAc
H
N
Rh
Ph
Ph
N
-16.4, -11.5
IXACu
Ph
N
O
Cl
Ph
H
Ph
Cp*
Ph
N
Ph
H
N
Ph
Cl
Cu
O
O
N
H
N
O
Rh
O
O
Rh
N
TS(X-XI)BCub
Ph
O
Cp*
Ph
O
XBCub
-30.5, -27.1
Cu
-33.7, -27.0
Cl
Ph
Ph
N
Cp*
Ph
Ph
Ph
Rh
O
O
Ph
D
Cl
Ph
H
Rh
Ph
Cu
Ph
Ph
Cu
O
N
C
O
Cp*
B
Ph
O
Cl
O
Ph
BCD = 157.3
Ph
Cu
Cl
Ph
Rh
Ph
XIBCub
O
Ph
-74.7, -74.3
Cu
O
O
XIIBCub
Ph
-88.6, -85.5
CuCl(OAc)
coordination
alkyne
coordination
2nd diyne insertion
closing 1st fused aromatic ring
Figure 4. Energy profile for the insertion-reductive elimination steps of complexes IXA and IXB with CuII salts in the gas phase (M06/6-311++G(d,p)(C,H,N,O,Cl),
LANL2TZ(f)(Cu,Rh)//B3LYP/6-31G(d)(C,H,N,O,Cl), LANL2DZ(Cu,Rh). Single point solvation energy corrections (SMD model) in 1,4-dioxane are indicated in red.
Relative G values in kcal·mol1 at 298 K). Hydrogen bonds between Cp* ligand and carbonyl group are indicated.
favored when the amount of CuII is increased seemed to indicate
that this metal could play a relevant role in the reaction outcome
Complex polycyclic systems with extended -conjugation
(products PCS). To explain the formation of products PCS, we
beyond regenerating the Rh-catalyst. In fact, when the structures
next investigated the reasons behind the regioselectivity switch
of the regioisomers IXA and IXB were optimized incorporating
in the 1,2-migratory insertion of the second unit of diyne. The
experimental observation that polycyclic products (PCS) are
CuCl(OAc) (Figure 4),[24] the resulting complex IXBCu was
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significantly less stable than IXACu. In principle, both complexes
show a similar coordination mode of the copper atom with only
one of the alkyne moieties. However, the orientation of the diyne
unit does not allow an additional coordination with Cu in IXBCu,
and the steric hindrance with the alkyne-Cu moiety provokes a
stronger deformation of the diyne unit in the case of IXBCu than
in the case of IXACu. The angle BCD decreases from IXB to
the alkyne moiety, making the closest phenyl group more prone
to further functionalization, presumably through an electrophilic
aromatic substitution process.[25] According to this, we could
explain we had never detected the corresponding regioisomeric
isoquinoline 1-carboxamide intermediate.[26]
From this point on, the arene-alkyne cyclization would be
initiated through TS(XII-XIII) (Figure 5, only roman numbers are
kept for simplicity),[27] leading to the Wheland-type intermediate
XIII. This intermediate shows a bond between both metals
(RhCu: 2.60 Å) – a feature that seems to be the key for the
subsequent cyclization. Then, coordination of an acetate ion to
Rh promotes the displacement of the chloride ligand to Cu (XIV).
Subsequent intramolecular deprotonation of the Wheland-type
intermediate by Rh-coordinated acetate [TS(XIV-XV)] followed
by release of HOAc would result into intermediate XVI, having
the rhodium coordinated to the other alkyne unit. This
intermediate would evolve through alkyne insertion into the
RhCu bond involving oxidation of both metals (see natural
charges) and cleavage of the RhCu bond (RhCu: 2.89 Å) to
afford intermediate XVII. In this intermediate, the Cu-atom has
been displaced from the arene carbon by rhodium that is also
coordinated to the alkyne moiety. A change in the coordination
mode of both metals to the alkyne would afford XVIII, in which
chloride ligand has been removed from the coordination sphere
of metals but keeps small interactions with the Cp* ligand.
Because of the departure of this ligand, the positive charges of
both metals increase. Finally, a reductive elimination step
through TS(XVIII-XIX), that implies a decrease in the positive
charge of both metals, would afford intermediate XIX with the
polycyclic system and all the CC bonds completed. Further
studies are ongoing in our group to understand these redox
processes as well as the following steps to reach the final
product.
IXBCu (BCD = 4.8
IXA to IXACu (BCD = 0.1
ͦ
) whereas remains almost constant from
).
ͦ
From complexes IXCu, the insertion step would take place
with a lower barrier for model B through TS(IX-X)BCub (12.4 and
11.3 kcal·mol-1 in gas phase or 1,4-dioxane respectively) than for
model A through TS(IX-X)ACua (15.9 and 16.1 kcal·mol-1 in gas
phase or 1,4-dioxane, respectively). Therefore, we could explain
the favored regioselectivity towards the formation of the
isoquinoline 1-carboxamide intermediate with the alkynyl
substituents at vicinal. Following this pathway, the resulting
complex XBCub would easily evolve through TS(X-XI)BCub to
give XIBCub, featuring a 3-fold-coordinated copper ion set up by
two π-bonded alkyne ligands and one acetate ion. The structure
of this intermediate brings to light that, along with the reductive
elimination process leading to the formation of the new CC
bond, an electron transfer between both metals through the
chloride bridge ligand, might have taken place. The arrangement
of RhClCu atoms in TS(X-XI)BCub (RhCl: 2.60 Å, CuCl:
2.31 Å, RhClCu: 99.4 )ͦ resembles that found by Funes-Ardoiz
and Maseras in their recently reported DFT-based mechanistic
studies on the cooperative role of Cu(OAc)2 in the reductive
elimination process of the rhodium-catalyzed oxidative coupling
of benzoic acid and alkynes.[24] Moreover, in the resulting
XIBCub, the chloride ligand is almost completely transferred to
the Rh-atom, that is eventually displaced towards the carbonyl
group. Subsequent to this, complex XIBCub would easily evolve
to XIIBCub. In this intermediate, both metals are coordinated to
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Ph
N
H
Ph
N
O
N
H
Cp*
H
N
O
O
Rh
O
Cp*
H
Ph
Ph
Rh
Cu
O
Ph
Ph
Cl
TS(XIV-XV)
Cl
O
XIV
Cu
-48.1
Ph
N
Ph
-48.5 Ph
O
-OAc
XIII
-58.0
TS(XII-XIII)
O
H
H
N
O
Ph
-53.5
N
N
O
Cp*
Rh
Cu
Cp*
H
HO
Ph
O
Ph
O
O
Rh
N
H
N
H
Ph
Ph
Ph
Ph
N
N
XII
-74.4
O
O
RhCu:3.69
qRh : 0.100
qCu : 0.678
qCl : -0.960
Cu
Ph
N
Cp*
H
G
O
Cl
Cl
O
O
O
Cp*
H
XV
Rh
Ph
Ph
N
Ph
Ph
Cl
Ph
Ph
Cl
O
-83.1
Rh
O
Cu
Cu
Ph
O
Cp*
Rh
Ph
HOAc
O
O
Ph
Ph
TS(XVIII-XIX)
H
N
XVI
N
H
Ph
-98.7
O
RhCu: 2.60
-102.9
XVIII
Cu
O
Ph
N
N
H
Ph
Cp*
Rh
O
N
Cl
-107.5
H
N
O
Ph
O
Cl
H
XVII
Cp*
Rh
Cu
RhCu: 2.66
qRh :0.015
qCu :0.594
qCl : -0.696
Ph
Ph
-119.1
Cp*
O
O
Ph
O
Cl
RhCu: 2.89
qRh : 0.074
qCu : 0.662
qCl : -0.678
Ph
Ph
RhCu: 3.20
qRh : 0.125
qCu : 0.785
qCl : -0.937
Cu
O
Ph
Cl Rh
H
O
Cu
O
XIX
-137.4
alkyne insertion
intoRhCu bond recoordination
metals
construction of the 2nd fused aromatic ring via S
EAr
reductive elimination
assembly of the last five-membered ring
Figure 5. Energy profile for the final cyclization of intermediate XII in 1,4-dioxane (B97D/6-311++G(d,p)(C,H,N,O,Cl),LANL2TZ(f)(Rh,Cu)//6-31G(d)(C,H,N,O,Cl),
LANL2DZ(Rh,Cu), SMD model). Relative G values in kcal·mol1 at 298 K. Hydrogen bonds between Cp* ligand and carbonyl group or chloride ligand are indicated
with dashed bonds. Natural charges (qi, in a.u.) and relevant distances RhCu (Å) are also indicated.
Simplify plausible mechanistic pathways. A simplified general
catalytic cycle for the formation of products IQ and PCS is shown
in Scheme 6 based on our preliminary mechanistic investigation
and the proposals put forth in the literature for annulative
processes of (hetero)arenes with alkynes. Ligand exchange from
[RhCp*Cl2]2 promoted by silver salt in the presence of an excess
of acetate ions would form the presumed active catalyst
[RhCp*X(OAc)] (A) (X = Cl or OAc). Then, displacement of an
acetate or chloride from A by the picolinamide substrate would
lead to intermediate B, which would undergo “rollover”
cyclometalation[28] to afford C. This process requires N-
decomplexation and rotation around the carbonyl–Py bond
followed by ortho-C–H bond activation, presumably by an
acetate-assisted CMD pathway with loss of a second molecule
of acetic acid. Intermediate C would evolve through alkyne
coordination (D) and subsequent 1,2-migration of the rhodium–
carbon bond across the alkyne, resulting in the formation of the
seven-membered rhodacycle E, with the alkyne substituent
regioselectively placed at the position closer to the rhodium
atom. Protonation of the amide nitrogen of E by AcOH could
trigger a second cyclometalation at C4 of the pyridine ring (via
concerted CMD), leading to a more stable five-membered
complex F. Alternatively, if cyclometalation from E is hampered
(e.g., by steric crowding), reductive elimination becomes a more
favorable pathway, leading to the mono-insertion product
(“interrupted” pathway). From the key intermediate F, two
alternative mechanisms can operate depending on the reaction
conditions. Under standard conditions, the coordination of a
second diyne molecule in an orientation favoring an alternate
arrangement of aryl and alkynyl groups followed by
regioselective migratory insertion of the alkeneRh bond across
the coordinated alkyne (with the alkyne substituent positioned
closer to the rhodium atom) would lead to G. Finally, a reductive
elimination step releases the alkynyl-substitued isoquinoline
product (IQ) with concomitant oxidation of the formed RhI
species (H) by CuII to regenerate the Cp*RhIIIcatalyst.
In the presence of increased amounts of CuII salt, an
alternative reaction pathway from complex F involving RhCu
bimetalic complexes tends to predominate. In this case,
coordination of the Cu to the alkyne moiety of F introduces steric
interactions with the incoming diyne unit that makes more
favorable an approach in which the two-alkyne moieties are
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10.1002/chem.201900162
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projected facing each other. In this orientation, insertion of the
C4(Py)Rh bond across the triple bond is favored over insertion
of the alkeneRh bond (again the alkyne substituent ends up
closer to the rhodium atom), thereby furnishing complex I
(intermediate X in Figure 4). This vicinal arrangement of the
alkynes favors a reductive elimination involving electron transfer
between both metals, to afford complex J (intermediate XII in
Figure 4) in which the copper ion is π-coordinated to the two
alkynes and the rhodium ion is -bonded to one of the alkyne
groups. Next, the alkyne moiety that is coordinated to both
metals would promote cyclization with the proximal phenyl ring
through electrophilic aromatic substitution, leading to complex K
(intermediate XVI in Figure 5), which has the rhodium
coordinated to the other alkyne unit. Intermediate K would evolve
through alkyne insertion into the RhCu bond to afford complex
L (intermediate XIX in Figure 5). This complex would undergo
protodemetalation promoted by HX (X = Cl or OAc) to afford the
pentacyclic system (PCS), along with RhI (H) species and
CuX(OAc). CuII would further oxidize the RhI species to RhIII,
thus closing the cycle.
Bn
N
H
N
O
[RhCp*Cl2]2
Ar
HX
CuX(OAc)
AgSbF6, Cu(OAc)2
Cl
Cp*
AgCl, Cu(SbF6)2
BnNHCOPy
Ar
Ar
Rh
I
HX (X: Cl or OAc)
O
Cu
O
Cu
Ph
Ar
CuII
H
O
[Cp*RhX(OAc)L]
N
N
L (Int XIX)
Bn
A
N
O
*Cp Rh
N
Cp*
Ar
I
X
HX
O
[RhCp*L2]
H
B
Ar
Rh
Cu
H
Ar
N
Bn
Ar
N
Ar
Ar
Cl
Ar
Ar
Ar
O
Ar
Ar
O
*Cp Rh
K (Int XVI)
BnHNOC
Ar
N
L
C
Ar
OC
HN
N
O
Cp*
L
Rh
N
Ar
Bn
O
HN
Products PCS
Ar
Bn
Bn
N
AcOH
AcO
Ph
G
N
Products IQ
Ar
*Cp Rh
N
H
N
O
Ar
Ar
D
Cp*
Rh
O
Cl
Ar
BnHNOC
Ar
N
CuCl(OAc)
Bn
N
BnHNOC
Ph
Ar
N
N
reductive elimination
(interruptedpathway)
*Cp
Cu
O
Ar
Ar
Rh
O
Rh Cp*
L
L
Rh
L
Ph
Ar
Ar
Ar
Cp*
Ph
Ar
J (Int XII)
Cu
Ar
E
Ar
F
O
N
Ph
O Cl
Bn
N
O
I (Int X)
Scheme 6. Simplified catalytic cycle for the rhodium-catalyzed intermolecular C–H annulation of 1,3-diynes with picolinamides.
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Conclusions
Synthesis
of
N-benzyl-10-methyl-5,7,8-tri-p-tolylbenzo[5,6]
indeno[1,7-gh]isoquinoline-1-carboxamide (24). An oven-dried,
argon-flushed 20.0 mL vessel was charged with N-benzylpicolinamide (1)
(31.8 mg, 0.15 mmol, 1.00 equiv), [RhCp*Cl2]2 (18.6 mg, 0.03 mmol,
20 mol %), Cu(OAc)2 (109 mg, 0.60 mmol, 4.00 equiv) and AgSbF6
(20.6 mg, 0.06 mmol, 40 mol %). Under argon atmosphere 1,4-dioxane
(1.00 mL) and 1,4-di-p-tolylbuta-1,3-diyne (II) (75.9 mg, 0.33 mmol,
2.200 equiv) were added via syringe and the resulting mixture was stirred
at 130 °C for 3 h. After the reaction was complete, the volatiles were
removed in vacuo and the residue was purified by column chromatography
(Cy/DCM/EtOAc 8:1:1), yielding 24 as a yellow solid; yield: 62.3 mg (62%).
1H NMR (Chloroform-d, 300 MHz, δ): 8.48 (d, J = 5.4 Hz, 1H), 8.45 (d,
J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.67 (s, 1H),
7.46 – 7.32 (m, 10H), 7.17 (dd, J = 8.5, 1.4 Hz, 1H), 6.83 – 6.71 (m, 4H),
4.61 (d, J = 4.3 Hz, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.26 (s,
3H). 13C NMR (Chloroform-d, 75 MHz, δ): 167.3, 151.8, 150.9, 140.8,
140.3, 140.0, 139.4, 138.6, 137.9, 137.0, 136.0, 135.8, 134.4, 133.9, 133.8,
133.6, 131.9, 131.4, 131.1, 131.0, 129.3, 129.0, 128.8, 128.6, 128.4, 128.3,
128.0, 127.8, 127.8, 127.7, 127.5, 122.3, 122.0, 121.4, 44.1, 21.8, 21.4,
21.2, 21.2. HRMSESI (m/z): [M + H]+ calcd for C49H39N2O: 671.3057;
Found: 671.3050.
In conclusion, the Rh-catalyzed oxidative annulation of
picolinamide derivatives with diaryl 1,3-diynes can be directed to
the formation of either isoquinoline 1-carboxamides incorporating
alkyne handles or structurally complex polycyclic extended
-systems by modifying the catalyst system and reaction
conditions. The latter pathway represents a new reactivity pattern
involving a double C–H bond activation and iterative annulation of
two units of 1,3-diyne, resulting in the formation of five new C–C
bonds and construction of four fused rings in a single operation.
DFT mechanistic studies have provided understanding of the
factors that govern the regioselectivity in the 1,2-migratory
insertion of the first unit diyne as well as the origin of the divergent
regiochemical outcome in the second diyne insertion. Importantly,
a cooperative participation of copper, favored under an excess
amount of copper(II) salt, facilitates reversal of the regioselectivity
in the second diyne insertion and plays an important role in
assisting orchestrated alkyne insertion processes and rhodium
displacement throughout the heterocyclic framework, thereby
enabling distant activation and sequential construction of multiple
ring systems. We believe that this work could inspire the
development of other novel metal-catalyzed annulations of 1,3-
diynes toward more complex systems, as well as contribute to the
understanding of cooperative participation of copper in rhodium-
catalyzed multiple annulation processes.
Acknowledgements
We thank the Spanish Ministerio de Economía, Industria y
Competitividad (MINECO, Grants CTQ2012-35790 and
CTQ2015-66954-P, MINECO/FEDER, UE) for financial support.
N.R. thanks the MICINN for a Ramón y Cajal contract and the
European Commission for a for a Marie Curie Career Integration
Grant (CIG: CHAAS-304085). The Centro de Computación
Científica (UAM) is acknowledged for generous allocation of
computer time. We also thank Dr J. Lloret for helpful discussions.
Experimental Section
.
General methods. The corresponding starting materials were synthetized
using oven-dried glassware under an argon atmosphere containing a
Teflon-coated stirrer bar and dry septum. All reactions were performed
under argon atmosphere in oven-dried 10 mL vessels equipped with a
Teflon-coated stirrer bar and sealed with a cap designed to vent and
re-seal in the case of overpressure during reaction. Solvents were purified
by standard procedures prior to use. All other compounds are
commercially available and were used without further purification. Flash
column chromatography was performed using 230-400 mesh ultra-pure
silica gel. Mass spectral data were acquired on a VG AutoSpec mass
spectrometer.
Keywords: Cascade C–H annulation • 1,3-diynes • rhodium •
isoquinoline • -extended systems
[1]
Selected general reviews on CH functionalization: a) J. Wencel-Delord,
T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740; b) T.
Newhouse, P. S. Baran, Angew. Chem. 2011, 123, 3422; Angew. Chem.
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Science 2012, 335, 807; g) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu,
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2900; q) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281. For a
comprehensive overview of directing groups applied in metal-catalyzed
C–H functionalization: r) C. Sambiagio, D. Schönbauer, R. Blieck, T.
Dao-Huy, G. Pototschnig,; P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-
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Synthesis
of
N-benzyl-6,8-diphenyl-5,7-bis(phenylethynyl)-
isoquinoline-1-carboxamide (2). An oven-dried, argon-flushed 20.0 mL
vessel was charged with N-benzylpicolinamide (1) (31.8 mg, 0.15 mmol,
1.00 equiv), [RhCp*Cl2]2 (4.64 mg, 0.0075 mmol, 5 mol %), Cu(OAc)2
(54.5 mg, 0.30 mmol, 2.00 equiv) and AgSbF6 (10.3 mg, 0.03 mmol,
20 mol %). Under argon atmosphere the solvent DCE (1.00 mL) and the
1,4-diphenylbuta-1,3-diyne (I) (90.9 mg, 0.45 mmol, 3.00 equiv) were
added via syringe and the resulting mixture was stirred at 120 °C for 12 h.
After the reaction was complete, the volatiles were removed in vacuo and
the residue was purified by column chromatography (Cy/DCM/EtOAc,
8:1:1), yielding 2 as a pale orange solid; yield: 90.3 mg (98%). 1H NMR
(Chloroform-d, 300 MHz, δ): 8.56 (d, J = 5.6 Hz, 1H), 8.42 (d, J = 5.6 Hz,
1H), 7.70 – 7.62 (m, 2H), 7.60 – 7.41 (m, 6H), 7.36 – 7.26 (m, 10H),
7.21 – 7.12 (m, 4H), 6.94 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 7.8 Hz, 2H), 6.49
(t, J = 4.9 Hz, 1H), 4.01 (d, J = 5.0 Hz, 2H).13C NMR (Chloroform-d,
75 MHz, δ): 167.3, 155.3, 148.5, 142.8, 142.1, 139.5, 139.3, 137.4, 131.7,
131.6, 131.4, 131.3, 130.3, 128.8, 128.7, 128.5, 128.4, 128.3, 128.1, 128.1,
128.0, 127.7, 127.6, 127.3, 125.0, 124.0, 122.9, 122.9, 121.1, 119.6, 99.8,
99.4, 88.4, 85.7, 44.1. HRMS-ESI (m/z): [M + H]+ calcd for C45H31N2O:
615.2431; Found: 615.2435.
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gives rise to the formation of hydrogen bonds between a F atom and the
closest CH bond of the diyne Ph group in the case of IV’(CF3) and
TS(IV’-V’)(CF3) (FH distances: 2.42 and 2.47 Å respectively). These
interactions decrease the barrier differences from 2.3 (in Figure 1) to 1.1
kcalmol1, in the gas phase, and could be at the origin of the lack of
selectivity observed in the preparation of products 21 (see SI).
[22] No significant steric interactions are observed in the structure of
TS(VII-VIII), whereas a H-bond between both N atoms provides an
important stabilization. These structural features agree with the fact that
the second C–H functionalization always takes place unless certain
groups close to the reaction center hamper it (“interrupted annulation” in
Scheme 4).
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[24] Since a scarce effect of silver salts was observed, a chlorine atom was
kept in the copper salt employed as a model to assess the possible
interaction between Rh and Cu through a chlorine bridge in any of the
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following steps. These types of interactions had been proposed in the
bibliography: a) I. Funes-Ardoiz, F. Maseras, Angew. Chem. 2016, 128,
2814; Angew. Chem. Int. Ed. 2016, 55, 2764. In this precedent, the effect
of copper salts was also evaluated in the C–H activation and insertion
steps in which a decrease in the barrier was obtained. This effect cannot
be ruled out in our case. The cooperation of rhodium and copper
throughout the oxidative coupling mechanism between benzoic acid and
alkynes has also been proposed recently by the same authors: b) I.
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[25] This electrophilic cyclization was also considered in previous steps
(TSIXBSEAr, TSIXASEAr, TSXBSEAr) being less favorable than the
formation of the isoquinoline skeleton. For a complete energy profile of
this step, see SI.
[26] Other possibilities for the cyclization with only Rh were also explored.
However, they were more energy demanding and afforded a five-
membered cycle, instead of a six one, what ruled out these proposals
(see SI) reinforcing the hypothesis of the participation of both metals, Rh
and Cu, during the cyclization process.
[27] Taking into account the importance of dispersion forces in the system,
we decided to change the functional (B97D instead of B3LYP) and to
include the solvent in the optimization of all structures involved in the
following steps. Although comparable in energy relative to mod 1,
complex XII showed a slight shortening of distances CM and a preferred
conformation with the benzyl group in a parallel arrangement to the
polycyclic aromatic moiety. This conformational stabilization could be at
the origin of the better results obtained with the N-Bn group.
[28] For a review on “rollover” cyclometalation, see: B. Butschke, H. Schwarz,
Chem. Sci. 2012, 3, 308.
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Entry for the Table of Contents
FULL PAPER
Ángel Manu Martínez, Inés Alonso,*
Nuria Rodríguez,* Ramón Gómez
Arrayás,* and Juan C. Carretero
Page No. – Page No.
Rhodium-Catalyzed Copper-Assisted
Intermolecular Domino C–H
Annulation of 1,3-Diynes with
Picolinamides: Access to Pentacyclic
-Extended Systems
A Rh-catalyzed Cu-assisted method for the intermolecular annulation of
picolinamides with two molecules of diaryl-1,3-diynes is described. The four alkyne
units participate in an orchestrated sequence of insertions/annulations, thereby
enabling the assembly of up to four fused rings in a single step through double C–H
bond activation and construction of five C–C bonds.
Ar
H
Ar
O
O
H
R1
Ar
Cu
Ar
[Cp*RhIII
cat.
]
Ar
O
Ar
N
NHR2
Cl Rh
Cu(OAc)2
Ar
Cp*
O
R1
Ar
OC
NHR2
N
2 Ar
N
R2N
H
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