Primary amines as directing groups in the Ru-catalyzed synthesis of isoquinolines, benzoisoquinolines, and thienopyridines

Article abstract of DOI:10.1021/jo400344m

Isoquinolines, benzoisoquinolines, thieno[3,2-c]pyridines and fused heteroaryl[2,3-c] pyridines, with a wide variety of substituents at different positions of the aromatic or heteroaromatic rings, have been synthesized by Ru-catalyzed oxidative coupling of a broad range of benzylamines or heterocycles with internal alkynes. All benzylamines and heterocycles have unprotected primary amines as efficient directing groups.

Full text of DOI:10.1021/jo400344m

Article
pubs.acs.org/joc
Primary Amines as Directing Groups in the Ru-Catalyzed Synthesis of
Isoquinolines, Benzoisoquinolines, and Thienopyridines
Pedro Villuendas and Esteban P. Urriolabeitia*
́ ́
Instituto de Síntesis Quimica y Catalisis Homogenea, CSIC-Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
S
* Supporting Information
ABSTRACT: Isoquinolines, benzoisoquinolines, thieno[3,2-
c]pyridines and fused heteroaryl[2,3-c] pyridines, with a wide
variety of substituents at different positions of the aromatic or
heteroaromatic rings, have been synthesized by Ru-catalyzed
oxidative coupling of a broad range of benzylamines or
heterocycles with internal alkynes. All benzylamines and
heterocycles have unprotected primary amines as efficient
directing groups.
isoquinolines is often limited to electron-rich carbocycles,8
while multistep procedures, low yields, harsh conditions, and a
narrow scope of substituents is usually encountered in the
design of synthetic routes for the different isomers of
thienopyridines and related compounds.9
INTRODUCTION
■
The bicyclic isoquinoline core, and its related derivatives
containing heterocycle-fused pyridines, are structural motifs
almost ubiquitous among natural products and compounds
with pharmaceutical and biological activity.1 For instance,
quinisocaine2 and papaverine,3 shown in Figure 1, are
Therefore, the development of alternative preparative
pathways using conceptually different routes is still of high
interest. The use of transition metals for the activation and
functionalization of C−H bonds as a synthetic strategy has
gained an increasing interest during the last years due to its
versatility, efficiency, selectivity, and tolerance to a wide array of
functional groups.10 One of the most successful metal-mediated
methods for the synthesis of N-heterocycles is the catalytic
dehydrogenative coupling of internal alkynes with (hetero)aryl-
based substrates, directed through ortho-metalation, where the
directing group in the aryl or heteroaryl moiety usually carries
the N atom which is finally incorporated to the N-heterocycle.
Impressive recent work in this area has been performed by
Ackermann, Fagnou, and others, mostly involving aryl
precursors. As a result, isoquinolines, isoquinolinium salts,
isoquinolinones, pyridines, pyridones, or indoles, have been
obtained.11,12 In contrast, the synthesis of thienopyridines or
other fused bis-heterocycles using the same strategy is scarcely
developed and few examples have been reported.12
In addition to this synthetic limitation, the reported cases
show other methodological restrictions (eq 1 in Scheme 1),
since the functional group containing the N-atom has to be an
imine, an oxime, or a CN double bond formed “in situ” by
reaction of a keto-precursor with an amine or a related
derivative (for instance, hydroxylamine). Even when arylamides
or heteroarylamides are used as precursors (eq 2, Scheme 1),
the N atom has to be at least partially substituted. This means
that not all N-containing functional groups are allowed for the
promotion of the coupling and that the N atom in the
Figure 1. Isoquinolines and thienopyridine derivatives of pharmaceut-
ical importance.
isoquinoline-based commercial drugs, the former being widely
used as a topical anesthetic, while the latter is used as
vasodilator and antispasmodic. In the same context, the
clopidrogel, widely used due to its impressive antithrombotic
activity, is based on the thieno[3,2-c]pyridine scaffold.4,5
Due to their practical importance, diverse synthetic methods
for the preparation of isoquinolines6 and thienopyridines7 have
been developed and reported. Isoquinolines have been
traditionally prepared using the Pomeranz−Fritsch,6a−c Bis-
chler−Napieralski,6d,e and Pictet−Spengler6f,g methods, while
the Skraup reaction7a (also used for the preparation of
quinolines) has been the main route for the synthesis of
thienopyridines.7b In spite of the existence of these well
established procedures,6,7 isoquinolines and thienopyridines
(and other heterocycle-fused pyridines) still are specially
difficult to synthesize in specific cases. The obtention of
Received: February 15, 2013
© XXXX American Chemical Society
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Scheme 1. Most Remarkable Previous Work Performed in
the Synthesis of Isoquinolines and Related Derivatives and
Comparison with This Contribution
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 3aa
a
b
c
entry
solvent
toluene
additive
T (°C)/time (h) 3aa/4aa/5aa
d
d
d
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
80/24
80/24
80/24
80/24
80/24
80/24
80/24
80/6
−/−/65
75/25/−
−/−/15
−/−/10
97/−/−
98/−/−
71/−/−
64/−/−
97/−/−
methanol
dichloroethane
methanol
methanol
methanol
methanol
methanol
methanol
PhI(OAc)2
Cu(OAc)2
e
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
f
100/6
a
Standard reaction conditions: 1a (1 mmol), 2a (2 mmol), [Ru(p-
cymene)Cl2]2 (Ru; 0.1 mmol), KPF6 (0.1 mmol), and the additive (1
mmol) were dissolved in the solvent and heated at the indicated
b
temperature during the specified time. Equimolar with respect to 1a.
c
d
e
f
Isolated yields (%). 2 mmol. 3 mmol of 2a. 1 mmol of 2a.
precursors must be protected. It is clear that this mandatory N-
protection introduces additional steps into the whole synthetic
sequence of a target compound, making it longer in comparison
with those using unprotected precursors. Moreover, most of
these processes are catalyzed by expensive Rh(III) deriva-
tives,12c−f,i,k while the cheaper Ru(II) complexes are by far
much less studied.12g,j,13
Ru.15 Gratifyingly, a mixture of 4,5-diethylthieno[2,3-c]pyridine
3aa (75% yield) and the corresponding 7-methoxylated
derivative 4aa (25% yield) was obtained (entry 2), the two
compounds being easily separated by column chromatography.
Further screening of different solvents did not afford 3aa or 4aa
(entry 3) since only 5aa was detected in variable amounts.
Therefore, MeOH was shown to be the optimal solvent,
although the formation of 4aa through nucleophilic attack of a
methoxide anion to the iminic carbon of 3aa and rear-
omatization has to be minimized or suppressed.
The use of unprotected primary amines as directing groups,
for example, the −CH(R4)NH2 moiety shown in eq 3 of
Scheme 1 has not been reported before. We found that
(hetero)aryl-containing primary amines are suitable precursors
for the synthesis of our target isoquinolines, thienopyridines
and other fused heteroarylpyridines, since they are very
accessible and well-known, most of them are commercially
available or can be prepared through well established synthetic
procedures with a wide scope of different substituents and, in
general, they are stable against the oxygen and the moisture (in
contrast, for instance, with imines or oximes) and available in
bulk quantities. Moreover, primary amines are actually
susceptible to be orthometalated by transition metals,14 and
we have selected the inexpensive ruthenium catalysts because
there are precedents of such metalation.14a We disclose here
our results on the synthesis of a wide variety of isoquinolines,
benzoquinolines and fused bis-heterocycles by an unprece-
dented reaction of amine-based (hetero)aryl derivatives with
internal alkynes catalyzed by Ru(II) derivatives.
Among the different oxidants tested for this process,
Cu(OAc)2 was shown to be the best choice, since other strong
oxidants such as PhI(OAc)2 promotes the fast oxidation of the
amine to the nitrile group (entry 4) and 5aa was formed
together with other unidentified products.16b Moreover,
Cu(OAc)2 plays also the role of source of acetate ligands,
needed for an efficient C−H activation of 1a.17 Other sources
of acetate ligands, such as NaOAc, or other copper salts did not
afford successful results. The amount of Cu(OAc)2 has also a
critical effect on the outcome of the reaction. We have found
that the use of an equimolar ratio 1a/Cu produces 3aa as the
unique reaction product (entry 5) in very good yields. Under
these reaction conditions the methoxylated 4aa was not
observed. The amount of alkyne has also been optimized,
and a 2:1 molar ratio (2a:1a) appears to be the best ratio. An
increase in the amount of alkyne (3:1 molar ratio) does not
produce a noticeable improvement of the yield of 3aa (entry 6),
while a decrease of 2a (1:1 molar ratio) drops the yield of 3aa
(entry 7). Further optimization has been focused on the correct
choice of the temperature and time of the reaction. The
decrease of the reaction time from 24 h to 6 h produces only a
moderate yield of 3aa (entry 8), which was clearly improved up
to 97% (entry 9) increasing the reaction temperature to 100
°C. With the optimized conditions in hand, we tested the
reaction scope, using a variety of heterocycles 1 and internal
alkynes 2. The results obtained using 3-hexyne 2a but changing
the heterocycle 1 are shown in Scheme 2.
RESULTS AND DISCUSSION
■
Catalytic Synthesis of Fused Heteroarylpyridines. The
coupling of thiophene-2-methylamine 1a with 3-hexyne 2a,
catalyzed by [Ru(p-cymene)Cl2]2 (Ru), was used as model
reaction for process optimization. The obtained results are
shown in Table 1. We have started using the conditions
previously reported by us for the C−H activation of thiophene-
imines (toluene, 80 °C, 24 h),15 but using a 10% (in mol) of Ru
with respect to 1a and Cu(OAc)2 as oxidant in excess (entry 1).
Under these conditions, the 2-cyano-3-vinylthiophene 5aa was
obtained, showing that the amine oxidation, probably also
catalyzed by Ru,16a occurs faster than the C−H activation,
insertion, and annulation steps. We then change the solvent to
methanol, which gave good results in the annulation of alkynes
with orthoruthenated thiophene-imines using stoichiometric
The reaction tolerates the presence of substituents at 5-
position of the thiophene ring, both electron-donating (3ba)
and electron-withdrawing (3da), although better yields were
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Scheme 2. Scope of Heterocycle-Fused Pyridines 3 Changing
the Heterocycle 1
Scheme 3. Scope of Heterocycle-Fused Pyridines 3 Changing
the Alkyne 2
In clear contrast with the selective insertion of one alkyne
observed in 3aa−ja and 3ab−ac, the reaction of 1a with aryl-
containing alkynes, for instance PhCCMe (2d) or PhC
CPh (2e), goes one step beyond. The first insertion produces a
5-phenylthieno[2,3-c]pyridine core, with an additional alkyl/
aryl substituent at the 4-position. It is very remarkable that this
first insertion occurs with full regioselectivity in the case of
alkyne 2d, showing that steric hindrance is not the only
operative factor in the control of the regioselectivity. This core
is formally analogous to a 2-phenylpyridine ligand, which is
amenable to undergo a further C−H activation regioselectively
at the ortho position of the 5-phenyl ring and a second alkyne
insertion to give the corresponding alkenylated derivative.20
This scarce double insertion is quite remarkable and provides a
new pathway to the more complex structures 3ad−af shown in
Scheme 3. In all studied cases the basic structure thus obtained
is a 5-arylthieno[2,3-c]pyridine ortho-alkenylated at the 5-aryl
ring. It is worthy of note that the synthesis of 5-arylthieno[2,3-
c]pyridines is known,12 but that here reported for the ortho-
olefinated derivatives is unprecedented. Symmetrical alkynes
obviously affords single compounds, as is the case of PhC
CPh (2e) and p-nBuC6H4CCC6H4-p-nBu (2f), which give
3ae and 3af, respectively. Obviously, this additional reactivity
further expands the synthetic applicability of this method.
Catalytic synthesis of isoquinolines. Prompted by the
excellent results obtained in the synthesis of fused heteroaryl
pyridines, we have explored additional possibilities, aiming to
give more generality to the method. Therefore, other primary
amines have been subjected to Ru-catalyzed dehydrogenative
coupling with different internal alkynes. Benzylamines have
shown to be very good starting materials for this type of
coupling. The reaction of benzylamine 6a with 3-hexyne 2a,
under the conditions described in Table 1, affords isoquinoline
7aa in low yield, with most of the starting amine 6a being
recovered unchanged. The solvent, temperature, and reaction
time were varied in order to optimize this process. We found
that this low conversion can be improved notably if the reaction
time is prolongued up to 24 h at the same temperature (100
°C). Under these conditions, 7aa is obtained analytically pure
in 95% yield, as represented in Scheme 4. Other changes
produced lower yields of the target product 7aa, contaminated
obtained for the formers, as expected according to previous
work of Pfeffer et al.18 In the same way, benzothiophene-
methylamine reacts to give the fused tris-heterocycle 3ea in a
55% yield. This lower reactivity of the benzannulated derivative
also agrees with previous results.15 From the precursor
thiophene-3-methylamine 1f only the isomer 6,7-diethylthieno-
[3,2-c]pyridine 3fa was obtained, in keeping with the easier
ruthenation at the more active 2-position of the thiophene ring,
compared with the 4-position. The reaction also tolerates
substituents at the α-position of the 2-methylamino directing
group, regardless their electronic nature, and good yields were
obtained when methyl (3ga) or carbomethoxy (3ha) moieties
are present. It is also quite remarkable that the scope of the
reaction could be expanded to other electron-rich heterocycles.
Fused bis-heterocycle 3ja derived from pyrrole was isolated
in 96% yield, while the tricyclic 3ia, prepared from benzofuran,
was obtained in 50% yield. It is necessary to remark that
benzofurane derivatives need longer reaction times to achieve
similar yields due to its lower reactivity. Surprisingly, in the case
of the indole-amine derivative we constated a total lack of
reactivity. We are not aware about the reasons of this behavior,
because we have shown that orthoruthenated indole-imines
react with alkynes to give pyrido[3,4-b]indolium salts.15
Concerning the scope of alkynes 2, alkylic electron-rich
species such as 3-hexyne (2a), 2-hexyne (2b) and 4,4-dimethyl-
2-pentyne (2c) reacts straightforwardly with 1a to give the
corresponding 4,5-dialkylthieno[2,3-c]pyridines 3aa−ac shown
in Scheme 3 in moderate to excellent yields. Another classical
electron-rich alkyne, as is Me3SiCCSiMe3, was also tested.
However, due to the fact that the reaction is performed in
refluxing methanol, full decomposition of the alkyne by
methanolysis was observed. When nonsymmetrical alkynes
are used, the selectivity of the insertion depends largely on
steric factors.19 Thus, the reaction of 1a with 2-hexyne (2b)
results in a 60:40 mixture of the two isomers of 3ab, due to the
similarity between the methyl and n-propyl fragments, while in
the case of the reaction of 1a with 4,4-dimethyl-2-pentyne (2c)
3ac is obtained regioselectively in 89% yield. The stereo-
chemistry of 3ac has been determined by the observation of a
NOE effect (Supporting Information) between the signals at
2.69 ppm (4-Me) and 7.34 ppm (H3).
Scheme 4. Synthesis of 3,4-Diethylisoquinoline 7aa and
Optimized Reaction Conditions
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with variable amounts of byproducts or with starting amine 6a.
Therefore, the experimental conditions shown in scheme 4
were used as the optimized conditions. The larger reaction
times involved here, compared with those required for the
heterocycles 1 (24 h vs 6 h) suggest that the reaction is favored
for electron-rich substrates.
A wide variety of substituted benzylamines 6 have been
reacted with 3-hexyne 2a in order to check the scope of the
reaction, changing the nature and the position of the
substituents. The results are shown in Scheme 5. In the case
It is noteworthy that during the synthesis of compound 7ja
we have detected a minor second component in the crude of
the reaction (8ja, 8%), which can be separated from the main
product 7ja by column chromatography. The analytic and
spectroscopic data of 8ja show that a second alkyne molecule
has been incorporated at the benzo ring of the isoquinoline 7ja,
introducing a vinyl substituent at the 8-position. This process,
shown in Scheme 6, can be formally considered as the
hydroarylation of 3-hexyne, being the aryl unit the isoquinoline
7ja.
Scheme 5. Scope of Isoquinolines 7 Changing the
Benzylamine 6
Scheme 6. Reactivity of Benzylamines To Give Isoquinolines
7 and 8-Vinylisoquinolines 8
The same result is observed when the starting benzylamine 6
has strong electron-attracting substituents, such as nitro (6f),
chloro (6h) of CF3 (6i). In all three cases, a mixture of the
isoquinolines 7 and the corresponding 8-vinylisoquinolines 8
was obtained (Scheme 6), being always 7 the main component
of the mixture (Scheme 5). Compounds 7 can be obtained in
analytically pure form by column chromatography (see
Supporting Information), while minor components 8 were
always mixed with small (but detectable) amounts of 7,
precluding the characterization of 8 in pure form. On the other
hand, the molar ratio 7/8 changes as a function of the
substituent. While in the case of the methyl group we isolate
only an 8% of 8ja, the yield of 8fa, 8ha and 8ia after
chromatographic separation is around 20%. The selectivity
observed in the incorporation of the second alkyne moiety at
the 8-position is remarkable, and no other isomers were
detected. It is also relevant the fact that when methoxy
substituents are present in the benzylamine (6b−e) no
vinylation products were detected, neither in the case of the
unsubstituted 6a, even at the level of traces.
Other substrates were also investigated. 1-Naphthylmethyl-
amine 6l reacts with 3-hexyne affording the benzo[h]-
isoquinoline 7la (Scheme 5), while the related 1-(2-naphthyl)-
ethylamine 6m gives the corresponding benzo[g]isoquinoline
7ma with excellent yields in both cases (85% and 91%,
respectively). The reaction occurs in both cases with full
regioselectivity. In the case of amine 6l the reason of this
selectivity could reside in the competitive activation of the C−
H bonds at the 2- and 8-positions and further alkyne insertion
and annulation. This reactivity at 2-position affords the
aromatic 6-membered benzo[h]isoquinoline 7la, while that at
8-position would give a nonaromatic, and then probably less
favored, 7-membered naphthoazepine. In addition, allylamine
6n reacts, under the standard reaction conditions, to give the
2,3-diethylpyridine 7na. Despite the full conversion observed,
and only in this case, the purification of 7na proved to be very
difficult and the pure compound could not be isolated.
of electron-releasing groups, very good yields were obtained in
all attempted cases, better (in general) than those described in
the previous section for the fused heteroarylpyridines. For
instance, the presence of one methoxy group either in para
(7ba) or in ortho (7da) to the cyclometalation position gives
the corresponding isoquinolines in similar high yields (95% vs
88%). The presence of two methoxy groups in the two meta
3,5-positions does not hinder the C−H activation and allows
for the synthesis of 7ca in a remarkable 93% yield. When the
two methoxy groups are in positions 3 and 4 two cyclo-
metalation sites are available. Compound 7ea is thus obtained
in 76% yield as the mixture of the two possible isomers,
although one of them is clearly favored (16:1 molar ratio,
Scheme 5). This high selectivity is easily explained taking into
account that the less sterically hindered C−H bond in the
cycloruthenation step (in this case the 6-position) is
preferentially activated.21 Other electron-donating alkyl groups
(Me, tBu) give also the corresponding 3,4,6-trisubstituted
isoquinolines in good to excellent yields, regardless the alkyl
substituent is on the aryl ring (7ja and 7ka, 91% and 82% yield,
respectively) or at the Cα position (7ga, 58%).
The scope of available isoquinolines 7 changing the alkyne 2
follows similar trends than those described previously for the
fused pyridines. Therefore, alkylic electron-rich species such as
3-hexyne (2a), 2-hexyne (2b), and 4,4-dimethyl-2-pentyne (2c)
D
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afford the corresponding isoquinolines 7aa−ac (Scheme 7) in
moderate to excellent yields. Compound 7ab is obtained as the
Scheme 8. Mechanistic Proposal for the Synthesis of
Compounds 3, 7, and 8
Scheme 7. Scope of Isoquinolines 7 Changing the Alkyne 2
mixture of regioisomers (70/30), improving the selectivity
observed in 3ab (60/40), while 7ac is obtained regioselectively
as the 3-t-Bu-4-Me isomer.
In the same way as described in preceding paragraphs for
fused pyridines 3ad−af, the reaction of benzylamine 6a with
aryl-containing alkynes such as PhCCMe (2d) or PhC
CPh (2e) occurs with insertion of two alkynes. The first
insertion affords the expected 3,4-diphenylisoquinoline, which
further undergoes a second C−H bond activation at the 3-
phenyl ring and the subsequent insertion of the alkyne to give
the olefinated derivatives 7ad and 7ae.20 Remarkably, the
insertion of PhCCMe (2d) is once again regioselective, and
7ad is the only observed isomer.
orthoruthenation of thiophene-imines is possible, but also that
it takes some hours, therefore the presence of free imine should
be evident in the first steps of the reaction. However, the H
1
Mechanistic Considerations. In the preceding paragraphs,
we have described the reactivity of primary amines such as
benzylamines and aminomethyl-heterocycles toward internal
alkynes, allowing for the obtention of, at least, four different
types of products: (i) fused heteroaryl-pyridines (3aa−ja, 3ab−
ac); (ii) isoquinolines (7aa−ma, 7ab−ac); (iii) thienopyridines
and isoquinolines ortho-vinylated at the 3-phenyl ring (3ad−af,
7ad−ae); and (iv) isoquinolines vinylated at the 8-position
(8fa−ja). The synthesis of the fused heteroarylpyridines (3)
and isoquinolines (7) from the unprotected primary amines (1
or 6, respectively) and alkynes 2 implies not only the C−H
activation at the aromatic ring but also the dehydrogenation
and deprotonation of the CH2NH2 moiety with concomitant
obtention of an aromatic molecule. Aiming to gain more insight
into the mechanism of the catalytic cycle, we have monitored
the reaction of 1a with 2a by 1H NMR spectroscopy in CD3OD
at 60 °C. The disappearance of one of the signals assigned to
the thiophene ring in 1a and the observance of an AB spin
system for the diastereotopic CH2N protons strongly suggest
that orthoruthenation of amine 1a has taken place and that the
resulting cyclometalated ligand is located on an asymmetric
environment, such as that depicted in Scheme 8 (cycle I) for
species (A) (see the Supporting Information). This proposal is
based on previous work of Pfeffer et al.18 and on our own
work.15 The detection of species (A) also suggests that this is
the resting state of the catalyst, and that the limiting rate step is
the insertion of the alkyne in the Ru−C bond, in good
agreement with previous results.18b More importantly, these
observations strongly suggest that the dehydrogenation of the
CH2NH2 directing group is produced after the C−H bond
activation step, probably at the latest stages of the reaction and
without the participation of the metal.22 If the dehydrogenation
of 1a occurred prior to the C−H bond activation, it would
produced a thiophene-imine. We have shown recently that the
NMR spectrum of the reaction mixture (see the Supporting
Information) does not show signals in the 8−9 ppm region,
where the NCH iminic protons usually appears. On the
other hand, the orthoruthenation of imines affords very stable
complexes, even characterized by X-ray methods.15 However,
all attempts to isolate an analogous metalated complex from 1a
under the catalytic conditions were not successful. Moreover,
we have performed additional control experiments in order to
determine which could be the conditions for hypothetical imine
formation. The treatment of free amine 1a in CD3OD at 100
1
°C for 6h does not promote any evident change on the H
NMR spectrum, giving proof of the stability of this material
under the reaction conditions. When 1a is heated in the
presence of Cu(OAc)2, the formation of imine was not
detected either, and the same result is obtained after heating of
1a with the dimeric species [Ru(cym)Cl2]2. In the latter, the
change of the shape and the position of the peaks due to the
three protons of the thiophene moiety was observed, suggesting
the interaction of this fragment with the Ru species (probably
through N-coordination). All these facts militate against the
participation of imines in the catalytic cycle, and in favor of the
amine involvement.
We can tentatively close the catalytic cycle I by similarity
with previous works. Therefore, we suggest that (A) reacts with
KPF6 generating a vacant coordination site. Alkyne 2 bonds in
this vacant site, and further undergoes a migratory insertion
process followed by C−N reductive coupling giving Ru(0)
species (B). The exact nature of intermediate (B) is not known,
but it is proposed to be a η4-dehydroisoquinolinium Ru(0)
intermediate by analogy with previous work of Pfeffer.18 Other
recent proposals for the alkyne insertion on cycloruthenated
imines are based on Ru(II) species,15 but they do not apply
here due to the different nature of the amine vs imine as
E
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directing groups. Smooth oxidation of (B) with Cu(II) releases
the dihydropyridinium cation (C) and regenerates the catalyst
Ru.23 The elimination of HCl from (C) and subsequent
dehydrogenation of the dihydropyridine intermediate to give
the bicyclic structures 3 or 7 likely occurs under the reaction
conditions without participation of the metallic catalyst.
A second alkyne incorporation occurs in compounds derived
from the insertion of diarylacetylenes, affording species 3ad−af,
7ad and 7ae. The mechanistic proposal for these processes is
shown in Scheme 8, cycle II. Therefore, once the first insertion
has taken place, a new Ru-mediated C−H bond activation can
occur at the ortho C−H bond of the aryl ring located on the
carbon adjacent to the N atom, affording presumably the
intermediate (D). Obviously, the pyridinic nitrogen behaves as
a directing group. Compound (D) can then react with an
additional equivalent of internal alkyne giving (E), which is
protonated at the vinyl carbon releasing the formally hydro-
arylated derivatives 3 or 7, as a function of the starting amine. It
is quite remarkable that, as far as we know, the hydroarylation
of internal alkynes using 2-phenylpyridine as aryl source has
been catalyzed with Rh(I) or Co(II), but never with Ru(II)
complexes.24
While the ortho-vinylation of the 3-Ph ring has been observed
in fused heteroaryl-pyridines 3 and isoquinolines 7, some
isoquinolines 7 have shown an additional reactivity pattern for
the incorporation of a second alkyne (7fa,ha−ja), which takes
place specifically at 8-position of the benzo ring. Both facts, the
substitution at the benzo ring and its occurrence at the 8-
position, strongly suggest that this 8-vinylation is a Ru-
mediated process where the ruthenation step occurs through
an aromatic electrophilic substitution mechanism (SEAr). Once
the Ru moiety has been incorporated to the benzo ring, the
coordination of the alkyne, followed by its migratory insertion
and protonation of the vinyl intermediate, as described for the
previous case, will result in the formation of species 8, similarly
to what is shown in Scheme 8 as cycle II. An alternative
mechanism to explain the formation of species 8 should involve
the protonation of the metalated vinyl-intermediate previous to
the N−C coupling in B, this reaction affording an ortho-
alkenylbenzylamine. Further C−H activation of the H6 proton
followed by a second alkyne insertion through cycle I would
afford the 8-vinyl-substituted isoquinolines 8. However, this
second mechanism does not seem to be operative on the
following grounds. First, we have stopped the reaction at short
reaction times, when it is more likely to find the o-
alkenylbenzylamine, but we have not spectroscopic evidence
for the formation of this product; however, isoquinolines 7
were already present in the reaction mixture from the very
beginning of the reaction. Second, the first alkyne insertion
should give two competitive products, the isoquinolines 7 and
the o-alkenylbenzylamines; however, there are cases where
conversion of benzylamine is complete and 7 can be isolated in
95% yield, rendering the process weakly favorable for the
formation of the o-alkenylbenzylamine. Third, if after the first
insertion the favored process is the protonation and formation
of the o-alkenylbenzylamine, then after the second insertion the
same process should occur, because the directing group is
exactly the same. Therefore the bis-o-alkenylbenzylamine
should be expected as reaction product, and the isoquinolines
should not be observed; obviously, this is not the case and our
proposal is that shown in Scheme 8.
detailed analysis. In principle, when an electron-releasing group,
such as methyl, tert-butyl or methoxy, is present at 6-position of
7, the electrophilic substitution at 5-position should be favored
on electronic grounds with respect to that at 8-position, while
the steric hindrance exerted by the 4- and 6-substituents
hampers the reaction at 5-position and should direct the
reactivity to the less favored 8-position. Therefore the final
activated site should be the result of a delicate balance between
the two factors. In the light of the observed reactivity, it seems
that in the presence of electro-donating groups the steric factors
prevail over the electronic ones. Therefore, when bulky
substituents such as tert-butyl, or even not so bulky but
strongly donating such as methoxy, are present, the substitution
at 5-position is blocked sterically while that at 8 is not favored
electronically, and then the 8-vinyl derivatives 8 are not formed
at all, or only in a very low amount (8ja, 8%). It is clear that 7aa
escapes to this argument, but we are unaware about the reasons
of the lack of reactivity for this species. However, when the
substituent located at 6-position has an electron-withdrawing
character, the electrophilic substitution at 8-position (vs 5-
position) is favored both on electronic and steric grounds, and
therefore, the 8-vinyl derivatives 8 are obtained in a 20% yield.
The low yield for species 8 also suggests that the rate of the
vinylation of compounds 7 is much slower than that of the
annulation of benzylamines 6 to give 7, and therefore,
isoquinolines 7 are the main product of the reaction.
CONCLUSION
■
Primary amines, such as benzylamines, naphthylmethylamines,
naphthylethylamines, heteroarylmethylamines, or even allyl
amines, substituted at various positions, are good starting
materials for the synthesis of a wide variety of isoquinolines,
benzoisoquinolines, and fused heteroarylpyridines. In addition
of the broad range of targeted compounds achievable, different
isomers of each one are accessible, and the presence of a large
number of electron-attracting and -releasing substituents in
different positions is tolerated. The method is based on the
directed C−H bond activation of a broad range of unprotected
primary amines as efficient directing groups, followed by
dehydrogenative coupling with internal alkynes, all processes
catalyzed by Ru(II) complexes. The method is actually
competitive with standard organic procedures, and further
development and expansion to other interesting substrates,
such as alkenes, is currently being under study.
EXPERIMENTAL SECTION
■
General Methods. Solvents were used as received from
commercial sources. They were not distilled nor subjected to
additional purification. All reactions were carried out without
protecting atmosphere. Column liquid chromatography were
performed on aluminum oxide 90 neutral (50−200 μm) or silica gel
1
(70−230 μm). H and 13C NMR spectra were recorded in CDCl3
solutions at 25 °C on spectrometers (δ in ppm, J in Hz) at 1H
operating frequency of 400.13 MHz. 1H and 13C spectra were
referenced using the solvent signal as internal standard. The
1
assignment of H NMR peaks has been performed through standard
2D 1H−COSY (2K points in t2 using a spectral width of 10 ppm; 128
t1 experiments were recorded and zero-filled to 1K; for each t1 value
four scans were signal-averaged using a recycle delay of 1 s) and
selective 1D 1H-NOESY experiments. Typical mixing times in the case
of selective 1D-NOESY experiments were 800 ms or 1s, as a function
of the irradiated signal. These values of optimized mixing times were
set equal to the longitudinal relaxation time T1, which in turn was
determined using the inversion−recovery sequence. Once the 1H
In addition, the observed distribution of products 7/8 and
the selectivity of the vinylation at 8-position in 8 merits a more
F
dx.doi.org/10.1021/jo400344m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
NMR signals were fully assigned, the corresponding 13C NMR peaks
were identified using standard 1H−13C edited-HSQC and 1H−13C
HMBC 2D-experiments. In both cases 4K points in t2 using spectral
widths of 10 ppm (1H) and 220 ppm (13C) were used, with averaged
3fa. Yellow oil (66 mg, 33% yield). H NMR (CDCl3, 400 MHz)
3
3
δH: 1.26 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6 Hz,
3
3
CH2CH3), 2.87 (2H, q, JHH 7.6 Hz, CH2CH3), 2.88 (2H, q, JHH 7.6
Hz, CH2CH3), 7.33 (2H, m, Hthio), 8.85 (1H, s). 13C{1H} NMR
(CDCl3, 100 MHz) δC: 13.6, 14.6, 24.8, 27.5, 123.1, 126.4, 129.7,
134.5, 136.8, 142.8, 153.5. (ESI)+ m/z: [M + H]+ (100) 192. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H14NS 192.0847, found
192.0841.
3ga. Yellow wax (195 mg, 95%). H NMR (CDCl3, 400 MHz) δH:
1.16 (3H, t, JHH 7.6 Hz, CH2CH3), 1.23 (3H, t, JHH 7.6 Hz,
CH2CH3), 2.65 (3H, s, CH3), 2.83 (2H, q, JHH 7.6 Hz, CH2CH3),
values of the coupling constants 1JCH = 145 Hz and long-range nJCH
=
8 Hz. Typically 512 t1 experiments were recorded and zero-filled to
2K. For each t1 value 16 scans were signal-averaged using a recycle
delay of 2 s. HRMS and ESI (ESI+) mass spectra were recorded using
an MicroToF Q, API-Q-ToF ESI with a mass range from 20 to 3000
m/z and mass resolution 15000 (fwhm). The synthesis of the
ruthenium catalyst [Ru(p-cymene)(μ-Cl)Cl]225 and amines 1b, 1c, 1d,
1e, 1f, 1g, 1i, and 1j26 have been carried out following published
procedures. Other starting amines 1 and 6 and alkynes were purchased
from commercial sources.
1
3
3
3
3
3
2.85 (2H, q, JHH 7.6 Hz, CH2CH3), 7.28 (1H, d, JHH 5.6 Hz, Hthio),
7.49 (1H, d, JHH 5.6 Hz, Hthio). 13C{1H} NMR (CDCl3, 100 MHz)
3
δC: 14.2, 14.3, 21.7, 22.3, 26.6, 121.1, 126.7, 129.4, 132.2, 143.9, 148.3,
152.9. (ESI)+ m/z: [M + H]+ (100) 206. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C12H16NS 206.1003, found 206.0998.
Typical Experimental Procedure for the Fused Heterocycle−
Pyridines 3. The corresponding heterocycle-methylamine 1 (1
mmol) and alkyne 2 (2 mmol) were added to a solution of [Ru(p-
cymene)Cl2]2 (0.061 g, 0.1 mmol), [Cu(OAc)2] (0.181 g, 1.0 mmol),
and K[PF6] (18.7 mg, 0.1 mmol) in MeOH (3 mL) into a Young’s
flask. The solution was then heated at 100 °C for 6h. After that, the
solvent was removed and the residue subjected to flash chromatog-
raphy on neutral alumina eluting with DCM (DCM = CH2Cl2), then
DCM/MeOH (95:5). Both eluted fractions were mixed and
evaporated to dryness, affording 3 as oily materials or waxy solids,
which were washed with Et2O (10 mL) and pentane (10 mL).
Compounds 3da, 3ab and 3ae were further purified by a second
column chromatography on silica gel eluting with mixtures hexane/
ethyl acetate (9/1 to 1/1).
3ha. Orange oil (185 mg, 74% yield). 1H NMR (CDCl3, 400 MHz)
δH: 1.22 (3H, t, 7.6 Hz, CH2CH3), 1.28 (3H, t, 7.6 Hz, CH2CH3), 2.97
(2H, q, 7.6 Hz, CH2CH3), 2.98 (2H, q, 7.6 Hz, CH2CH3), 4.01 (3H, s,
COOCH3), 7.36 (1H, d, 5.6 Hz, Hthio), 7.68 (1H, d, 5.6 Hz, Hthio).
13C{1H} NMR (CDCl3, 100 MHz) δC: 14.9, 15.1, 23.3, 27.7, 53.1,
120.8, 134.6, 134.8, 135.2, 139.0, 146.8, 154.9, 166.3. (ESI)+ m/z: [M
+ H]+ (100) 250. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H16NSO2 250.0902, found 250.0920.
3ia. Yellow wax (113 mg, 50% yield). 1H NMR (CDCl3, 400 MHz)
δH: 1.27 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6 Hz,
3
3
3
3
CH2CH3), 2.90 (2H, q, JHH 7.6 Hz, CH2CH3), 3.06 (3H, q, JHH 7.6
Hz, CH2CH3), 7.29 (1H, td, 3JHH 7.6 Hz, 4JHH 1.2 Hz, ArH), 7.46 (1H,
td, 3JHH 7.6 Hz, 4JHH 1.2 Hz, ArH), 7.5 (1H, d, 3JHH 7.6 Hz, ArH), 7.93
3aa. Yellow oil (186 mg, 97% yield). 1H NMR (CDCl3, 400 MHz)
3
3
δH: 1.21 (3H, t, JHH 7.6 Hz, CH2CH3), 1.27 (3H, t, JHH 7.6 Hz,
(1H, d, JHH 7.6 Hz, ArH), 8.66 (1H, s, CHN). 13C{1H} NMR
3
3
3
CH2CH3), 2.87 (2H, q, JHH 7.6 Hz, CH2CH3), 2.91 (2H, q, JHH 7.6
(CDCl3, 100 MHz) δC: 13.9, 14.8, 22.6, 27.3, 112.4, 122.6, 123.2,
123.4, 128.9, 129.6, 130.8, 131.1, 151.4, 154.1, 156.9. (ESI)+ m/z: [M
+ H]+ (100) 226. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H16NO 226.1232, found 226.1226.
3
4
Hz, CH2CH3), 7.31 (1H, dd, JHH 5.2 Hz, JHH 0.8 Hz, Hthio), 7.58
(1H, d, JHH 5.2 Hz, Hthio), 8.88 (1H, s, CHN). 13C{1H} NMR
3
(CDCl3, 100 MHz) δC: 14.8, 15.1, 22.9, 27.5, 121.4, 130.2, 131.3,
134.2, 141.7, 145.0, 153.9. (ESI)+ m/z: [M + H]+ (100) 192. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H14NS 192.0847, found
192.0842.
3ja. Yellow wax (181 mg, 96% yield). 1H NMR (CDCl3, 400 MHz)
3
3
δH: 1.18 (3H, t, JHH 7.6 Hz, CH2CH3), 1.23 (3H, t, JHH 7.6 Hz,
CH2CH3), 2.82 (2H, q, JHH 7.6 Hz, CH2CH3), 2.84 (2H, q, JHH 7.6
3
3
3ba. Yellow oil (167 mg, 81% yield). 1H NMR (CDCl3, 400 MHz)
4
3
3
Hz, CH2CH3), 3.74 (3H, s, NCH3), 6.36 (1H, d, JHH 2.8 Hz, Hpyrr),
δH: 1.18 (3H, t, JHH 7.6 Hz, CH2CH3), 1.25 (3H, t, JHH 7.6 Hz,
7.05 (1H, d, JHH 2.8 Hz, Hpyrr), 8.47 (1H, s, CHN). 13C{1H} NMR
4
4
3
CH2CH3), 2.55 (3H, d, JHH 1.2 Hz, CH3), 2.82 (2H, q, JHH 7.6 Hz,
3
4
(CDCl3, 100 MHz) δC: 15.0, 15.2, 22.5, 27.2, 33.1, 98.9, 127.3, 129.5,
132.3, 132.5, 134.0, 148.4. (ESI)+ m/z: [M + H]+ (100) 189. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C12H17N2 189.1392, found
189.1386.
CH2CH3), 2.83 (2H, q, JHH 7.6 Hz, CH2CH3), 6.96 (1H, JHH
quintuplet, 1.2 Hz, Hthio), 8.70 (1H, s, CHN). 13C{1H} NMR (CDCl3,
100 MHz) δC: 14.7, 15.0, 16.5, 22.8, 27.5, 119.3, 129.3, 134.3, 140.8,
145.9, 146.5. (ESI)+ m/z: [M + H]+ (100) 206. HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C12H16NS 206.1003, found 206.1005.
4aa. Yellow oil (55 mg, 25% as byproduct of 3aa). 1H NMR
(CDCl3, 400 MHz) δH: 1.15 (3H, t, 3JHH 7.6 Hz, CH2CH3), 1.25 (3H,
3ca. Yellow wax (203 mg, 76% yield). 1H NMR (CDCl3, 400 MHz)
3
3
3
3
t,, JHH 7.6 Hz, CH2CH3), 2.75 (2H, q, JHH 7.6 Hz, CH2CH3), 2.81
δH: 1.24 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6 Hz,
(2H, q, 3JHH 7.6 Hz, CH2CH3), 4.02 (3H, s, OCH3), 7.27 (1H, d, 3JHH
3
3
CH2CH3), 2.87 (4H, q, JHH 7.6 Hz, CH2CH3), 2.93 (4H, q, JHH 7.6
Hz, CH2CH3), 7.3 (1H, m, ArH), 7.4 (2H, m, ArH), 7.50 (1H, d, 0.8
Hz, Hthio), 7.7 (2H, m, ArH), 8.82 (1H, s, CHN). 13C{1H} NMR
(CDCl3, 100 MHz) δC: 13.7, 14.1, 21.8, 26.6, 115.8, 125.9, 128.0,
128.1, 128.9, 132.7, 132.8, 140.3, 144.9, 148.4, 153.3. (ESI)+ m/z: [M
+ H]+ (100) 268. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H18NS 268.1160, found 268.1151.
5.2 Hz, Hthio), 7.51 (1H, d, JHH 5.6 Hz, Hthio). 13C{1H} NMR
3
(CDCl3, 100 MHz) δC: 14.4, 15.4, 22.4, 26.9, 53.2, 120.2, 122.0, 130.4,
147.8, 151.4, 156.1. (ESI)+ m/z: [M + H]+ (100) 222. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C12H16NOS 222.0953, found
222.0945.
1
3ab (Both Isomers). yellow oil (167 mg, 87% yield). H NMR
(CDCl3, 400 MHz) δH: 0.92 (t, 3JHH 7.6 Hz, CH2CH2CH3, both), 1.50
(m, CH2CH2CH3), 1.71 (m, CH2CH2CH3), 2.44 (s, CH3), 2.55 (s,
1
3da. Yellow oil (97 mg, 43% yield). H NMR (CDCl3, 400 MHz)
3
3
δH: 1.23 (3H, t, JHH 7.6 Hz, CH2CH3), 1.31 (3H, t, JHH 7.6 Hz,
3
3
3
CH3), 2.80 (m, CH2CH2CH3), 2.81 (m, CH2CH2CH3), 7.25 (d, JHH
CH2CH3), 2.87 (4H, q, JHH 7.8 Hz, CH2CH3), 2.89 (4H, t, JHH 7.8
Hz, CH2CH3), 7.22 (1H, s, Hthio), 8.73 (1H, s, CHN). 13C{1H} NMR
(CDCl3, 100 MHz) δC: 14.5, 15.0, 22.8, 27.6, 120.6, 129.5, 133.3,
137.6, 140.4, 144.0, 154.9. (ESI)+ m/z: [M + H]+ (100) 226. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H13ClNS 226.0457, found
226.0439.
5.6 Hz, Hthio, both), 7.50 (d, 3JHH 5.6 Hz, Hthio, both), 8.80 (s, CHN),
8.83 (s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.2, 14.3 15.2,
21.4, 23.0, 23.2, 32.1, 37.0, 121.4, 121.6, 124.2, 129.4, 131.1, 131.2,
133.8, 134.2, 141.2 (2C), 145.6 (2C), 149.1, 153.2. (ESI)+ m/z: [M +
H]+ (100) 192. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H14NS 192.0847, found 192.0842.
3ea. Yellow wax (134 mg, 55% yield). 1H NMR (CDCl3, 400 MHz)
δH: 1.27 (3H, t, 7.6 Hz, CH2CH3), 1.31 (3H, t, 7.6 Hz, CH2CH3), 2.87
(2H, q, 7.6 Hz, CH2CH3), 2.92 (2H, q, 7.6 Hz, CH2CH3), 7.4 (2H, m,
ArH), 7.8 (1H, m, ArH), 8.1 (1H, m, ArH), 9.12 (1H, s, CHN).
13C{1H} NMR (CDCl3, 100 MHz) δC: 12.4, 13.4, 24.0, 26.7, 120.5,
121.8, 124.0, 126.1, 129.1, 129.1, 133.7, 137.9, 139.6, 147.6, 155.8.
(ESI)+ m/z: [M + H]+ (100) 242. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H15NS 242.1003, found 242.0998.
3ac. Yellow wax (183 mg, 89% yield). 1H NMR (CDCl3, 400 MHz)
δH: 1.45 (9H, s, C(CH3)3), 2.69 (3H, s, CH3), 7.34 (1H, dd, 3JHH 5.2
5
3
Hz, JHH 0.4 Hz, Hthio), 7.55 (1H, d, JHH 5.6 Hz, Hthio), 8.85 (1H, s,
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 17.8, 30.7, 38.4, 27.5,
121.9, 124.8, 130.7, 133.8, 139.8, 147.1, 158.8. (ESI)+ m/z: [M + H]+
(100) 206. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H16NS
206.1003, found 206.0998.
G
dx.doi.org/10.1021/jo400344m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3ad. Yellow oil (205 mg, 60% yield). 1H NMR (CDCl3, 400 MHz)
δH: 1.83 (3H, s, CH3), 2.42 (3H, s, CH3), 6.4 (1H, m, Halkene), 7.1
(2H, m, ArH), 7.2 (1H, m, ArH), 7.3 (2H, m, ArH), 7.4−7.5 (5H, m,
Hz, CH2CH3), 2.88 (2H, q, 3JHH 7.6 Hz, CH2CH3), 3.14 (2H, q, 3JHH
7.2 Hz, CH2CH3), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 6.53 (1H,
4
4
d, JHH 2.4 Hz, ArH), 6.64 (1H, d, JHH 2.4 Hz, ArH), 8.78 (1H, s,
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.8, 16.0, 23.4, 28.2,
55.3, 55.5, 97.7, 102.3, 124.0, 130.1, 130.2, 148.5, 153.2, 157.6, 157.7.
(ESI)+ m/z: [M + H]+ (100) 246. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H20NO2 246.1494, found 246.1506.
3
ArH), 7.73 (1H, d, JHH 5.4 Hz, Hthio), 9.09 (1H, s, CHN). 13C{1H}
NMR (CDCl3, 100 MHz) δC: 16.4, 19.2, 122.0, 125.4, 126.2, 126.9,
127.9, 128.0, 128.3, 128.7, 130.3, 130.4, 131.6, 134.8, 138.1, 138.6,
138.8, 141.2, 145.3, 145.4, 152.7. (ESI)+ m/z: [M + H]+ (100) 342.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20NS 342.1316,
found 342.1323.
7da. Waxy white solid (190 mg, 88% yield). 1H NMR (CDCl3, 400
3
3
MHz) δH: 1.19 (3H, t, JHH 7.6 Hz, CH2CH3), 1.26 (3H, t, JHH 7.6
3ae. Yellow wax (186 mg, 40% yield). 1H NMR (CDCl3, 400 MHz)
δH: 5.89 (1H, s, Halkene), 6.4 (2H, m, ArH), 6.78 (4H, m, ArH), 6.90
(1H, tt, 3JHH 7.6 Hz 4JHH 2.4 Hz, ArH), 6.96 (3H, m, ArH), 7.08 (4H,
Hz, CH2CH3), 2.91 (2H, q, 3JHH 7.6 Hz, CH2CH3), 2.94 (2H, q, 3JHH
3
7.6 Hz, CH2CH3), 3.90 (3H, s, OCH3), 6.70 (1H, d, JHH 7.3 Hz,
ArH), 7.43 (1H, t, 3JHH 7.6 Hz, ArH), 7.46 (1H, d, 3JHH 7.6 Hz, ArH),
9.39 (1H, s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.7, 15.0,
21.1, 28.4, 55.6, 103.6, 114.9, 119.4, 128.5, 130.4, 136.4, 145.1, 154.4,
157.0. (ESI)+ m/z: [M + H]+ (100) 216. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C14H18NO 216.1388, found 216.1390.
3
4
m, ArH), 7.25 (5H, m, ArH), 7.35 (1H, dd, JHH 7.6 Hz JHH 2.4 Hz,
ArH), 7.49 (1H, d, JHH 5.6 Hz, ArH), 8.72 (1H, s, CHN). 13C{1H}
3
NMR (CDCl3, 100 MHz) δC: 123.3, 126.4, 126.5, 127.1, 127.1, 127.5,
127.6, 127.7, 127.8, 129.3, 129.6, 130.3, 130.7, 131.4, 131.6, 134.9,
137.4, 137.4, 139.9, 140.2, 142.3, 142.5, 144.0, 144.6, 151.2. (ESI)+ m/
z: [M + H]+ (100) 466. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C33H24NS 466.1629, found 466.1645.
7ea. Waxy white solid (187 mg, 76% yield). 1H NMR (CDCl3, 400
3
3
MHz) δH: 1.18 (3H, t, JHH 7.6 Hz, CH2CH3), 1.26 (3H, t, JHH 7.6
Hz, CH2CH3), 2.86 (2H, q, 3JHH 7.6 Hz, CH2CH3), 2.91 (2H, q, 3JHH
7.6 Hz, CH2CH3), 3.89 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.04 (1H,
s, ArH), 7.06 (1H, s, ArH), 8.78 (1H, s, CHN) (signals due to the
major isomer). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.6, 14.7, 55.9,
101.2, 105.8, 123.3, 127.9, 131.5, 147.6, 149.1, 152.6, 152.7 (signals
due to the major isomer). (ESI)+ m/z: [M + H]+ (100) 246. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H20NO2 246.1494, found
246.1489.
3af. Yellow wax (297 mg, 43% yield). 1H NMR (CDCl3, 400 MHz)
δH : 0.9 (12H, m, CH2 CH2 CH2 CH3 ), 1.5 (16H, m,
CH2CH2CH2CH3), 2.4 (4H, m, CH2CH2CH2CH3), 2.6 (4H, m,
CH2CH2CH2CH3), 5.86 (1H, s, H, Halkene), 6.44 (2H, d, 3JHH 10.8 Hz,
3
3
ArH), 6.45 (2H, d, JHH 10.8 Hz, ArH), 6.84 (2H, d, JHH 10.8 Hz,
ArH), 6.88 (2H, d, 3JHH 10.8 Hz, ArH), 6.98 (1H, d, 5JHH 2 Hz, ArH),
3
5
7.1 (5H, m, ArH), 7.21 (1H, dd, JHH 7.2 Hz, JHH 1 Hz, Hthio), 7.31
(1H, d, 3JHH 10.4 Hz, ArH), 7.54 (1H, d, 3JHH 7.2 Hz, Hthio), 8.72 (1H,
s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 13.9, 14.0, 14.0, 14.1,
22.1, 22.2, 22.4, 22.4, 33.4, 33.5, 33.6, 33.7, 35.2, 35.4, 110.0, 123.5,
127.0, 127.5, 127.6, 127.7, 129.1, 129.4, 130.4, 130.9, 134.7, 134.7,
135.1, 137.2, 137.7, 140.8, 141.0, 141.4, 142.0, 142.0, 144.3, 144.5,
151.5. (ESI)+ m/z: [M + H]+ (100) 690. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C49H56NS 690.4133, found 690.4154.
7fa. Orange oil (142 mg, 43% yield). 1H NMR (CDCl3, 400 MHz)
3
3
δH: 1.26 (3H, t, JHH 7.6 Hz, CH2CH3), 1.32 (3H, t, JHH 7.6 Hz,
3
3
CH2CH3), 2.99 (2H, q, JHH 7.6 Hz, CH2CH3), 3.09 (2H, q, JHH 7.6
Hz, CH2CH3), 8.02 (1H, d, 3JHH 8.8 Hz, ArH), 8.21 (1H, dd, 3JHH 8.8
4
4
Hz, JHH 2.0 Hz, ArH), 8.71 (1H, d, JHH 2.0 Hz, ArH), 9.17 (1H, s,
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.4, 15.4, 21.0, 28.4,
119.2, 119.7, 128.7, 130.3, 131.0, 134.4, 142.0, 150.1, 156.3. (ESI)+ m/
z: [M + H]+ (50) 231. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H15N2O2 231.1134, found 231.1128.
Typical Experimental Procedure for the Isoquinolines 7. The
corresponding benzylamine 6 (1 mmol) and alkyne 2 (2 mmol) were
added to a solution of [Ru(p-cymene)Cl2]2 (0.061 g, 0.1 mmol),
[Cu(OAc)2] (0.181 g, 1.0 mmol) and K[PF6] (18.7 mg, 0.1 mmol) in
MeOH (3 mL) into a Young’s flask. The solution was then heated at
100 °C for 24h. After that, the solvent was removed and the residue
subjected to flash chromatography on neutral alumina eluting with
DCM (DCM = CH2Cl2), then DCM/MeOH (95:5). Both eluted
fractions were mixed and evaporated to dryness, affording 7 as oily
materials or waxy solids, which were washed with Et2O (10 mL) and
pentane (10 mL). Compound 7fa was further purified by a second
column chromatography on silica gel eluting with mixtures hexane/
ethyl acetate (9/1 to 1/1). Compounds 7la and 7ma were purified by
column chromatography on silica gel eluting with mixtures hexane/
diethyl ether (5/1 to 1/1).
7ga.28 Yellow oil (116 mg, 58% yield). 1H NMR (CDCl3, 400
3
3
MHz) δH: 1.20 (3H, t, JHH 7.6 Hz, CH2CH3), 1.25 (3H, t, JHH 7.6
Hz, CH2CH3), 2.83 (3H, s, CH3), 2.87 (2H, q, 3JHH 7.6 Hz, CH2CH3),
2.89 (2H, q, 3JHH 7.6 Hz, CH2CH3), 7.40 (1H, ddd, 3JHH 8.4 Hz, 3JHH
4
3
3
6.8 Hz, JHH 1.4 Hz, ArH), 7.56 (1H, ddd, JHH 8.4 Hz, JHH 6.8 Hz,
4JHH 1.4 Hz, ArH), 7.88 (1H, d, JHH 8.0 Hz, ArH), 7.46 (1H, d, JHH
8.0 Hz, ArH). 13C{1H} NMR (CDCl3, 100 MHz) δC: 15.0, 15.3, 20.7,
22.4, 28.5, 123.3, 125.3, 126.1, 126.2, 127.2, 129.5, 135.1, 152.6, 155.8.
(ESI)+ m/z: [M + H]+ (100) 200. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H18N 200.1439, found 200.1434.
3
3
7ha. Yellow oil (150 mg, 68% yield). 1H NMR (CDCl3, 400 MHz)
3
3
δH: 1.19 (3H, t, JHH 7.6 Hz, CH2CH3), 1.26 (3H, t, JHH 7.6 Hz,
3
3
CH2CH3), 2.91 (2H, q, JHH 7.6 Hz, CH2CH3), 2.93 (2H, q, JHH 7.6
7aa.27 Waxy white solid (176 mg, 95% yield). H NMR (CDCl3,
1
Hz, CH2CH3), 7.36(1H, dd, 3JHH 8.7 Hz, 4JHH 1.9 Hz, ArH), 7.75 (1H,
3
3
3
4
400 MHz) δH: 1.23 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH
d, JHH 8.7 Hz, ArH), 7.85(1H, d, JHH 1.9 Hz, ArH), 9.05 (1H, s,
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 13.5, 13.9, 19.8, 27.3,
121.0, 124.4, 125.7, 127.3, 128.8, 134.9, 135.4, 148.8, 153.9. (ESI)+ m/
z: [M + H]+ (100) 220. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H15ClN 220.0893, found 220.0888.
3
7.6 Hz, CH2CH3), 2.93 (2H, q, JHH 7.6 Hz, CH2CH3), 3.00 (2H, q,
3JHH 7.6 Hz, CH2CH3), 7.43 (1H, td, JHH 7.6 Hz JHH 0.8 Hz, ArH),
7.62 (1H, ddd, 3JHH 8.4 Hz, 3JHH 7.6 Hz, 4JHH 1.2 Hz, ArH), 7.62 (1H,
ddd, 3JHH 8.4 Hz, 3JHH 7.6 Hz 4JHH 1.2 Hz, ArH), 7.83 (1H, d, 3JHH 8.0
3
4
Hz, ArH), 7.90 (1H, dd, JHH 8.4 Hz, 4JHH 0.8 Hz, ArH), 9.01 (1H, s,
7ia. Yellow oil (178 mg, 70% yield). H NMR (CDCl3, 400 MHz)
3
1
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.7, 15.1, 20.1, 122.8,
125.6, 127.3, 128.2, 129.0, 130.0, 135.1, 150.2, 153.8. (ESI)+ m/z:
[M]+ (100) 186. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H16N 186.1283, found 186.1276.
δH: 1.22 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6 Hz,
3
3
3
3
CH2CH3), 2.95 (2H, q, JHH 7.6 Hz, CH2CH3), 3.03 (2H, q, JHH 7.6
3
4
Hz, CH2CH3), 7.60 (1H, dd, JHH 8.8 Hz, JHH 1.6 Hz, ArH), 7.96
(1H, d, 3JHH 8.8 Hz, ArH), 8.19 (1H, s, ArH), 9.08 (1H, s, CHN). δF:
−62.71. 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.5, 15.1, 20.8, 28.4,
7ba. Yellow oil (205 mg, 95% yield). 1H NMR (CDCl3, 400 MHz)
3
3
4
1
δH: 1.17 (3H, t, JHH 7.6 Hz, CH2CH3), 1.23 (3H, t, JHH 7.6 Hz,
CH2CH3), 2.85 (2H, q, JHH 7.6 Hz, CH2CH3), 2.88 (2H, q, JHH 7.6
120.7 (q, JCF 18 Hz), 121.4 (q, JCF 1084 Hz), 127.4, 129.4, 129.9,
3
3
2
131.6 (q, JCF 124 Hz), 134.2, 150.1, 155.5. (ESI)+ m/z: [M + H]+
3
4
Hz, CH2CH3), 3.81 (3H, s, OCH3), 7.00 (1H, dd, JHH 8.8 Hz, JHH
(100) 254. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H15F3N
4
3
2.4 Hz, ArH), 7.43 (1H, d, JHH 2.0 Hz, ArH), 7.62 (1H, d, JHH 8.8
Hz, ArH), 8.82 (1H, s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC:
14.5, 14.6, 20.9, 28..4, 55.3, 101.0, 118.2, 123.1, 128.0, 129.9, 136.8,
149.3, 154.1, 160.8. (ESI)+ m/z: [M + H]+ (100) 216. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C14H18NO 216.1388, found 216.1383.
7ca. Waxy white solid (229 mg, 93% yield). 1H NMR (CDCl3, 400
254.1157, found 254.1151.
1
7ja. Waxy white solid (182 mg, 91% yield). H NMR (CDCl3, 400
3
3
MHz) δH: 1.24 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6
Hz, CH2CH3), 2.50 (3H, s, CH3), 2.92 (2H, q, 3JHH 7.6 Hz, CH2CH3),
3
3
4
2.98 (2H, q, JHH 7.6 Hz, CH2CH3), 7.28 (1H, dd, JHH 8.3 Hz, JHH
1.3 Hz, ArH), 7.67 (1H, s, ArH), 7.75 (1H, d, 3JHH 8.3 Hz, ArH), 8.95
(1H, s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.7, 15.0, 20.7,
3
3
MHz) δH: 1.15 (3H, t, JHH 7.5 Hz, CH2CH3), 1.23 (3H, t, JHH 7.3
H
dx.doi.org/10.1021/jo400344m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
22.5, 28.3, 121.8, 125.7, 127.9, 128.1, 128.5, 135.3, 140.2, 149.8, 153.8.
(ESI)+ m/z: [M + H]+ (100) 200. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H18N 200.1439, found 200.1434.
(1H, t, JHH 7.6 Hz, ArH), 7.0−7.3 (10H, m, ArH), 7.4−7.6 (3H, m,
ArH), 7.8 (1H, m, ArH), 8.84 (1H, s, CHN). 13C{1H} NMR (CDCl3,
100 MHz) δC: 125.9, 126.5, 126.7, 126.9, 127.1, 127.2, 127.4, 127.5,
127.7, 127.8, 129.2, 129.8, 130.1, 130.2, 130.5, 131.0, 131.5, 131.6,
135.1, 136.5, 137.4, 140.2, 140.4, 142.6, 143.9, 150.8, 151.3. (ESI)+ m/
z: [M + H]+ (100) 460. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C35H26N 460.2060, found 460.2068.
7ka. Waxy white solid (198 mg, 82% yield). 1H NMR (CDCl3, 400
3
3
MHz) δH: 1.24 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6
3
Hz,) CH2CH3, 1.36 (9H, s, C(CH3)3), 2.92 (2H, q, JHH 7.6 Hz,
CH24CH3), 3.02 (2H, q, 3JHH 7.6 Hz, CH2CH3), 7.53 (1H, dd, 3JHH 8.8
3
Hz, JHH 2.0 Hz, ArH), 7.78 (1H, d, JHH 8.8 Hz, ArH), 7.83 (1H, d,
3JHH 0.8 Hz, ArH), 8.95 (1H, s, CHN). 13C{1H} NMR (CDCl3, 100
MHz) δC: 14.7, 15.0, 20.8, 28.4, 31.2, 34.5, 117.7, 124.6, 125.7, 127.2,
129.0, 135.0, 149.6, 153.0, 153.8. (ESI)+ m/z: [M + H]+ (100) 242.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H24N 242.1909, found
242.1916.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra of all prepared compounds. In situ NMR
experiments. NOE spectrum of 3ac. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
1
7la. Yellow oil (201 mg, 85% yield). H NMR (CDCl3, 400 MHz)
3
3
δH: 1.20 (3H, t, JHH 7.6 Hz, CH2CH3), 1.29 (3H, t, JHH 7.6 Hz,
3
3
AUTHOR INFORMATION
Corresponding Author
*E-mail: esteban@unizar.es.
CH2CH3), 2.94 (2H, q, JHH 7.6 Hz, CH2CH3), 2.97 (2H, q, JHH 7.6
Hz, CH2CH3), 7.45 (1H, td, 3JHH 8.0 Hz, 4JHH 1.2 Hz, ArH), 7.56 (1H,
td, 3JHH 8.0 Hz, 4JHH 1.2 Hz, ArH), 7.73 (1H, dd, 3JHH 8.0 Hz, 4JHH 1.2
■
3
Hz, ArH), 7.74 (2H, s, ArH), 8.61 (1H, d, JHH 8.0 Hz, ArH), 9.76
(1H, s, CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.6, 15.6, 21.1,
28.5, 121.2, 121.9, 123.2, 126.9, 127.7, 128.6, 130.0, 130.2, 131.1,
131.2, 134.6, 144.2, 156.1. (ESI)+ m/z: [M + H]+ (100) 236. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C17H18N 236.1439, found
236.1434.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
Competitividad (MINECO) under Project No. CTQ2011-
22589 and the Regional Government of Aragon under project
́
E-97 is gratefully acknowledged. P.V. thanks CSIC for a Juan de
la Cierva contract.
■
́
7ma. Waxy white solid (226 mg, 91% yield). 1H NMR (CDCl3, 400
3
3
MHz) δH: 1.26 (3H, t, JHH 7.6 Hz, CH2CH3), 1.28 (3H, t, JHH 7.6
Hz, CH2CH3), 2.88 (2H, q, 3JHH 7.6 Hz, CH2CH3), 2.94 (3H, s, CH3),
3
3
4
3.04 (2H, q, JHH 7.6 Hz, CH2CH3), 7.36 (1H, td, JHH 8.0 Hz, JHH
1.2 Hz, ArH), 7.41 (1H, td, 3JHH 8.0 Hz, 4JHH 1.2 Hz, ArH), 7.88 (1H,
3
3
d, JHH 8.0 Hz, ArH), 7.90 (1H, d, JHH 8.0 Hz, ArH), 8.34 (1H, s,
ArH), 8.54 (1H, s, ArH). 13C{1H} NMR (CDCl3, 100 MHz) δC: 14.9,
15.2, 20.9, 22.8, 28.4, 121.7, 125.0, 125.6, 125.9, 126.0, 127.0, 128.2,
128.8, 130.8, 130.9, 132.0, 133.8, 149.9, 157.5. (ESI)+ m/z: [M + H]+
(100) 250. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H20N
250.1596, found 250.1590.
REFERENCES
■
(1) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles, Structure, Reactions, Synthesis and Applications; Wiley-
VCH: Weinheim, 2003.
(2) (a) Ullyot, G. E. US Patent 2612503-19520930, 1952.
(b) Migliarese, J. F.; De Salva, J. S. US Patent 3172805-19650309,
1965.
1
7ab (Both Isomers). Yellow oil (143 mg, 77% yield). H NMR
(CDCl3, 400 MHz) δH: 0.95 (3H, t, 3JHH 7.6 Hz, CH2CH3), 1.70 (2H,
m, CH3CH2), 2.53 (3H, s, CH3), 2.92 (2H, m, CH3CH2CH2), 7.36
(3) (a) Merck, G. Liebigs Ann. Chem. 1848, 66, 125. (b) Pictect, A.;
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(6) (a) Pomeranz, C. Monatsh. Chem. 1893, 14, 116. (b) Fritsch, P.
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Reactions; Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 191−
206. (d) Bischler, A.; Napieralski, B. Ber. Deutsch. Chem. Ges. 1893, 26,
1903. (e) Waley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 74−150. (f) Pictet,
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(7) (a) Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086.
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R.; Desphande, M. N. Synth. Commun. 1999, 29, 1835. (g) Graulich,
3
4
3
(1H, td, JHH 8.0 Hz, JHH 1.2 Hz, ArH), 7.41 (1H, ddd, JHH 9.2 Hz,
3JHH 6.8 Hz JHH 1.2 Hz, ArH), 7.61 (1H, ddd, JHH 9.2 Hz, JHH 6.8
4
3
3
Hz 4JHH 1.2 Hz, ArH), 7.83 (1H, d, JHH 9.2 Hz, ArH), 7.90 (1H, dq,
3
3JHH 8.8 Hz JHH 0.8 Hz, ArH), 9.00 (1H, s, CHN). 13C{1H} NMR
4
(CDCl3, 100 MHz) δC: 13.2, 22.2, 29.3, 36.9, 121.9, 122.3, 124.7,
125.9, 127.0, 128.9, 134.9, 148.8, 152.0. (ESI)+ m/z: [M + H]+ (40)
186. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H16N 186.1283,
found 186.1269.
7ac. Waxy white solid (185 mg, 93% yield). 1H NMR (CDCl3, 400
MHz) δH: 1.49 (9H, s, C(CH3)3), 2.72 (3H, s, CH3), 7.41 (1H, ddd,
3
4
3
3JHH 8.0 Hz, JHH 6.8 Hz JHH 1.2 Hz, ArH), 7.61 (1H, ddd, JHH 8.4
3
4
3
Hz, JHH 6.8 Hz JHH 1.6 Hz, ArH), 7.82 (1H, d, JHH 8.0 Hz, ArH),
3
4
7.93 (1H, dq, JHH 8.4 Hz JHH 0.8 Hz, ArH), 9.00 (1H, s, CHN).
13C{1H} NMR (CDCl3, 100 MHz) δC: 16.2, 31.0, 38.6, 122.9, 123.8,
125.8, 126.7, 127.7, 129.7, 137.1, 148.3, 158.7. (ESI)+ m/z: [M + H]+
(100) 200. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H18N
200.1439, found 200.1434.
7ad. Yellow oil (139 mg, 41% yield). 1H NMR (CDCl3, 400 MHz)
3
δH: 1.72 (3H, d, JHH 1.2 Hz, CH3), 2.38 (3H, s, CH3), 6.31 (1H, m,
Halkene), 6.94 (2H, d, JHH 8.0 Hz, ArH), 7.14 (2H, t, JHH 8.0 Hz,
3
3
3
3
ArH), 7.35 (5H, m, ArH), 7.54 (1H, ddd, JHH 8.4 Hz, JHH 7.6 Hz,
4JHH 1.2 Hz, ArH), 7.66 (1H, ddd, JHH 8.4 Hz, JHH 7.6 Hz, JHH 1.2
3
3
4
Hz, ArH), 7.92 (2H, dd, JHH 8.0 Hz, 4JHH 4.0 Hz, ArH), 9.12 (1H, s,
3
CHN). 13C{1H} NMR (CDCl3, 100 MHz) δC: 15.3, 19.2, 123.5,
123.6, 124.9, 126.2, 126.4, 126.6, 126.9, 127.3, 127.9, 128.0, 128.1,
128.3, 129.6, 130.3, 130.3, 130.4, 138.1, 145.4, 149.8. (ESI)+ m/z: [M
+ H]+ (100) 336. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C25H22N 336.1752, found 336.1752.
7ae. Orange oil (242 mg, 53% yield). 1H NMR (CDCl3, 400 MHz)
δH: 6.06 (1H, s, Halkene), 6.44 (2H, d, 3JHH 6.7 Hz, ArH), 6.75 (2H, d,
3JHH 7.6 Hz, ArH), 6.81 (2H, d, JHH 7.6 Hz, JHH 1.2 Hz, ArH), 6.88
́ ́
A.; Scuvee-Moreau, J.; Seutin, V.; Liegeois, J.-F. J. Med. Chem. 2005,
3
4
I
dx.doi.org/10.1021/jo400344m | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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