Ruthenium-catalyzed oxidative coupling of primary amines with internal alkynes through C-H bond activation: Scope and mechanistic studies

Article abstract of DOI:10.1002/chem.201500338

The oxidative coupling of primary amines with internal alkynes catalyzed by Ru complexes is presented as a general atom-economy methodology with a broad scope of applications in the synthesis of N-heterocycles. Reactions proceed through regioselective C-H bond activation in 15 minutes under microwave irradiation or in 24 hours with conventional heating. The synthesis of 2,3,5-substituted pyridines, benzo[h]isoquinolines, benzo[g]isoquinolines, 8,9-dihydro-benzo[de]quinoline, 5,6,7,8-tetrahydroisoquinolines, pyrido[3,4g]isoquinolines, and pyrido[4,3g]isoquinolines is achievable depending on the starting primary amine used. DFT calculations on a benzylamine substrate support a reaction mechanism that consists of acetate-assisted C-H bond activation, migratory-insertion, and C-N bond formation steps that involve 28-30 kcalmol^-1. The computational study is extended to additional substrates, namely, 1-naphthylmethyl-, 2-methylallyl-, and 2-thiophenemethylamines.

Full text of DOI:10.1002/chem.201500338

DOI: 10.1002/chem.201500338
Full Paper
&
Transition-Metal Catalysis
Ruthenium-Catalyzed Oxidative Coupling of Primary Amines with
Internal Alkynes through CÀH Bond Activation: Scope and
Mechanistic Studies
Sara Ruiz,[a] Pedro Villuendas,[a] Manuel A. OrtuÇo,[b] Agustꢀ Lledꢁs,*[b] and
Esteban P. Urriolabeitia*[a]
Abstract: The oxidative coupling of primary amines with in-
ternal alkynes catalyzed by Ru complexes is presented as
a general atom-economy methodology with a broad scope
of applications in the synthesis of N-heterocycles. Reactions
proceed through regioselective CÀH bond activation in
15 minutes under microwave irradiation or in 24 hours with
conventional heating. The synthesis of 2,3,5-substituted pyri-
dines, benzo[h]isoquinolines, benzo[g]isoquinolines, 8,9-dihy-
dro-benzo[de]quinoline, 5,6,7,8-tetrahydroisoquinolines, pyri-
do[3,4g]isoquinolines, and pyrido[4,3g]isoquinolines is ach-
ievable depending on the starting primary amine used. DFT
calculations on a benzylamine substrate support a reaction
mechanism that consists of acetate-assisted CÀH bond acti-
vation, migratory-insertion, and CÀN bond formation steps
that involve 28–30 kcalmolÀ1. The computational study is ex-
tended to additional substrates, namely, 1-naphthylmethyl-,
2-methylallyl-, and 2-thiophenemethylamines.
Introduction
The synthesis of nitrogen-containing heterocycles, such as pyri-
dines, quinolines, isoquinolines, and benzoisoquinolines, has
attracted the interest of the chemists since the early years of
organic synthesis.[1] This attention is mainly due to their ubiqui-
tous presence in natural products or drugs with a strong bio-
logical and pharmacological activity.[2] Some examples of such
molecules are presented in Figure 1. For instance, dinapsoline
is a drug that was developed for the treatment of the Parkin-
son’s disease because it is an agonist of dopamine,[3] whereas
cherylline, nomifensine, and dichlofensine show central-nerv-
ous-system activity as selective serotonin-reuptake inhibitors.[4]
Conventional methods employed for the synthesis of the
aforementioned N-heterocycles comprise the reactions report-
ed by Pomeranz and Fritsch,[5] Pictet and Spengler,[6] and Bis-
chler and Napieralski[7] in the case of isoquinolines or the pro-
cesses developed by Hantzsch,[8] Gattermann and Skita,[9] and
Figure 1. N-heterocycles from benzoisoquinoline or isoquinoline with bio-
logical and pharmacological activities.
Zecher and Krçhnke[10] in the case of pyridines. However, the
major problems found when using conventional methods for
the large-scale synthesis of these derivatives include tedious
reaction procedures, low yields, and harsh reaction conditions
for some products and a sometimes narrow scope of substitu-
ents in the formed cycle.
Alternatively, the synthetic scope of the preparation of virtu-
ally any type of N-heterocycle has been enlarged by the devel-
opment of methodologies that involve directed activation of
Csp2ÀH bonds by using catalytic amounts of a transition-metal
species.[11] In this respect, simple PdII, RhIII, or RuII complexes
have been widely used for the promotion of oxidative cou-
pling between internal alkynes and imines, amides, oximes,
and acetamides (among other nitrogen-containing materials)
to yield the corresponding isoquinolines, isoquinolones, isoqui-
nolinium salts, pyridines, pyridones, and indoles.[12]
[a] S. Ruiz, Dr. P. Villuendas, Dr. E. P. Urriolabeitia
Instituto de Sꢀntesis Quꢀmica y Catꢁlisis Homogꢂnea (ISQCH)
CSIC-Universidad de Zaragoza, Fac. de Ciencias, Edificio D
Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Fax: (+34)976761187
E-mail: esteban@unizar.es
[b] Dr. M. A. OrtuÇo, Prof. Dr. A. Lledꢃs
Departament de Quꢀmica
Edifici Cn, Universitat Autꢄnoma de Barcelona
08193 Cerdanyola del Vallꢂs, Barcelona (Spain)
Fax: (+34)935812920
In spite of this great development, the use of primary
amines as nitrogen sources for the building of a heterocycle is
seldom used. Miura and co-workers reported one of the few
reported examples of this approach, in which the synthesis of
benzo[h]quinolines by coupling 1-naphthylmethylamine with
E-mail: agusti@klingon.uab.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500338.
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and cheap, avoids inert condi-
tions and tedious workup proce-
dures, and takes place in few mi-
nutes by using microwave radia-
tion.
In addition, we observed
during this study different reac-
tivity trends as a function of the
structure of the precursor and
the reaction solvent. Clearly,
fine-tuning of the reaction con-
ditions is mandatory in each
case to achieve a successful pro-
cess, and the knowledge of the
intimate mechanism of the reac-
tion would help understand the
role of each parameter. The ex-
trapolation of previous mecha-
nistic data is not always possi-
ble; for instance, we have re-
Figure 2. Most relevant previous reports and the work presented herein.
cently shown that two stoichio-
metric Ru-mediated processes,
apparently closely related, can
aryl-substituted alkynes catalyzed by expensive RhIII complexes
is covered.[13] The scope of this reaction may be limited be-
cause only the reaction with 1-naphthylmethylamine was re-
ported. Also, when aliphatic alkynes were allowed to react,
they gave benzo[e]isoindoles instead (Figure 2). More recently,
almost simultaneous studies from Jun and co-workers[14] and
our group[15] reported the synthesis of isoquinolines from ben-
zylamines, but with substantial differences between the two
contributions. The study of Jun and co-workers was devoted
to the exclusive use of benzylamines (primary, secondary, and
tertiary) to afford the corresponding isoquinolines or isoquino-
linium salts,[14a] whereas our study was focused on the use of
primary amines from both aryl and heteroaryl fragments and
selected naphthyl and allyl groups, thus broadening the scope
of the substrates as much as possible and defining a more
general process. Further investigations by Jun and co-workers
also dealt with allylamines and will be discussed later.[14b] Re-
markably, all the processes reported by Jun and Miura were
Rh-catalyzed, whereas our approaches were Ru-catalyzed,
which is an important economical factor.
involve completely unrelated intermediate species in different
oxidation states.[16] Due to this fact and the shortage of com-
putational data for the Ru-catalyzed oxidative coupling of ni-
trogen-containing species with internal alkynes,[17,18] we have
determined the reaction mechanism for benzyl-, 1-naphthyl-
methyl-, 2-methylallyl-, and 2-thiophenemethylamines by using
DFT calculations. Herein, we report the obtained results.
Results and Discussion
Oxidative coupling reactions between primary amines 1a–1 f
and alkynes 2a–2 f were performed (Figure 3). These sub-
strates were selected to cover a wide scope of structural situa-
tions. The initial reaction conditions were as described in our
previous report.[15]
The proof of concept that the Ru-catalyzed functionalization
of primary amines can be as efficient as those processes pro-
moted by Rh species, or more so, prompted us to develop
a general strategy to provide access to new heterocycles from
modified primary amines. We have further expanded the scope
of the substrates used, including different naphthylmethyla-
mines, tetrahydronaphthylamines, cyclohexylamines, phenyle-
nebis(methylamines), and even allylamines, to afford new and
unexpected molecules that are difficult to synthesize by other
methods. This protocol is highly efficient in terms of atom
economy because unmodified amines are used (thus avoiding
the specific preparation of the substrates) and the whole skele-
ton of the amine forms the basic scaffold of an N-heterocycle.
As additional advantages, the experimental protocol is simple
Figure 3. Primary amines 1 and internal alkynes 2 used herein.
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Catalytic synthesis of benzoisoquinolines and related deriv-
atives
tion of 3aa at all. For that reason, we used the dimer [{Ru(h6-
cymene)(m-Cl)Cl}2] as a catalyst in subsequent reactions.
Under the optimized conditions, a variety of internal alkynes
2a–2 f were successfully coupled with 1-naphthylmethylamine
(1a). The CÀH bond activation of 1a is totally regioselective by
taking place at the 2 position of the naphthyl unit to afford
the corresponding 3,4-disubstituted-benzo[h]isoquinolines
3aa–3af (Scheme 1). Electron-rich alkynes 2a–2d give mono-
inserted products 3aa–3ad in moderate-to-good yields, with
small differences between conventional and microwave heat-
ing (Scheme 1), except for 2b, which was too volatile for the
microwave experiments. Obviously, the most important differ-
ence between the two methodologies is the reaction time. The
coupling takes place with a high degree of regioselectivity
when the alkyne has two substituents with large differences in
steric requirements, such as 4,4-dimethylpent-2-yne (2c;
a molar ratio of 3ac/3ac’ of up to 10:1 under microwave con-
ditions), whereas equimolar mixtures of regioisomers 3ad and
3ad’ were obtained in the absence of such differences (i.e., by
using 2-hexyne (2d)). As previously observed, the largest tBu
substituent in regioisomer 3ac’ is located adjacent to the ni-
trogen atom.[15,21] In both cases, the two isomers, that is, 3ac/
3ac’ and 3ad/3ad’, were successfully separated by column
chromatography and characterized separately (see the Sup-
porting Information). Moreover, each isomer was assigned with
its correct regiochemistry through selective 1D NOESY experi-
ments. When the starting alkyne contains aryl substituents
(i.e., 2e and 2 f), the 3,4-disubstituted isoquinoline first gener-
ated after the insertion and coupling reactions undergoes
a second alkyne insertion at the 3-aryl position to afford the
corresponding ortho-alkenylated derivatives 3ae and 3af’, re-
spectively.
We have previously shown that the coupling of 1a (1 mmol)
with 2a (2 mmol) catalyzed by [{Ru(h6-cymene)(m-Cl)Cl}2]
(0.1 mmol) in the presence of Cu(OAc)2 (1 mmol) and K[PF6]
(0.1 mmol) in methanol at 1008C for 24 hours affords benzo[-
h]isoquinoline 3aa in 85% yield.[15] A short screening of the re-
action conditions showed that both the solvent MeOH and the
oxidant Cu(OAc)2 were the optimal choices. However, a notable
improvement was achieved by using microwaves as the radia-
tion source[19] because the reaction time can be drastically de-
creased to only 15 minutes, thus increasing the yield of the iso-
lated product 3aa by up to 93% (Scheme 1).
We also studied the Ru-catalyzed coupling of 1-(2-naphthyl)-
ethylamine (1b) with alkynes 2a–2 f, which affords 3,4-disub-
stituted-benzo[g]isoquinolines 3ba–3bf’ (Scheme 2). Once
Scheme 1. Coupling of 1-naphthylmethylamine (1a) and alkynes 2 to give
benzo[h]isoquinolines 3aa–3af’.
To improve the catalytic results further, we decided to test
different Ru catalysts with variable Ru/OAc/Cl ratios in their
composition because it has been reported that the Ru/OAc/Cl
ratio is critical for the promotion of the CÀH bond activation.[20]
In this respect, previous studies showed that although [Ru(h6-
cymene)Cl(OAc)] could promote the CÀH bond activation in N-
aryl substrates, [Ru(h6-cymene)(OAc)2] was totally inert toward
the same substrates.[20] Notably, we obtained similar yields of
the isolated product 3aa by using the two complexes as cata-
lysts under the same reaction conditions, thus obtaining 54
and 62% yields of the isolated product by using [Ru(h6-cyme-
ne)Cl(OAc)] and [Ru(h6-cymene)(OAc)2], respectively. However,
both of these yields are lower than the yield obtained by
using [{Ru(h6-cymene)(m-Cl)Cl}2] (93%). This tolerance toward
different catalysts appears to be an important advantage with
respect to other systems. Other Ru complexes, such as
[RuCl2(PPh3)4] or [RuH2(CO)(PPh3)3], did not promote the forma-
Scheme 2. Coupling of 1-(2-naphthyl)ethylamine (1b) with alkynes 2a–2 f to
give benzo[g]isoquinolines 3ba–3bf’. cym=cymene.
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again the process is regioselective because only the 3-position
of the starting substrate 1b is activated by the Ru center. The
reaction takes place with alkyl- and aryl-substituted alkynes, al-
though better yields were obtained in the case of the electron-
rich alkynes 3-hexyne (2a), 4,4-dimethylpent-2-yne (2c), and 2-
hexyne (2d). Unfortunately, the reaction with 2-butyne (2b)
could not be performed under microwave irradiation due to
the volatility of the alkyne moiety, whereas the reaction with
conventional heating afforded a very low yield of a product re-
sistant to purification. More interestingly, the coupling of 1b
with unsymmetrical 2c is regioselective, and 3bc is obtained
as a single regioisomer (Scheme 2), the structure of which was
confirmed by selective 1D NOESY experiments. As expected,
the more voluminous tBu group is located near the N atom, as
in 3ac and previous benzylamines.[15] In the case of substitu-
ents with the same steric hindrance (i.e., 2d), an equimolar
mixture of the two possible regioisomers (3bd and 3bd’) is
obtained. In this case we could separate this mixture by means
of column chromatography and characterize the correspond-
ing benzo[g]isoquinolines separately, including the correct as-
signation of the structure by selective 1D NOESY experiments
(see the Supporting Information).
Scheme 3. Ru-catalyzed synthesis of dihydrobenzo[de]quinoline (3ca) and
5,6,7,8-tetrahydroisoquinoline (3da).
clohex-1-en-1-yl)ethan-1-amine (1d) were subjected to Ru-
mediated coupling with 3-hexyne (2a; see Scheme 3).
First attempts carried out in MeOH with conventional heat-
ing showed the formation of the expected products 2,3-dieth-
yl-8,9-dihydro-7H-benzo[de]quinoline (3ca) and 3,4-diethyl-1-
methyl-5,6,7,8-tetrahydroisoquinoline (3da), but in low yields.
In the case of 1d, stoichiometric amounts of the Ru catalyst
were used. Moreover, the byproduct (E)-8-(hex-3-en-3-yl)-3,4-di-
hydronaphthalen-1(2H)-one (4) was also formed in the case of
amine 1c, although it was cleanly separated from the benzo-
quinoline 3ca by means of column chromatography. Formally,
the formation of 4 from 1c implies that the carbon atom that
supports the amino group was oxidized to a keto function,[23]
thus giving a 8-vinyl-1-tetralone derivative. This oxidation likely
takes place after the insertion of the alkyne unit, but before
the CÀN bond formation. This scenario is suggested by the
fact that no reaction at all was observed between the pure 1-
tetralone and 3-hexyne under the Ru-catalyst conditions. The
change of the solvent from MeOH to tert-amyl alcohol
(tAmOH) promoted a remarkable increase of the yield in all
cases, although the formation of ketone 4 from amine 1c after
24 hours of reaction is still evident. When the reaction is car-
ried out with microwave radiation for 15 minutes, a double
benefit is achieved because the yield is further increased up to
53% and the formation of 4 is totally suppressed.
The synthesis of tetrahydroisoquinoline 3da means that this
method is valid not only for the activation of Csp2ÀH bonds in
aromatic (het)aryl rings, but also Csp2ÀH bonds in alkene-type
units. This fact prompted us to explore other related sub-
strates, such as allyl amines, which will be discussed later. The
selective synthesis of 3da also suggests that the activation of
the Csp2ÀH bonds is preferred to the activation of Csp3ÀH
bonds, which is usual for this type of substrate. In this respect,
we also performed the Ru-mediated reaction of cyclohexylme-
thylamine with 3-hexyne (2a) mediated by Ru catalysis; how-
ever, no detectable coupling product was observed under the
attempted reaction conditions.
We also attempted the coupling of 1b with aryl-containing
alkynes 2e and 2 f. Complete conversions were observed with
conventional heating and under microwave radiation, although
poor yields were obtained for the final isolated products and
only for the microwave-promoted reactions. Surprisingly, the
selective insertion of only one alkyne unit was observed in
both cases, therefore giving 1-methyl-3,4-diphenylbenzo[g]iso-
quinoline (3be) in 29% yield and the two isomers 1,3-dimeth-
yl-4-phenylbenzo[g]isoquinoline (3bf) and 1,4-dimethyl-3-phe-
nylbenzo[g]isoquinoline (3bf’) in 5 and 8% yield, respectively,
which were separated by means of column chromatography
(Scheme 2). Attempts to increase the yield by changing the re-
action temperature and/or the reaction time did not provide
any improvement. In spite of the low yields, what is really rele-
vant for these three compounds is that they represent the
only examples of the Ru-catalyzed coupling of amines in which
a selective single insertion is observed with aryl-containing in-
ternal alkynes. In fact, in our preceding report[15] and as report-
ed above (i.e., 3ae, 3af’), the double insertion of alkynes has
always been achieved. Therefore, the diversity of the products
achievable with this methodology increases notably. In this re-
spect, the reactivity described herein for 1-(2-naphthyl)ethyla-
mine (1b) as source of benzo[g]isoquinolines improved by
a considerable extent relative to previous observations of Gꢃl
and Nelson, who reported the complete lack of reactivity of
ortho-ruthenated N,N-dimethyl-a-(2-naphthyl)ethylamine with
internal alkynes.[22]
Once we had shown that primary amines are adequate pre-
cursors for the synthesis of tricyclic aromatic skeletons such as
benzo[h]isoquinolines and benzo[g]isoquinolines, we aimed to
expand the scope of reachable molecules further into two dif-
ferent directions: 1) di- and tricyclic cores that contain saturat-
ed rings and 2) tricyclic aromatic cores with two nitrogen-con-
taining rings. To achieve the first goal, the partially hydrogenat-
ed amines 1,2,3,4-tetrahydronaphthyl-1-amine (1c) and 1-(cy-
In a further step, 1,4-phenylenebis(methylamine) (1e) and
1,3-phenylenebis(methylamine) (1 f) were treated with an
excess of 2a under Ru-mediated conditions (Scheme 4), thus
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Scheme 4. Ru-mediated synthesis of pyridoisoquinolines 3ea and 3 fa.
Figure 4. Drawing of the cationic part of complex 3a·OM. Selected bond
distances [ꢄ] and angles [8]: Ru(1)ÀN(1): 2.094(3), N(1)ÀC(29): 1.503(4), C(29)À
C(21): 1.513(5), N(1)ÀC(18): 1.282(4), C(18)ÀC(8): 1.459(4), C(8)ÀC(9): 1.390(4),
C(9)ÀC(30): 1.484(4), C(30)ÀRu(1): 2.176(3), C(30)ÀC(32): 1.520(4), C(30)ÀC(31):
1.541(4), C(32)ÀO(1): 1.287(4), Ru(1)ÀO(1): 2.089(3); O(1)-Ru(1)-N(1): 80.35(11),
O(1)-Ru(1)-C(30): 63.31(11), N(1)-Ru(1)-C(30): 83.19(11).
giving the corresponding 3,4,8,9-tetraethylpyrido[3,4g]isoqui-
noline (3ea) and 3,4,6,7-tetraethylpyrido[4,3g]isoquinoline
(3 fa) as single isomers.
The activity of the Ru center that promotes this coupling is
remarkable because two coupling reactions on the same aro-
matic ring have to take place, regardless of whether they
occur consecutively or simultaneously. The synthesis of bis-cy-
cloruthenated compounds has experienced increasing interest
very recently due to their interesting electronic and optical
properties.[24] However, bis-cyclometalated species are seldom
used in metal-mediated synthesis to promote this type of
double functionalization.[25] In addition, the selectivity of this
reaction is notable because several isomers are envisageable in
both cases, but a single compound is isolated in each case.
The structure of 3 fa was assigned on the basis of the high
symmetry of the NMR signals, whereas the structure of 3ea is
based on the presence of strong NOE interactions between
the protons at positions 5 and 10 and the methylene protons
of the ethyl groups at positions 4 and 9 (see the Supporting
Information), thus meaning that the activation of CÀH bonds
has occurred at the 2,5 positions in 1e.
with selected bond distances and angles. Details of the isola-
tion and full characterization of 3a·OM are given in the Sup-
porting Information. This structure shows a really remarkable
C,N,O-tridentate ligand, presumably formed by a mechanism
that involves the self-condensation of two naphthylmethyla-
mine compounds to give an amine–imine unit, orthoruthena-
tion, alkyne coupling, and final hydration.
The formation of 3a·OM (and other related species) could
explain the low yield observed because reagents such as naph-
thylmethylamine are consumed and, more importantly, be-
cause the Ru catalyst is sequestered in the stoichiometric syn-
thesis of very stable complexes.
Catalytic synthesis of pyridines and related derivatives
We also achieved the synthesis of pyridines by using the same
methodology, but starting from allylamines. Most of the work
performed up to now for the metal-catalyzed synthesis of
densely substituted pyridines is based on vinyl–imines and RhIII
or RhI catalysts.[12o,p,27] Only one contribution, as far as we
know, reports the use of allylamines as a starting material, and
even in this case the authors propose that the catalytically rel-
evant species is the imine.[14b] Herein, we show not only that al-
lylamines are good precursors for the synthesis of pyridines,
thus showing a reactivity pattern different to what is expected
for a classical allyl group, but also that different products can
be obtained as a function of the reaction conditions. Of
course, this example is also the first time that such a process
has been catalyzed by RuII derivatives.
Characterization of the crude reaction products
From the above discussion, it seems clear that primary amines
can be used as versatile building blocks for the synthesis of di-
verse heterocycles through Ru-catalyzed oxidative coupling
with internal alkynes. The easy and selective CÀH bond activa-
tion step is remarkable, in spite of the very few examples re-
ported of the cycloruthenation of primary amines.[26] However,
the yields of the target compounds are not always high, even
if all the processes are carried out under optimized conditions,
thus suggesting that competitive processes take place at the
same time. Therefore, we investigated the composition of the
crude products just after removal of the copper salt. This anal-
ysis shows the presence of expected organic derivatives and,
in many cases, small but detectable amounts of h6-cymene or-
ganometallic complexes of the RuII species.
2-Methylallylamine (1g) was allowed to react with 3-hexyne
(2a) under the conditions reported previously (i.e., Cu(OAc)2,
MeOH, 24 h, 1008C), but less than 5% yield of the isolated
product of pure pyridine 3ga was obtained, which proved dif-
ficult to obtain in its pure form.[15] When oxone was used as
the oxidant and NaOAc as the base in MeOH at 1008C, the full
conversion of 1g was observed. However, the result of the re-
action is a new organometallic compound 3g·OM (Scheme 5),
We achieved the isolation of a very stable representative of
such species as 3a·OM in the reaction of 1a with alkyne 2c.
Single crystals of 3a·OM adequate for X-ray determination
studies were grown from CH2Cl2/n-hexane at 88C. A drawing
of the cationic organometallic complex is shown in Figure 4,
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tained yields range from moderate (45%) to good (>
70%) of the analytically pure products and, as ex-
pected, the reaction works for alkynes with alkyl and
aryl substituents. The observed regioselectivity is
high in the case of asymmetric alkynes, but not as
complete as it was in some of the preceding cases.
Interestingly, this regioselectivity is notably improved
(i.e., for 3gc and 3gf) when the reaction is carried
out under microwave conditions (Scheme 6). Finally,
as observed in the previous examples, a double inser-
tion of the alkyne unit takes place when an aryl ring
Scheme 5. Stoichiometric coupling of 1g with 3-hexyne (2a) in MeOH to give 3g·OM.
which contains the Ru center bonded to a h6-cymene ligand
and to a h1-h2-aminocyclopentene moiety, assigned on the
basis of analytic and spectroscopic data and comparison with
those complexes found in similar structural arrangements (see
the Supporting Information).[28] The synthesis of 3g·OM can be
explained (see Figure S3 in the Supporting Information)
through the formation of an h3-allyl intermediate, migratory in-
sertion, and Csp2–Csp2 coupling (similar to couplings reported
by Davies et al.)[29] or through directed ruthenation at the =CH2
position, migratory insertion, and a 1,3-sigmatropic shift.[30]
All our attempts to liberate the aminocyclopentene ligand
from the Ru center were unsuccessful, which suggests that
3g·OM is not an adequate precursor in the design of a plausi-
ble catalytic cycle. Therefore, 3g·OM represented a dead-end
pathway for the synthesis of pyridines, and a new optimization
process was needed.
is at position 2 (i.e., 3ge and 3gf’) due to the formation of the
2-phenylpyridine moiety.
DFT mechanistic studies
The experimental results proved the capability of Ru com-
plexes to catalyze the oxidative coupling of primary amines
with internal alkynes (Schemes 1–4 and 6). To investigate the
reaction mechanism to a greater extent, DFT calculations were
performed on the reaction shown in Scheme 7 (see the Com-
For the screening of new reaction conditions, we carried out
the process in tAmOH at 1008C due to the success obtained in
the catalytic couplings that started from 1c and 1d with differ-
ent oxidants and reaction times. Thankfully, we found that al-
lylamine 1g couples with 2a to give pyridine 3ga with
Cu(OAc)2 as the oxidant in tAmOH at 1008C. The optimum re-
action time is 24 hours, which could be reduced to 15 minutes
under microwave radiation. Under optimal conditions, 1g oxi-
datively couples with different internal alkynes 2a–2 f to give
the corresponding pyridines 3ga–3gf (Scheme 6). The ob-
Scheme 7. Ru-catalyzed reaction between 1h and 2b under theoretical
study.
putational Details for further information), that is, the Ru-cata-
lyzed coupling of benzylamine (1h) with 2-butyne (2b) to
form dihydroisoquinoline 1hbH. Further oxidation processes
are assumed to yield the final isoquinoline derivative 1hb.[15]
Regarding the catalyst, the monomer [Ru(p-cymene)(OAc)2]
(cat.) was used in the calculations. Although the related dimer
precursor [{Ru(p-cymene)(m-Cl)Cl}2] can provide better yields,
[Ru(p-cymene)(OAc)2] (cat.) is quite feasible in the presence of
Cu(OAc)2.[17,18]
Herein, the reaction mechanism is discussed for benzylamine
(1h), but it also works for 1-naphthylmethyl-, 2-methylallyl-,
and 2-thiophenemethylamines (1a,g,i, respectively; see the
Supporting Information) and, presumably, for other related an-
alogues. The DFT-proposed reaction mechanism entails three
main steps: 1) CÀH bond activation, 2) migratory insertion, and
3) CÀN bond formation (Scheme 8).[18,31] The Gibbs energy re-
action profile is depicted in Figure 5 and will be discussed as
follows. All the reported energies correspond to Gibbs energies
in methanol in kcalmolÀ1
.
The Ru catalyst cat., amine 1h, and alkyne 2b were taken
separately as zero of the Gibbs energies. The initial interaction
between 1h and cat. through hydrogen bonding forms the
adduct cat.·1h (5.9 kcalmolÀ1). Next, acetate-by-amine substi-
tution leads to 5·OAc (6.9 kcalmolÀ1), which keeps the formally
coordinated acetate species at the surroundings of the amine
moiety.
Scheme 6. Ru-catalyzed synthesis of pyridines 3ga–3gf’.
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Figure 5. Gibbs-energy profile for the Ru-catalyzed coupling of amine 1h with alkyne 2b. DGMeOH is given in kcalmolÀ1
.
Figure 6. Acetate-assisted CÀH bond activation transition states TS5i (IS,
left) and TS5o (OS, right). DGMeOH is given in kcalmolÀ1 and distances in ꢄ.
only 2.3 kcalmolÀ1 (Figure 5); therefore, the dominant reaction
mechanism cannot be discriminated unambiguously.
Scheme 8. General mechanism for the Ru-catalyzed oxidative coupling of
primary amines 1 with internal alkynes 2.
1) CÀH bond activation
2) Migratory insertion
Once 5·OAc is formed, the CÀH bond activation[32] takes place
regioselectively at the ortho carbon atom of the phenyl ring of
amine 1h. It is well known that the acetate ion can assist CÀH
bond activation reactions,[33] in which both innersphere (IS)[34,35]
and outersphere (OS)[36] mechanisms have been reported.
Herein, both pathways were computationally considered by
starting from 5·OAc. For the IS mechanism, TS5i (Figure 6
left)[37] shows the migration of the hydrogen atom from the
phenyl ring to one oxygen atom of the coordinated acetate.
TS5i is located at 26.9 kcalmolÀ1 above the reactants and
gives rise to 6·OAc. Further exchange of the resulting acetic
acid by the acetate species yields intermediate 7 at 3.8 kcal
Alkyne 2b can then coordinate to the Ru center through an
acetate-ligand exchange in 7, thus forming the Ru–alkyne in-
termediate 8 (20.4 kcalmolÀ1). The alkyne ligand in 8 under-
goes migratory insertion into the RuÀC bond via TS8 at
31.4 kcalmolÀ1 (Figure 7, left). However, when coordinating the
former acetate ion to the NH2 fragment, the new transition
state TS8·OAc is found (Figure 7, right). TS8·OAc is placed at
28.2 kcalmolÀ1, which is 3.2 kcalmolÀ1 less than TS8. Notewor-
thy, the acetate species does not play an active role during the
insertion step; the stabilization merely comes from additional
[Ru]···OAc interactions in TS8·OAc (Figure 7, right) that are not
present in TS8. The insertion process finally yields intermediate
9 (5.3 kcalmolÀ1), which coordinates to the phenyl moiety to
stabilize the freshly formed vacant site. The corresponding ace-
tate adduct 9·OAc is found at 1.8 kcalmolÀ1. Whether the va-
cancy is or is not stabilized by intramolecular interactions,
molÀ1 [38]
For the OS mechanism, TS5o (Figure 6 right) displays
.
the hydrogen abstraction by a non-coordinated acetate ion.
TS5o involves 24.6 kcalmolÀ1 and finally ends as intermediate
7. The OS mechanism is favored over the IS mechanism by
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16.8 kcalmolÀ1 (i.e., 25.1 kcalmolÀ1 above 9’·OAc) to yield 11
(À2.4 kcalmolÀ1). When considering one explicit acetate
moiety in TS9, the resulting transition state TS9·OAc is found
at 20.5 kcalmolÀ1 (i.e., 28.8 kcalmolÀ1 above 9’·OAc).[40] Finally,
the species 1hbH can be released from intermediate 11. Fur-
ther steps shall produce the final product 1hb and regenerate
the catalyst.
Overall, a plausible reaction mechanism has been proposed
by computational means. According to DFT calculations, no
unique rate-determining transition state could be found for
the Ru-catalyzed coupling of benzylamine (1h) with 2-butyne
(2b). The Gibbs energy barriers for the CÀH bond activation
(TS5I and TS5o) are 25–27 kcalmolÀ1, whereas the barriers for
the migratory insertion (TS8·OAc) and de-coordination of the
nitrogen atom (TS9·OAc above 9’·OAc) are in the range of 28–
30 kcalmolÀ1, which is in agreement with the experimental
conditions (i.e., T=1008C).
As concerns other nitrogen-containing substrates, the reac-
tion profile for the 1-naphthylmethyl derivative 1a also shows
a Gibbs energy barrier of approximately 28 kcalmolÀ1 (see Fig-
ure S4 in the Supporting Information). In the case of 2-methyl-
allylamine (1g), the CÀH bond activation through the OS
mechanism is favored with respect to the IS mechanism, and
the most demanding step corresponds to the migratory inser-
tion at approximately 28 kcalmolÀ1 (see Figure S5 in the Sup-
porting Information). Lastly, the migratory insertion for the re-
action profile for 2-thiophenemethylamine (1i) appears again
to be the most demanding step at approximately 30 kcalmolÀ1
(see Figure S6 in the Supporting Information). These results
agree with previous studies that suggest that the insertion
process is the most demanding process.[15]
Figure 7. Migratory-insertion transition states TS8 (left) and TS8·OAc (right).
DGMeOH is given in kcalmolÀ1 and distances in ꢄ.
a less favorable conformer 9’ (10.0 kcalmolÀ1) is found. Because
this vacant coordination site is solvent exposed, 9’ can eventu-
ally be trapped by other species present in solution, for in-
stance, a free acetate ion to form 9’·OAc (À8.3 kcalmolÀ1). Ac-
tually, resting states such as 9’·OAc (and analogues with other
substrates) may indeed facilitate detours that produce lower
yields as experimentally observed (see Figure 4 and Scheme 5).
3) CÀN bond formation
Finally, the CÀN bond formation step should proceed to give
rise to 11. Intermediate 9 can undergo a concerted reductive-
elimination process via TS9c at 32.3 kcalmolÀ1.[39] This transi-
tion state is, however, placed at 40.6 kcalmolÀ1 above 9’·OAc;
therefore, this route is likely blocked. Deprotonation of the
amine group in 9 by the acetate species prior to reductive
elimination is also considered. The resulting neutral species
9NH is found at 21.4 kcalmolÀ1, whereas the transition state
TS9cNH is placed at 41.4 kcalmolÀ1. This process also entails
a high barrier that is 49.7 kcalmolÀ1 above 9’·OAc and can be
ruled out. Consequently, an alternative pathway that starts
from 9 is proposed instead. This pathway involves two steps,
that is, de-coordination of the nitrogen atom and subsequent
intramolecular nucleophilic attack (Figure 5). The amine arm
first de-coordinates from the Ru center via TS9 (Figure 8, left)
at 21.0 kcalmolÀ1 (i.e., 29.3 kcalmolÀ1 above 9’·OAc). The re-
sulting intermediate 10 (14.0 kcalmolÀ1) exhibits a h4-coordina-
tion mode between the Ru center and the organic moiety.
Then, the free amine group in 10 easily attacks the carbon
atom intramolecularly through TS10 (Figure 8, right) at
Conclusion
A large variety of N-heterocycles such as benzo[h]isoquinolines,
8,9-dihydro-benzo[de]quinoline, 5,6,7,8-tetrahydroisoquinolines,
pyrido[3,4g]isoquinolines, pyrido[4,3g]isoquinolines, and 2,3,5-
substituted pyridines can be synthesized by a Ru-catalyzed oxi-
dative coupling of the corresponding unprotected primary
amines with internal alkynes. These syntheses can be accom-
plished in moderate-to-good yields in reaction times as short
as 15 minutes by using microwave irradiation. Stable organo-
metallic complexes, formed in alternative reaction pathways,
were characterized for cases in which low yields were ob-
tained. These species behave as Ru-sequestering agents and
show the complexity of this type of reaction. DFT calculations
support a reaction mechanism through acetate-assisted CÀH
bond activation, migratory-insertion, and CÀN bond formation
steps, which involve energy of approximately 28–30 kcalmolÀ1.
This latter process occurs in a stepwise fashion rather than
a concerted pathway. No unique rate-determining transition
state was found for benzyl- and 2-naphthylmethylamines, al-
though the migratory-insertion step appears to be the most
demanding process for 2-methylallyl- and 2-thiophenemethyla-
mines (28–30 kcalmolÀ1).
Figure 8. CÀN bond formation transition states though the de-coordination
of the nitrogen atom in TS9 (left) and intramolecular nucleophilic attack
TS10 (right). DGMeOH is given in kcalmolÀ1 and distances in ꢄ.
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26.5, 129.3, 134.8, 135.6, 145.8, 157.0 ppm; HRMS (ESI-TOF) m/z:
calcd for C10H17N: 150.1277 [M+H]+; found: 150.1265.
Experimental Section
General methods
NMR experiments in situ and the formation of complex
3g·OM
See the Supporting Information for full details.
In
a
Wilmad low-pressure NMR tube [{RuCl2(h6-cymene)}2]
General procedure for the catalytic synthesis of benzoiso-
quinoline derivatives
(0.05 mmol, 30.6 mg), H2NCH2C(Me)=CH2 (1g; 0.1 mmol, 11 mL), 3-
hexyne (2a; 0.3 mmol, 40 mL), NaOAc (0.1 mmol, 8.3 mg), oxone
(0.1 mmol, 30.7 mg), and KPF6 (0.1 mmol, 20 mg) were suspended
in CD3OD (0.6 mL). The reaction mixture was heated at 1008C and
a clear solution was obtained once this temperature was reached.
The NMR spectra were recorded at regular intervals over 24 h.
After heating for 24 h at 1008C, the only species detected in solu-
{[RuCl2(p-cymene)}2] (61.2 mg, 0.1 mmol), KPF6 (17 mg, 0.1 mmol),
and [Cu(OAc)2] (181 mg, 1 mmol) were added to a solution of the
corresponding amine 1a–f (1 mmol) and alkyne 2a–f (1 mmol) in
MeOH (5 mL; except for amines 1c and 1d, for which the reactions
were carried out in tAmOH). The reaction mixture was heated in
a microwave reactor at 1008C for 15 min or in a Young’s flask for
24 h with conventional heating. The solvent was removed and the
residue was redissolved in CH2Cl2 and purified by flash column
chromatography on neutral alumina with CH2Cl2 then CH2Cl2/
MeOH (95:5) as the eluents. Analytically pure materials were ob-
tained with further purification by column chromatography on
SiO2 with different mixtures of solvents. The characterization of
3ca is shown below (the data for the other compounds are collect-
ed in the Supporting Information).
tion was complex 3g·OM. 1H NMR (500.13 MHz, CD3OD): d=0.95
(s, 3H; RuCCH3), 1.16 (t, 3JHH =7.5 Hz, 3H; CH2CH3), 1.32 (d, JHH
7.2 Hz, 3H; CH(CH3)2), 1.33 (d, JHH =7.2 Hz, 3H; CH(CH3)2), 1.34 (t,
3JHH =6.9 Hz, 3H; CH2CH3), 1.61 (q, JHH =11.5 Hz, 1H; CH2CH3), 1.65
3
=
3
2
3
3
(d, JHH =7.6 Hz, 1H; RuCCH2), 2.10 (s, 3H; Me, cym), 2.32 (q, JHH
=
7.6 Hz, 1H; CH2CH3), 2.45 (q, 3JHH =7.6 Hz, 1H; CH2CH3), 2.77
(septet, 3JHH =6.7 Hz, 1H; CH(CH3)2), 2.83 (d, 2JHH =11.5 Hz, 1H;
RuCCH2), 2.95 (q, 3JHH =7.5 Hz, 1H; CH2CH3), 3.83 (s, 1H; RuCCH),
3
5.35 (d, JHH =6.0 Hz, 1H; CH cym), 5.70 (m, 2H; CH cym), 5.92 ppm
(d, 3JHH =6.0 Hz, 1H; CH cym); 13C{1H} NMR (125.76 MHz, CD3OD):
d=13.1 (CH2CH3), 14.9 (CH2CH3), 17.6 (CH3 cym), 19.2 (RuCCH3), 20.7
(CH(CH3)2), 22.6 (CH(CH3)2), 23.3 (CH2CH3), 24.3 (CH2CH3), 31.6
(CH(CH3)2), 38.7 (Ru-C), 50.7 (RuCCH2), 68.3 (RuCCH), 82.3, 82.5, 83.3,
86.2 (CH; cym), 95.9, 96.1 (C=C), 97.7, 112.2 ppm (Cquat, cym); MS
(ESI+) m/z (%): 389 (100) [M+H]+; HRMS (ESI-TOF) m/z: calcd for
C20H33NRu: 389.1656 [M+H]+; found: 389.1649.
2,3-Diethyl-8,9-dihydro-7H-benzo[de]quinoline (3ca): Yellow oil.
Yield on conventional heating: 60 mg (27%); yield on microwave
1
heating: 120 mg (53%). H NMR (400.13 MHz, CDCl3, 258C): d=1.31
3
3
(t, JHH =7.6 Hz, 3H; CH2CH3) 1.36 (t, JHH =7.6 Hz, 3H; CH2CH3), 2.18
(m, 2H; CH2), 2.99 (q, 3JHH =7.6 Hz, 2H; CH2CH3), 3.05 (q, JHH
7.6 Hz, 2H; CH2CH3), 3.12 (t, JHH =6.2 Hz, 2H; CH2), 3.24 (t, JHH
=
=
3
3
3
6.4 Hz, 2H; CH2), 7.27 (m, 1H; C6H3), 7.58 (m, 1H; C6H3), 7.80 ppm
(m, 1H; C6H3); 13C{1H} NMR (100.61 MHz, CDCl3, 258C): d=15.0,
15.2, 20.9, 23.4, 28.5, 34.4, 30.8, 120.7, 123.8, 129.6, 135.4, 139.1,
144.5, 152.4, 157.4 ppm; HRMS (ESI-TOF) m/z: calcd for C16H20N:
226.1590 [M+H]+; found: 226.1570.
X-ray crystallography
Crystallographic data (excluding structure factors) for the structure
of 3a·OM has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 1033948.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
General procedure for the catalytic synthesis of pyridine de-
rivatives
[{RuCl2(p-cymene)}2] (61.2 mg, 0.1 mmol), KPF6 (17 mg, 0.1 mmol),
and [Cu(OAc)2] (181 mg, 1 mmol) were added to a solution of allyl-
amine 1g (1 mmol) and alkyne 2a–f (1 mmol) in tAmOH (5 mL).
The reaction mixture was heated in a microwave reactor at 1008C
for 15 min or in a Young’s flask for 24 h with conventional heating.
After the reaction time, the solvent was removed and the residue
was redissolved in CH2Cl2 and purified by flash column chromatog-
raphy on neutral alumina with CH2Cl2 then CH2Cl2/MeOH (95:5) as
the eluents. The compounds were further purified by using differ-
ent methods to yield analytically pure products. The method will
be specified for each case: washing, column chromatography on
SiO2 with different mixtures of solvents, and so forth. The charac-
terization of 3ga is shown (data for the other pyridines are collect-
ed in the Supporting Information).
Computational details
All the calculations were performed at the density-functional
theory (DFT) level by using the M06 functional[41] (ultrafine grid[42]
)
as implemented in Gaussian 09.[43] This functional correctly repro-
duces dispersive interactions and performs well for transition-metal
chemistry.[44] The Ru atom was described by means of an effective
core-potential SDD for the inner electrons and its associated
double-z basis set for the outer electrons,[45] complemented with
a set of f-polarization functions.[46] The 6–31G** basis set was used
for the H, C, N, and O atoms.[47] All the intermediates and transition
states were fully optimized in solution (MeOH; e=32.61) by using
the continuum method SMD.[48] The transition states were identi-
fied by having one imaginary frequency in the Hessian matrix. IRC
calculations[49] were used to confirm that the transition state con-
nected the expected reactant and product states. All the reported
2,3-Diethyl-5-methylpyridine (3ga): After flash column chroma-
tography, the resulting solution was evaporated to dryness, and
the oily residue was extracted with Et2O (10 mL). The insoluble red
oil was discarded and the solution in diethyl ether was evaporated
to dryness to afford 3ga as a pale-yellow oil (yield on conventional
heating: 94 mg (63%); yield on microwave heating: 106 mg
energies correspond to Gibbs energies in MeOH in kcalmolÀ1
.
Acknowledgements
1
3
(71%)). H NMR (400.13 MHz, CDCl3, 258C): d=1.14 (t, JHH =7.4 Hz,
3
3H; CH3), 1.19 (t, JHH =7.5 Hz, 3H; CH3), 2.19 (s, 3H; CH3), 2.55 (q,
3JHH =7.4 Hz, 4H; CH2), 2.71 (q, 3JHH =7.4 Hz, 4H; CH2), 7.17 (d,
4JHH =1.4 Hz, 1H; H4), 8.13 ppm (d, 4JHH =1.4 Hz, 1H; H6);
13C{1H} NMR (100.61 MHz, CDCl3, 258C): d=12.7, 13.8, 16.9, 23.9,
Funding by the Ministerio de Economia y Competitividad
(MINECO) (Spain, Projects CTQ2011-22589 and CTQ2011-23336)
and Gobierno de Aragꢁn (Spain, group E97) is gratefully ac-
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knowledged. S.R. thanks Gobierno de Aragꢁn (Spain) for a PhD
grant, M.A.O. acknowledges Spanish MINECO for a PhD grant
(FPU), and P.V. thanks CSIC for a Juan de la Cierva contract.
Keywords: amines
calculations · nitrogen heterocycles · ruthenium
·
CÀH activation
· density functional
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Received: January 26, 2015
Published online on && &&, 0000
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FULL PAPER
Efficiency of ruthenium: The oxidative
coupling of primary amines with inter-
nal alkynes catalyzed by Ru complexes
is presented as a general atom-econom-
ical methodology with a broad scope of
applications in the synthesis of N-het-
erocycles (see figure). DFT calculations
support a reaction mechanism that con-
sists of acetate-assisted CÀH bond acti-
vation, migratory-insertion, and CÀN
bond formation steps.
&
Transition-Metal Catalysis
S. Ruiz, P. Villuendas, M. A. OrtuÇo,
A. Lledꢃs,* E. P. Urriolabeitia*
&& – &&
Ruthenium-Catalyzed Oxidative
Coupling of Primary Amines with
Internal Alkynes through CÀH Bond
Activation: Scope and Mechanistic
Studies
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ÝÝ These are not the final page numbers!