Ruthenium-catalyzed α-(hetero)arylation of saturated cyclic amines: Reaction scope and mechanism

Article abstract of DOI:10.1002/chem.201204438

Transition-metal-catalyzed sp³ C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru₃(CO)₁₂] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru^II-H species. Copyright

Full text of DOI:10.1002/chem.201204438

DOI: 10.1002/chem.201204438
Ruthenium-Catalyzed a-(Hetero)Arylation of Saturated Cyclic Amines:
Reaction Scope and Mechanism
Aldo Peschiulli,[a] Veerle Smout,[a] Thomas E. Storr,[a] Emily A. Mitchell,[a]
Zdeneˇk Eliꢀsˇ,[a] Wouter Herrebout,[b] Didier Berthelot,[c] Lieven Meerpoel,[c] and
Bert U. W. Maes*[a]
Abstract:
Transition-metal-catalyzed
study on the substrate and reagent
scope of this transformation is dis-
closed in this paper. The effect of sub-
stitution on both the piperidine ring
and the arylboronic ester has been in-
vestigated. Smaller (pyrrolidine) and
larger (azepane) saturated ring systems,
as well as benzoannulated derivatives,
were found to be compatible substrates
with the a-arylation protocol. The suc-
cessful use of a variety of heteroaryl-
boronic esters as coupling partners fur-
ther proved the power of this direct
functionalization method. Mechanistic
studies have allowed for a better un-
derstanding of the catalytic cycle of
this remarkable transformation featur-
sp3 C H activation has emerged as a
powerful approach to functionalize sa-
turated cyclic amines. Our group re-
cently disclosed a direct catalytic aryla-
tion reaction of piperidines at the a po-
sition to the nitrogen atom. 1-(Pyridin-
2-yl)piperidine could be smoothly a-
arylated if treated with an arylboronic
ester in the presence of a catalytic
amount of [Ru3(CO)12] and one equiva-
lent of 3-ethyl-3-pentanol. A systematic
À
À
Keywords: C H activation · homo-
geneous catalysis · hydrogen · nitro-
gen heterocycles · ruthenium
ing an unprecedented direct transmeta-
II
À
lation on a Ru H species.
Introduction
The development of transition-metal-catalyzed methods for
À
the direct functionalization of C H bonds has attracted
much attention during the past decade.[1] While the direct
2
À
functionalization of sp C H bonds is an active field of re-
search,[2] the corresponding knowledge on sp C H bonds is
3
Figure 1. Examples of biologically active a-substituted saturated cyclic
amines.
À
still limited and remains one of the current challenges in or-
ganic chemistry.[3] Within the area of sp C H activation, the
3
À
À
transformation of the C H bond in the a position to the ni-
trogen atom of saturated cyclic amines is of particular im-
portance because such heterocyclic motifs can be found in a
number of natural products and marketed drugs
(Figure 1).[4]
forts have focused on the low-temperature organolithium-
mediated a-deprotonation and subsequent functionalization
of N-(tert-butoxycarbonyl)-protected pyrrolidines and, more
recently, N-(tert-butoxycarbonyl)piperidines.[7] Besides pro-
tocols proceeding via an a-anionic species, a-cationic inter-
mediates have also received a great deal of attention.[6] With
some notable exceptions,[8] these oxidative procedures,
based on the formation of an electrophilic iminium ion from
a given cyclic amine, have been mainly employed for the
functionalization of the benzylic position of N-substituted
tetrahydroisoquinolines.[9] Lately, a number of reports de-
scribing the generation of a-amino radical intermediates
and their subsequent reaction with a range of radicophiles
have also been published.[10] These direct a-functionalization
procedures, however, all require a stoichiometric reagent to
A number of methods exist for the direct a-functionaliza-
tion of saturated cyclic amines, which have been reviewed
by Campos[5] and Maes and co-workers.[6] Major research ef-
[a] Dr. A. Peschiulli, V. Smout, Dr. T. E. Storr, Dr. E. A. Mitchell,
ˇ
Z. Eliꢀs, Prof. Dr. B. U. W. Maes
Organic Synthesis, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Fax : (+32)32653233
E-mail: bert.maes@ua.ac.be
[b] Prof. Dr. W. Herrebout
Cryospectroscopy, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
activate the cyclic amine.
Transition-metal-catalyzed sp C H activation represents
3
[c] Dr. D. Berthelot, Dr. L. Meerpoel
Janssen Research & Development
À
an elegant alternative synthetic approach to the direct func-
tionalization of saturated cyclic amines involving stoichio-
metric reagents. Nevertheless, only a limited number of re-
ports where the main focus is on five-membered cyclic sub-
A Division of Janssen Pharmaceutica N.V.
Turnhoutseweg 30, 2340 Beerse (Belgium)
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204438.
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FULL PAPER
strates have appeared in the literature.[11–13] This is remarka-
ble, given the importance of such cyclic amines in medicinal
chemistry. A pioneering study appeared in 2001, in which
Murai and co-workers reported a method for the a-function-
alization of cyclic amines through transition-metal-catalyzed
beneficial. Moreover, the execution of the reaction in an
ꢂopen vialꢃ was identified as a crucial parameter to avoid
catalyst poisoning and to obtain high conversion levels.[20]
As shown in Scheme 1 for the phenylation of 1-(pyridin-2-
yl)piperidine (1a), the reaction proceeds most effectively by
heating 1a with three equivalents of phenylboronic acid ne-
coupling of the sp3 C H bonds adjacent to the nitrogen
À
atom with unfunctionalized alkenes.[12d] The process is cata-
lyzed by [Ru3(CO)12] and the presence of a pyridine direct-
ing group[14] on the nitrogen atom was found to be essential
for the reaction to proceed. A number of alkenes were suc-
cessfully employed to bring about the alkylation of pyrroli-
dine, with a,a’-dialkylated derivatives being obtained as the
major reaction products as a mixture of diastereoisomers.
With ethene as the alkene, the substrate scope of the reac-
tion could also be extended to six- and seven-membered
cyclic amines. However, when we applied the described al-
kylation protocol to other alkenes (for example, 1-hexene)
and less reactive substrates (for example, piperidine and
substituted derivatives thereof), we failed to isolate the an-
ticipated C2-functionalized products in synthetically useful
yields.[15] This is due to the chair conformation of the six-
membered piperidine ring being inherently less reactive
than the five-membered ring counterpart.[16] Only recently,
Scheme 1. Direct a-phenylation of 1-(pyridin-2-yl)piperidine (1a) under
optimized reaction conditions.
opentylglycol ester (2a) in the presence of 6 mol% of
[Ru3(CO)12] and one equivalent of 3-ethylpentan-3-ol at
reflux temperature for 24 h. Under these conditions, we ob-
tained the functionalized products 1b and 1c, readily sepa-
rated by column chromatography, in 76% yield (38% of 1b
and 38% of 1c). A further increase in the amount of boron-
ic ester (4 equiv) and catalyst (8 mol%) favors the forma-
tion of diarylated 1c, which is then obtained as the major
product in 60% yield.[18] A protocol to smoothly and effi-
ciently remove the pyridine directing group, which is gener-
ally considered to be unremovable from a tertiary amine,
was also developed for 1b as a model compound.[18]
With the optimal reaction conditions in hand, we set out
to explore the substrate and reagent scope of our novel cat-
alytic method for the direct C2 arylation of piperidines with
arylboronic esters and we wish to disclose the results of our
study herein. Substitutions in both the piperidine substrate
and the arylboronic reagent were investigated. The applica-
bility of the protocol on structurally related cyclic amines,
involving other ring sizes and benzoannulation, and the use
of heteroarylboronic esters were also examined. In addition,
more evidence supporting the previously reported mechanis-
tic proposal will be disclosed herein.[18]
our group has succeeded in developing novel reaction condi-
3
À
tions that allow the efficient ruthenium-catalyzed sp C H
alkylation of piperidines that is not possible under the origi-
nal conditions of Murai and co-workers.[15]
The first direct arylation reaction of saturated cyclic
amines through transition-metal-catalyzed sp3 C H activa-
À
tion was disclosed by Sames and co-workers in 2006.[13] The
protocol is based upon the direct arylation of aromatic ke-
tones developed by Kakiuchi et al.[17] Pyrrolidines were suc-
cessfully arylated adjacent to the nitrogen atom by using a
À
Ru-catalyzed C H activation process and employing aryl-
boronic esters as the coupling partners. The process is di-
rected by a pyrroline group on the nitrogen atom and medi-
ated by a ketone, which also acts as a solvent. The method-
ology was successfully applied to a small set of 2-substituted
pyrrolidines to produce 2,5-difunctionalized derivatives in
excellent yields as a mixture of diastereomers. One example
of a piperidine substrate also appeared in this work, which
was p-methoxyphenylated, but the anticipated product could
only be isolated in a moderate yield (38%). Similarly, as ob-
served in the direct alkylation reaction, we previously dis-
closed in a communication that the reaction conditions re-
ported by Sames and co-workers[13] for the C2 arylation of
pyrrolidines cannot be directly applied to the six-membered
analogues with the same efficiency and we therefore devel-
oped suitable reaction conditions for these substrates.[18]
Substrate instability (directing-group cleavage) and low con-
version values were observed when using pyrroline as the di-
recting group in the arylation reaction of piperidine deriva-
tives. Hence, pyridine, already known as an effective and
Results and Discussion
Substrate scope: Firstly, the influence of the substitution
pattern in the phenylboronic ester was systematically inves-
tigated and our findings are summarized in Scheme 2. A va-
riety of arylboronic esters with different electronic and
steric features were coupled with 1-(pyridin-2-yl)piperidine
(1a) in the presence of a catalytic amount of [Ru3(CO)12]
(6–8 mol%) and one equivalent of alcohol. Piperidine 1a
was successfully C2 functionalized with arylboronic esters
bearing electron-withdrawing substituents in the meta or
para position. The anticipated mono- and diarylated prod-
ucts, readily separated by column chromatography, were ob-
tained in good total yields (4–9, up to 74%). Notably, halo-
[12d,19]
À
stable directing group in C H activation processes,
was
found to provide optimal results. Although the presence of a
ketone in the reaction mixture was found to be not necessa-
ry, the addition of a tertiary alcohol was discovered to be
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B. U. W. Maes et al.
gens are well tolerated, which allows for further functionali-
zation through Pd-catalyzed cross-coupling reactions. Re-
duced yields were observed in the cases of benzenes substi-
tuted with functionalities with strong electron-withdrawing
properties, such as an ester or a cyano group (10–12, 29–
37%). With electron-rich arylboronic esters, the total yields
of the C2-functionalized piperidine products were particular-
ly satisfying in the case of meta and para substitution (14–
16, 61–89%). Remarkably, aniline derivatives can be used in
the reaction without protecting the amino group. Generally,
lower yields were observed in the case of ortho-substituted
phenylboronic esters. Products 3, 13, 17, and 18, possessing
2-fluoro, 2-methoxy, and 2-methyl substituents, respectively,
were isolated in 37–50% yields. Sterically hindered ortho-
substituted phenylboronic esters are also tolerated, as dem-
onstrated by the synthesis of the a-isopropylphenyl deriva-
tive 19b, but a lower yield (41%) was obtained, in accord-
ance with the results with other 2-substituted derivatives. No
product formation occurred in the case of ortho substitution
with highly electron-withdrawing functional groups, such as
an ester or a trifluoromethyl group.
Importantly, the scope of the reaction is not limited to 1-
(pyridin-2-yl)piperidine (1a) and the protocol could be suc-
cessfully extended to the functionalization of C-substituted
piperidine derivatives (Scheme 3). Phenylation of 2-methyl-
1-(pyridin-2-yl)piperidine yielded product 20b as a mixture
of diastereomers (trans/cis 3:1) in 70% yield. From 2-
phenyl-1-(pyridin-2-yl)piperidine (1b), the 2,6-diphenylated
product 1c could be obtained in 75% yield (trans/cis 5:1).
To our delight, not only alkyl/aryl substituents were tolerat-
ed, but good isolated yields were also obtained for the
direct phenylation of 1-(pyridin-2-yl)piperidines containing
a ketal or ester group in the C4 position (products 21 and
22, respectively). Interestingly, when applied to C3-substitut-
ed piperidines, the reaction was found to be completely re-
gioselective. Derivatives possessing
a
trifluoromethyl,
phenyl, or methoxymethyl substituent in the C3 position all
underwent smooth arylation at the sterically less hindered
a-position, with the resulting 2,5-disubstituted piperidines
(23b–25b) being isolated in 52–63% yield. As is the case
with C2-substituted piperidines, preferential formation of
the trans diastereomer of the reaction product also occurred
with C3 substituted piperidines.
The effect of benzoannulation was also studied. Excellent
product yields resulted from the phenylation of 1-(pyridin-2-
yl)-1,2,3,4-tetrahydroquinoline (to give 26b, 91% yield).
The corresponding tetrahydroisoquinoline derivative was
also tested under optimized conditions and provided unex-
pected results in terms of regioselectivity. GC-MS analysis
of the crude reaction mixture indicated the formation of
high amounts of the 1,3-diphenylated product together with
the two possible monophenylated products (at the C1 and
C3 positions) in an approximately 1:1 ratio. This is surpris-
ing because the C1 position is benzylic and therefore is ex-
pected to be much more reactive than the C3 position. A re-
duction in the amount of boronic ester to 1.5 equivalents did
not suppress the formation of the C3-phenylated regioisom-
Scheme 2. Direct a-arylation of 1-(pyridin-2-yl)piperidine (1a) with a va-
riety of arylboronic esters. For simplicity, only the structures of the mon-
oarylated products are represented. All reactions were performed in du-
plicate on a 0.5 mmol scale in an ꢂopen vialꢃ equipped with a reflux con-
denser and under an argon atmosphere (ref. [20]). Isolation was per-
formed on two combined reactions. [a] [Ru3(CO)12]: 6 mol%; arylboronic
acid neopentylglycol ester: 3.0 equiv. [b] [Ru3(CO)12]: 8 mol%; arylbor-
onic acid neopentylglycol ester: 4.0 equiv. [c] Compound previously re-
ported; see ref. [18].
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Ruthenium-Catalyzed a-(Hetero)Arylation of Saturated Cyclic Amines
FULL PAPER
Scheme 4. Direct a-arylation reaction of 2-(pyrrolidin-1-yl)pyridine
(28a), 1-(pyridin-2-yl)azepane (29a), and its benzoannulated analogues
(32a and 33a). For simplicity, only the structures of the monoarylated
products are represented. All reactions were performed in duplicate on a
0.5 mmol scale in an ꢂopen vialꢃ equipped with a reflux condenser and
under an argon atmosphere (ref. [20]). Isolation was performed on two
combined reactions. [a] [Ru3(CO)12]: 6 mol%; phenylboronic acid neo-
pentylglycol ester: 3.0 equiv. [b] [Ru3(CO)12]: 8 mol%; arylboronic acid
neopentylglycol ester: 4.0 equiv. [c] Compound previously reported; see
ref. [18].
Scheme 3. Direct a-phenylation reaction of substituted piperidine deriva-
tives (1b, 20a–25a) and benzoannulated analogues (26a and 27a). For
simplicity, only the structures of the monophenylated products are repre-
sented. All reactions were performed in duplicate on a 0.5 mmol scale in
an ꢂopen vialꢃ equipped with a reflux condenser and under an argon at-
mosphere (ref. [20]). Isolation was performed on two combined reactions.
[a] [Ru3(CO)12]: 6 mol%; phenylboronic acid neopentylglycol ester:
3.0 equiv. [b] [Ru3(CO)12]: 8 mol%; phenylboronic acid neopentylglycol
ester: 4.0 equiv. [c] Compound previously reported; see ref. [18].
synthetically attractive yields. 2-(Pyrrolidin-1-yl)pyridine
(28a) proved reactive, with the 2,5-diphenyl derivative (28c)
being isolated as the major product of the reaction in 36%
yield (trans/cis 3:1). For 1-(pyridin-2-yl)azepane (29a), the
best conversion values were observed in the presence of an
increased catalyst loading (8 mol%) and the formation of
the difunctionalized product was found to be marginal even
under these forcing conditions. Electronic effects on the ar-
ylboronic ester were found to have little impact on the out-
come of the reaction (29b–31b, 52–62% yield). The use of
benzoannulated analogues of azepane (32a and 33a) was
also successful.
Heteroaryl motifs are regarded as privileged scaffolds in
medicinal chemistry[21] and a general method allowing the
direct C2 heteroarylation of piperidine and related cyclic
amines is therefore of high importance. The use of heteroar-
yl donors has been limitedly explored by Sames and co-
workers in the context of the pyrrolidine ring system, for
which, remarkably, pyridine-derived boronic esters were
found to be suitable reagents despite the basic sp2 nitrogen
atom.[13] No examples of direct C2 functionalization of the
(less reactive) piperidine derivatives with heteroarene
donors have appeared in the literature. We therefore
became interested in evaluating a representative set of het-
eroarylboronic esters under our optimized reaction condi-
tions. As summarized in Scheme 5, both six- and five-mem-
bered heteroarenes were found to be compatible with our
er, which encouraged us to investigate the outcome of the
reaction in the case of substrates already bearing a substitu-
ent in the benzylic position. Taking into account the fact
that 1-substituted 1,2,3,4-tetrahydroisoquinolines can be
readily obtained through iminium ion generation,[6] our pro-
tocol could offer a convenient synthetic route to 3-arylated
1-substituted 1,2,3,4-tetrahydroisoquinolines. Indeed, with 1-
methyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (27a)
as the substrate, the reaction proceeded cleanly and pro-
duced a high yield of the C3-phenylated product (27b, 64%
yield, trans/cis 2:1).
The compatibility of our Ru-catalyzed direct arylation
protocol with smaller (azetidine and pyrrolidine) and larger
(azepane) saturated ring systems was also tested
(Scheme 4). Although only traces of the desired phenylated
product were detected in the case of 2-(azetidin-1-yl)pyri-
dine (uncorrected GC-FID conversion: 5%), both five- and
seven-membered-ring analogues of piperidine could be
transformed into the anticipated functionalized products in
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B. U. W. Maes et al.
studied. Unfortunately, the use of pyridine-derived boronic
esters (2-, 3-, and 4-pyridylboronic acid pinacol esters were
all screened under optimized conditions) proved unsuccess-
ful in our protocol. However, as observed for N-methylpyr-
role, benzoannulation of the pyridine reagents provided
good results. Both quinolin-3-yl- and quinolin-4-ylboronic
acid neopentylglycol esters smoothly coupled with 1a. In
the latter case, an additional halogen atom was present in
the core, which made the reaction even more challenging
(40, 50% yield). Coupling through the arene ring of the qui-
noline system was also possible, as exemplified by the syn-
thesis of 41 (45% yield). Quinolin-6-ylboronic acid neopen-
tylglycol ester reagent was subsequently also selected to test
the scope for heteroarylation with smaller (pyrrolidine) and
larger (azepane) ring analogues of piperidine (to give 42
and 43). Finally, direct heteroarylation of 1a with an aza an-
alogue of quinoline, quinoxalin-6-ylboronic acid pinacol
ester, was investigated and the anticipated product (44) was
isolated in 52% yield. Remarkably, no bis-functionalized
products are observed during the isolation of monoheter-
oarylated products
Reaction mechanism: In our previous communication, a
proposal for the mechanism of the direct a-arylation of
cyclic amines was disclosed (Figure 2).[18] It involves com-
plexation of a Ru0 species to the pyridine and subsequent di-
3
À
rected oxidative addition of an a-sp C H bond next to the
0
II
À
nitrogen atom to the Ru species. The resulting Ru H spe-
cies C undergoes transmetalation with the arylboronic ester
F to yield the Ru Ar species D and dialkoxyborane G. Re-
II
À
Scheme 5. Direct a-heteroarylation reaction of 1-(pyridin-2-yl)piperidine
(1a) and its five- and seven-membered ring analogues (28a and 29a). All
reactions were performed in duplicate on a 0.5 mmol scale in an ꢂopen
vialꢃ equipped with a reflux condenser and under an argon atmosphere
(ref. [20]). Isolation was performed on two combined reactions. [a] The
heteroarylboronic acid pinacol ester was used. [b] The heteroarylboronic
acid neopentylglycol ester was used. [c] Three equivalents of heteroaryl-
boronic acid pinacol ester were used.
ductive elimination finally gives the a-arylated reaction
product E and regenerates the Ru0 species to make the
process catalytic. The dialkoxyborane side product formed
in the catalysis is a poison for the catalyst because it can oxi-
datively add to the Ru0 species (with the formation of H),
thereby removing the catalyst from the catalytic cycle.[22]
The role of the alcohol reagent (3-ethyl-3-pentanol in
Figure 2) is to destroy G with the formation of trialkoxybor-
ane I and hydrogen gas.[23] The use of an ꢂopen vialꢃ for the
reaction is crucial, otherwise H2 cannot escape and will oxi-
datively add to the Ru0 species (to form J), which would
also lead to catalyst poisoning (Figure 2).[24]
The direct reaction of a transition-metal hydride with an
arylboronic ester is not known, so additional experiments
were performed to support the direct transmetalation of C.
Notably, trialkoxyborane 45 could be detected with GC-MS
in the reaction mixture of substrate 1a with pinacolboronic
ester 2b (Scheme 6). Scavenging of the gas formed during
this direct arylation reaction revealed that hydrogen gas is
indeed formed (Raman spectroscopy of H2: 4163.3 (w),
4157.4 (s), 4145.7 (w) and 4128.4 cmÀ1 (w)). Moreover, in an
independent experiment, heating of 4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (46) with 3-ethyl-3-pentanol at 1508C
yielded trialkoxyborane 45 and H2, in accordance with our
À
C H activation protocol and, in general, moderate to good
yields of the desired monofunctionalized reaction products
were obtained. Firstly, five-membered heteroarene donors
were studied. The methodology proved particularly success-
ful for the coupling of regioisomeric 1-methylpyrazolylbor-
onic acid esters (to give 34 and 35, 44 and 63% yield). Dis-
appointingly, very little product formation was observed if
the pinacol ester of N-methylpyrrol-2-ylboronic acid was
employed as the heteroaryl donor (uncorrected GC-FID
conversion: 7%). Replacement of the N-methyl group for
an N-tosyl group resulted in no reaction product being
formed. Interestingly, N-methylindole-2-boronic acid pinacol
ester, the benzoannulated derivative of N-methylpyrrole,
gave a moderate yield of the anticipated C2-substituted pi-
peridine derivative (36, 33% yield). The protocol could be
applied to oxygen- and sulphur-containing heteroarene re-
agents (37 and 38, 65 and 37% yield). Next, the coupling of
six-membered heteroarene reagents with piperidines was
mechanistic proposal (Scheme 7). The occurrence of a
II
À
mechanism involving a protonation reaction of Ru H spe-
II
À
cies C with the alcohol, yielding an Ru OR species (allow-
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Ruthenium-Catalyzed a-(Hetero)Arylation of Saturated Cyclic Amines
FULL PAPER
served by both GC-MS and
11B NMR analysis in the crude
reaction mixture (see the Sup-
porting Information). Bis boryl-
oxide 47 formation from pina-
colborane (46) is well docu-
mented in the literature.[26]
To prove the poisoning effect
of the H2 gas, the arylation re-
action of 1-(pyridin-2-yl)piperi-
dine (1a) was executed in a
pressure-cap-sealed vessel. As
expected, conversion values
into 1b and 1c dropped signifi-
cantly (Scheme 9). In agree-
ment with this, the direct aryla-
tion reaction in a pressure-cap-
sealed vessel under a H2 atmos-
phere (created with a balloon)
gave even lower amounts of the
desired phenylated products
(14% 1b and 1% 1c). GC-MS
analysis also revealed formation
Figure 2. Proposed mechanism for the direct a-arylation of saturated cyclic amines and catalyst poisoning
pathways.
of trialkoxyborane 45 in these reactions (Scheme 9).
II
À
The unprecedented direct transmetalation on Ru H spe-
II
À
cies C, yielding Ru Ar, prompted us to check whether
other Ru-catalyzed direct arylation reactions follow the
original mechanistic proposal[17] or occur through an alterna-
tive pathway, as discovered by us. With this goal in mind, we
tested the Ru-catalyzed a-arylation protocol of aromatic ke-
tones, reported by Kakiuchi et al., for H2 formation
(Scheme 10).[17] Kakiuchi and co-workers proposed a path-
way for this transformation that is based on the insertion of
Scheme 6. Ru-catalyzed direct arylation of 1-(pyridin-2-yl)piperidine (1a)
with phenylboronic acid pinacol ester (2b) in the presence of 3-ethyl-3-
pentanol (in an ꢂopen vialꢃ). Raman spectroscopy shows H2 gas and GC-
MS analysis reveals the formation of 2-(1,1-diethylpropoxy)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (45). [a] GC-FID corrected conversion values
by using 1,3,5-trimethoxybenzene (TMB) as an internal standard.
ing for a classical transmetalation) and H2, could be exclud-
ed on the basis of a reaction of 1a with boronic ester 2b in
the absence of alcohol, because arylated products 1b and 1c
were still formed, albeit in lower amounts (Scheme 8).
Raman spectroscopy indicated that hydrogen gas is also
formed in the absence of the alcohol. In this case, 2,2’-
oxybis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (47) was ob-
Scheme 7. Reaction of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46) with
3-ethyl-3-pentanol. Raman spectroscopy shows H2 gas and GC-MS analy-
sis reveals the formation of 2-(1,1-diethylpropoxy)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (45).
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B. U. W. Maes et al.
Scheme 8. Ru-catalyzed direct arylation of 1-(pyridin-2-yl)piperidine (1a)
with phenylboronic acid pinacol ester (2b) in the absence of alcohol (in
an ꢂopen vialꢃ). Raman spectroscopy shows H2 gas and GC-MS analysis
reveals the formation of 2,2’-oxybis(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane) (47). [a] GC-FID corrected conversion values by using TMB as an
internal standard.
Scheme 10. Ru-catalyzed a-phenylation of acetophenone (48a) under the
reaction conditions reported by Kakiuchi and co-workers. Raman spec-
troscopy shows no H2 gas and GC-MS analysis reveals the formation of
pinacolyl alcohol. [a] Uncorrected GC-FID conversion values.
II
À
pinacolone into the Ru H species (49) to deliver inter-
mediate 50 (Figure 3). Interestingly, H2 formation was not
observed in the phenylation of acetophenone (48a)
(Scheme 10), which supports the suggestion that the mecha-
nism observed indeed occurs through ketone insertion fol-
II
À
lowed by a classical transmetalation to deliver the Ru Ar
species. Next, we tested the direct arylation protocol of pyr-
rolidines developed by Sames and co-workers for H2 forma-
tion.[13] The development of this protocol is based on the
work of Kakiuchi and it was reported to proceed through a
similar reaction mechanism (Figure 4). Unexpectedly, we
found that H2 gas was formed in the phenylation of 2-
Figure 3. Proposed mechanism for the direct sp2 C H arylation of aro-
À
matic ketones developed by Kakiuchi et al.[17]
phenyl-1-(3,4-dihydro-2H-pyrrol-5-yl)pyrrolidine
(52a)
(Scheme 11). Pinacolyl alcohol was also formed, based on
GC-MS analysis of the crude reaction mixture. The alcohol
can be formed directly through ketone insertion into an
nation of the ketone (reagent and solvent) by the hydrogen
gas formed (the reported experiments are performed in
closed vessel).[27] Our experi-
II
À
Ru H species or indirectly through Ru-catalyzed hydroge-
ment therefore supports the
fact that direct arylation, at
least partially, occurs through
direct transmetalation on the
II
À
Ru H species with the aryl-
boronic ester in this literature
protocol. However, a combina-
tion of the two reaction mecha-
nisms cannot be excluded be-
cause ketone insertion also gen-
erates alcohol. Importantly, our
Raman measurements point to
Scheme 9. Ru-catalyzed direct arylation of 1-(pyridin-2-yl)piperidine (1a) with phenylboronic acid pinacol
ester (2b) in an ꢂopen vesselꢃ (ref. [20]), in a closed vessel, and in a closed vessel under a H2 atmosphere. GC-
MS analysis reveals the formation of 2-(1,1-diethylpropoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45).
[a] GC-FID corrected conversion values by using TMB as an internal standard.
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Chem. Eur. J. 2013, 19, 10378 – 10387

Ruthenium-Catalyzed a-(Hetero)Arylation of Saturated Cyclic Amines
FULL PAPER
Scheme 12. Intramolecular KIE experiment: The heteroarylation reaction
of 2,2-dideutero-1-(pyridin-2-yl)piperidine ([D2]-1a).
tion reaction also hampers interpretation of the result. Re-
markably, this experiment revealed no KIE, which indicates
À
that the C H bond activation step is actually a facile process
Figure 4. Proposed mechanism for the direct sp3 C H arylation of pyrro-
À
lidines developed by Sames and co-workers.[13]
in our substrates (Scheme 12). This is in accordance with the
phenylation of 1-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquino-
line, in which no selectivity between the benzylic C1 posi-
tion and the ꢂunactivatedꢃ C3 position was observed and
with hydrogen–deuterium exchange experiments with
[Ru3CO12] in [D8]-2-propanol reported by Murai and co-
workers on 1-(pyridin-2-yl)pyrrolidine.[12d] To support the
À
feasibility of a C H oxidative addition step, as proposed in
our catalytic cycle (Figure 2), stoichiometric quantities of
both [Ru3CO12] and 1-(pyridin-2-yl)piperidine (1a) were
combined in mesitylene and heated at 1508C for 20 min
under an argon atmosphere. The resulting crude mixture
1
was subsequently analyzed by H NMR spectroscopy, which
revealed the presence of a ruthenium hydride species (d=
À17.8 ppm).[29,30] The absence of a KIE and the stoichiomet-
À
ric oxidative addition experiment support C H activation
through oxidative addition and a rate-limiting transmetala-
tion step in the developed direct arylation reaction.
Conclusion
In conclusion, we have fully explored the scope of our previ-
ously disclosed direct arylation method for the C2 (hetero)-
arylation of 1-(pyridin-2-yl)piperidine and C2-, C3-, and C4-
substituted derivatives. The process also allows the function-
alization of other structurally related saturated cyclic amines
(pyrrolidines, azepanes, and benzoannulated derivatives).
The direct arylation involves the use of a catalytic amount
of [Ru3(CO)12], a (hetero)arylboronic acid ester as a (heter-
o)arene donor, and a tertiary alcohol as a dialkoxyborane
scavenger. The development of this new (hetero)arylation
method stems from a better understanding of the transmeta-
lation step of the catalytic cycle. Removal of the dialkoxy-
borane formed during this process is critical because other-
wise the catalyst would be poisoned. In the presence of the
tertiary alcohol, the dialkoxyborane is transformed into a
trialkoxyborane and hydrogen gas, the latter necessitating
an ꢂopen vialꢃ to avoid oxidative addition of hydrogen,
which would poison the catalyst. Our results indicate that
Scheme 11. Phenylation of 2-phenylpyrrolidine 52a under the reaction
conditions reported by Sames and co-workers. Raman spectroscopy
shows H2 gas and GC-MS analysis reveals the formation of pinacolyl al-
cohol. [a] Uncorrected GC-FID conversion values.
distinct reaction mechanisms for Ru-catalyzed direct aryla-
2
3
À
À
tion of sp C H versus sp C H bonds.
3
À
The cleavage of an sp C H bond is generally more diffi-
cult than that of an sp C H bond, so we decided to perform
an intramolecular primary kinetic isotope effect (KIE) ex-
periment on 2,2-dideutero-1-(pyridin-2-yl)piperidine ([D2]-
1a) because this gives information on the kinetic relevance
2
À
À
of the C H bond activation process in our direct arylation
reaction (Scheme 12).[28] For this experiment, the optimal re-
action conditions in the absence of alcohol were used, in
order to avoid a possible undesired background deuterium–
hydrogen exchange. We also selected a boronic ester that
does not give 2,6-difunctionalization because a second aryla-
direct Ru-catalyzed arylation of sp3 C H bonds occurs
À
through a distinct reaction mechanism to that of the corre-
2
3
À
sponding sp C H bond arylation process. Moreover, the sp
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10385

B. U. W. Maes et al.
À
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C H bond activation step is remarkably facile. Such insights
are crucial to further develop the field of direct sp3 C H
À
bond functionalizations.
Experimental Section
C2 (Hetero)arylation of N-(pyridin-2-yl)piperidines and analogues: Gen-
eral procedure: Two 10 mL vials were each charged with the appropriate
N-(pyridin-2-yl) cyclic amine (0.5 mmol) and (hetero)arylboronic ester
(3.0–4.0 equiv), [Ru3(CO)12] (6–8 mol%), and 3-ethyl-3-pentanol
(0.5 mmol, 1 equiv). The vials were flushed with argon and equipped with
a condenser fitted with a rubber septum and an argon-filled balloon. The
reaction mixtures were then heated to reflux, with the temperature of the
oil bath being set at 1538C, under an argon atmosphere and with magnet-
ic stirring for 24 h. After this time, the reaction mixtures were cooled
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down and combined into
a 250 mL round-bottomed flask by using
CH2Cl2. A commercially available ruthenium scavenger (2 g; Siliabond
DMT, Silicycle) and CH2Cl2 (100 mL) were added to the residue. The re-
sulting suspension was stirred at room temperature for 16 h (overnight).
Subsequently, the solids were removed by filtration through celite, the
pad was washed with CH2Cl2 (5ꢄ20 mL), and the combined filtrate was
evaporated to dryness. The residue was purified by flash chromatography
to obtain the desired (hetero)arylated product(s).
Acknowledgements
This work was financially supported by the University of Antwerp
(BOF), the Hercules Foundation and Janssen Research & Development
(A Division of Janssen Pharmaceutica N.V.). The authors would like to
thank Dr. Hana Prokopcovꢀ, Dr. Stefan Verbeeck, Audrey Velleine, and
Dr. Artem Kulago for their contribution to this work.
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Ruthenium-Catalyzed a-(Hetero)Arylation of Saturated Cyclic Amines
FULL PAPER
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[29] Experimental details and the NMR spectrum for this experiment
can be found in the Supporting Information.
À
[30] An alternative for the cleavage of the C H bond is iminium forma-
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À
À
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Received: December 12, 2012
Revised: April 11, 2013
Published online: June 18, 2013
Chem. Eur. J. 2013, 19, 10378 – 10387
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www.chemeurj.org
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