A comparative mechanistic study of Cu-catalyzed oxidative coupling reactions with N-phenyltetrahydroisoquinoline

Article abstract of DOI:10.1021/ja211697s

A comparative mechanistic study of Cu-catalyzed oxidative coupling reactions of N-phenyltetrahydroisoquinoline with different nucleophiles was conducted. Two previously reported combinations of catalyst and oxidant were studied, CuCl₂2H₂

Full text of DOI:10.1021/ja211697s

Article
pubs.acs.org/JACS
A Comparative Mechanistic Study of Cu-Catalyzed Oxidative
Coupling Reactions with N-Phenyltetrahydroisoquinoline
Esther Boess, Corinna Schmitz, and Martin Klussmann*
Max-Planck-Institut fuer Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Muelheim an der Ruhr, Germany
S
* Supporting Information
ABSTRACT: A comparative mechanistic study of Cu-catalyzed
oxidative coupling reactions of N-phenyltetrahydroisoquinoline
with different nucleophiles was conducted. Two previously
reported combinations of catalyst and oxidant were studied,
CuCl2·2H2O/O2 and CuBr/tert-butyl hydroperoxide (TBHP).
On the basis of a synthetic study with different nucleophiles, the
electrophilicity of the intermediate iminium ion was estimated
and differences between the two methods were revealed. The key
intermediate in the aerobic method is shown to be an iminium
ion, formed through oxidation by copper(II), which can react with any nucleophile of sufficient reactivity. The role of oxygen is
the reoxidation of the reduced catalyst. In the CuBr/TBHP system, an α-amino peroxide is proposed as a true intermediate
within the catalytic cycle, formed from the amine and TBHP by a Cu-catalyzed radical reaction pathway and acting as a precursor
to the iminium ion intermediate.
pioneering studies of Murahashi and Li.4 Various nucleophiles
INTRODUCTION
The activation of carbon−hydrogen (C−H) bonds for coupling
■
have been employed, including cyanides,4e,5 nitroalkanes,5k,6
activated methylene compounds,5f,6b,d,g,7 ketones,8 electron-rich
reactions is an important area in research on sustainable
arenes,4g,9 alkynes,4f,10 organometallic11 or siloxy compounds,12
chemistry. C−H bonds are ubiquitous in organic molecules,
and their functionalization enables the direct synthesis of
and heteroatom nucleophiles.4c,d,6g,13 The oxidation protocols
involve predominantly metal catalysts together with oxygen or
synthetic oxidants, but organocatalytic,8c photochemica-
l,5a,6f,g,13e electrochemical,5b,14 and noncatalytic method-
s5d,e,j,9e,12d are also known. Even a nonoxidative method that
releases hydrogen has been reported.15 Many methods reported
in the literature focus on one particular type of catalyst, oxidant,
or nucleophile, while there are only a few reports of a truly
diverse scope of nucleophiles.16 The most notable exception is
the combination of CuBr as catalyst and tert-butyl hydro-
peroxide (TBHP) in decane as oxidant, introduced by the C.-J.
Li group, which has been used for a large number of
nucleophiles.4f,g,5f,6a,9b,10a,11,12h,13a
complex products from simple starting materials, without prior
introduction of activating groups. Under oxidative conditions,
two C−H or heteroatom−H bonds can be coupled directly to
form a new bond (Scheme 1a).1 Oxidative coupling reactions
Scheme 1. (a) Oxidative Coupling for the Functionalization
of C−H Bonds. (b) Oxidative Coupling of N-
Phenyltetrahydroisoquinoline 1 with Nucleophiles via
Proposed Iminium Ion 2
The generally proposed rationale for oxidative coupling
reactions with tertiary amines and 1 in particular is the
formation of an intermediate iminium species 2, which reacts
with nucleophiles to product 3 (Scheme 1b). Given the large
number of catalysts, oxidants, and nucleophiles reported for this
reaction, the question remains whether all methods are in
principle interchangeable, i.e., whether each oxidation mode can
be combined with each nucleophile. If so, one could choose the
most suitable method based on practicability, cost, and
sustainability and combine it with the desired nucleophile. In
general, detailed mechanistic studies in this area are lacking.
Studies which highlight the similarities and differences between
can meet the criteria of green chemistry:2 using a catalyst and
low molecular weight oxidants such as elemental oxygen, they
are atom economic and produce at best only water as the
byproduct.
Among these reactions, the oxidative coupling of amines, in
particular N-phenyltetrahydroisoquinoline (1), with nucleo-
philes has received alot of attention (Scheme 1b).3 A large
number of different methods has been developed since the
Received: December 15, 2011
Published: February 16, 2012
© 2012 American Chemical Society
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individual methods may prove particularly useful. In some
cases, potential intermediates have been investigated or radical
mechanisms have been probed by the addition of inhibitors, but
no comprehensive mechanistic picture has been gain-
ed.4f,g,10e,12b,i,14 The proposed iminium ion 2 has been observed
for the first time by Todd and co-workers, isolated from a
catalyst-free reaction using DDQ as the oxidant.17
Here, we present a mechanistic study of oxidative coupling
reactions according to Scheme 1b, investigating the generality
of nucleophiles and the role of the oxidant. Two methods will
be compared: the CuCl2·2H2O/O2 system developed in our
own group12c and the CuBr/TBHP system developed by Li et
al.4f
reduction to 1.5 equiv is also possible, giving a nearly
unchanged yield of 89% after 24 h (entry 5).
A cyanide group can be introduced in good yields by using
either TMS-CN or sodium cyanide (entries 6 and 7). In the
latter case, the use of acetic acid as cosolvent was beneficial, as
was observed previously by Murahashi in Ru-catalyzed
reactions.4e In the absence of acetic acid, only traces of the
product 3c were visible after a reaction time of three weeks. N-
Methylpyrrole 6d and indoles 6e and 6f gave medium to good
yields of the expected products 3d−f (entries 8−10). The
relatively low yield of 41% for the coupling product 3d is
probably due to the formation of a mixture of regioisomers or
double addition products, as had been observed previously
using an Fe catalyst.9d
Isocyanides 6g−i are good nucleophiles,19f yet they have not
been utilized in oxidative coupling reactions with amines
previously. We tested three different ones with N values from
5.47 to 4.90 and found that the corresponding amide products
3g−i could be formed with 58−76% yield in DMF as solvent
(entries 12−14), making this an interesting alternative to form
amino acid derivatives. Methanol was not a suitable solvent,
giving very low yields. In acetone as solvent, medium yields
were achieved, but the desired product was accompanied by up
to 20% of the coupling product with acetone. In all cases, full
conversion was not achieved; the reactions were arbitrarily
stopped after several days. Potentially, the isocyanides suppress
catalytic activity by strong coordination to copper. Better yields
could be achieved at higher catalyst loadings: with 10 mol %,
only 39% of product 3g was formed after one week, while with
20 mol %, 76% could be isolated after four days (entries 11 and
12).
RESULTS AND DISCUSSION
■
We have previously reported the observation and character-
ization of the intermediates 2a, 4, and 5 in oxidative coupling
reactions of 1 with silyl enolates using the CuCl2·2H2O/O2
system.12g X-ray structural analysis revealed iminium 2a to be
an ionic compound with a dichlorocuprate(I) counterion
(Figure 1), in contrast to the common suggestion of a π-bound
Figure 1. Characterized intermediates in the oxidative coupling with 1
using CuCl2·2H2O as catalyst and O2 as oxidant.
metal−iminium species.1a,4e,g Compounds 4 and 5 were shown
to be off-cycle intermediates formed reversibly from 2a in the
presence of methanol and water, respectively. The formation of
4 was suggested to provide a stabilizing reservoir for 2a, making
methanol the solvent of choice if weak nucleophiles are used.
The use of CuBr under otherwise identical conditions resulted
in the formation of an iminium ion 2b with a (Cu2Br4)2‑
counterion.
In further mechanistic studies and to address the above
questions, we screened selected nucleophiles 6 from different
substrate classes to test the generality of the aerobic copper-
catalyzed reaction (Table 1). In order to estimate the
electrophilicity of 2a, we used predominantly compounds
with reported nucleophilicity values. We refer to the reactivity
scales developed by the Mayr group for nucleophiles and
electrophiles.18,19 The products were isolated after complete
conversion of amine 1 as indicated by thin layer chromatog-
raphy, unless noted otherwise.
The coupling product 3a with nitromethane (6a) was
received in good yield if the nucleophile was used as the
reaction solvent (Table 1, entry 1), as had been observed
previously in reactions using other oxidation protocols.6
Dimethyl malonate 6b also reacted well, and the coupling
product 3b was isolated in 94% yield after 13 h (entry 2). With
3b as a representative example, we also attempted to optimize
the reaction with respect to more sustainable conditions. Air
instead of pure oxygen was a nearly equally effective oxidant,
resulting in 82% yield after 28 h (entry 3). Reducing the
catalyst loading to 2 mol % was possible, leading to slightly
prolonged reaction times but still giving a good yield of 82%
(entry 4). Instead of 3.0 equiv of nucleophile, which was
originally chosen to provide fast reaction rates and high yields, a
Phenylacetylene 6j reacted fast under standard conditions,
giving product 3j in 89% yield after stirring overnight (entry
15). The low nucleophilicity value of 0.34 for 6j cannot be used
for the discussion, because the acetylene will be activated as a
more reactive acetylide by the copper catalyst.4f,10a−d
A selection of other nucleophiles that have previously been
employed12c,g in coupling reactions with 1 under the same
reaction conditions as in Table 1 are shown in Scheme 2, with
an emphasis on the nucleophilicity range. Most of these
nucleophiles fall within the nucleophilicity range of the
substrates used in Table 1. Methylallylsilane 10 and enolate
11 are the least nucleophilic reagents we found that are still
reactive enough to form the coupling products (N = 4.41 and
3.78).19d In order to determine the reactivity threshold, we also
looked at weak nucleophiles that failed to react (Figure 2).
We found that no reaction took place in the presence of 1,3-
dimethoxybenzene 13 (N = 2.48),19d allylsilane 14 (N =
1.79),19d p-cresol 15, or 2-naphthol 1621 (no N value reported,
for comparison: N(phenol) = 1.9).20 In the reaction with 2-
methylfuran 12 (N = 3.61),19d analysis by TLC indicated the
formation of a new product over three days, which could,
however, not be isolated. These results indicate that the
nucleophilicity threshold necessary for a reasonable rate lies
approximately at 3.8, corresponding to enolate 11.
On the basis of Mayr’s rule of thumb “that electrophiles can
be expected to react with nucleophiles at room temperature
when E + N > −5”,19g one can estimate the electrophilicity E of
2a to be around −8 and −9. Because the concentration of 2a
during the reaction is always low, the true value of E(2a) could
actually be higher.22 This correlates relatively well with the
electrophilicity parameters determined by Mayr et al. for
comparable iminium ions, which lie between −5 and −10.19g,h
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a
Table 1. Oxidative Coupling of N-Phenyltetrahydroisoquinoline with Various Nucleophiles
a
b
c
General conditions: 0.36 mmol of 1, 1.5 mL of MeOH, 1.08 mmol of 6, 0.036 mmol of CuCl2·2H2O, O2. Nucleophilicity parameter N. Isolated
d
e
f
g
h
i
yield. Nitromethane as solvent. Nucleophilicity parameter N of the corresponding anion. Air as oxidant. 2 mol % catalyst. 1.5 equiv of 6b. N of
the diethyl malonate anion. 1.5 mL of MeOH:AcOH 4:1 as solvent. DMF as solvent. DMF as solvent, 20 mol % catalyst.
j
k
l
Scheme 2. Literature-Reported Successful Nucleophiles in
the Aerobic Cu-Catalyzed Oxidative Coupling of 112c,g (in
While this is just an estimate based on a synthetic study which
does not aim to deliver a precise electrophilicity parameter, it
still provides a correlation that can serve in future studies with
other nucleophiles. It also supports the notion that the key step
of the reaction is the oxidative formation of an iminium ion that
reacts with any nucleophile of sufficient reactivity without
significant involvement of the catalyst.
brackets: nucleophilicity parameter N19d,g
)
In order to gain further information on the occurrence of
intermediates 2a, 4, and 5 depending on the nucleophiles used,
we monitored the reaction of 1 with a diverse set of substrates
over a wide range of nucleophilicity N. We investigated the
coupling with nitromethane (6a, N = 20.71), dimethyl
malonate (6b, N(diethyl malonate) = 20.22), and indole (6f,
N = 5.55) by taking samples for NMR analysis over the course
of the reaction (Scheme 3).
Under these conditions, hemiaminal 5 was not observed or
only in very low amounts. The products 3 were formed with
different rates, which do not clearly follow their nucleophilicity
values. This is, however, not surprising, because the reaction
conditions in the kinetic studies by Mayr et al. often involve
preformed electrophile and nucleophile salts with chemically
inert counterions, whereas in our study, both the formation of
the iminium ion 2a and the reaction with the nucleophile might
Figure 2. Nucleophiles unreactive under the conditions of Table 1; in
brackets: corresponding nucleophilicity parameters N.19d,20
.
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Accordingly, copper(II) is oxidizing the amine, being reduced
to copper(I) in turn, and oxygen as the terminal oxidant is only
involved in the reoxidation of copper.23 The oxidation of 1
most likely involves single-electron transfer (SET) to Cu(II),
forming an ammoniumyl radical cation 17. Hydrogen transfer
or a combination of electron and proton transfer then forms the
iminium salt 2a (Scheme 4a).
Scheme 3. (a) Monitoring the Formation of Products 3
(squares, solid line) and Intermediate 4 (triangles, dashed
line) in the CuCl2·2H2O/O2 System with Nucleophiles 6a
a
(red), 6b (blue), and 6f (green). (b) Monitoring the
Presence of Iminium Ion 2a (open circles) in the Same Set
b
of Reactions
Scheme 4. (a) Potential Mechanism of Oxidation of 1 to 2a.
(b) Kinetic Isotope Effect Experiment with Monodeuterated
1-d1
Further information on this part of the reaction was gained
from a kinetic isotope effect (KIE) experiment (Scheme 4b).
The monodeuterated amine 1-d1 was employed in the oxidative
coupling reaction with dimethyl malonate 6b, forming a
mixture of 3b and 1-deuterated 3b. After full conversion of
the amine, a primary KIE value kH/kD of 4.5 was calculated
from the ratio of the signal intensity in the 1-position relative to
reference signals. This is in accordance with a fast SET
preceding rate-determining C−H bond cleavage (see the
Supporting Information for full details).24
a
Reaction conditions: 0.36 mmol of 1, 3.0 equiv of 6, 5 mol % catalyst,
1.5 mL of MeOH, O2.
b
A catalytic cycle that summarizes all our results is given in
Scheme 5. Amine 1 is oxidized by two molecules of the
For a full display over 24 h, see the Supporting Information.
be subject to some interactions between catalyst and substrates.
More importantly, the N values for 6a and 6b have been
determined for the corresponding anions while the current
reactions conditions (in the presence of amines 1 and 3) are
not basic enough to provide complete deprotonation of these
nucleophiles.
Scheme 5. Mechanism of the Cu-Catalyzed Aerobic
Oxidative Coupling
The methoxy amine 4 was visible in all reactions during the
initial stages and eventually vanished at full conversion to
products 3. It also shows a clear correlation to the rate of
product formation: with 6b as the fastest reacting nucleophile,
the product 3b is formed in a much larger amount than 4; with
a nucleophile of medium reactivity (6f), both 3f and 4 are
formed in comparable amounts, and in the slowest reaction
using 6a, 4 clearly dominates. The iminium ion 2a was also
visible and showed an approximately stationary concentration,
especially in the reactions with 6a and 6b (Scheme 3b).
These trends further support a competition between
methanol and the nucleophiles 6 for the iminium ion 2a.
With reactive nucleophiles, 2a is quickly trapped to give the
product 3 and only small amounts of 4 are formed. With less
reactive nucleophiles, 4 builds up in larger amounts. However,
because of reversible formation, it is ultimately converted to the
more stable products 3. The same trends were observed
previously with enolate 8 and allyl silane 10.12g
copper(II) catalyst to give CuICl and the iminium dichlor-
ocuprate 2a. In methanol as a solvent or in the presence of
water, off-cycle equilibria form the hemiaminal ether 4 or
hemiaminal 5, providing a reservoir of 2a that can have a
stabilizing effect.12g,25 Any sufficiently reactive nucleophile can
trap the iminium ion, giving the desired products and releasing
CuCl and HCl. The latter could be buffered by the amines
present. Reaction of CuCl and HCl with oxygen produces
water and regenerates the active catalyst CuCl2.
It is likely that other reported aerobic methods for the
oxidative coupling with 1 proceed by very similar mechanisms.
For example, aerobic coupling reactions using CuBr as catalyst
will proceed analogously via iminium salt 2b. However, a
comparison with the widely applied method by Li using TBHP
The role of the oxidant was probed by reacting amine 1 with
CuCl2·2H2O in methanol in the absence of oxygen. Iminium
ion 2a was formed immediately, visible to the naked eye by an
orange solution and the precipitation of 2a as yellow crystals.
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as oxidant indicated differences that prompted us to further
investigate and compare both methods using the same tools as
described above.
Li et al. reported the successful coupling of 2-naphthol (18)
with 1 using their CuBr/TBHP system at 50 °C, giving the
cross-coupling product 19 next to significant amounts of
binaphthol 20 (Scheme 6a).4g In contrast, the same reaction
Scheme 8. Monitoring the Formation of Products 3
(squares, solid line) and Intermediate 21 (triangles, dashed
line) in the CuBr/TBHP System with Nucleophiles 6a (red),
a
6b (blue), and 6f (green)
Scheme 6. 2-Naphthol as a Nucleophile in the Oxidative
Coupling with 1
did not occur under the conditions of the CuCl2·2H2O/O2
system, even if it was performed at 50 °C, in different solvents
or with prolonged reaction times (Scheme 6b). As mentioned
above, this was rationalized by the low nucleophilicity of 2-
naphthol.20
We next investigated the occurrence of potential inter-
mediates in the CuBr/TBHP system. Analogous to our
previous studies,12g we reacted amine 1 with 50 mol % of
catalyst in the presence of oxidant (TBHP) but in the absence
of any nucleophile. NMR analysis of the resulting mixture did
not show any signals corresponding to the iminium ion 2a that
was observed under aerobic conditions using either CuBr or
CuCl2 dihydrate. The only new species identifiable was the
amino peroxide 21 (Scheme 7). A tert-butyl hemiaminal ether
analogous to 4 was not observed.
a
See the Supporting Information for further details.
products; amine 1 was simply converted to peroxide 19 instead.
Potentially, the isocyanides deactivate the catalyst, as they were
also suppressing the reaction rate in the CuCl2·2H2O/O2
system. We also found that the use of TMS-CN as a
nucleophile resulted in the inhibition of the reaction, not
even forming any 21. This is possibly due to a reaction of TMS-
CN with TBHP, silylating and deactivating the oxidant.
However, the exact reasons for the failure of these nucleophiles
are at present unknown. Insufficient nucleophilicity is unlikely
to be the cause: the N values of the failing nucleophiles 6c, 6g,
and 8 (16.27 (anion), 5.47, 5.41) are very close to the N value
of indole 6f (5.55), which converts to product 3f,9b as reported.
No iminium ion 2 could be observed during the reaction, and
the only other amine species identifiable next to products and
starting material was the peroxide 19, which was consumed
toward the end of the reaction. In contrast to the hemiaminal
intermediate 4 formed in the CuCl2·2H2O/O2 system, the
amount of peroxide 21 surpasses that of product 3 in the initial
stages of the reaction, being formed in 20−70% yield during the
first 30 min. Although the amount of 21 varies somewhat
depending on the nucleophile used, it can be clearly correlated
neither to their nucleophilicities nor to the rate of product
formation, as was the case in Scheme 3. The slightly sigmoidal
shape of the product curves also suggests that the rate of
product formation is rising during the initial stages of all
reactions. This could indicate that they are formed from a
transient intermediate that is accumulated during the initial
stages of the reaction and not from an intermediate with a
quasistationary concentration such as the iminium ion 2a under
aerobic conditions.
Scheme 7. Attempted Observation of Iminium Ions Using
CuBr/TBHP, Generating Only 21 as the Major Product
Peroxide 21 had been observed previously in oxidative
coupling reactions and was discussed as a potential reaction
intermediate, albeit with no definite conclusion.4f,9b,10e It was
also intentionally prepared,26 for example as a potential
precursor to an iminium ion 2,4c and a related compound
had been observed in a Rh-catalyzed oxidative coupling
reaction.12b In light of the aerobic reaction mechanism of
Scheme 5, the question arises whether 21 is an off-cycle
byproduct, similar to the structurally related hemiaminal ether
4, or if 21 is a true reaction intermediate within the catalytic
cycle.
To shed further light on the role of 21, we monitored
oxidative coupling reactions of 1 with various nucleophiles
using the CuBr/TBHP method, looking for the occurrence of
reaction intermediates by NMR (Scheme 8), analogous to the
experiments shown above in Scheme 3.
For an off-cycle formation of 21 to be operative analogous to
the formation of 4, its nucleophilicity would have to surpass
that of all the nucleophiles used, by approximately 1 order of
magnitude. To our knowledge, a direct nucleophilicity value for
TBHP has not been reported. However, the reactivity of the
tert-butylperoxy anion has been compared with related
nucleophiles in several kinetic studies: in water, its reactivity
was found to be in between that of hydroxide and
In contrast to the CuCl2·2H2O/O2 system, isocyanide 6g and
the silyl nucleophiles 8 and 10 did not yield the desired
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hydroperoxide27 and similar to hydrazine.27a On the basis of the
Mayr nucleophilicity values of these compounds (N(OH−) =
10.47,19i N(OOH−) = 15.44,19i N(H2NNH2) = 13.4719j), the
value for the tert-butylperoxy anion can be estimated to lie
around N = 13, certainly not larger than 15.44, which is in any
case well below the nucleophilicity of the nitromethane and
malonate anions at N > 20.19a,b
operative in the present CuBr/TBHP system (eqs 1−5).
Copper(I) is oxidized to copper(II) by TBHP, generating a
However, under the conditions of the oxidative coupling
reactions, the nucleophiles and TBHP will not be fully
deprotonated, making an assessment of their relative
nucleophilicities difficult.28 Under such conditions, the
equilibrium between protonated and deprotonated state will
strongly influence the apparent nucleophilicity. The pKa values
of nitromethane and TBHP in water have been determined as
10.0−10.329 and 12.8,30 respectively. Thus, nitromethane
should have a kinetic advantage over TBHP in a competition
for attack on the iminium ion.
To probe how such an acid−base equilibrium affects the
reaction rate, we conducted the reaction between 1 and
nitromethane in the presence of 5 mol % methanesulfonic acid
(Scheme 9). Under these conditions, the iminium ion 2 could
tert-butyloxy radical (eq 1), which can abstract a hydrogen atom
from 1, forming the radical species 22 and tert-butyl alcohol (eq
4). Such hydrogen abstraction reactions from the α-carbon of
tertiary amines are well established.34 Copper(II) can react with
a second molecule of TBHP to form a tert-butylperoxy complex
(eq 2) that transfers the peroxide group to the radical 22,
producing 19 (eq 5). Alternatively, the tert-butyloxy radical can
abstract hydrogen from TBHP, generating a tert-butylperoxy
radical (eq 3), which could combine with 22 to form 21. This
reaction is generally fast, but disfavored under concentrated and
basic conditions, making it less likely to contribute to the
formation of 21 under the present conditions.32b The selective
formation of 21 without larger amounts of a tert-butyl
hemiaminal ether, formed by combination of 22 and a tert-
butyloxy radical, for example, or a dimer of 22 could be
explained by a persistent radical effect, as discussed for related
reactions.35
Scheme 9. Reaction Progress of the Oxidative Coupling with
Nitromethane Using the CuBr/TBHP Method in the
Presence of 5 mol % Methanesulfonic Acid
In contrast to what would be expected for a radical
mechanism, the addition of 2.0 equiv of the radical inhibitor
2,6-di-tert-butyl-4-methylphenol (BHT) was reported to have
no significant effect on the CuBr/TBHP method (70% versus
84% yield in the oxidative coupling reaction of 1 with
nitromethane).4g Because the reaction time in these experi-
ments was overnight and thus considerably longer then
necessary (see Scheme 8) we decided to monitor the effect
of BHT addition more closely by NMR spectroscopy (Scheme
10). Indeed, BHT was found to have a significant effect, as it
slowed the conversion of 1 to the intermediate 21 and the
product 3a and eventually stopped the reaction after several
hours. However, the product was still formed in ca. 34% yield.
be observed as an intermediate. The formation of the reaction
product 3a is slowed considerably; after 2 h, ca. 10% of 3a is
formed in contrast to ca. 95% under standard conditions. This
agrees well with a suppressed nucleophilicity of nitromethane
by reducing the amount of its conjugate base. In contrast, the
formation of 21 appears to be largely unaffected by the
presence of the acid, suggesting a formation via a nonionic
pathway. The transient appearance of 21 together with the
clearly sigmoidal product formation profile suggests that 21 acts
as a direct precursor to 3a. The same trend was also observed
when the reaction was performed in the presence of 10 mol %
acid (see the Supporting Information).
Scheme 10. Coupling of Nitromethane with 1 in the
Presence of the Radical Inhibitor BHT
Accordingly, an off-cycle formation of 21 as is the case with 4
in Scheme 5 above appears not to be operative. Instead, 21 is
most likely a species within the catalytic cycle that is formed by
a radical pathway and acts as a direct precursor to the presumed
iminium ion 2.
Kharasch and Fono had previously suggested a radical
mechanism for the synthesis of a peroxide derived from N,N-
dimethylaniline and TBHP by copper catalysis.31 Kochi and
Minisci have later proposed more refined models for the
mechanism of the Kharasch reaction and the related Gif
reaction by Barton.32,33 An analogous mechanism is probably
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It can be seen that the oxidant TBHP is consumed after ca. 2 h,
during which time ca. 45% of amine 1 was converted.
Apparently, the inhibiting effect of BHT is too slow to fully
suppress the reaction. Even after TBHP is fully consumed, the
amount of product is still rising through conversion of 21 and
possibly other mechanisms, for example by oxidation with
oxygen being present in solution (the reaction was performed
under one atmosphere of argon, but without degassing the
solution). In conclusion, the significant suppression of the
reaction by BHT provides support for a mechanism proceeding
via radical intermediates. The results also show that such
experiments have to be treated with caution and that a mere
analysis of product yield after extended reaction time can be
misleading.
In conclusion, the substitution of the peroxy residue in 21 by
the employed nucleophile is catalyzed by the copper catalyst,
but a background reaction contributes significantly to this
transformation. A catalytic cycle that summarizes the
mechanistic findings discussed above is given in Scheme 12.
Scheme 12. Mechanism of the Oxidative Coupling Using the
CuBr/TBHP System
A kinetic isotope study was conducted, analogous to the one
shown in Scheme 4b, employing 1-d1 in the oxidative coupling
with 6b under the standard conditions of the CuBr/TBHP
system. A primary KIE value of 3.4 was determined, consistent
with C−H bond cleavage occurring in the rate-limiting step.
Another indication for the formation of 21 via a radical
mechanism without involvement of iminium ions 2 comes from
the above-mentioned coupling reaction with 2-naphthol
(Scheme 6a). Its nucleophilicity is apparently not high enough
to react with 2a, because cross-coupling product 19 was not
formed with the CuCl2·2H2O/O2 system. The formation of
binaphthol 20 by copper catalysis has been suggested to
proceed via the coupling of naphthyl radicals or rather copper-
bound naphthyl radical equivalents.36 Accordingly, the
formation of both 19 and 20 under the conditions of the
CuBr/TBHP system suggests a mechanism involving such
naphthyl radicals and 22, respectively, and not a free iminium
ion.
The substitution of the peroxide residue in 21 by a
nucleophile to give the final reaction product most likely
occurs via an iminium ion 2, formed by reversible heterolytic
bond cleavage, catalyzed by CuBr acting as a Lewis acid.
However, the substitution of an α-tert-butylperoxy residue in an
amine with methanol as a nucleophile was shown to occur even
in the absence of a catalyst.12b To clarify whether Cu catalysis is
operative in the present reaction, we studied the reaction
between nitromethane and 21. The latter was purified by
filtration over magnesium silicate and essentially free of copper
(<2 ppm), as revealed by trace element analysis using ICP-
OES. A mixture of 21 and nitromethane in decane slowly
converted to product 3a over 24 h, clearly showing that Cu
catalysis is not required, at least for this nucleophile. However,
the reaction rate is considerably slower than that for the
oxidative coupling reaction: after 2 h, 15% of 21 was converted
to 3a, while in the Cu-catalyzed reaction, nearly full conversion
to 3a was achieved at that time (Scheme 11).
Amine 1 reacts with two molecules TBHP under Cu catalysis
via a radical mechanism to peroxide 21 and tert-butyl alcohol.
An iminium salt 2c is formed in small amounts in rapid
equilibrium from 21, aided by Lewis acid catalysis by CuBr.
Trapping of 2c with a nucleophile furnishes product 3 and
regenerates one molecule of the oxidant TBHP.
It is likely that other transition-metal-catalyzed oxidative
coupling reactions with peroxides as oxidant proceed in a
manner similar to that shown in Scheme 12.5i,8b,12b,e,37 A radical
mechanism as indicated in eqs 1−5 has been suggested for the
transformation of various organic substances into tert-
butylperoxides in the presence of Cu, Co, Mn, and Fe catalysts,
for example.31,32b Details such as the involvement of specific
radicals (e.g., tert-butyloxy vs tert-butylperoxy), individual
reaction rates (e.g., eq 3), or radical recombination vs radical
oxidation can of course depend on reaction conditions and the
nature of substrates.34b,35a
When comparing the reaction progress of the two methods
under study (Schemes 5 and 12), two other major differences
become apparent: the failure to observe the iminium ion 2
under the CuBr/TBHP conditions and the different rates of
product formation, which is most obvious for nitromethane as
nucleophile. Apart from concentration and solvent38 effects on
the rate, the mechanisms suggested provide an explanation for
both differences by predicting a difference in pH. In the aerobic
method using CuCl2, HCl is formed, making the reaction
mixture more acidic than in the CuBr/TBHP system. This will
shift the equilibria between 2a, 4, and 5 toward the iminium
ion, allowing it to be observed. At the same time, the acidic
conditions will suppress the reactivity of C−H acidic
nucleophiles such as nitromethane. In the CuBr/TBHP system,
the more basic conditions favor deprotonation of such
nucleophiles, thus enhancing their reactivities. On the other
hand, these conditions will also shift the putative equilibrium
between 2a and 21 so that the iminium ion 2 cannot be
observed.
Scheme 11. Coupling Nitromethane with 1 under Standard
Reaction Conditions and with 21 in the Absence of CuBr
Indeed, the effect of acid on the CuBr/TBHP system as seen
in Scheme 9 supports this interpretation: the rate of product
formation is suppressed, while an iminium species 2 can be
observed. This reasoning is further corroborated by measuring
the solution pH value during the reaction between 1 and
nitromethane. Using the CuCl2·2H2O/O2 method, a slightly
acidic pH range of 5.3−6.1 was measured, while with the CuBr/
5323
dx.doi.org/10.1021/ja211697s | J. Am. Chem. Soc. 2012, 134, 5317−5325

Journal of the American Chemical Society
Article
was directly purified by flash column chromatography on silica gel (5−
10% EtOAc/pentane) to afford the corresponding coupling product.
TBHP method, more basic conditions with a pH of 6.3−7.2
were found.
ASSOCIATED CONTENT
■
SUMMARY AND CONCLUSIONS
■
S
* Supporting Information
We have conducted a comparative mechanistic study of Cu-
catalyzed oxidative coupling reactions of N-phenyltetrahydroi-
soquinoline 1 with various nucleophiles, using two previously
reported methods: the CuCl2·2H2O/O2 system and CuBr/
TBHP. For the CuCl2·2H2O/O2 system, the nucleophile scope
was shown to be only limited by the reactivity of the
nucleophile, the threshold lying at a nucleophilicity parameter
of ca. N = 3.8 with respect to Mayr’s reactivity scales. These
synthetic studies allowed a rough estimation of the electro-
philicity parameter E for the observable intermediate iminium
ion 2a. On the basis of these and previous studies, a catalytic
cycle is proposed, where the actual oxidant for 1 is the
copper(II) catalyst and the role of the terminal oxidant O2 is
the reoxidation of copper(I).
Differences in the reaction mechanism were found when the
same investigation was conducted with the CuBr/TBHP
system. Despite a relatively low nucleophilicity parameter, 2-
naphthol is oxidatively coupled with 1 under these conditions
(as previously reported), while it does not react in the
CuCl2·2H2O/O2 system. Also, silyl nucleophiles were found to
be unreactive with the CuBr/TBHP method. An iminium ion 2
could not be observed when the reaction progress was
monitored by NMR spectroscopy; the amino tert-butylperoxide
21 was the only identifiable intermediate. Regardless of the
reactivity of the nucleophiles used, 21 is always formed in large
amounts at the beginning of the reaction. On the basis of these
and other observations, 21 is proposed to form by a radical
mechanism and to be an intermediate within the catalytic cycle,
acting as a precursor to the iminium ion 2c. The latter then
reacts with nucleophiles to give the final reaction products. The
differences in individual rates and in the visibility of the
iminium ion in the two methods are explained by a difference
in overall pH of the reaction solutions.
Experimental details including product characterization and
NMR experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
klusi@mpi-muelheim.mpg.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the MPI fuer Kohlenforschung and Prof.
Benjamin List is gratefully acknowledged. We thank Markus
Kochius and Cornelia Wirtz for NMR measurements and
Steffen Mueller and Prof. Herbert Mayr for helpful discussions.
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