Reaction progress kinetic analysis of a copper-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline

Article abstract of DOI:10.1021/jo5018876

The results from a kinetic investigation of a Cu-catalyzed oxidative coupling reaction between N-phenyl tetrahydroisoquinoline and a silyl enol ether using elemental oxygen as oxidant are presented. By using reaction progress kinetic analysis as an evaluation method for the obtained data, we discovered information regarding the reaction order of the substrates and catalysts. Based on this information and some additional experiments, a refined model for the initial oxidative activation of the amine substrate and the activation of the nucleophile by the catalyst was developed. The mechanistic information also helped to understand why silyl nucleophiles have previously failed in a related Cu-catalyzed reaction using tert-butyl hydroperoxide as oxidant and how to overcome this limitation.

Full text of DOI:10.1021/jo5018876

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Article
Reaction Progress Kinetic Analysis of a Copper-Catalyzed Aerobic
Oxidative Coupling Reaction with N-Phenyl Tetrahydroisoquinoline
Martin Scott, Abhishek Sud, Esther Böß, and Martin Klussmann
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Sep 2014
Downloaded from http://pubs.acs.org on September 10, 2014
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Reaction Progress Kinetic Analysis of a Copper-Catalyzed Aerobic
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Oxidative Coupling Reaction with N-Phenyl Tetrahydroisoquinoline
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Martin Scott,‡ Abhishek Sud,† Esther Boess,† and Martin Klussmann*†
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†MaxꢀPlanckꢀInstitut fuer Kohlenforschung, KaiserꢀWilhelmꢀPlatz 1, 45470 Muelheim an der Ruhr, Germany
‡Cologne University, Department of Chemistry, Greinstrasse 4, 50939 Koeln, Germany.
*Eꢀmail: klusi@mpiꢀmuelheim.mpg.de
ABSTRACT
The results from a kinetic investigation of a Cuꢀcatalyzed oxidative coupling reaction between
Nꢀphenyl tetrahydroisoquinoline and a silyl enol ether using elemental oxygen as oxidant are
presented. By using Reaction Progress Kinetic Analysis as evaluation method for the obtained
data, information regarding the reaction order of substrates and catalyst was discovered.
Based on this information and some additional experiments, a refined model for the initial
oxidative activation of the amine substrate and the activation of the nucleophile by the
catalyst was developed. The mechanistic information also helped to understand why silyl
nucleophiles have previously failed in a related Cuꢀcatalyzed reaction using tertꢀbutyl
hydroperoxide as oxidant and how to overcome this limitation.
1. INTRODUCTION
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Oxidative coupling reactions, also called Cross Dehydrogenative Coupling (CDC) reactions,
have received considerable interest in recent years due to their ability to directly convert two
CꢀH bonds into a new CꢀC bond.1 Such a transformation makes prior activation or
introduction of leaving groups unnecessary and thus, can help to streamline synthesis, save
time, materials and reduce the amount of waste, thereby contributing to sustainable chemistry.
The use of air or oxygen as oxidant is very attractive as an abundant and lowꢀcost reagent that
also creates at best only water as the waste product.2 Amongst the many substrates that can be
utilized in such reactions, amines and most notably Nꢀaryl tetrahydroisoquinolines stand out
because they have seen the development of a large number of methods for their oxidative
coupling with other substrates, mostly reactive nucleophiles.3,4 However, more detailed
investigations of the mechanism of these reactions have only recently begun and some issues
remain unsolved.5
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Previously, we reported experimental mechanistic studies of the oxidative coupling reaction
between Nꢀphenyl tetrahydroisoquinoline (1) and various nucleophiles, including silyl enol
ether 2, catalyzed by copper(II)chloride dihydrate under oxygen atmosphere (Scheme 1).6
Scheme 1: The oxidative coupling reaction under study in this investigation.
This reaction was originally developed by our group in order to introduce carbonyl residues
into the αꢀposition of Nꢀaryl amines, giving products like 3.7 With Nꢀaryl
tetrahydroisoquinolines, generally clean reactions with high yields are achieved, which make
these reactions very suitable for mechanistic studies. We could characterize and isolate the
reactive intermediate of this reaction, iminium dichlorocuprate 4, which is formed upon
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reaction with Cu(II), providing the coupling products after conversion with any nucleophile of
sufficient reactivity (Scheme 2a).6 In the presence of water (the reactions are performed
without prior purification of reagents and solvent) or methanol (the solvent of choice for
nucleophiles of lower reactivity), an offꢀcycle equilibrium is established between iminium 4
and a hemiaminal (R = H) or hemiaminal ether (R = Me) 5. These species can be beneficial
for the final product yield if less reactive nucleophiles are utilized, as they provide a reservoir
for the reactive iminium ion 4, which otherwise can undergo undesired side reactions.
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Scheme 2: a) Previously proposed mechanism for the reaction of Scheme 1; b) proposed formation of the iminium ion 4 from
1 by single electron transfer (SET) and proton transfer steps.
For the generation of iminium 4 from 1, a combination of single electron transfer (SET) and
proton transfer steps are usually suggested (Scheme 2b).5f,6b,8 After one SET step, for example
by reaction with the high valent Cu catalyst, an ammoniumyl radical cation 6 is formed. The
iminium ion 4 presumably is formed either stepwise by deprotonation to give Cꢀradical 7 and
subsequent SET, or directly by hydrogen atom transfer.5a,9 The latter scenario, protonꢀcoupled
electron transfer, has been suggested in a computational study by Cheng et al. for the Cuꢀ
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catalyzed oxidative coupling with 1.5b We could previously show that CuCl2•2H2O alone can
mediate this transformation and that oxygen is not required, suggesting that the SET steps
involve Cu(II) directly and that the role of oxygen is to reoxidize the reduced catalyst.6b
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Herein, we report the results from kinetic studies of the reaction shown in Scheme 1, using
Reaction Progress Kinetic Analysis10 as method to evaluate the data. Silyl enol ether 2 was
considered as particularly suitable being one of the fastest reacting substrates in a series of Cꢀ
H and silyl nucleophiles in previous investigations,6 which could facilitate to elucidate kinetic
details of the oxidation of amine 1. The reaction timescale of several minutes to a few hours
and its exothermic nature make it very suitable to obtain kinetic data by reaction calorimetry.
This in situ technique delivers heat flow data, which is directly proportional to the reaction
rate, over the entire course of the reaction. Thus, it is a method of choice for Reaction
Progress Kinetic Analysis,11 relying on a large kinetic dataset with good quality for graphical
data evaluation, which is discussed in the following.
2. RESULTS AND DISCUSSION
The reaction of Scheme 1 was performed in a reaction calorimeter at 25°C, under essentially
the same conditions as reported previously for synthetic purpose.7 Parallel analysis of a
reaction by reaction calorimetry and 1HꢀNMR (by taking several samples over the course of
the reaction) revealed that the reaction profiles obtained by both methods were essentially
identical. The heat flow data obtained from calorimetric experiments was converted to
reaction rate and conversion profiles as described in the experimental section, following
established procedures.10b As a reference for further kinetic studies, a “Standard Reaction”
was defined, using 0.012 M CuCl2•2H2O (10 mol%), 0.12 M amine 1 and 0.19 M enol ether 2
in acetone at 25°C (Figure 1). The curves derived from repeated experiments were found to be
reproducible within an acceptable scope of deviation (see the Supporting Information).
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Figure 1: Reaction rate (black line) and conversion (red line) profiles of the “standard reaction”, using 0.012 M CuCl2•2H2O,
0.123 M 1 and 0.185 M 2 in acetone at 25°C.
2.1. Same excess experiment. In order to probe for potential problems like catalyst
deactivation, a “same excess” experiment was performed, which effectively models the
standard reaction after a certain conversion. Herein, “excess” is defined as the concentration
excess, [excess], of the enol ether 2 over the limiting reagent, amine 1 (equation 1).
[
excess
]
=
[
2
]
−
[
1
]
(1)
Figure 2 shows a plot of reaction rate versus the concentration of the amine substrate, also
called a “graphical rate equation”.10 Note that the reaction progress is plotted from right to
left. Clearly, it can be seen that the “same excess” experiment does not overlay with the
experiment run under standard conditions, but lies slightly above.
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Figure 2: Same excess experiment and the effect of added product under standard conditions. “Standard” (black line): 0.123
M 1, 0.185 M 2; “same excess” (magenta line): 0.081 M 1, 0.141 M 2; “same excess + product” (magenta dashed line): 0.081
M 1, 0.143 M 2, 0.041 M 3; all experiments: 0.012 M CuCl2*2H2O, acetone, 25°C.
The same excess experiment starts with substrate concentrations as present in the standard
reaction after ca. 34% conversion, without product being present and without any turnover of
the catalyst, respectively. The fact that the rate of the standard reaction is lower at each
concentration of amine 1 could indicate catalyst deactivation. To probe for inhibition by the
product, the same excess experiment was repeated in the presence of 0.04 M product – the
amount that corresponds to ca. 34% conversion. As seen in Figure 2, this has some
diminishing effect on the rate, although it still does not overlay with the standard reaction
curve. Accordingly, some degree of product inhibition is occurring but another effect is also
slightly reducing the rate during reaction progress. This could be the precipitation of insoluble
CuCl(OH), formed from CuCl by oxidation in the presence of water, which has been
characterized before in reactions at very high catalyst loading of 50 mol%.6a
2.2. Catalyst reaction order. To determine the reaction order of the catalyst, five
experiments with different catalyst concentrations ranging from 10 to 24 mol% CuCl2•2H2O
were conducted while keeping all other reaction parameters as in the standard reaction. The
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“graphical rate equation” plot shows a clear increase in rate upon increasing the initial catalyst
concentration, indicating a positive reaction order (Figure 3a)
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Figure 3: a) reaction rate versus amine concentration at different catalyst concentrations; b) reaction rate divided by initial
catalyst concentration to the power of 1.25, achieving overlay of the different curves. CuCl2*2H2O concentrations: “10
mol%” (“Standard”, black line): 0.012 M; “15 mol% (magenta line): 0.018 M; “18 mol% (blue line): 0.022 M; “20 mol%”
(red line): 0.025 M; “24 mol%” (green line): 0.030 M; all experiments: 0.12 M 1, 0.18 M 2; acetone, 25°C.
The apparent reaction order of the catalyst, x, can be determined from this data set by dividing
the reaction rate r by the initial concentration of the catalyst taken to the power of the reaction
order.10 This should cause the curves from the experiments with different catalyst
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concentrations to overlay, given that their rates differ only by the factor of [catalyst]x, and all
other parameters are being kept constant. As depicted, this was found to be the case for a
reaction order larger than one with a value of approximately 1.25 (Figure 3b). This value
suggests a complex reaction mechanism with a combination of steps involving more than one
molecule of catalyst.
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Since it was proposed that the oxidation of 1 is mediated by two molecules of Cu(II), as
visualized in Scheme 2b, it is reasonable to assume that both SET steps are contributing to the
reaction rate equation. A consecutive reaction of 1 with two molecules of CuCl2, first to form
the radical cation 6 and then to form the iminium ion 4, would result in a higher order rate
dependence on [CuCl2]. Alternatively, the apparent reaction order in the catalyst could be
related to the reoxidation of Cu(I) to Cu(II) by oxygen. For example, the reoxidation of simple
copperꢀamine complexes has been shown to involve four molecules of Cu(I).12
The graphical evaluation as shown in Figure 3a might not be precise enough to distinguish
between true first order and higher order reactions, given the error range of the experiments
and the fact that the graphical overlay is not perfect. Thus, the same set of data was used to
derive the reaction order in catalyst by plotting rates versus catalyst loading and fitting the
data to linear or power law functions. This also indicated that values of around 1.25 are very
likely, although a value of 1.0 could not be ruled out with certainty. The same apparent
catalyst reaction order of 1.25 was also obtained from graphical rate equations when the
experiments were conducted at lower excess of enol ether 2 (see the Supporting Information,
also see below for a discussion of the effects of enol ether concentration). It has been shown
before that this graphical evaluation of obtaining kinetic information is in reasonable
agreement with mathematical approaches.10c
2.3. Different excess experiment – amine reaction order. “Different excess experiments”10
were conducted to probe for the reaction order of the amine substrate, varying its
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concentration while keeping all other parameters at standard conditions. As can be seen from
the plot of rate versus enol ether concentration, the reaction rate increases with decreasing
[excess], that is, with increasing amine concentration (Figure 4a). Accordingly, the
concentration of amine 1 has a positive influence on the reaction rate and is expected to have
a positive reaction order. As for the experiment probing the catalyst’s reaction order above,
the reaction order for the amine can be determined from this data set by dividing the reaction
rate r at any time by the concentration of 1 at that time, taken to the power of x. The best
overlay was achieved in this case for a reaction order x of 0.45 (Figure 4b).
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Figure 4: Different excess experiments varying the concentration of the amine 1; a) reaction rate versus enol ether (2)
concentration; b) reaction rate divided by [1] to the power of 0.45, achieving overlay of the different curves. Concentrations
of 1: “0.11 M excess” (green line): 0.080 M; “Std., 0.06 M excess” (black line): 0.123 M; “0.04 M excess” (magenta line):
0.143 M; “0.02 M excess” (blue line): 0.163 M; all experiments: 0.012 M CuCl2*2H2O, 0.18 M 2, acetone, 25°C.
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The fact that the curves in Figure 4b stop to overlay at higher conversions, i.e. at lower enol
ether concentrations, can be rationalized because the concentration of 1, the limiting reagent,
approaches zero at these stages. Under such conditions, the reaction rate necessarily
approaches zero also and the data towards the end of the reaction is best excluded from the
comparison of the rate curves.10b Two possibilities of interpreting the amine reaction order of
0.45 come to mind. The reaction order could appear to be smaller than 1 because of saturation
kinetics, due to strong binding between the copper catalyst and amine 1. This would result in
the reaction rate becoming independent of [amine] at high concentrations and the resting state
of the catalyst would be a Cuꢀamine complex. However, both cases could not be further
investigated; at the highest possible amine concentration that we could investigate, the rate
was still dependent on its concentration, and upon mixing CuCl2•2H2O with 1, rapid oxidation
to the iminium salt 4 occurs.6 A second explanation for a fractional reaction order could be the
involvement of species containing two or more molecules of 1. For example, a rapid
equilibrium could exist between copper complexes 8 and 9 with one and two amines as
ligand, respectively (Scheme 3). Cu(II) is known to favour fourfold coordination, making the
rapid formation of 9 in the presence of an excess of 1 likely.
Ph
Ph
Cl
Cu
N
N
+ 1
ꢀ 1
CuCl2 + 1
CuCl2
ꢀ 1
N
Cl
8
9
Ph
SET
SET ꢀ 1
6 + CuCl2
Scheme 3: Potential reason for the fractional amine reaction order, equilibria between copper complexes 8 and 9 containing
one and two molecules of amine 1 and formation of radical cation 6 from 8 and 9, respectively, after dissociation of 1.
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The subsequent SET reaction could occur directly from complex 8, from 9 after dissociation
of one molecule of 1, or from 9 directly by dissociation into the ammoniumyl radical cation 6
and amine 1. In the computational study by Cheng et al., water was used as an auxiliary
ligand on Cu(II) for the SET reaction of Scheme 2b;5b this role could also be taken over by a
second molecule of 1. The counterion of 6 is likely to be dichlorocuprate, in analogy to the
iminium salt 4.
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In a series of related experiments at lower [excess], essentially the same result was obtained,
i.e. a reaction order of 0.45 for amine 1 (see the Supporting Information).
2.4. Different excess experiment – silyl enol ether reaction order. For the determination of
the reaction order for enol ether 2, a new set of “different excess experiments” was conducted,
this time varying the concentration of 2 while keeping all other parameters as in the standard
experiment. The evaluation for the “same excess” experiment was performed as described
above by variation of the amine concentrations. The plot of reaction rate versus [amine]
shows that the rate increases slightly upon increasing the enol ether concentration up to 0.24
M (Figure 5a). By further increasing the enol ether concentration to 0.30 M (0.18 M excess),
the rate drops below that of the experiment with the lowest concentration of 2 (0.02 M
excess).
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Figure 5: Different excess experiments varying the concentration of enol ether 2; a) reaction rate versus [amine]; b) reaction
rate divided by [2] to the power of 0.2, achieving overlay of the different curves. Concentrations of 2: “0.02 M excess”
(magenta line): 0.142 M; “Std., 0.06 M excess” (black line): 0.185 M; “0.12 M excess” (green line): 0.241 M; “0.18 M
excess” (blue line): 0.302 M; all experiments: 0.012 M CuCl2*2H2O, 0.12 M 1, acetone, 25°C.
Good overlay was found by dividing the rate curves by [enol ether]0.2, indicating an apparent
reaction order in 2 of 0.2 (Figure 5b). As expected, an overlay is not achieved for the curve of
the “0.18 M excess” experiment. The low reaction order found for enol ether concentrations
up to 0.24 M (0.12 M excess) could indicate that the addition of nucleophile is partially rate
controlling but that a preceding step dominates the rate equation, making the reaction order
nearly zero for the enol ether. As the deviation between these rate curves is small and similar
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to the one seen in repetitive experiments of the standard experiment, it is supposable that it
lies within the error of measurement and the reaction order in 2 is actually zero. This is in line
with our previous studies, in which 2 was found to be one of the fastest reacting nucleophiles
and the intermediates 4 and 5 were basically not visible during the reaction progress, in
contrast to slower reacting nucleophiles.6
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The drop in reaction rate seen for the “0.18 M excess experiment” indicates an unfavorable
interaction dominating at high enol ether concentrations, being a reproducible observation. As
there is no detectable interaction between substrates 1 and 2 in the absence of catalyst, it is
reasonable to assume an interaction between 2 and the catalyst. The wellꢀknown reactivity of
silyl groups towards halide nucleophiles, which is used in the activation of silyl nucleophiles
as well as the deprotection of silyl protecting groups, comes to mind. A reaction between
CuCl2 and enol ether 2 could mediate OꢀSi bond cleavage by attack of a chloride ion on
silicon, leading to a loss of chloride from the catalyst. The formed trimethylsilyl chloride will
eventually be hydrolysed, releasing the chloride (Scheme 4).
Scheme 4: Possible interactions between enol ether 2, CuCl2 catalyst and water.
At high enol ether concentrations, this reaction could dominate over interactions between the
catalyst and the amine, and the concentration of water in the system may no longer be high
enough to ensure efficient hydrolysis of trimethylsilyl chloride. Thus, the formation of
insoluble CuCl(OH) or other species of lower chloride content could reduce the catalyst’s
activity of the reaction. For example, the use of CuCl as catalyst in the reaction of Scheme 1
increased the reaction time and reduced the yield of 3.7 In line with this rationale, adding
water to the reaction at high enol ether concentration significantly increased its rate. This
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effect also occurs at lower enol ether concentrations; for example, conducting the standard
reaction in the presence of 2.4 M water, full conversion is achieved after 15 instead of 100
minutes. Preliminary experiments with the addition of defined amounts of water indicate an
increase in the reaction order of the amine and a decrease in the reaction order of the enol
ether. On the other hand, additional thermal effects become visible by reaction calorimetry,
complicating the analysis. Thus, further studies are needed to unravel the complex kinetic role
of water.
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2.6. Activating silyl nucleophiles in reactions using tBuOOH as oxidant. In light of these
findings, our previous observations that CuBr completely fails as catalyst in the reaction
under study makes sense.7 CuBr was shown to be an active catalyst under aerobic conditions
using CꢀH nucleophiles4c,13 and was shown to form an iminium tetrabromodicuprate with 1
under oxygen.6a Its failure in the present reaction must therefore be linked to the attack of the
nucleophile 2. Likewise, our observation that the combination of CuBr as catalyst together
with tertꢀbutyl hydroperoxide as alternative oxidant fails for silyl nucleophiles (2, allyl silanes
or TMSꢀCN),6b can be explained. This method has been developed by the Li group and is
highly successful for oxidative coupling reactions between amines like 1 and various
nucleophiles, yet silyl nucleophiles were not reported.14 In contrast, when we employed
CuCl2•2H2O as catalyst in these reactions with tertꢀbutyl hydroperoxide as oxidant and 2 and
TMSꢀCN, respectively, as nucleophiles, the products 3 and 10 were formed in significant
amounts (Scheme 5).
OTMS
[Cu] (10 mol%)
CuBr: 0%
CuCl2—2H2O: 43%
+
N
N
tBuOOH
(1.0 equiv.),
r.t., 17 h
Ph
Ph
1
2
3
(3.0 equiv.)
O
[Cu] (10 mol%)
CuBr: 0%
CuCl2—2H2O: 53%
1 +
TMS CN
N
tBuOOH
(1.0 equiv.),
r.t., 17 h
Ph
(3.0 equiv.)
10
CN
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Scheme 5: CuCl2 versus CuBr in oxidative coupling reactions of 1 with silyl nucleophiles using tBuOOH as oxidant.
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5
6
7
8
It appears that CuCl2 can easily activate silyl nucleophiles while CuBr, only bearing a single
and larger halide counterion, cannot, supporting the postulated interaction between
nucleophile and catalyst shown above in Scheme 4.
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2.7. Intermolecular kinetic isotope effect. Previously, we measured an intramolecular
kinetic isotope effect (KIE) of 4.5 for the reaction between 1ꢀmonodeuterated amine, 1ꢀd1,
and dimethyl malonate.6b This value indicates that CꢀH bond cleavage is productꢀdetermining
but not whether it is also rateꢀdetermining.15 The developed technique of using reaction
calorimetry for this study allowed us to easily conduct separate kinetic experiments to
determine intermolecular kinetic isotope effects. The 1ꢀdideuterated amine 1ꢀd2 was
synthesized from tetrahydroisoquinoline 11 in a four step sequence following reported
procedures (Scheme 6a).16
Scheme 6: Synthesis of the 1ꢀdideuterated amine 1ꢀd2 and application in the oxidative coupling with 2.
When 1ꢀd2 was subjected to standard reaction conditions, the conversion to product 3ꢀd1 was
found to be only slightly slower than compared to 1 (Scheme 6b, Figure 6).
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Figure 6: Conversion profiles for reactions with 1 and 1ꢀd2, kinetic isotope effect from conversion ratio.
Dividing the conversion profile of 1 by that of 1ꢀd2 reveals a ratio of approximately 1.3 over
the course of the reaction, which excludes the cleavage of the CꢀH bond as the rate
determining step. Reversible CꢀH bond cleavage appears not to take place, as there was no
H/Dꢀscrambling observed in product 3ꢀd1. In case of a rate determining nucleophile addition
to a deuterated iminium 4ꢀd1, an inverse kinetic isotope effect of <1 would be observed. Thus,
the low value of 1.3 suggests a
β secondary KIE that arises due to hyperconjugation of the Cꢀ
H/D bonds to the nitrogen atom during a rate determining SET step.
3. SUMMARY AND CONCLUSIONS
The discussed kinetic experiments provide more details on the mechanism of the aerobic Cuꢀ
catalyzed oxidative coupling with Nꢀphenyl tetrahydroisoquinoline 1. The nonꢀinteger
reaction orders determined for the substrates and the catalyst indicate a complex rate equation,
which is approximately half order in amine 1 and 1.25 order in catalyst (equation 2).
1.25
1.25
r ∝
[
1 0.45
]
[
2]0.2 [CuCl2
]
≈
[
1]0.5 [CuCl2
]
(2)
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In line with previous mechanistic studies, new conclusions and a refined mechanistic proposal
can be derived from these results (Scheme 7).
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Scheme 7: Refined mechanistic proposal for the aerobic Cuꢀcatalyzed oxidative coupling of 1 with 2.
It is not clear if there is a single rateꢀcontrolling step or a combination of steps dominating the
reaction rate.17 In any case, the rate is determined by events preceding CꢀH bond cleavage and
nucleophile addition, and therefore is obviously connected to the two single electron transfer
(SET) steps involved in oxidizing the amine to the iminium ion 4 via radical cation 6. This
hypothesis is supported by the secondary kinetic isotope effect of around 1.3, the positive
reaction order in 1 and the reaction order close to zero found for nucleophile 2.
These SET reactions could be caused by the coordination of two molecules of amine 1 to the
copper catalyst, forming complexes 8 and 9 in equilibrium, as suggested by the reaction order
close to 0.5 for this substrate. It is likely that this reduces the precipitation of insoluble
species, for example CuCl(OH), which forms easily from the reduced copper(I) chloride and
was characterized in reactions at very high catalyst loadings. The higher reaction order of 1.25
in the catalyst supports the involvement of more than one molecule of catalyst in the reaction,
which is in line with two separate SET steps, each involving the reduction of Cu(II) to Cu(I).
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The reoxidation to Cu(II) with oxygen follows the addition of the nucleophile to 4 and is
4
5
6
therefore not likely to control the reaction rate.
7
8
9
The computational study by Cheng et al. suggested the first Cu(II)ꢀmediated SET step
forming the ammoniumyl radical cation 6 as thermodynamically and kinetically facile, while
the subsequent transformation to iminium ion 4 was suggested as rate determining.5b This
involved coordination of Cu(II) to radical cation 6 as the energetically least favored step prior
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to protonꢀcoupled electron transfer to form 4, which could also be an explanation for the
β
secondary KIE.
The fact that the rate actually decreases at very high concentrations of 2 points towards a
complex interaction between this substrate and the catalyst. In oxidative coupling reactions of
1 with various silyl nucleophiles, CuCl2•2H2O proved to be a superior catalyst to CuBr and
CuCl, supporting the role of the chloride counterions in activating the silyl reagents by
nucleophilic attack on the silicon atom. Water addition was shown to significantly increase
the reaction rate, possibly by accelerating the hydrolysis of the byꢀproduct
trimethylsilylchloride, thereby liberating chloride to regenerate the active catalyst. The role of
water is obviously not limited to the formation of the offꢀcycle hemiaminal 5 shown in
Scheme 2a (R = H), which is beneficial for the product yield but does not increase the rate.
4. EXPERIMENTAL SECTION
General methods. Unless otherwise indicated, all reagents and solvents were purchased from
commercial distributors and used as received. TLC was used to check the reactions for full
conversion. TLC spots were visualized by UVꢀlight irradiation and staining with KMnO4.
Flash column chromatography was carried out using silica gel (40ꢀ63 ꢁm) with ethyl acetate
and pentane of technical grade after distillation in a rotary evaporator. Yields refer to pure
isolated compounds. 1H and 13C NMR spectra were measured at 500 and 125 MHz,
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respectively. All chemical shifts are given in ppm downfield relative to TMS and were
referenced to the solvent residual peaks.18 1HꢀNMR chemical shifts are designated using the
following abbreviations as well as their combinations: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad signal. High resolution mass spectra were recorded with a
FTICRꢀMS, quadrupole MS and double focusing sector field MS, respectively.
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Starting materials. Compounds 1,16d 1316b and 11ꢀd216c were synthesized following reported
procedures.
Oxidative coupling reactions. Following previously reported procedures for the coupling of
1 and 2 using CuCl2•2H2O under oxygen7 and for the coupling of 1 with nucleophiles using
CuBr and tBuOOH.6b,14b Spectroscopic data of the products 3 and 9 was identical with
previous reports.6b,7
Kinetic experiments by reaction calorimetry. Into a 10 ml screwꢀcap vial, Nꢀphenyl
tetrahydroisoquinoline 1, silyl enol ether 2 and acetone were placed. The vial was equipped
with a magnetic stirring bar, flushed with oxygen and closed with a piercable screwꢀcap. The
vial was placed into the reactor port of a reaction calorimeter and connected to an external
oxygen balloon via a cannula and silicon tube. A syringe filled with a solution of
CuCl2•2H2O in acetone (1.3 wt%) was placed into a temperatureꢀcontrolled syringe port.
Reactions were conducted at 25°C and thermal equilibrium was attained after keeping the
vials within the calorimeter for at least 25 minutes and the syringes for at least 15 minutes.
The reactions were initiated by injecting the catalyst solution. The injected amount was
determined by subtracting the amount remaining in the syringe from the one filled into it. The
reaction progress could be controlled online. Agitation speed was 300 mot/min.
The reaction conversion after completion of the reaction was determined by taking a sample
from the reaction mixture by syringe and quenching it by injection into a wellꢀstirred mixture
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of a saturated aqueous solution of NaHCO3 and ethyl acetate. After extracting the aqueous
phase two more times with ethyl acetate, drying the combined organic phases by passing over
MgSO4 and removing the solvent in vacuum, the residue was redissolved in DMSOꢀd6 and
analyzed by 1HꢀNMR spectroscopy. Conversion at the end of the reaction, fconv(tend), was
determined from the ratio of substrate to product peak integrals (1 vs. 3). A purified sample of
3 was obtained according to a published procedure.7 Data points were taken every 6 seconds
over the course of the reaction. The calorimetric experiments were evaluated according to
known procedures and techniques.10b The reaction heat flow q is proportional to the reaction
rate r where ꢀHrxn is the heat of the reaction and V is the reaction volume (equation 3).
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dq
r =
= ꢀHreact ⋅V ⋅r
(3)
dt
The observed heat flow profiles may also be used to obtain the fractional conversion fconv of
limiting substrate by calculation of the fractional area under the temporal heat flow curve as
given in equation 4, where the numerator represents the area under the heat flow curve at any
time point t and the denominator represents the total area under the heat flow curve after
completion of the reaction at time tend.
t
q(t)dt
∫
0
fconv = fconv
(
tend
)
⋅
(4)
tend
q(t)dt
∫
0
Conversion determined from heat flow was compared in all cases to conversion by NMR
measurement, determined by taking samples from one reaction over the course of the reaction,
quenching and analyzing them as described above. This confirmed that the observed heat flow
represents an accurate measure of rate of the reaction under study.
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3,4-Dihydroisoquinoline (12). Synthesized related to a published procedure.16a Nꢀ
Bromosuccinimide (14.7 g, 82.64 mmol) was added to a methylene chloride solution (113 ml)
containing 1,2,3,4ꢀtetrahydroisoquinoline 11 (10 g, 75.12 mmol) under iceꢀcooling over 20
minutes. After stirring for 2 h, an aqueous 30 percent sodium hydroxide solution (50 ml) was
added to the reaction solution. The organic layer was washed with water and then extracted
with a 10 percent aqueous hydrochloric acid solution (50 ml). The aqueous layer was washed
with methylene chloride, basified with aqueous ammonia, and then extracted with methylene
chloride. The extract was dried over magnesium sulfate and then evaporated. The resulting
residue was received as a yellow oil with 88.6% (8.72 g) isolated yield and was directly used
in the next step without further purification.
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1H NMR (500 MHz, DMSO): δ 8.33 (t, J = 2.06 Hz, 1H), 7.41 – 7.30 (m, 3H), 7.23 – 7.20
(m, 1H), 3.64 (dt, J = 2.16 and 8.85 Hz, 2H), 2.68 (t, J = 7.84 Hz, 2H). 13C NMR (125 MHz,
DMSO): δ 159.5, 136.0, 131.0, 128.2, 127.4, 127.1, 127.0, 46.8, 24.3. HRMSꢀ(EI) (m/z):
+
calcd for C9H9N1 131.073498, found 131.073368.
2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1,1-[2H2] (1-d2). Prepared by a reported procedure
for the nonꢀdeuterated compound16d and isolated by column chromatography in 71 % yield as
a white solid.
1H NMR (500 MHz, DMSO): δ 7.25ꢀ7.13 (m, 6H), 7.01ꢀ6.96 (m, 2H), 6.74 (app.t, J = 7.15
Hz, 1H), 3.52 (t, J = 5.89 Hz, 2H), 2.89 (t, J = 5.89 Hz, 2H). 13C NMR (125 MHz, DMSO): δ
150.1, 134.7, 134.4, 129.1, 128.4, 126.6, 126.2, 125.9, 117.9, 114.7, 45.6, 28.0. HRMSꢀ(EI)
+
(m/z): calcd for C15H13N1D2 211.133001, found 211.133092.
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl-1-[2H])propan-2-one (3-d1). Prepared
following a previously reported procedure for the nonꢀdeuterated compound7 and isolated by
column chromatography in 72% yield as a white solid.
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1H NMR (500 MHz, DMSO): δ 7.21ꢀ7.11 (m, 6H), 6.97ꢀ6.92 (m, 2H), 6.68 (app. t, J = 7.25
Hz, 1H), 3.68 (ddd, J = 4.1, 5.7 and 13.4 Hz, 1H), 3.50 (ddd, J = 4.7, 9.9 and 13.4 Hz, 1H),
3.06 (d, J = 16.4 Hz, 1H), 2.93 (ddd, J = 5.7, 9.9 and 16.5 Hz, 1H), 2.85 (d, J = 16.4 Hz, 1H),
2.74 (app. dt, J = 4.3 and 16.4 Hz, 1H), 2.07 (s, 3H). 13C NMR (125 MHz, DMSO): δ 206.9,
148.8, 138.1, 134.4, 129.2, 128.7, 126.7, 126.6, 125.9, 117.6, 114.4, 43.5, 40.6, 30.5, 25.6.
HRMS (m/z): calcd for C18H18N1O1D1Na1 [M+Na]+ 289.142162, found 289.141903.
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ASSOCIATED CONTENT
Supporting Information
Complete copies of 1H and 13C NMR spectra for compounds 13
, 11ꢀd2, 1ꢀd2 and 3ꢀd1 and
additional kinetic experiments. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: klusi@mpiꢀmuelheim.mpg.de. Web: http://www.kofo.mpg.de/en.
Author Contributions
M.S. and A.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support from the DFG (Heisenberg scholarship to M.K., KL 2221/4ꢀ1), the MPI fuer
Kohlenforschung and Prof. Benjamin List is gratefully acknowledged.
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