Investigations of the generality of quaternary ammonium salts as alkylating agents in direct C-H alkylation reactions: Solid alternatives for gaseous olefins

Article abstract of DOI:10.1039/c9ob00243j

C-H alkylation reactions using short chain olefins as alkylating agents could be operationally simplified on the lab scale by using quaternary ammonium salts as precursors for these gaseous reagents: Hofmann elimination delivers in situ the desired alkenes with the advantage that the alkene concentration in the liquid phase is high. In case a catalytic system did not tolerate the conditions for Hofmann elimination, a very simple spatial separation of both reactions, Hofmann elimination and direct alkylation, was achieved to circumvent possible side reactions or catalyst deactivation. Additionally, the truly catalytically active species of a rhodium(i) mediated alkylation reaction could be identified by using this approach.

Full text of DOI:10.1039/c9ob00243j

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Takeharu Haino et al.
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Investigations of the generality of quaternary ammonium salts as
alkylating agents in direct C-H alkylation reactions: solid
alternatives for gaseous olefins
Received 00th January 20xx,
Accepted 00th January 20xx
David Schönbauer,a Manuel Spettel,a Robert Pollice,a,b Ernst Pittenauer,c and Michael Schnürch*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
C-H alkylation reactions using short chain olefins as alkylating agents could be operationally simplified in the lab scale by
using quartenary ammonium salts as precursors for these gaseous reagents: Hofmann elimination delivers in-situ the
desired alkenes giving the advantage that the alkene concentration in the liquid phase is high. In case a catalytic system
did not tolerate the conditions for Hofmann elimination, a very simple spatial separation of both reactions, Hofmann
elimination and direct alkylation, was developed to circumvent possible side reactions or catalyst deactivation.
Additionally, the truly catalytic active species of a rhodium(I) mediated alkylation reaction could be identified by using this
approach.
entering the catalytic cycle upon reductive elimination and the
product is released (Cycle  in Scheme 2).27 In this process alkyl
halides are reduced, and an acid equivalent is generated,
which is usually quenched by addition of a base. On the other
hand, alkylation of aromatic C-H bonds with olefins includes
usually a hydroarylation step of the olefin and hence no acid
equivalent is formed (Cycle ).
Introduction
In recent years, the direct functionalization of C-H bonds has
established itself as an increasingly important method for the
formation of new C-C bonds.,1-6 A key contribution to this field
was the acetyl directed alkylation of aromatic C-H bonds
disclosed by Murai in 1993.7 (Scheme 1).
HX
+
O
O
1 - 6 equiv.
R1
R
R2
H
R1
X
2 - 6 mol% RuH2(CO)(PPh3)3
R2
R2
[M]
X
R1
toluene, reflux
R1
[M]
X
H
R
R = H, CH2SiMe3, t-Bu, o-tolyl
[M]
[M]

Scheme 1 Murai reaction
[M]
This paper inspired much subsequent research and can be
considered as the starting point of directing group (DG)
assisted C-H activation chemistry.8, 9
Among the many transformations known in metal-catalyzed
direct C-H functionalization, alkylation reactions have received
specific attention10-12 and have been the focus of interest of
our research in recent times as well.13-16 Generally, either alkyl
halides17-24 or olefins10,

H
[M] R2
H
R1
R2
[M] R2
H
[M]
R1
R1
R1
R2
H
R2
Scheme 2 Schematic mechanisms for alkylation reactions with alkyl halides (Cycle ) or
olefins as reagents (Cycle ).
25, 26
are used as alkylating agents.
Consequently, these reactions are typically carried out in
absence of base.10 It has to be mentioned that the application
of short chain olefins is clearly underrepresented,28-30 which is
certainly due to their gaseous nature and the problems of
dosing gases in the nowadays typically applied mmol or sub-
mmol scale. Additionally, the need for using high- or at least
medium-pressure equipment is another factor contributing to
the scarcity of examples with gaseous olefins. Hence, it can be
seen that unactivated alkenes only from C6 on (e.g. n-hexane)
are used,10 or polar groups are attached to the double bond as
Usually the former are attached to the catalyst by oxidative
addition and coupled with the substrate. The catalyst is re-
a. Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, 1060
Wien, Austria.
b. Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-
Weg 1-5/10, 8093 Zürich, Switzerland
c. Institute of Chemical Technologies and Analytics, TU Wien, Getreidemarkt 9/164,
1060 Wien, Austria.
Electronic Supplementary Information (ESI) available: [Detailed experimental
procedures and copies of spectra]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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in acrylates and derivatives thereof. The simplest alternatives
would be alkyl halides,17-24 since they are typically liquid.
However, also these reagents have drawbacks since they are
environmentally problematic, toxic or carcinogenic and
therefore not an attractive substitute. Due to these
complications, it would be ideal to find alternative solid
reagents for short linear olefins. They should be cheap, bench
stable and therefore easy to handle and hence usable for small
scale synthesis (up to ~1 mmol) in academia or also in
pharmaceutical industry for instance during an initial library
synthesis for subsequent screening of potential drug
candidates. Within this contribution, our efforts in this
direction are reported.
R
View Article Online
DOI: 10.1039/C9OB00243J
H
a) or b)
N
N
H
N
N
H
1
Et
N
N
H
Ph
N
N
H
Ph
N
N
H
Ph
a) 68%
b) 25%
a) 62%
b) 55%
a) 60%
b) 56%
2
3
4
n-Pr
n-Bu
n-Hex
Results and discussion
Benzylic Amines and Catalytic Active Species
N
N
H
Ph
N
N
H
Ph
N
N
H
Ph
Recently we showed that those requirements were met with
tetraalkylammonium salts as surrogates for olefins.15 Upon
addition of potassium hydroxide to the reaction mixture it was
possible to generate the corresponding olefin in situ using
Hofmann elimination.31 During this work we demonstrated
ethylation and other n-alkylations (up to n-octylation) of N-
benzyl-2-aminopyridines (1) via C-H activation using the
corresponding quaternary ammonium salts and with moderate
to good yields. A recent contribution by Chatani and coworkers
used PhMe3NI as alkylating agent for aromatic C-H bonds as
well.32 Since quaternary ammonium salts are typically
prepared from the corresponding alkyl halides, we also
investigated a protocol which tried to use the alkyl halides
directly as olefin precursors.16 Also this transformation could
be realized successfully and Scheme 3 gives a comparison
between the two methods. Yields are usually 5-10% lower
(Scheme 1, products 3-7) for the alkyl halide protocol but only
for ethylation towards 2, a major difference between the
reaction with ethyl bromide (25%) and NEt4Br (68%) was
observed. It has to be mentioned that the latter reaction also
gave 63% yield if the reaction was performed under air,
showing that inert conditions or even handling of the reaction
in a glovebox is unnecessary.
a) 58%
b) 54%
a) 61%
b) 50%
a) 40%*
b) 42%
Et
5
6
7
N
N
H
N
N
H
N
N
H
8
a) 53%
9
a) 77%
10 a) 64%
Scheme 3 Comparison of alkylation with quaternary ammonium salt (a) or alkyl
bromides as alkylating agents (b); a) 1.0 equiv. quartanery ammonium salt, 3.0
equiv. KOH, 5 mol% [Rh(cod)Cl]2, toluene, 140 °C, overnight; b) 3.0 equiv. alkyl
bromide, 4.5 equiv. K2CO3, 5 mol% [Rh(cod)Cl]2, toluene, 160 °C, overnight;
reactions were conducted on a 50 mmol scale. * 84 h reaction time
Both protocols rely on the efficient generation of olefins by
elimination, which is the reason for the elevated temperature
for alkyl bromides (160 °C compared to 140 °C). In this case the
elimination requires not only higher temperatures, but also
the presence of the rhodium catalyst, which was shown by
control experiments (1-bromododecane or 1-bromo-2-
phenylethane were heated together with K2CO3 in toluene
with or without the presence of [Rh (cod)Cl]2. The
corresponding elimination products, dodec-1-en resp. styrene
were only detected by GC/MS when the catalyst was present)
in our previous publication.13
Both protocols require the addition of base to either neutralize
the formed acid (alkyl halide protocol) or to enable efficient
Hofmann elimination. Hence, it was expected that when using
hex-1-ene instead of 1-bromohexane as alkylating agent, the
base can be avoided since this is an overall neutral
transformation. However, we found that this is not that case
and base is also necessary, when using an olefin directly.13 The
curious reason for this was identified when the catalytically
active species was identified, which is described in the next
paragraphs.
The need for three equivalents of KOH to facilitate Hofmann
elimination has to be considered as a limitation for a broad
applicability, due to incompatibility with certain catalytic
systems since the Hofmann elimination and the alkylation
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n-Bu
occurred in a one-pot setup. Hence, we were searching for a
possibility to overcome this issue and the easiest way would
be a spatial separation of the olefin formation and the C-C
bond forming reaction, where in one reaction compartment
the gaseous olefin is produced, whereas on the other side the
C-H activation reaction can take place. Such a spatial
separation between the formation of a gaseous reagent and
another synthetic transformation was already developed by
Skrydstrup, in context of carbonylation reactions.33-35 As a first
test system we used again our model substrate 1. In chamber
one of a so called COware vial, the substrate and [Rh(cod)Cl]2
where placed, whereas the second chamber contained NEt4Br
and KOH (Scheme 4). Interestingly, there was no conversion
whatsoever in this experiment.
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[ filtration ]
a)
DOI: 10.1039/C9OB00243J
[Rh(cod)Cl]2
+
10 min
K2CO3
N
N
H
b)
6
n-hex-1-en + 1
a) r = 5.7 ± 0.4
b) r = 5.2 ± 0.3
Scheme 5: Filtration Experiments: 5 mol% [Rh(cod)Cl]2, and 3.0 equiv. K2CO3,
were prestirred in toluene at 150 °C for 10 min. Then, in experiment a) the solids
were removed by filtration and substrate 1 (1 equiv.) and n-hex-1-ene (3.0
equiv.) were added; in experiment b), the same prestirring conditions were used
and also the same amount of reagents added but without an intermediate
filtration step. Rates were determined by GC analysis of three individual runs
with dodecane as internal standard and are given in [10−5 mol·L−1·s−1].
Evaporation of the filtrate before adding substrate or olefin
gave a solid, which showed absorption at 1572.6 cm-1 in ATR-IR
measurements. This could be interpreted as a carbonato
species, since similar values were reported for such rhodium
complexes (1629 cm-1 for Cp*Rh(µ-O)2CO36 and 1586 cm-1 for
Ru(NHC)2(CO)2(CO3)37) which we proposed to be the most
likely catalytic active species. However, at that point we also
could not rule out a rhodium hydroxide species formed from
deprotonation of H2O introduced with K2CO3.14 Unfortunately,
it was not possible to confirm the identity of the obtained
material by X-ray crystallography, since no crystalline material
could be obtained. Now, in light of the result that our
Hofmann elimination protocol is carried out in presence of
KOH and not K2CO3 a rhodium carbonato species can be ruled
out. These new circumstances motivated us to investigate the
nature of the catalytically active species again and we
subjected the solids from the filtration experiments to MALDI-
MS analysis.
[Rh(cod)Cl]2
N
NH
x
N
NH
NEt4Br
+
KOH
1
2
COware
Ph
Ph
Scheme 4 Spatial separation of Hofmann elimination and alkylation.
Interestingly, [Rh(cod)Cl]2 was not detected even in trace
amounts and the only rhodium species found was
[Rh(cod)(OH)]2 (for details see supporting information). Origin
of the OH groups is the absorbed water on K2CO3, which also
explains our previous finding that the reaction rate drops with
the water content of K2CO3.14 In the quaternary ammonium
salt protocol, KOH can naturally serve as OH- source. This
strongly suggests that this hydroxido species is the catalytically
active one, which could be confirmed by a simple control
experiments using hex-1-ene as olefin (Scheme 6): When
[Rh(cod)(OH)]2 was used without the addition of base the
reaction proceeded even slightly better than with the
combination of [Rh(cod)Cl]2 and K2CO3.
In light of our previous efforts to determine the catalytically
active species,14 this result was not totally surprising to us.
There, we could associate a first order dependence for the
addition of inorganic base and an induction period in which we
hypothesized that the base (in this study K2CO3) reacts with
the catalyst to form the catalytic active species.14 In the course
of this study some filtration experiments were conducted. The
most important ones were the following: catalyst, K2CO3 and
toluene were heated to 150 °C the solids (basically K2CO3)
were filtered and substrate 1 and n-hexene were added to the
filtrate. It was found that in this reaction solution the
alkylation towards 6 proceeded with essentially the same rate
as compared to an experiment without filtration of solids
(Scheme 5). This result shows that the presence of K2CO3 is
only necessary during the first few minutes of the reaction in
the formation of the catalytically active species and does not
need to interact with the olefin or substrate.
5 mol% [Rh(cod)(OH)]2
or
5 mol% [Rh(cod)Cl]2
and 3.0 equiv. K2CO3
n-Bu
N
N
H
Ph
140 °C, toluene, overnight
N
N
H
Ph
1
6
+
3.0 equiv. n-hexene
72 % with [Rh(cod)(OH)]2
61 % with [Rh(cod)Cl]2
Scheme 6 Control experiments using different rhodium catalysts. Reactions were
performed on a 50 mmol scale.
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Having established [Rh(cod)(OH)]2 as catalytically active
species when olefins are used as alkylating agents, this had to
be confirmed for the Hofmann elimination protocol as well.
Hence, we carried out this method with either [Rh(cod)Cl]2 or
[Rh(cod)(OH)]2 and compared the kinetic profile (Figure 1). It
was found that when the hydroxido dimer was used as
catalyst, the reaction proceeds slightly faster, indicating the
absence of an induction period resulting from the initial
formation of the catalytic active species from [Rh(cod)Cl]2. At
the end of the reaction time, the overall conversion reaches
the same value of 80% after 3 hours (for [Rh(cod)(OH)]2 even
after 90 minutes).
View Article Online
DOI: 10.1039/C9OB00243J
catalyst
N
NH
NEt4Br
+
KOH
N
NH
2
COware
1
Ph
Ph
catalysis chamber
Catalyst
[Rh(cod)Cl]2
[Rh(cod)(OH)]2 65%
Hofmann elimination
chamber
Yield
0%
Scheme 7 Finding of catalytic active species. Chamber A: Substrate (0.5 mmol),
5 mol% catalyst, 2.0 mL toluene; chamber B. 2.0 equiv. Et4NBr, 6.0 equiv. KOH,
2.0 mL toluene. Reaction was run at 140 °C overnight.
At this time, we have demonstrated the possibility to
substitute olefins for alkyl bromides or quaternary ammonium
salts in direct alkylation reactions on a model substrate.
Additionally, we also identified the catalytically active species
in these reactions and showed that the Hofmann elimination
step can be separated from the alkylation reaction, opening
new possibilities regarding the catalyst systems to be applied
in combination with our Hofmann elimination/alkylation
method. The next task was to show that this method can be
applied in a more general manner to other substrates as well.
Investigating the generality of the Hofmann elimination/alkylation
protocol
Figure 1 Kinetic profile and comparison of the performance between [Rh (cod)
Cl]2 and [Rh (cod) (OH)]2 as catalysts in the ethylation reaction of 1.GC-Yields
were determined with dodecane as internal standard.
We already demonstrated the possibility to use tetraethyl
ammonium bromide as ethylene precursor in single examples
one two other systems with different catalysts, showing that
not only [Rh(cod)(OH)]2 can be used, but also other rhodium
and also ruthenium catalysts (see Scheme 8A7 and Scheme
8B38).15
Now, the two-chamber approach via COware vials was
revisited. This time, as indicated in Scheme 7, we charged
chamber A with [Rh(cod)(OH)]2 and substrate and chamber B
with KOH and ammonium salt. Contrary to the analogous
experiment with [Rh(cod)Cl]2 as catalyst, the reaction worked
well, and 65% of 2 were isolated.
A natural first choice for further application was the famous
Murai reaction.7 When we used acetophenone as substrate we
observed almost full conversion to a mixture of mono- (67%)
or bis-ethylated (25%) product when using 3.0 equivalents
ammonium salt and base in the one-pot approach (Scheme
8A). However, when we tried to broaden the scope towards
longer chain lengths a significant drop in conversion was
observed under the same conditions: Only 60% conversion was
reached when nPr4NBr was used as propylene precursor.
Prolonged reaction times and/or higher catalyst loadings could
not improve the yields. Only when a substantially excess of
base was added (9.0 equiv.), the reaction commenced to
almost full conversion, giving the desired product 13 now in
excellent 87% yield (Scheme 8A). In this case only small
amounts of bis-alkylated product were detected in GC/MS,
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indicating that mono-selectivity is brought about when longer concentration of olefin in the solution phase, since in the
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chain lengths are introduced.
originally published contribution, alsDoOI:h1i0g.h1039a/mC9oOuBn0t0s243oJf
unactivated olefins (5.0 equiv.) were necessary for full
conversion of the material. In such cases, a pressurized
reaction with olefin gas might be the better choice since
alternatively large quantities of solid quaternary ammonium
salts have to be applied.7
R
A
3.0 equiv. KOH
3.0 equiv. Alk4NBr
O
O
4-5 mol% RuH2(CO)(PPh3)3
toluene, 150 °C, overnight
The next substrate to be tested was 16 carrying
a
11
dihydrooxazole as directing group. Initially, again the one-pot
protocol was investigated, since it is the operationally simpler
one. Originally, this transformations was published with
Ru3CO12 as catalyst and 7 atm of ethylene yielding 53%
product and 20% of a CO containing by-product.40 However, in
our hands Ru3CO12 proved to be unreactive towards alkylation
either in a one-pot fashion or in COware vials. Hence, we
tested again [Rh(cod)Cl]2 as catalyst and now ethylation was
achieved giving 17 in 29% yield (Scheme 10A, 40% starting
material were recovered, → 48% base on recovered starting
material).
O
O
O
+
13 87%a
12a 67%
12b 25%
B
5 mol% RhCl(PPh3)3
3.0 equiv. KOH
150 °C, toluene
OMe
+
O
overnight
N
N
12.0 equiv. KOH
4.0 equiv. Et4NBr
then 1N HCl
Br
3.0 equiv.
Me
O
Me
O
14
12a 39%
12 mol% [Rh(cod)Cl]2
a
Scheme 8 A: Alkylation with acetophenone as substrate; 0.5 mmol scale, 9.0
equiv. KOH were used. Yield was determined out of the mixture of substrate and
product. B: Imine-directed C−H alkylation reaction with tetraethylammonium
bromide as an alkyl source
N
N
toluene, 140 °C, 144 h
17 29 %
16
Scheme 10 A: Ethylation with dihydroxazole directing group.
When further increasing the chain length to n-butyl, the
conversion was diminished to only 40% and isolation of the
product was not possible any more due to additional by-
product formation. Apparently, the ammonium salt is not the
only species reacting with OH- to induce Hofmann elimination,
but also the enolate of the substrate is generated forming
product 15 (detected by GC/MS) upon reaction with the
ammonium salt as indicated in Scheme 9.
As final example 2-phenylpyridine 18 was tested, since this
substrate is often used as model system for developing new C-
H activation reactions41-48 Intrigued by the reported high yields
and mono-selectivity, we probed an alkylation protocol with
terminal olefins initially published in the group of Ackermann
(Scheme 10B).49
First, the reaction was tested with tetraethyl ammonium
bromide in a one-pot approach. Here a maximum conversion
of 80% was achieved according to GC/MS. When ammonium
salts with longer alkyl chains were used, the desired products
were only formed in traces, indicating again a special role for
ethylene. These findings motivated us to probe the reaction in
the two-chamber reactor. Gratifyingly, this solved the problem
and all reactions performed with good conversion (>80%) for
all tested ammonium salts (see Table 1). A direct comparison
to the Ackermann results is only possible for hexylation, since
no shorter olefins were used in this contribution due to the
already mentioned issues with the physical properties of
shorter olefins. Our yield for the n-hexylated product 23 was
comparable to the one achieved in literature with the olefin
with 72% of 23 in our protocol and 78% in literature (see entry
5).49 The yields remain essentially the same if shorter olefin
surrogates were used (Entry 3, 21, n-butyl 75% and Entry 4, 22,
n-pentyl 71%). However, when Et4NBr and n-Pr4NBr were
used, the bis-alkylated (19b and 20b) products were also
formed. While for the propyl-derivative only 4% side product
20b was generated (Entry 2), the bis-ethylated product 19b
was produced in almost the same amounts as the desired
K+
O
O
nBu4NBr
+
N(n-Bu)3
15
Scheme 9 Possible side-product formation during the modified Murai–Chatani–
Kakiuchi reaction
The aforementioned two chamber approach would clearly
avoid this problem. However, when applied even with the
more reactive propene surrogate, the conversion was lower
compared to the one-pot protocol (60% for 9.0 equiv. KOH and
3.0 equiv. ammonium salt). Still, GC/MS analysis showed
essentially complete absence of side products.
The fact that the conversion decreases with increasing chain
length of the ammonium salt and that the elimination to the
alkene gets slower by longer chain lengths39 facilitates the
occurrence of side reactions induced by the presence of KOH.
Hence, additional base cannot completely solve this problemin
this specific case, since it increases not only the rate of
Hofmann elimination, but also of by-product formation. Why
the two-chamber approach does not improve the butylation
reaction significantly might be explained by a too low
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product 19a (Entry 1). This interesting effect suggests that the to be transformed to [Rh(cod)(OH)]2 first. Efforts for further
View Article Online
DOI: 10.1039/C9OB00243J
excellent mono-selectivity of the original protocol (no generalization of our protocol are ongoing in our laboratory.
formation of any bis-alkylation products) is not only
determined by the in-situ formed sterically demanding
ruthenium complex, but also by the size of the olefin. It can be
Conflicts of interest
expected that this specific example will not be unique in this
regard.
There are no conflicts to declare.
Table 1 Reactions were run in two chamber reactor. Chamber A was charged with 0.4-
0.5 mmol 2-phenylpyridine, 5 mol% catalyst and 15 mol% KO2CMes. Chamber B
contained 3.0 – 3.5 equiv. ammonium salt and a threefold amount of KOH. 1 mL
toluene was added to both chambers. Mixtures were heated at 140 °C overnight. a
Literature 78%
Notes and references
1.
2.
3.
4.
F. Roudesly, J. Oble and G. Poli, J. Mol. Catal. A: Chem.,
2017, 426, 275-296.
J. R. Hummel, J. A. Boerth and J. A. Ellman, Chem. Rev.,
2017, 117, 9163-9227.
J. Wencel-Delord, F. W. Patureau and F. Glorius, Top.
Organometal. Chem., 2016, 55, 1-27.
catalysis chamber (A)
R
[Ru(p-cym)Cl2]2
N
M. Moselage, J. Li and L. Ackermann, ACS Catal., 2016, 6,
498-525.
KO2CMes
+
N
N
5.
6.
J. Q. Yu, Adv. Synth. Catal., 2014, 356, 1393-1393.
X. S. Xue, P. Ji, B. Zhou and J. P. Cheng, Chem. Rev., 2017,
117, 8622-8648.
R
R
R
19-23
18
7.
8.
S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M.
Sonoda and N. Chatani, Nature, 1993, 366, 529-531.
C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G.
Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-
Delord, T. Besset, B. U. W. Maes and M. Schnürch, Chem.
Soc. Rev., 2018, 47, 6603-6743.
KOH
Hofmann elimination
chamber (B)
+
NR'4Br
Entry
R
Monoalkylation [%}
Bisalkylation [%]
9.
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H
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65 (20a)
75 (21)
71 (22)
72a (23)
35 (19b)
Me
Et
4 (20b)
10.
0
0
0
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n-Bu
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be used as solid surrogates for simple unactivated alkenes
using Hofmann elimination for in situ formation of olefins. The
method is especially useful for substituting olefins with up to
five carbons, since these olefins are either gaseous or very low
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Even though Hofmann elimination requires excess of KOH, the
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propylene gave mixtures of mono- and bis-alkylation products,
whereas from butylene on the reaction was mono-selective.
Furthermore, the two-vessel approach also allowed the
identification of the catalytically active species of the originally
investigated alkylation reaction of N-benzyl-2-aminopyridines,
by showing that [Rh(cod)Cl]2 is catalytically inactive and needs
6 | J. Name., 2012, 00, 1-3
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