Quaternary Ammonium Salts as Alkylating Reagents in C-H Activation Chemistry

Article abstract of DOI:10.1021/acs.orglett.7b01946

A rhodium(I)-catalyzed alkylation reaction of benzylic amines via C(sp³)-H activation using quaternary ammonium salts as alkyl source is described. The reaction proceeds via in situ formation of an olefin via Hofmann elimination, which is the actual alkylating reagent. This represents an operationally simple method for substituting gaseous and liquid olefins with solid quaternary ammonium salts as alkylating reagents, which is transferable to other C-H activation protocols as well.

Full text of DOI:10.1021/acs.orglett.7b01946

Letter
pubs.acs.org/OrgLett
Quaternary Ammonium Salts as Alkylating Reagents in C−H
Activation Chemistry
Manuel Spettel, Robert Pollice, and Michael Schnurch*
̈
Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163-OC, Vienna 1060, Austria
S
* Supporting Information
ABSTRACT: A rhodium(I)-catalyzed alkylation reaction of benzylic amines via C(sp3)−H activation using quaternary
ammonium salts as alkyl source is described. The reaction proceeds via in situ formation of an olefin via Hofmann elimination,
which is the actual alkylating reagent. This represents an operationally simple method for substituting gaseous and liquid olefins
with solid quaternary ammonium salts as alkylating reagents, which is transferable to other C−H activation protocols as well.
introduction of short-chained alkyl chains using solid starting
materials.
Our approach was based on a very fundamental organic
reaction, taught in every basic Organic Chemistry course: the
Hofmann elimination.6 In this transformation a quaternary
ammonium salt eliminates to the least substituted olefin and a
tertiary amine (Scheme 1). Since quaternary ammonium salts are
elective C−C bond-forming reactions are very fundamental
Sand often-used reactions in organic chemistry, since they are
key to building the skeletons of any organic compound. Among
the plethora of reported C−C bond forming reactions, metal-
catalyzed transformations have gained significant prominence,
initially, due to the Nobel prize-winning chemistry of cross-
coupling reactions,1 and, more recently, due to transition-metal-
catalyzed C−H activation reactions,2 which can be considered as
the logical advancement of cross-coupling reactions. These
reactions generally eliminate the need for at least one
prefunctionalized substrate by replacing it with a C−H bond,
giving rise to more step- and atom-efficient transformations.
Additionally, C−H activation methods often show remarkable
functional group tolerance. Thus, in recent years, C−H activation
processes forassemblyand functionalization oforganic molecules
were able to greatly simplify the synthesis of pharmaceuticals,
natural products, and general feedstock chemicals.3
Among C−H transformation methods, alkylation reactions are
tremendously important and frequently used in the organic
laboratory. Conventional approaches use either primary alkyl
halides4 or olefins5 as alkylation agents, whereas both alkyl
sources have their advantages and disadvantages. Alkyl halides are
applied in general when an electrophilic carbon atom is needed.
Using alkyl halides faces the drawback of producing stoichio-
metric amounts of byproducts, which lowers the overall atom
efficiency of the reaction. Olefins as alkylating reagents are highly
atom efficient in C−C bond-forming reactions, and they have
been also used successfully in transition-metal-catalyzed C−H
activation reactions in numerous examples in the past two
decades.5 However, one drawback is faced when short-chained
alkyl chains should be introduced, since the required olefins are
gaseous and therefore high-pressure equipment is typically
required. The goal of the present work was to find an alternative
alkyl source, which acts as an olefin surrogate and allows
Scheme 1. A Hofmann Elimination Step Generates the Olefin
in Situ.
solid materials, they would represent an easy-to-handle olefin
replacement, eliminating the need for high-pressure equipment if
the elimination can take place under the same reaction conditions
required for the subsequent C−H activation step.
In our case, we had previously reported on a Rh(I)-catalyzed
alkylation reaction of 1 with olefins, which served as a model
reaction to test our hypothesis (Scheme 2).7
In a first experiment, the reaction conditions of this original
protocol were used on substrate 1 but the olefin was replaced with
Scheme 2. Reaction Scheme for Using the Olefin Directly
Received: June 26, 2017
© XXXX American Chemical Society
A
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Table 1. Selected Base Screening Results for Alkylation of 1
a
Using Quaternary Ammonium Salts
b
entry
1
no.
R
base
time [h]
yield [%]
2
4
4
4
4
4
4
4
4
ethyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
K2CO3
K2CO3
C4H9OK
NaH
28
28
28
28
28
28
3
80
4
c
2
3
4
5
6
24
traces
56
72
72
71
72
NaOH
KOH
d
7
KOH
e
8
f
KOH
3
9
KOH
3
a
General reaction conditions: Substrate 1 (50 mmol, 1 equiv),
Figure 2. Using quaternary ammonium salts with longer alkyl chains
resulted in low conversion when employing the initial reaction
conditions.
tetraalkylammonium salt (1 equiv), additive Ag2CO3 (5 mol %),
catalyst [RhCl(cod)]2 (5 mol %), toluene (2 mL), 140 °C, argon
b
atmosphere. Yields determined by calibrated GC-Analysis relative to
c
d
dodecane as internal standard. Temperature 160 °C. No additive.
e
f
No additive, 2 equiv tetraalkylammonium salt. No additive, 10 mol %
had already completed after 3 h. Encouraged by these good initial
results, we tried to use other quaternary ammonium salts with
longer alkyl chains (Figure 2, entries 2−6). Surprisingly, all of
these examples showed very low conversion, and only 3−11% of
the corresponding product was detected by GC-MS analysis
(Figure 2).
[RhCl(cod)]2.
Scanning the literature to find an explanation for this
observation brought forward a study by Pivovar and co-workers.9
In a computational study of reactions of hydroxide with
quaternary ammonium salts they calculated the Gibbs free
energies of activation for the Hofmann elimination of
tetraalkylammonium salts and found that, when moving from
tetraethylammonium to tetrapropylammonium salts, the Gibbs
free energy of activation increases significantly. However, it does
not get much higher when going to even longer alkyl chains.
Thus, further optimization focused on accelerating the
Hofmann elimination step in order to produce olefin in the
reaction mixture more rapidly and to increase the overall rate of
the reaction. These reactions were carried out using tetrabuty-
lammonium chloride as a but-1-ene source. Since a higher
temperature (Table 1, entry 2) did not improve conversion, it was
tested whether bases other than K2CO3 would have a beneficial
impact. Potassium tert-butoxide already showed an improved
conversion of 24% (Table 1, entry 3), but sodium hydride gave
only traces of the desired product (Table 1, entry 4).
A major leap forward was the use of NaOH, which already gave
56% conversion (Table 1, entry 5), which was further surpassed
by using KOH (Table 1, entry 6). This goes in line with the lower
stability, and hence more rapid Hofmann elimination, of
quaternary ammonium hydroxides in comparison to the
corresponding halides.10 The better conversion of KOH could
be attributed to the lower water content of this base as compared
to NaOH, which is very hygroscopic. In previous experiments, we
have already shown that a too high water content is detrimental
for the alkylation reaction with olefins.7 Moreover, when using
KOH, no more additives were needed and the base loading could
be reduced slightly as well. In addition, the reaction accelerated
significantly and completed within 3 h. Additionally, the yield is
similar to that of the transformation using olefins as the alkyl
source (Table 1, entry 7). Since the reaction always stopped
around 68−73% conversion to the desired alkylated product,
Figure 1. Reaction always leads to the same byproducts to some extent.
tetraethylammoniumbromide. ItwasfoundthatusingK2CO3 asa
base in the ethylation, although not very fast, yields the desired
product showing good conversion within 28 h (Table 1, entry 1).
Before further optimization efforts were undertaken, it was tested
whether the counterion has an impact on the conversion. It was
found that switching to tetraethylammonium chloride or iodide
gave essentially the same yield (see Supporting Information),
which means that quaternary ammonium salts can be selected
according to their availability and price without worrying about
the nature of the halide ion. Notably, 1 equiv of the
tetraalkylammonium salt is sufficient to obtain good conversion.
It has to be mentioned that it was not possible to achieve full
conversion of the product and about 5−10% of starting material
remained, which could be recovered. Additionally, the same
byproducts were detected in every reaction (Figure 1). We had
shown previously that the substrate 1 and byproducts of type BP1
and BP2 are in equilibrium,7a which explains the incomplete
conversion of the starting material. All three byproducts require
that the catalyst is able to break C−C bonds as well, besides
forming the desired new C−C bond. This behavior of rhodium
was reported previously.8
The long reaction time of 28 h suggested that the turnover-
limiting step is the Hofmann elimination under these conditions,
since the corresponding reaction with olefins (e.g., hex-1-ene)
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Figure 3. Scope of the reaction using different lengths of alkyl chains at
the tetraalkylammonium salt. General reaction conditions: Substrate 1
(50 mmol, 1 equiv), tetraalkylammonium bromide (1 equiv), catalyst
[RhCl(cod)]2 (5 mol %), KOH (3 equiv), dry and degassed toluene (2
mL), 140 °C, overnight, argon atmosphere.
modifying the amount of reagent or catalyst was tested, but did
not show beneficial impact (Table 1: entries 8−9).
With the optimized protocol in hand, we performed alkylation
reactions with different quaternary ammonium salts using various
substrates similar to 1 to demonstrate the scope of the present
transformation. First, we used different tetraalkylammonium salts
with a carbon chain length up to C8 (Figure 3, products 2−7).
Prolonging the chains up to C6 gave the same isolated yield,
within experimental error (compounds 2−6, 58−68%). Only
with tetraoctylammonium bromide, the reaction slowed down,
always stopping at 40% yield (Figure 3, 7).
Figure 4. Scope of isolated compounds using our alkylation conditions
exploiting different substrates similar to 1. General reaction conditions:
Benzylic amine (50 mmol, 1 equiv), tetraethylammonium bromide (1
equiv), catalyst [RhCl(cod)]2 (5 mol %), KOH (3 equiv), dry and
degassed toluene (2 mL), 140 °C, overnight, argon atmosphere.
reactions usingolefinsshouldbeaccessible toourprotocol aslong
as the catalyst and substrates tolerate the presence of KOH.
About three decades ago, the Murai group set a landmark in
directing group-assisted C−H activation.11 They used a ketone as
directing group to guide the alkylation in a specific position. More
specifically, the group used acetophenone and alkylated the
aromatic ortho-position, exploiting a Ru(II)-catalyst and using
olefins as alkylating agents. We choose this very fundamental
reaction for the field of C−H activation to test our new protocol
further, using the 1993-published reaction conditions, but
substituting olefins for tetraalkylammonium salts and adding
KOH to the reaction (Scheme 3).
To increase atom efficiency, it was also tested whether
trimethylhexylammonium bromide could be used for hexylation
of 1. Interestingly, in this case only 8% of hexylated product 7 was
detected, accompanied by 12% of the methylated product. Since
the methylation cannot proceed via an olefin intermediate, it is
hypothesized that a Rh-carbene species is involved in this
reaction, but further investigations are required to confirm this.
Furthermore, we changed the substitution pattern at the 3-
pyridyl-position, as well as at the benzylic para-position of our
starting material. These substrates were tested solely in the
ethylation reaction, since this is the most attractive application of
ourprotocol. AscanbeseeninFigure4(compounds8−16)again
the same range of yield was obtained (50−71%). The substituent
in position 3 of the pyridine has basically no influence on the yield
of the transformation (Figure 4, 8−11). The substituents on the
benzyl group did have an influence, although not a significantly
dramatic one. It was observed that electron-donating moieties at
the benzylic para-position increase the conversion and yield in
comparison to the unsubstituted starting compound 1 (Figure 4,
13 and 15). A 4-methoxy- or 4-isopropoxy group gave good yields
of 71% and 69%, respectively. On the other hand, electron-
withdrawing substituents seem to have an unfavorable impact on
the conversion since both a 4-CF3- and 4-F-group decreased the
yield to 53% and 50%, respectively (Figure 4, 14 and 16).
Next, it was tested whether the developed alkylation protocol is
only limited to our type of substrate and catalyst, since the utility
andacceptanceoftheprotocoldependlargelyonthepossibilityof
general applicability. It was hypothesized that other alkylation
Scheme 3. Reaction Scheme for Applying Our Ethylation
Protocol to the C−H Alkylation Reaction Conditions
Published by Shinji Murai in 19935
The reaction worked well with a 67% yield of 18 (Murai
reported 75% using triethoxyvinylsilane as an alkylating
reagent11), showing that a different directing group can be
applied for use in conjunction with our method and that it is not
limited to rhodium catalysts. As typically found in direct
functionalization of acetophenone, considerable amounts of
diethylated byproduct 19 were formed.
C
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ORCID
Scheme 4. Reaction Scheme for Imine-Directed C−H
Alkylation Reaction with Tetraethylammonium Bromide as an
Alkyl Source8
Michael Schnurch: 0000-0003-2946-9294
Notes
̈
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01946.
Detailed experimental procedures and analytical data of all
synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.schnuerch@tuwien.ac.at.
D
DOI: 10.1021/acs.orglett.7b01946
Org. Lett. XXXX, XXX, XXX−XXX