New Insights into the Reaction Capabilities of Ionic Organic Bases in Cu-Catalyzed Amination

Article abstract of DOI:10.1002/ejoc.201900109

The application of ionic organic bases in the copper-catalyzed amination reaction (Ullmann reaction) has been studied at room temperature, with sub-mol-% catalyst loadings, and with more challenging amines at elevated temperatures. The cation present in the base has been shown to have little effect on the reaction at standard catalyst and ancillary ligand loadings, whereas the choice of anion is crucial for good reactivity. A substrate scope carried out at room temperature with the best performing bases, TBAM and TBPM, showed both bases to be highly effective under these mild reaction conditions. Moreover, under sub-mol % catalyst loadings and room temperature conditions, TBPM gave good to excellent yields for a number of different amines and functionalized aryl iodides (14 examples). However, reactions involving more challenging amines gave little or no yield. By using more forceful conditions (120 °C) moderate to excellent yields of cross-coupled products containing more challenging amines was achievable using TBPM and to a lesser extent with TBAM. As part of this work a study on the stability of the organic bases at 120 °C was undertaken. TBAM is shown to decompose to give nBu₃N and mono-butylmalonate at higher temperatures, and this can be correlated to a decrease in performance in the coupling reaction. The phosphonium cations in TBPM did not undergo analogous reactivity but were shown instead to experience some degree of deprotonation at the α-CH₂ to generate phosphonium ylides. This however did not lead to a significantly degradation in the activity of the TBPM in the cross-coupling reaction.

Full text of DOI:10.1002/ejoc.201900109

DOI: 10.1002/ejoc.201900109
Full Paper
Cross Coupling
New Insights into the Reaction Capabilities of Ionic Organic
Bases in Cu-Catalyzed Amination
[
a]
[b]
[a]
[a]
Quintin A. Lo, David Sale, D. Christopher Braddock, and Robert P. Davies*
Abstract: The application of ionic organic bases in the copper- little or no yield. By using more forceful conditions (120 °C)
catalyzed amination reaction (Ullmann reaction) has been stud- moderate to excellent yields of cross-coupled products contain-
ied at room temperature, with sub-mol-% catalyst loadings, and ing more challenging amines was achievable using TBPM and
with more challenging amines at elevated temperatures. The to a lesser extent with TBAM. As part of this work a study on
cation present in the base has been shown to have little effect the stability of the organic bases at 120 °C was undertaken.
on the reaction at standard catalyst and ancillary ligand load- TBAM is shown to decompose to give nBu N and mono-butyl-
3
ings, whereas the choice of anion is crucial for good reactivity. malonate at higher temperatures, and this can be correlated to
A substrate scope carried out at room temperature with the a decrease in performance in the coupling reaction. The phos-
best performing bases, TBAM and TBPM, showed both bases to phonium cations in TBPM did not undergo analogous reactivity
be highly effective under these mild reaction conditions. More- but were shown instead to experience some degree of deproto-
over, under sub-mol % catalyst loadings and room temperature nation at the α-CH to generate phosphonium ylides. This how-
2
conditions, TBPM gave good to excellent yields for a number of ever did not lead to a significantly degradation in the activity
different amines and functionalized aryl iodides (14 examples). of the TBPM in the cross-coupling reaction.
However, reactions involving more challenging amines gave
Introduction
ported by Liu et al. in 2009,[17] where they were shown to be
able to efficiently promote Ullmann C–N cross coupling reac-
tions with aryl iodide and bromide substrates at room tempera-
ture or 0 °C in the presence of 10 mol-% of copper and 20 mol-
A substantial number of pharmaceuticals, organic materials,
and natural products contain C–N bonds, with aryl amines serv-
ing as important building blocks in many organic synthesis
endeavors. The preparation of these aryl amines commonly in-
volves the activation of aryl halide precursors using a Pd-based
%
ligand (N,N′-dimethylglycine or L-proline). We have recently
reported upon the use of bis(tetra-(n-butyl)phosphonium) mal-
onate (TBPM) for the C–N cross coupling reaction between
[
1–5]
catalytic system.
in the equivalent Cu-catalyzed cross-coupling reaction (the Ull-
However, there is a rapidly growing interest
[
22]
piperidine and iodobenzene.
Unlike inorganic bases such as
K PO , TBPM is completely soluble in the reaction medium
3
4
[
6–11]
mann reaction) both from academia and industry.
is copper significantly cheaper and less toxic than palladium, it
also uses cheaper and lower molecular weight ligands such as
Not only
DMSO. Hence by using TBPM we were able to mitigate mass
transfer effects commonly observed with poorly soluble inor-
ganic bases in organic solvents and therefore obtain in-situ
kinetic data on these systems. This allowed us to suggest
improvements to the understanding of the reaction mechanism
[
12–19]
1,10-phenanthroline or amino acids.
Many recent advan-
ces in copper catalyzed amination have concerned the discov-
ery of new ligand systems to improve the reactivity, particularly
towards more challenging substrates such as aryl chlorides.
[
21,22]
and catalyst deactivation pathways.
[
11]
Despite these recent advances there are still very few reports
concerning the study and optimization of room-temperature
However, the base has also been shown to play a crucial role
in the reaction, in some cases acting as a ligand as well as a
[
21,23–26]
[
19–21]
reactions in copper catalysis.
work on room-temperature reaction systems with inorganic
PO base using relatively high catalyst and ligand loadings
10 and 20 mol-% respectively),
Following on from our
base,
and playing a role in catalyst deactivation pathways.
We have recently been interested in the application of solu-
ble organic bases for copper catalysis.[
21,22]
K
(
3
4
These were first re-
[
21]
we sought to investigate a
range of organic ammonium and phosphonium bases for use
in Ullmann catalytic systems. An initial organic base screening
was first carried out in order to widen the scope of studied
species. As a consequence, a room temperature reaction system
using low catalyst and ligand loadings has now been devel-
oped, and studies on the stability and performance of the or-
ganic bases with challenging substrates at elevated tempera-
tures are reported.
[
[
a] Department of Chemistry, Imperial College London
White City Campus, 80 Wood Lane, London W12 0BZ, United Kingdom
E-mail: r.davies@imperial.ac.uk
https://www.imperial.ac.uk/people/r.davies
b] Process Studies Group, Syngenta
Jealott's Hill Research Centre, Bracknell, Berkshire RG42 6EY,
United Kingdom
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900109.
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Results and Discussion
could be indicative of N-methylglycinate and L-prolinate anions
being poor bases for the cross-coupling reaction (pKa of
Organic Base Screening
N-methylglycine and L-proline in H O are 2.23 and 1.19 respec-
2
tively, while pK of oxalic, malonic, succinic, adipic and phthalic
a
Previous studies on the application of organic bases in copper-
catalyzed couplings have mainly focused upon the use of phos-
phonium or ammonium cations with relative simple inorganic
[
32]
acids in H O are > 4.19).
We therefore turned our attention
2
to dicarboxylate bases. In general, these bases gave moderate
to excellent reactivity in the C–N cross coupling reaction. In-
spection of the results obtained with TMAM, TBAM and TBPM
anions such as PO43 CO3 , OAc , or C O
–
2–
–
2– [17]
.
However the
most efficacious systems were shown to be based on organic
,
2 4
(B3, B4 and B7 respectively, Table 1) suggests that the cation
[
17]
carboxylates such as malonate and adipate.
In addition, we
has little effect on reactivity under these conditions. However,
the structure of the dicarboxylate plays a larger part in the ob-
served reactivities with malonate giving the highest yield of
product.
have previously demonstrated how malonate anion in the base
is also able to act as a ligand for the copper center in the cou-
pling reaction, leading to improved kinetic reactivity than ex-
[
21,22]
pected based on just pK considerations.
Given this we
a
now report upon the preparation of a number of organic
ammonium and phosphonium carboxylate bases and their ap-
plication in the room temperature copper-catalyzed reaction
Substrate Scope with TBAM
The initial organic base screening results show both TBAM and
TBPM (B4 and B7, Table 1) to be the most effective bases in
promoting C–N cross coupling reactions at room temperature
(
Table 1). As far as we are aware, with the exception of TBPM,
[
17]
TBAA and TBPA (B5, B7 and B9 respectively, Table 1),
all
organic bases reported in Table 1 have not previously been
employed in Ullmann C–N cross coupling reactions. However
some have been used as ionic liquids or as catalysts for aminox-
(
Table 1). Although TBPM (B7) has been reported before by Liu
[
17]
et al.,
TBAM (B4) has not previously been studied in this
[
27–31]
reaction. Advantages of using TBAM (B4) over TBPM (B7) in-
clude the lower cost of the tetraalkylammonium hydroxide pre-
cursor relative to its phosphonium counterpart. In addition, it
was observed during the synthesis of ammonium bases that
they are significantly less hygroscopic relative to phosphonium
bases, with lower rates of water absorption (see ESI, Table S1).
This allows better reaction performance to be obtained in the
ylation of aldehydes.
All organic bases were prepared by
reacting either tetraalkylammonium hydroxide or tetraalkyl-
phosphonium hydroxide with the corresponding acid. They
were subsequently dried under high vacuum for 2 to 3 days.
Table 1. Room temperature Ullmann coupling with organic bases.
Table 2. Room temperature Ullmann coupling with TBAM and TBPM across a
range of subtrates.
Although N-methylglycine and L-proline as auxiliary ligands
are known to promote high yields and reactivity in C–N cross
[
21]
coupling reactions,
the organic bases containing these li-
gands in deprotonated form, namely TBANM and TBALP (B1
and B2, Table 1), both demonstrated no reactivity (Table 1). This
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C–N cross-coupling reaction as addition of just 10 mol-% of catalyst loading even further with this base unfortunately led
H2O will lead to a reduction in yield from 98 % to 0 % with to a significant decrease in yield (Table 4). As before, extending
TBPM. No residual water was present in organic bases prepared the reaction time to 36 h gave no noticeable improvement in
in Table 1.
A substrate scope involving both TBAM and TBPM (red and
reaction performance with either 0.05 or 0.1 mol-% Cu loading.
Table 4. C–N coupling reactions with TBPM using different catalyst and ligand
loadings.
blue respectively, Table 2) was carried out with 14 different
primary/secondary amines and aryl halides. Both TBAM and
[
17]
TBPM gave similar yields (entries 1a – 1j, Table 2).
While aniline itself (1j, Table 2) was found to be a competent
N-nucleophile under conditions shown in Table 2, further sub-
stitution to the aniline core proved to be deleterious (entries
1
k - 1n, Table 2) – this is a previously reported issue for all
[
21]
Ullmann amination reactions.
Entry
CuI (mol %)
Yield [%]
1
2
3
4
5
6
7
0
0
Room-Temperature Sub-Mol % Reactions
0.05
0.1
0.5
2.5
5
38
42
98
98
98
98
One of the main practical challenges facing the Ullmann reac-
tion is the requirement for high copper catalyst loadings
(
< 5 mol-% is rare). Nevertheless, recent work carried out in the
groups of Norrby, Ling, Jiang and Ma have shown that the use
of sub-mol % Cu loadings in the Ullmann amination reaction is
10
[
33–39]
achievable in some situations.
However, these reactions
Attempts to optimize the sub-mol % reaction systems by
still required either high loadings of auxiliary ligand (10–20 mol- varying reaction concentration (i.e. solvent volume) were car-
[
33–37]
%
DMEDA),
or elevated reaction temperatures (50– ried out with TBAM, TBPM and K
tively). Although diluting the reaction gave a modest improve-
By exploiting the high activity observed with organic bases ment in yield with TBAM and K PO (B4 and B11), the perform-
3 4
PO (B4, B7 and B11 respec-
[
33–36,38,39]
135 °C).
3
4
it was thought that it might be possible to achieve a room ance of these reactions was still sluggish relative to TBPM (B7)
temperature sub-mol % Ullmann reaction system that does not at similar catalyst loadings (Figures S1–S2). No improvements in
require a large excess of auxiliary ligand relative to Cu. Thus, yield on dilution were observed with TBPM (B7) at any of the
several ammonium and phosphonium bases were selected studied Cu loadings (Figure S3).
based on their performance in the initial base screening
Table 3), where sub-mol % catalyst loading (0.5 mol-%) was tems,[
used in the reaction between benzylamine and phenyl iodide lyst in our system did not aid reactivity with either TBAM, TBPM
Table 3). Much to our delight, TBPM proved to be a suitable or K PO bases (B4, B7 and B11 respectively). In fact, using a
Contrary to observations by Norrby and Ling for their sys-
33,37]
(
using a large excess of ligand relative to the Cu cata-
(
3
4
base at a catalyst loading of 0.5 mol-% whereas other organic large excess of ligand led to a decrease in reaction yield
bases were less effective. A greater variation in reaction yield (Table 5). This is possibly due to catalyst deactivation – previous
vs. base was observed at the lower catalysts loading of 0.5 mol- mechanistic studies have demonstrated how an excess of
%
CuI compared to 10 mol-% CuI. Extending the reaction time N-methylglycine can lead to catalyst deactivation and low turn-
to 36 hours gave no noticeable improvement in reaction yield over numbers.
[
21]
for all bases. Therefore, the difference in reactivity exhibited by
different bases is most likely caused by catalyst deactivation
under these conditions.
Table 5. C–N coupling reactions with different bases using different ligand
loadings.
Table 3. C–N coupling reactions using 0.5 and 10 mol-% Cu loading.
Entry
Base
Yield [%] 1 mol-%
Yield [%] 20 mol-%
N-methylglycine
N-methylglycine
1
2
3
TBAM (B4)
TBPM (B7)
K PO (B11)
3 4
68
80
35
92
98
98
Entry
Base
Yield [%] 0.5 mol-% CuI Yield [%] 10 mol-% CuI
1
2
3
4
5
TMAM (B3)
TBAM (B4)
TBPO (B6)
TBPM (B7)
68
80
76
98
35
92
98
95
98
98
Based on these results TBPM (B7) was taken forward for fur-
ther study as the most promising base under these conditions.
A range of amines were aminated at room temperature with
3 4
K PO (B11)
Results in Table 3 reveal TBPM (B7) to give the best perform- excellent reactivity observed (entries 1a – 1j, Table 6). The re-
ance under sub-mol % catalyst loadings. Attempts to lower the quired reaction time varied depending on the substrate: the
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syntheses of 1a and 1e were complete in approximately 5 and within 0.5 h (Figure S4). However, when TBAM (B4) was heated
1
7
hours respectively, while other substrates required 18–24 to 120 °C for a more prolonged period of time (Table 7), H and
1
3
hours to reach maximum yield. Hence, all reactions were carried
out for 24 hours.
C NMR analysis showed significant degradation of the TBAM
(up to 26 % after 24 h) and generation of equimolar amounts
of nBu N and mono-butylmalonate (Table 7 and Figures S4–S6).
3
Table 6. Coupling reaction between amines and aryl iodides using sub-mol %
catalyst loadings.
These products are most likely formed via a S 2 attack of the
N
[
40]
malonate nucleophile on the tetrabutylammonium cation.
Unfortunately attempts to isolate a pure sample of tetra-n-
butylammonium mono-butylmalonate were unsuccessful.
3
Table 7. Degredation of TBAM (B4) to form nBu N and mono-butylmalonate.
Entry
Time [h]
% degradation
1
2
3
4
0
1
4
24
0
Trace
22
26
1
VT- H NMR analysis (30–120 °C) was also carried out with the
phosphonium salt analog TBPM (B7). A complete H/D exchange
reaction occurred at the α-CH of the phosphonium cation at
2
>
50 °C (Figures S7 and S8). A similar exchange reaction has
[
41]
been reported by Chu et al. in phosphonium ionic liquids. It
has also been reported in the ionic liquid literature that under
suitably basic conditions phosphonium cations can be deproto-
nated to generate phosphonium ylides, with H/D exchange at
the α-CH of the phosphonium cation most likely proceeding
2
As far as we are aware this is the first reported room-temper-
ature copper-catalyzed sub-mol % catalytic system that can be
carried out without the need for an excess of auxiliary ligand
[42–44]
via such a ylide.
Since a basic malonate dianion is present
in TBPM (B7), we wanted to determine if it too will exhibit
similar reactivity. To this end, benzaldehyde was added to a
[
37]
loading.
However, similar to entries 1k - 1n in Table 2, chal-
solution of TBPM (B7) in [D ]DMSO and allowed to stir at 120 °C
6
lenging amines exhibited little or no reactivity (entries 1k - 1n,
Table 6). Attempts to carry out sub-mol % catalytic reactions
with TBPM (B7) in other solvents such as acetonitrile, 2-prop-
anol and toluene were also unsuccessful.
for 24 hours. The formation of alkenes in the final reaction mix-
ture (Scheme 1) confirmed the presence of such a phosphon-
ium ylide intermediate. Carrying out the same reaction at room
temperature did not result in the formation of alkenes.
Reactions under sub-mol % catalyst loadings were generally
limited to aryl iodide substrates. Substituting aryl iodides with
more challenging aryl bromide and aryl chlorides led to a (in
some cases significant) decrease in reaction yield (Tables S2 and
S3, see ESI).
Organic Ammonium and Phosphonium Bases at Elevated
Temperatures
Scheme 1. Wittig reaction between benzaldehyde and TBPM.
Given the success of organic bases in these coupling protocols
In order to determine the effect of these undesired reaction
at low temperatures, we also wanted to explore their applica- pathways exhibited by TBAM and TBPM (B4 and B7) on the
tion at higher temperatures for the activation of more challeng- cross-coupling reaction, a series of coupling experiments be-
ing substrates (such as entries 1k – 1n, Table 2 and Table 6). As tween benzylamine and bromobenzene was carried out at
the first step towards this the stability of the organic bases at 120 °C (Table 8). The reaction mixture was pre-heated for 0, 1,
higher temperatures was examined.
4 or 24 hours at 120 °C before the copper catalyst was injected.
1
1
Variable H NMR analysis (VT- H NMR in [D ]DMSO, 30– N,N′-dimethylglycine was used as the ligand as it has been
6
120 °C) of TBAM (B4) showed no signs of base degradation shown that N-methylglycine can undergo competitive cross-
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coupling with aryl halides at temperatures above 40 °C.[45] The
reaction proceeded with complete conversion of bromo-
benzene for both TBAM and TBPM (B4 and B7) when the reac-
tion mixture was not pre-heated (0 h). However, pre-heating
the reaction at 120 °C prior to the addition of the catalyst led
to a decrease in yield for TBAM (B4) but not TBPM (B7). These
results correlate with previous findings that mono-butyl-
malonate is unable to act as base in C–N cross coupling reac-
Table 9. Coupling reactions involving bulky secondary amines and iodo-
benzene at 120 °C with TBAM (B4) or TBPM (B7) using 10 mol-% CuI loadings.
[
22]
tions.
However, phosphonium ylide formation is evidently a
non-deleterious and benign background event (Table 8). To ver-
ify this, a reaction using identical reaction conditions in Table 8
was carried out in the presence of [D ]DMSO and TBPM (B7).
6
1
H NMR analysis of the final reaction mixture clearly showed
H/D exchange at the α-CH of the phosphonium cation but
2
98 % yield of the cross-coupled product was still obtained.
Product
Yield [%] TBAM (B4)
Yield [%] TBPM (B7)
1
1
1
1
k
l
m
n
30
25
77
80
41
36
98
98
Table 8. Cross-coupling reaction between benzylamine and bromobenzene
in which the reaction was initiated using CuI after pre-heating the reaction
mixture at 120 °C for 0, 1, 4 or 24 hours.
room temperature sub-mol % reactions, with isolated yields of
5, 24, 36 and 33 % (1k - 1n respectively). To the best of our
2
knowledge, this is the first report of challenging secondary
amines (1m and 1n) being used successfully in a transition-
metal catalyzed (Cu, Pd or Ni) reaction using an organic ionic
Delay in CuI
addition [h]
0
1
4
24
[17,46–50]
base.
Base
Yield [%]
Yield [%]
Yield [%]
Yield [%]
Conclusions
TBAM (B4)
TBPM (B7)
98
98
90
98
40
98
30
95
A range of organic ionic bases have been synthesized and eval-
uated for applications in the room temperature Ullmann amin-
Most screening studies reported to date with organic base ation reaction. Results obtained here have shown that the base
promoted transition metal-catalyzed processes (Cu, Pd or Ni) cation has little effect on the reaction at standard catalyst and
[
17,46–50]
have focused on simple primary and secondary amines.
ancillary ligand loadings (10 and 20 mol-% respectively). The
Coupling of more challenging amines with aryl halides under base anion however has a large effect on the observed reactiv-
sub-mol % conditions either gave very poor reaction yields or ity, with malonate bases giving the highest product yields un-
[
33,35,39,51]
were not reported during substrate scope studies.
At- der these reaction conditions. A substrate scope carried out at
tempts to improve the reactivity of these challenging amines in room temperature with TBAM and TBPM (B4 and B7) show
sub-mol % copper-catalyzed reactions have yet to be reported. both bases are excellent reagents for the Ullmann reaction un-
In order to address the very low conversions experienced der these mild room-temperature conditions, demonstrating
with more challenging substrates at room temperature (entries similar yields over a range of primary and secondary amines.
1
k - 1n, Table 2), these reactions were now repeated at higher
Studies involving more challenging sub-mol-% catalyst load-
temperatures (Table 9, 120 °C). The reaction mixtures were not ings at room temperature were subsequently explored, with
pre-heated prior to addition of the copper catalyst. This is to TBPM (B7) performing better than TBAM (B4) under these con-
prevent undesired decomposition products from having an ef- ditions. The cross-coupling reactions for a number of different
fect on the cross-coupling reaction, especially in the case of amines and functionalized aryl iodides have been reported (14
TBAM (B4, Table 7). All reactions gave a significant improve- examples), with good to excellent yields observed in most
ment in yield, with the most acidic substrates showing the cases. The exception was reactions involving more challenging
greatest improvement (entries 1m and 1n, Table 9). As ex- amines which gave little or no yield of the desired cross-
pected, TBPM (B7) exhibited better reactivity than TBAM (B4) coupled product. This is a commonly encountered problem for
at 120 °C (Table 9).
challenging amines. In order to address this, we have also ex-
Given the promising results obtained with TBPM (B7) under plored the use of ionic organic bases under more forceful con-
these conditions, we also tried to carry out sub-mol % reactions ditions (namely higher temperatures). The stability of the bases
with the same challenging substrates (1k – 1n) at 120 °C with at these higher temperatures was first assessed. Heating TBAM
both TBPM and K PO (B7 and B11). While only a trace amount (B4) at 120 °C led to the formation of nBu N and mono-butyl-
3
4
3
of product was obtained using K PO , we are pleased to report malonate and this was correlated to a decrease in performance
3
4
an improvement in reactivity using TBPM (B7) compared to of the base at these temperatures. The phosphonium cations in
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TBPM (B7) did not undergo analogous reactivity but were 1.59 (m, 9H), 1.58–1.45 (m, 1H), 1.43–1.31 (m, 8H), 0.99 (t, 3JHH
=
7
1
1
.3 Hz, 12H); 13C NMR (101 MHz, [D ]Acetonitrile, 23 °C, TMS): δ =
shown instead be subject to deprotonation at the α-CH to
generate phosphonium ylides leading to H/D exchange in
3
2
77.15 (s), 63.55 (s), 58.33 (s), 47.50 (s), 31.76 (s), 26.49 (s), 23.37 (s),
9.36 (s), 12.82 (s); CHN analysis (%) for C H N O : C (70.93), H
12.19), N (7.88); found C (70.98), H (12.23), N (7.98). This compound
21 43 2 2
[
D ]DMSO. This however did not significantly degrade the activ-
6
(
ity of the base and using TBPM (B7) at 120 °C gave moderate
to excellent yields of cross-coupled products with a range of
structurally complex amines.
[
27]
has been previously reported.
1
TMAM (B3): White solid (90 % yield, 5.63 g). H NMR (400 MHz, D O,
2
2
3 °C, TMS) δ = 3.09 (s, 24H), 3.01 (s, 2H); 13C NMR (101 MHz, D O,
2
23 °C, TMS): δ = 177.16 (s), 55.18 (s), 47.17 (s); CHN analysis (%) for
C H N O : C (53.21), H (9.74), N (11.28); found C (53.31), H (9.92),
11 24 2 4
Experimental Section
N (11.35).
TBAM (B4): Sticky white solid (91 % yield, 13.4 g). H NMR (400 MHz,
[D ]Acetonitrile, 23 °C, TMS) δ = 3.19–3.06 (m, 16H), 2.58 (s (broad),
2H), 1.65–1.50 (m, 16H), 1.40–1.24 (m, 16H), 0.93 (t, JHH = 7.3 Hz,
24H); 13C NMR (101 MHz, [D
]Acetonitrile, 23 °C, TMS): δ = 175.01
(s), 59.18 (s), 53.33 (s (broad)) 24.35 (s), 20.31 (s), 13.84 (s); CHN
analysis (%) for C35 : C (71.74), H (12.56), N (4.78); found
C (71.67), H (12.65), N (4.62). This compound has been previously
General Information
1
All reactions were carried out under a nitrogen atmosphere and
scrupulously dry conditions using standard Schlenk techniques or
in a nitrogen-filled glovebox. Glassware used were dried in an oven
at 120 °C prior to use. The quantities of the coupling product
formed from the catalytic C-N coupling reactions between the
amine and aryl iodide was determined using H NMR, where
naphthalene was used as an internal standard. Percentage yields
reported were the mean of at least two independent runs.
3
3
3
H N O
74 2 4
1
[
31]
reported.
TBAA (B5): White solid (85 % yield, 13.3 g). 1H NMR (400 MHz,
[D ]Acetonitrile, 23 °C, TMS) δ = 3.19–3.06 (m, 16H), 1.83 (m, 4H),
1.59 (m, 16H), 1.42–1.26 (m, 20H), 0.95 (t, JHH = 7.4 Hz, 24H);
NMR (101 MHz, [D ]Acetonitrile, 23 °C, TMS): δ = 177.37 (s), 59.28
(s), 40.73 (s), 29.03 (s), 24.34 (s), 20.33 (s), 13.82 (s); CHN analysis (%)
for C38 : C (72.67), H (12.68), N (4.46); found C (72.57), H
(12.64), N (4.42). This compound has been previously reported.
TBPO (B6): White solid (91 % yield, 13.8 g). 1H NMR (400 MHz,
All reagents and ligands were purchased commercially and were
dried in a sealed vacuum tube (solids) or thoroughly degassed and
dried using 4 Å molecular sieves (liquids). They were subsequently
stored in a nitrogen-filled glovebox. Stock solutions were produced
using volumetric flasks and liquid amounts were accurately added
to the reaction vials using microliter pipettes.
1H and 13C NMR spectroscopy data were obtained at room tempera-
ture using Bruker AV-400 spectrometers (400 MHz for H and
1
3
3
13
C
3
H N O
79 2 4
[17]
1
[D ]Acetonitrile, 23 °C, TMS) δ = 2.28–2.20 (m, 16H), 1.58–1.43 (m,
3
01 MHz for 13C). Chemical shifts (δ) are reported in parts per mil- 32H), 0.96 (t,
3
J
HH = 7.0 Hz, 24H); C NMR (101 MHz, [D
13
]Aceto-
3
3
lion (ppm) from tetramethylsilane (TMS) and are referenced to the
residual solvent resonances in H and C NMR spectra. Coupling
constants (J) are given in Hz units. H and C NMR spectra were
nitrile, 23 °C, TMS): δ = 175.43 (s), 23.55 (d, JCP = 15.7 Hz), 23.16
(d, JCP = 4.5 Hz), 18.01 (d, JCP = 47.9 Hz), 12.70 (s); CHN analysis
(%) for C34 : C (67.29), H (11.96); found C (67.15), H (12.09).
1
13
2
1
1
13
H O P
72 4 2
[
28]
analyzed using MESTRELAB MestReNova software. CHN microanaly- This compound has been previously reported.
ses were carried out at the London Metropolitan University.
TBPM (B7): White solid (93 % yield, 14.5 g). 1H NMR (400 MHz,
General Procedure for the Preparation of organic bases as [D
]DMSO, 23 °C, TMS): δ = 2.41 (s (broad), 2H), 2.15–2.27 (m, 16H),
6
3
13
shown in Table 1
1.35–1.54 (m, 32H), 0.92 (t, JHH = 6.9 Hz, 24 H); C NMR (101 MHz,
[
D ]DMSO, 23 °C, TMS): δ = 173.20 (s), 50.20 (s(broad)), 23.35 (d,
6
An equimolar amount of tetra-(n-alkyl)phosphonium or ammonium
hydroxide in water was treated with the corresponding acid
3
2
1
JCP = 15.6 Hz), 22.65 (d, J = 4.4 Hz), 17.29 (d, J = 47.6 Hz),
CP
CP
1
3.26 (s); CHN analysis (%) for C H O P : C (67.10), H (12.01); found
35 74 4 2
(25 mmol). The reaction mixture was left to stir at room temperature
C (67.60), H (12.12). This compound has been previously re-
ported.
overnight in air. Water was removed via rotary evaporation and the
product was subsequently dried under high vacuum at 40 °C for
[
17]
TBPS (B8): White solid (80 % yield, 12.7 g). 1H NMR (400 MHz,
24 h to remove any residual water. With the exception of bis(tetra-
(
n-butyl)phosphonium oxalate (TBPO), the evaporated residue was
[D
1.35 (m, 32H), 0.92 (t,
[D
6
]DMSO, 23 °C, TMS): δ = 2.26–2.15 (m, 16H), 1.81 (s, 4H), 1.53–
3
13
dissolved in anhydrous acetonitrile (50 mL) to give a mixture con-
taining an insoluble solid. The mixture was filtered under gravity
J
HH = 7.0 Hz, 24H); C NMR (101 MHz,
3
]DMSO, 23 °C, TMS): δ = 176.64 (s), 38.41 (s), 23.84 (d,
J
CP
=
6
2
1
and the solvent was removed via rotary evaporation until a viscous 15.6 Hz), 23.14 (d, JCP = 4.4 Hz), 17.81 (d, JCP = 47.6 Hz), 13.75 (s);
liquid was obtained. The product was then dried under high vac-
uum at 40 °C for 3 days and stored in a nitrogen-filled glovebox.
H and C NMR spectra of all organic bases can be found in the
ESI.
CHN analysis (%) for C36
(68.25), H (12.01). This compound has been previously reported.
TBPA (B9): White solid (92 % yield, 15.2 g). 1H NMR (400 MHz,
H O P : C (68.21), H (11.93); found C
75 4 2
[29]
1
13
[
D ]DMSO, 23 °C, TMS) δ = 2.27–2.14 (m, 16H), 1.73–1.64 (m, 2H),
6
1
13
TBANM (B1): Off white solid (76 % yield, 6.26 g). H NMR (400 MHz,
1.53–1.36 (m, 32H), 1.31–1.24 (m, 2H), 0.92 (t, J = 7.0 Hz, 24H);
NMR (101 MHz, [D
(s), 29.14 (s), 24.58 (d, JCP = 15.6 Hz), 24.02 (d, JCP = 4.6 Hz), 18.91
C
[
2
7
D ]DMSO, 23 °C, TMS) δ = 3.26–3.12 (m, 8H), 2.58 (s (broad), 1H),
3
]Acetonitrile, 23 °C, TMS): δ = 177.21 (s), 40.87
6
3
3
2
.18 (s, 2H), 1.67–1.50 (m, 8H), 1.41–1.26 (m, 8H), 0.94 (t, JHH
=
.3 Hz, 12H); 13C NMR (101 MHz, [D ]DMSO, 23 °C, TMS): δ = 173.07
1
(d, JCP = 48.0 Hz), 13.65; CHN analysis (%) for C38
H O P : C (68.84),
80 4 2
6
(
s), 57.97 (s (broad)), 57.87 (s), 37.39 (s), 23.54 (s), 19.68 (s), 13.96 (s);
H (12.16); found C (68.80), H (12.10). This compound has been previ-
ously reported.
[
17]
CHN analysis (%) for C H N O : C (69.25), H (12.54), N (8.50); found
1
9 41 2 2
C (69.15), H (12.52), N (8.55).
TBPP (B10): White solid (85 % yield, 14.5 g). 1H NMR (400 MHz,
1
TBALP (B2): Off white solid (77 % yield, 6.86 g). H NMR (400 MHz,
[D ]Acetonitrile, 23 °C, TMS) δ = 7.21–7.16 (m, 2H), 6.98–6.88 (m,
3
3
[
D ]Acetonitrile, 23 °C, TMS) δ = 3.19–3.13 (m, 8H), 3.11–3.08 (m, 2H), 2.23–2.14 (m, 16H), 1.52–1.36 (m, 32H), 0.91 (t, J = 7.1 Hz,
3
HH
1
H), 3.05–2.98 (m, 1H), 2.61–2.52 (m, 1H), 1.89–1.79 (m, 1H), 1.70–
24H); 13C NMR (101 MHz, [D ]Acetonitrile, 23 °C, TMS): δ = 174.29
3
Eur. J. Org. Chem. 0000, 0–0
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
s), 127.85 (s), 125.31 (s), 24.55 (d, J = 15.6 Hz), 24.09 (d, 2JCP
3
=
4.32 (s, 2H), 3.82 (s (broad), 1H), 3.77 (s, 3H); 13C NMR (101 MHz,
(
4
CP
1
.5 Hz), 18.93 (d, JCP = 47.8 Hz), 13.68 (s); CHN analysis (%) for
CDCl , 23 °C, TMS): δ = 152.20 (s), 142.46 (s), 139.68 (s), 128.60 (s),
3
C H O P : C (70.45), H (11.09); found C (70.57), H (11.22). This
compound has been previously reported.
127.56 (s), 127.18 (s), 114.92 (s), 114.11 (s), 55.83 (s), 49.27 (s). This
compound has been previously reported.
40 75 4 2
[30]
[53]
1
General reaction procedure for the reaction between benzyl-
amine and aryl halides as shown in Table 1, Table 3, Table 4,
Table 5, Table 8 and Figures S1–S3 (ESI)
1d: White solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.45–
3
3
7.31 (m, 7H), 6.62 (d, J = 6.6 Hz, 2H), 4.83 (s (broad), 1H), 4.41 (d,
JHH = 5.6 Hz, 2H); C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 151.24
HH
3
13
3
(
1
s), 137.92 (s), 133.72 (s), 128.88 (s), 127.67 (s), 127.31 (s), 120.57 (s),
In a nitrogen-filled glovebox, benzylamine (164 μL, 1.50 mmol), aryl
halide (1.00 mmol), base (1.75 mmol), ligand, naphthalene (internal
standard) and DMSO (required amount to make up to 500 μL total
volume unless otherwise stated) were added to a reaction vial with
a magnetic stirring bar. Copper(I) iodide (0.100 M solution in DMSO)
was added to initiate the reaction. The vial was sealed using an
open top cap with a 6 mm septum and the reaction stirred at room
temperature for 24 hours. The reaction mixture was diluted with
CDCl3 (1 mL) and washed with three portions of distilled water
12.45 (s), 98.80 (s), 47.43 (s). This compound has been previously
[
53]
reported.
1
1
e: Orange oil. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.41 (q,
3
3
3
3
JHH = 7.4 Hz, 2H), 7.11 (t, J = 7.1 Hz, 2H), 6.99 (t, J = 7.0 Hz,
HH
HH
3
1
H), 3.31 (t, J = 3.3 Hz, 4H), 1.94–1.80 (m, 4H), 1.79–1.67 (m, 2H);
HH
13
C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 152.42 (s), 129.14 (s),
3
1
19.32 (s), 116.68 (s), 50.83 (s), 26.07 (s), 24.52 (s). This compound
[54]
has been previously reported.
(
3 × 1 mL). The resulting solution was dried using MgSO and fil-
4
1
1
1f: Orange oil. H NMR (400 MHz, CDCl
3
, 23 °C, TMS): δ = 7.28 (t,
tered into a NMR tube for H NMR analysis.
3
3
3
JHH = 7.3 Hz, 2H), 6.71 (t, J = 6.7 Hz, 1H), 6.64 (d, J = 6.6 Hz,
HH
HH
General reaction procedure for the reaction between benzalde-
hyde and TBPM as shown in Scheme 1
3
3
13
2
H), 3.34 (t, J = 3.4 Hz, 4H), 2.06 (t, J = 3.0 Hz, 4H); C NMR
HH HH
(101 MHz, CDCl , 23 °C, TMS): δ = 147.99 (s), 129.15 (s), 115.46 (s),
3
In a nitrogen-filled glovebox, benzaldehyde (104 μL, 1.00 mmol),
TBPM (0.621 g, 1.00 mmol), naphthalene (100 μL of 1.00 M solution
in DMSO, 0.100 mmol) and DMSO (2 mL) were added to a reaction
vial with a magnetic stirring bar. The vial was sealed using an open
top cap with a 6 mm septum and was taken out of the glovebox
and placed in a temperature-controlled sand bath where it was left
to stir for 24 hours at 120 °C. The reaction mixture was diluted with
CDCl3 (1 mL) and washed with three portions of distilled water
111.72 (s), 47.65 (s), 25.49 (s). This compound has been previously
reported.
[
55]
1
1
g: Orange oil. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.30 (t,
3
3
3
3
JHH = 7.3 Hz, 2H), 6.97 (d, J = 7.0 Hz, 2H), 6.89 (t, J = 6.9 Hz,
HH
HH
3
3
1
3
H), 3.26 (q, J = 3.3 Hz, 4H), 2.63 (q, J = 2.6 Hz, 4H), 2.40 (s,
HH HH
13
H); C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 151.23 (s), 129.13
3
(
s), 119.75 (s), 116.09 (s), 55.14 (s), 49.04 (s), 46.12 (s). This compound
[56]
has been previously reported.
(
3 × 1 mL). The resulting solution was dried using MgSO and fil-
4
1
1
1h: Orange oil. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.38–7.28
tered into a NMR tube for H NMR analysis.
3
1
3
(
m, 2H), 7.02–6.89 (m, 3H), 3.94–3.86 (m, 4H), 3.30–3.12 (m, 4H);
C
General reaction procedure for the reaction between amines
and aryl iodides with TBAM/TBPM as shown in Table 2, Table 6
and Table 9
NMR (101 MHz, CDCl , 23 °C, TMS): δ = 151.30 (s), 129.21 (s), 120.08
3
(
s), 115.74 (s), 66.97 (s), 49.39 (s). This compound has been previ-
[
57]
ously reported.
In a nitrogen-filled glovebox, amine (1.50 mmol), aryl iodide
1
1
i: Colorless oil. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.22 (t,
3
(1.00 mmol), base (1.75 mmol), ligand and DMSO (required amount
3
3
3
JHH = 7.2 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.65 (t, J = 6.7 Hz,
H), 3.51–3.44 (s (broad), 1H), 3.32 (tt, J = 10.1, 3.8 Hz, 1H), 2.17–
.08 (m, 2H), 1.87–1.78 (m, 2H), 1.77–1.67 (m, 1H), 1.51–1.14 (m, 5H);
C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 147.45 (s), 129.29 (s),
HH
HH
to make up to 500 μL total volume) were added to a reaction vial
with a magnetic stirring bar. Copper(I) iodide (0.100 M solution in
DMSO) was added to initiate the reaction. The vial was sealed using
an open top cap with a 6 mm septum and stirred at room tempera-
ture or in a temperature-controlled sand bath (120 °C) where it was
left to stir for 24 hours. The reaction mixture was diluted with ethyl
acetate and washed with water and brine. The organic phase was
3
2
2
HH
13
3
1
16.87 (s), 113.20 (s), 51.74 (s), 33.54 (s), 26.01 (s), 25.09 (s). This
[
58]
compound has been previously reported.
1
1j: Orange solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.30 (t,
3
3
3
3
dried using MgSO and concentrated in vacuo. All products were
JHH = 7.8 Hz, 4H), 7.11 (d, J = 7.9 Hz, 4H), 6.97 (t, J = 7.3 Hz,
2H), 5.72 (s (broad), 1H); C NMR (101 MHz, CDCl , 23 °C, TMS): δ =
4
HH HH
1
13
isolated after purification using silica gel chromatography. H and
3
1
3
C NMR spectra of all C-N cross coupled products can be found in
the ESI.
a: White solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.50–
143.13 (s), 129.35 (s), 121.00 (s), 117.82 (s). This compound has been
[
59]
previously reported.
1
1
1
3
1k: White solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.63–
3
3
7
.40 (m, 4H), 7.39–7.34 (m, 1H), 7.27 (t, J = 7.6 Hz, 2H), 6.81 (t,
HH
7.57 (m, 2H), 7.51–7.43 (m, 2H), 7.40–7.27 (m, 5H), 7.22–7.13 (m, 3H),
3
3
JHH = 7.3 Hz, 1H), 6.72 (d, J = 7.9 Hz, 2H), 4.40 (s, 2H), 4.09 (s
13
HH
7.12–7.07 (m, 1H), 7.01–6.96 (m, 1H), 5.83 (s (broad), 1H); C NMR
(
broad), 1H); 13C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 148.24 (s),
3
(101 MHz, CDCl , 23 °C, TMS): δ = 206.81 (s), 143.64 (s), 143.06 (s),
3
1
1
39.54 (s), 129.33 (s), 128.70 (s), 127.57 (s), 127.29 (s), 117.63 (s),
12.93 (s), 48.39 (s). This compound has been previously re-
1
1
42.55 (s), 141.18 (s), 129.71 (s), 129.40 (s), 128.69 (s), 127.34 (s),
27.12 (s), 121.18 (s), 119.94 (s), 118.08 (s), 116.62 (s), 116.48 (s). This
[52]
ported.
[60]
compound has been previously reported.
1
1
b: Yellow liquid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.50–
1
3
1l: Orange solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 8.07–
3
3
7
.40 (m, 4H), 7.40–7.34 (m, 1H), 7.08 (d, JHH = 7.1 Hz, 2H), 6.65 (d,
3
8.03 (m, 1H), 7.91–7.88 (m, 1H), 7.60 (dd,
JHH = 7.5, 1.9 Hz, 1H),
3
JHH = 6.7 Hz, 2H), 4.39 (s, 2H), 3.96 (s (broad), 1H), 2.34 (s, 3H); 13
C
7.54–7.49 (m, 2H), 7.44–7.37 (m, 2H), 7.32–7.25 (m, 2H), 7.02 (d,
NMR (101 MHz, CDCl , 23 °C, TMS): δ = 146.00 (s), 139.75 (s), 129.82
3
3
3
JHH = 7.0 Hz, 2H), 6.94 (t, J = 7.4 Hz, 1H), 5.97 (s (broad), 1H);
HH
(
2
s), 128.66 (s), 127.56 (s), 127.21 (s), 126.78 (s), 113.06 (s), 48.69 (s),
13
C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 144.80 (s), 138.80 (s)
3
0.49 (s). This compound has been previously reported.[53]
134.71 (s), 130.86 (s), 129.34 (s), 128.54 (s), 126.10 (s), 126.02 (s),
1
1
c: Yellow liquid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.44– 125.67 (s), 122.98 (s), 121.80 (s), 120.49 (s), 117.40 (s), 115.90 (s). This
3
[
61]
7
.34 (m, 4H), 7.34–7.26 (m, 1H), 6.84–6.78 (m, 2H), 6.68–6.60 (m, 2H),
compound has been previously reported.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
1
m: White solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 7.82 (d,
[28] M. Quiroz-Guzman, D. P. Fagnant, X.-Y. Chen, C. Shi, J. F. Brennecke, G. S.
Goff, W. Runde, RSC Adv. 2014, 4, 14840–14846.
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3
3
3
JHH = 7.7 Hz, 1H), 7.70 (d, JHH = 7.6 Hz, 1H), 7.62–7.61 (m, 4H),
.48–7.43 (m, 2H), 7.35–7.28 (m, 2H), 6.81 (d, J = 3.2 Hz, 1H);
NMR (101 MHz, CDCl , 23 °C, TMS): δ = 139.70 (s), 135.81 (s), 129.59
s), 127.93 (s), 126.43 (s), 124.38 (s), 122.33 (s), 121.10 (s), 120.33 (s),
3
13
7
C
HH
1
13583–113595.
30] T. Ando, Y. Kohno, N. Nakamura, H. Ohno, Chem. Commun. 2013, 49,
0248–10250.
3
[
[
(
1
1
10.48 (s), 103.55 (s). This compound has been previously re-
31] N. Ferlin, M. Courty, S. Gatard, M. Spulak, B. Quilty, I. Beadham, M. Ghavre,
[62]
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A. Haiß, K. Kümmerer, N. Gathergood, Tetrahedron 2013, 69, 6150–6161.
1
[32] F. G. Bordwell, G. E. Drucker, H. E. Fried, J. Org. Chem. 1981, 46, 632–635.
1
n: White solid. H NMR (400 MHz, CDCl , 23 °C, TMS): δ = 8.33–
3
[
33] P. F. Larsson, A. Correa, M. Carril, P. O. Norrby, C. Bolm, Angew. Chem. Int.
Ed. 2009, 48, 5691–5693; Angew. Chem. 2009, 121, 5801.
8
.28 (m, 2H), 7.73–7.68 (m, 4H), 7.61–7.54 (m, 5H), 7.48–7.40 (m, 2H);
C NMR (101 MHz, CDCl , 23 °C, TMS): δ = 141.09 (s), 137.90 (s),
29.97 (s), 127.54 (s), 127.27 (s), 126.07 (s), 123.56 (s), 120.44 (s),
20.07 (s), 109.91 (s). This compound has been previously re-
13
3
[
[
34] P. F. Larsson, C. Bolm, P. O. Norrby, Chem. Eur. J. 2010, 16, 13613–13616.
35] P. F. Larsson, P. Astvik, P. O. Norrby, Beilstein J. Org. Chem. 2012, 8, 1909–
1
1
1
915.
[36] P. F. Larsson, C. J. Wallentin, P. O. Norrby, ChemCatChem 2014, 6, 1277–
282.
[63]
ported.
1
[
[
37] R. Xie, H. Fu, Y. Ling, Chem. Commun. 2011, 47, 8976.
38] K. Yang, Y. Qiu, Z. Li, Z. Wang, S. Jiang, J. Org. Chem. 2011, 76, 3151–
Acknowledgments
3
159.
This work was supported by Syngenta and the UK EPSRC (Grant
EP/M507878/1).
[
[
[
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Keywords: Copper · Ullmann reaction · Amination · C–N
bond coupling · Organic bases
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Received: January 23, 2019
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Cross Coupling
Q. A. Lo, D. Sale, D. C. Braddock,
R. P. Davies* ...................................... 1–10
New Insights into the Reaction Ca-
pabilities of Ionic Organic Bases in
Cu-Catalyzed Amination
Room-temperature sub-mol % Ull- and phosphonium based organic ionic
mann amination has been realized, bases at higher temperatures was in-
promoted by the organic ionic base vestigated, leading to a new protocol
TBPM (14 examples). In addition, the for the activation of structurally com-
stability and application of ammonium plex amines.
DOI: 10.1002/ejoc.201900109
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim