Altering Copper-Catalyzed A3 Couplings by Mechanochemistry: One-Pot Synthesis of 1,4-Diamino-2-butynes from Aldehydes, Amines, and Calcium Carbide

Article abstract of DOI:10.1002/anie.201805505

The ability of mechanochemistry to alter established chemical selectivity is demonstrated. A copper(I)-catalyzed mechanochemical aldehyde/alkyne/amine coupling using calcium carbide as the acetylene source provides selective access to 1,4-diamino-2-butynes, which contrasts classical approaches that provide propargylamine-type products. Solventless milling conditions were found to be essential to unmask A³ coupling products with new compositions.

Full text of DOI:10.1002/anie.201805505

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
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Accepted Article
Title: Altering Copper-Catalyzed A3-Couplings by Mechanochemistry;
One-Pot Synthesis of 1,4-Diamino-2-butynes
Authors: Mathias Turberg, Karen Janella Ardila-Fierro, Carsten Bolm,
and José G. Hernández
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805505
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Angewandte Chemie International Edition
10.1002/anie.201805505
COMMUNICATION
3
Altering Copper-Catalyzed A -Couplings by Mechanochemistry;
One-Pot Synthesis of 1,4-Diamino-2-butynes
+
+
Mathias Turberg, Karen J. Ardila-Fierro, Carsten Bolm* and José G. Hernández*
a) Previous work: Solvent-based approach
Abstract: The ability of mechanochemistry to alter an established
R2 R3
N
chemical selectivity is here demonstrated. A copper(I)-catalyzed
CuI
O
R2
R3
mechanochemical aldehyde-alkyne-amine-coupling using calcium
carbide as the acetylene source, allows a selective access to 1,4-
diamino-2-butynes, which contrasts classical approaches providing
propargylamine-type products. Solventless milling conditions were
+
N
H
+
CaC2
R1
R1
CH3CN
0 °C, 18 h
8
propargylamines
major product)
(
b) This work: Mechanochemical strategy
3
found essential to unmask a new A -coupling product composition.
R3
O
R2 R3
N
H
Cu salts
ball milling
R2
N
R1
+
+
CaC2
R1
In recent years, the use of mechanical energy to induce or
facilitate chemical transformations has become an important
R1
R2
N
R2
[
1]
approach in chemical synthesis.
One unique feature of
1,4-diamino-2-butynes
(
major product)
mechanochemistry is the possibility to alter chemical reactivity,
thereby allowing to access otherwise disallowed or unfavorable
products. For example, exertion of mechanical forces by
sonication and pulling has led to the discovery of the anti-
3
Scheme 1. Solution-based and mechanochemical Cu-catalyzed A -coupling
using calcium carbide as the acetylene source.
As a starting point, we focused on the aldehyde-alkyne-
Woodward-Hoffmann
electrocyclic
ring
opening
of
3
amine-coupling (A -coupling), a well-established and convenient
[
2]
[3]
benzocyclobutene, the trapping of a diradical transition state,
and recently to an alternative retro-Diels-Alder product
atom-economical
synthetically valuable propargylamines.
co-workers reported the use of CaC
multicomponent
reaction
[11,12]
to
access
In 2012, Zhang and
[
4,5]
composition in furan/maleimide adducts.
Thus, activation of
2
as an acetylene surrogate
chemical systems by ball milling has also unmasked reaction
pathways that differ from their solution-based thermal
[13]
in such couplings.
Heating a mixture of aldehydes, amines
and CaC in undried acetonitrile led to the formation of terminal
2
counterparts, clearly highlighting
a
synthetic value of
propargylamines as major product (Scheme 1a). Being attracted
[
6]
mechanochemistry.
by this work we decided to study a mechanochemical activation
3
of CaC
2
by ball milling and its application in an A -coupling
From a practical perspective, the implementation of ball
milling techniques offers the possibility to carry out chemical
reactions in the absence of bulk reaction media. This allows
reacting substances of very poor solubility or to combine
reaction partners of different solubility profiles. In this context,
(
Scheme 1b). On the one hand, milling of CaC
2
could help
breaking its crystal structure, thereby accelerating its availability
for the reaction. In addition, solventless condensations of
amines and carbonyl compounds should provide the conditions
2
for the activation of CaC without the use of wet solvents or
calcium carbide (CaC
2
) has recently proven useful as a solid
added water. Controlling the neat mechanochemical reaction
conditions was anticipated to prevent quenching of charged
chemical species (e.g., by water), leading to a change in the
replacement of hazardous and difficult to handle acetylene
[
7-9]
gas.
However, due to the poor solubility of CaC
2
in organic
[
10]
solvents, procedures for CaC
2
upgrading often require three-
3
[
9m]
[9n]
established product composition of the A -coupling by
phasic reaction mixtures,
superbasic reaction media,
high
[
9c,i]
[9c,k]
mechanochemistry (Scheme 1b).
temperatures,
current limitations for utilizing CaC
we surmised that the application of mechanochemical
techniques to the valorization of CaC could overcome the
and long reaction times.
Challenged by the
2
as a surrogate for acetylene,
At the onset of this study, we tested the mechanochemical
3
A -coupling between benzaldehyde (1a), pyrrolidine (2a) and
2
calcium carbide by ball milling (Table 1). To prevent any reaction
between 1a and 2a before the milling had started and to protect
calcium carbide from reacting with atmospheric moisture, 1a and
abovementioned practical drawbacks. Additionally, the
development of a solventless alternative for the activation of
CaC
2
in ball mills was foreseen as an opportunity to help
2
CaC were sealed inside glass ampules (for details see Figure
discovering new chemical reactivity.
[14]
S1, Supporting Information). An initial milling experiment at 25
Hz in the absence of a catalyst enabled crushing the glass
1
ampules and mixing of the reagents. Disappointingly, H NMR
analysis of the crude reaction mixture revealed no new product.
(
Table 1, entry 1). On the other hand, under identical milling
[
[
*]
M. Turberg, K. J. Ardila-Fierro, Prof. Dr. C. Bolm, Dr. J. G.
Hernández.
conditions the presence of copper iodide (20 mol %) favored the
[
15]
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+49) 241-8092-391
E-mail: carsten.bolm@oc.rwth-aachen.de, jose.hernandez@oc.rwth-
aachen.de
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
consumption of starting materials after only 90 min of milling.
Now, however, to our surprise, the mechanochemical reaction
afforded 1,4-diamino-2-butyne 3a as the major product (Table 1,
entry 2). Such reactivity stands in stark contrast to the previous
observations by Zhang and coworkers, who obtained the typical
propargylamine 4a in undried acetonitrile (at 80 °C after 18-72
+]
[
13,16]
h).
In fact, it was reported that in solution 4a was formed
exclusively and “no bis-substituted propargylic amine product
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Angewandte Chemie International Edition
10.1002/anie.201805505
COMMUNICATION
3
[a]
with the same reaction in the absence of water (Table 1, entries
Table 1. Screening of the mechanochemical Cu-catalyzed A -coupling.
2
and 7), thereby supporting our hypothesis on the role of water
O
catalyst
N
Ph
N
N
on the selectivity of the reaction with CaC . Next, to evaluate the
2
+
+
CaC2
+
N
H
product composition of the mechanochemical reaction over time,
an experiment was halted after 30 min of milling. The analysis of
the reaction mixture revealed traces of unreacted starting
materials. However, the ratio 3a:4a (82:13) was comparable with
the milling experiment carried out for 90 min (Table 1, entries 2
and 8). Decreasing the catalyst loading proved possible, as
shown by using copper (I) iodide in 5.0 mol % or 10 mol %,
which afforded primarily 1,4-diamino-2-butyne 3a without the
need for lengthening the milling time (Table 1, entries 9-10).
Finally, a liquid-assisted grinding (LAG) experiment was carried
ball milling
Ph
Ph
Ph
2
5 Hz
1
a
2a
3a
4a
Yield
[
b]
Entry
Catalyst (mol %)
Conversion [%]
[
b]
3
a:4a
1
2
3
4
5
6
-
-
-
CuI (20)
CuBr (20)
CuCl (20)
>99
>99
83
85:11
85:10
47:46
79:14
16:74
44:31
82:13
CuBr
2
(20)
⋅6H
99
[
18,19]
Cu(BF
4
)
2
2
O
96
out.
presence of catalytic amounts of undried MeCN, a solvent
typically used in solvent-based protocols with CaC still
Repeating the copper-catalyzed reaction in the
[
[
c]
d]
7
8
9
1
1
CuI (20)
CuI (20)
CuI (10)
CuI (5)
98
95
2
,
>99
98
88:12
83:13
74:6
maintained the preference of the LAG reaction towards the bis-
substituted propargylic product 3a (Table 1, entry 11).
0
1
[
e]
CuI (20)
>99
Having identified the best milling parameters as 90 min of
milling at 25 Hz, the substrate scope of the mechanochemical
[
[
a] 1a (53.1 mg, 0.5 mmol), 2a (35.6 mg, 0.5 mmol), CaC
2
(33 mg; 0.5 mmol)
technical grade, 74.24% purity, corresponding to approx. 0.8 equiv.] and
3
A -coupling was investigated (Scheme 2). In general, the
catalyst were milled for 90 min in a 10 mL stainless steel milling jar with one
0 mm milling ball of the same material; 1a and CaC were loaded into the
synthetic protocol involved milling of a mixture of 1 : 2 : CaC
2
(1 :
1
2
1
: 1 equiv.) with CuI (10 mol %) as the catalyst. Under these
1
milling jar in sealed glass ampules. [b] Determined by H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard. [d] Water (1.2 equiv.)
was added in the milling jar. [d] After 30 min of milling. [e] LAG reaction
conditions, aromatic aldehydes bearing halogen substituents
were tolerated. For example, p-fluorobenzaldehyde (1b) reacted
2
with pyrrolidine (2a) and CaC to afford the corresponding 1,4-
(
MeCN); η = 0.25 µL/mg.
diamino-2-butyne 3b in 67% after column chromatography
(Scheme 2). Similarly, the use of p-chloro and p-
bromobenzaldehyde led to the formation of products 3c and 3d
in 75% and 79% yield, respectively (Scheme 2). Additionally, o-
and m-bromobenzaldehyde were successfully tested as
was observed even with inorganic base present in the reaction
[
13]
system”.
undried or dry acetonitrile led predominantly to the formation of
a (for details see ESI). Additionally, in the ball mill only trace
quantities of the Glaser-Hay homocoupling product were
Indeed, repeating the protocol in solution using
4
3
substrates in the mechanochemical A -coupling, leading to 1,4-
[
17]
detected. Consequently, the high selectivity of the reaction by
milling and, in particular, the change in product composition by
diamino-2-butynes 3e and 3f in up to 72% yield (Scheme 2). p-
Tolualdehyde (1g), 4-carbomethoxybenzaldehyde (1h) and p-
anisaldehyde (1i) proved suitable for the reaction as well. In
these cases, the corresponding bis-substituted propargylic
products 3g-i were obtained in yields ranging from 72% to 81%
mechanochemistry requested
a
deeper study of the
3
mechanochemical Cu-catalyzed A -coupling.
I
II
First, a variety of Cu and Cu salts were screened as
(
Scheme 2). Employing 3,5-bis(trifluoromethyl)benzaldehyde (1j)
3
potential catalysts for the mechanochemical A -coupling. Copper
as a substrate gave product 3j in 72% yield (Scheme 2).
Interestingly, the expected product 3k was not detected when 2-
cyanobenzaldehyde (1k) was used as substrate. Instead,
unprecedented isoindolinone 5 was obtained in 75% yield
(
I) bromide was found to catalyze the reaction to a similar extend
compared to CuI, providing 3a as the major product after 90 min
of milling at 25 Hz (3a:4a; 85:10; Table 1, entry 3). Conversely,
copper (I) chloride proved less effective as catalyst in terms of
reactivity and selectivity, affording both 1,4-diamino-2-butyne 3a
and propargylamine 4a (Table 1, entry 4). On the other hand,
when copper (II) bromide was tested as catalyst the selectivity
towards product 3a was regained (Table 1, entry 5). Using
(
Scheme 2). This result suggests that intramolecular hydrolysis
of the nitrile group occurs faster than the addition of the carbide
anion to the iminium ion intermediate. Moreover, reacting
polyaromatic aldehydes such as 1l and 1m afforded 1-naphthyl-
and 9-phenanthryl-substituted 1,4-diamino-2-butynes 3l and 3m
in 56% and 76%, respectively (Scheme 2). Pivaldehyde (1n)
was also compatible with the milling conditions and gave 3n in
Cu(BF
preferentially to the formation of propargylamine 4a over 3a
3a:4a; 16:74; Table 1, entry 6). This change in selectivity was
4
)
2
·6H
2
O
in the mechanochemical reaction led
(
5
7% yield. Replacing pyrrolidine with piperidine (2b) was also
attributed to the crystalline water contained in the copper (II) salt.
Thus, the presence of water during the milling could have aided
quenching of the mono anionic intermediate obtained after the
possible leading to the formation of product 3o in 75% yield.
Conversely, primary amines only provided the corresponding
imine whereas acyclic secondary amines (e.g., diethylamine)
gave the desired 1,4-diamino-2-butynes in low yields. In general,
most of the products 3 appeared homogeneous by thin-layer
2
−
first addition of C
providing 4a. To test this hypothesis, a mixture of 1a, 2a, CaC
and CuI was milled in the presence of 1.2 equiv. of added water
Table 1, entry 7). Under these conditions, the formation of the
mono-substituted propargylic amine 4a was favored compared
2
to the iminium ion, thus preferentially
2
chromatography and NMR spectroscopy, however the presence
(
[20]
of diastereomers or rotamers cannot be excluded,
(for a
detailed study on 3m see Supporting Information).
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Angewandte Chemie International Edition
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COMMUNICATION
-
Synthesis of unsymmetric 1,4-diamino-2-butynes
R2
a; R1 = R2 = H
3b; R = R = F
3
n
1
2
N
O
1
2
O
CuI (10 mol %)
CaC2
3g; R = R = Me
3i; R1 = R2 = OMe
CaC
2
; CuI
N
R
+
n
N
H
R
+
2a
R
1
2
25 Hz, 90 min
ball milling
3p; R = F, R = H
ball milling
25 Hz
N
1
2
N
3q; R = F, R = Me
1
2
R /R
1
2
1
2
3
n
3r; R = F, R = OMe
3
1
R1
Ratioa
Yield of 3b
F
Cl
Products
1
2
1
b; R = F, 1a; R = H
3
3
a / 3b / 3p 1.0 / 0.7 / 2.2
g / 3b / 3q 1.0 / 1.4 / 3.3
1.0 / 7.3 / 8.0
Determined by GC-MS
Determined by 1H NMR spectroscopy
74%
89%
80%
N
N
N
1b; R1 = F, 1g; R2 = Me
1
2
1
b; R = F, 1i; R = OMe
3i / 3b / 3r
a
b
3
-
Mechanochemical A -coupling using terephthaldehyde (1s)
N
N
N
F
Cl
O
N
N
CuI (10 mol %)
3
a (87%; 82%a)
3b (67%)
3c (75%)
O
CaC2
+
N
n
Br
ball milling
H
O
2
5 Hz
N
N
1s
2a
N
N
O
4
0 %
N
Br
Br
3s
3
Br
Scheme 3. Applications of the mechanochemical Cu-catalyzed A -coupling.
Top: mechanosynthesis of unsymmetric 1,4-diamino-2-butynes. Bottom:
mechanosynthesis of 3s by ball milling.
Br
N
N
N
Br
3
d (79%)
3e (72%)
3f (70%)
Reacting a mixture of benzaldehyde (1a), p- fluorobenzaldehyde
MeO
2
C
MeO
Me
(
2
1b), 2a, CaC (0.25 : 0.25 : 0.5 : 0.5 mmol) and CuI (10 mol %)
N
N
N
led to full conversion of the aldehydes 1a and 1b, with
preferential formation of the unsymmetric 1,4-diamino-2-butyne
3
p (3a / 3b / 3p; 1.0 / 0.7 / 2.2). Replacing 1a with p-
N
N
N
tolualdehyde (1g) or p-anisaldehyde (1i) generated, once again,
the unsymmetric diamino-2-butynes 3q-r as major products
CO
2
Me
OMe
Me
3
h (81%)
3i (72%)
3
CF
g (77%)
(
Scheme 3; top). Finally, the usefulness of the
3
3
mechanochemical Cu-catalyzed A -coupling to prepare 1D-
polymeric materials containing 1,4-diamino-2-butyne units was
isolated:
O
N
N
N
3
F C
NH
tested. Pleasingly, reacting terephthaldehyde (1s), 2a and CaC
2
CN
CN
under the standard reaction conditions led to the formation of a
polymeric material in 40% yield (Scheme 3; bottom). Analysis of
the sample by NMR spectroscopy and High Resolution Mass
Spectrometry (HRMS) revealed that 3s (with n = 1) was
predominant in the mixture.
N
CF
3
N
N
N
CF
3
3k (not observed)
5 (75%)
3l (56%)
3
j (72%)
N
A plausible mechanism to explain the formation of symmetric
N
N
and unsymmetric 3 is shown in Scheme 4.
N
N
CaC2
O
+
N
H
N
R3 R4
+
[Cu]
[Cu]
Ca(OH)
R3 R4
R3 R4
N
1
2
OH-
R /R
3
m (75%)
3n (57%)
3o (75%)
1
2
R1
N
Scheme 2. Substrate scope for the mechanosynthesis of symmetric 1,4-
diamino-2-butynes 3. Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), CaC
R4
R1
Cu]
2
R3
N
R1
[
(
33 mg; 0.5 mmol) [technical grade, 74.24% purity, corresponding to approx.
R1
R4
N
R3
[Cu]
0
.8 equiv.] and CuI (10 mol %) were milled for 90 min in a 10 mL stainless
symmetric 3
R3 R4
steel milling jar with one 10 mm milling ball of the same material. The use of
R4
N
Ca(OH)2
N
[
a]
[Cu]
R3 R4
2
0 mol% of CuI led to similar yields. Experiment carried out on a 1.0 mmol
R3
R2
H2O
N
R1
4
scale.
A
Ca(OH)
R1
R4
R1
N
R3
R3 R4
B
OH-
unsymmetric 3
[Cu]
From a practical point of view, the one-pot mechanosynthesis of
N
+
Cu]
H2O
[
symmetric 1,4-diamino-2-butynes
3
is significantly more
R2
4
3
advantageous compared to reported approaches in solution,
Scheme 4. Plausible mechanism for the mechanochemical A -coupling.
[
20a]
which required two-step protocols
or higher catalyst loadings
[
20b]
In summary, mechanochemistry enabled altering the typical
at high temperatures.
Additionally, due to the simplicity of the
3
product composition of copper-catalyzed A -couplings. The
mechanochemical strategy to enable the formation of two new
N–C bonds and two new C–C bonds in one step, we decided to
carry out intermolecular competition experiments with pyrrolidine
mechanical milling of the reagents in the absence of solvent
favored the formation of 1,4-diamino-2-butynes over the typically
generated propargylamines. This one-pot mechanochemical
reaction simplifies the existing procedures for the preparation of
(
2a), substituted benzaldehydes and CaC
2
to attempt the
synthesis of unsymmetric 1,4-diamino-2-butynes 3 (Scheme 3;
[
22]
[
21]
valuable 1,4-diamino-2-butynes,
and rises the degree of
top).
complexity in the field of mechanochemical multicomponent
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
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COMMUNICATION
[
23]
reactions. The application of mechanical forces by ball milling
also permits exploring otherwise dormant chemical reactivity.
Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem. Soc. 2010, 132, 2522–
2
3
523; s) X. Jie, Y. Shang, P. H, W. Su, Angew. Chem. 2013, 125,
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[
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through the RWTH Start-up grant StUpPD_221-16 and the
Distinguished Professorship Program funded by the Excellence
Initiative of the German Federal and State Governments. Dr.
Christoph Räuber (RWTH Aachen University) is thanked for
assistance with special NMR experiments.
(
2
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3
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[
[
[
14] Adding the reactants directly into the milling jar led to similar selectivity.
However, loading and CaC2 in glass ampules assured higher
reproducibility. Therefore, glass does not seem to play any catalytic role
in the reaction. Conversely, the use of SiO as a milling additive favored
3
1
Keywords: mechanochemistry • A -coupling • calcium carbide •
1
,4-diamino-2-butynes
2
the formation of 4a due to its higher water content. For details, see ESI.
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2
2
345; for other catalytic reactions of terminal alkynes, see: r) Y. Wei, H.
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Angewandte Chemie International Edition
10.1002/anie.201805505
COMMUNICATION
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Layout 2:
COMMUNICATION
Mathias Turberg, Karen J. Ardila-Fierro,
Carsten Bolm* and José G. Hernández*
Typical reactivity
New reactivity
(by mechanochemistry)
(in solution)
R
n
O
n
Page No. – Page No.
Altering Copper-Catalyzed A -
Couplings by Mechanochemistry;
One-Pot Synthesis of 1,4-Diamino-2-
butynes
N
N
3
CuI
CuI
R
n
N
H
1
8 h
+
90 min
25 Hz
ball milling
N
8
0 °C
MeCN
CaC2
n
R
R
Different is always better: Mechanochemical activation of aldehydes, amines and
calcium carbide in the presence of copper (I) iodide enabled the unprecedented
formation of 1,4-diamino-2-butynes under solventless conditions.
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