Mechanochemical Cobalt-Catalyzed C?H Bond Functionalizations by Ball Milling

Article abstract of DOI:10.1002/adsc.201800161

Ball milling techniques have been applied in the development of a mechanosynthesis of [Cp*Co(CO)I₂], which proved highly efficient as catalyst in mechanochemical C?H bond amidations of indoles in a mixer ball mill. A wide range of amidated prod

Full text of DOI:10.1002/adsc.201800161

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DOI: 10.1002/adsc.201800161
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Mechanochemical Cobalt-Catalyzed CÀH Bond Functionalizations
by Ball Milling
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a
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Hanchao Cheng, Jose G. Hernandez, and Carsten Bolm *
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
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Fax: +492418092391
E-mail: carsten.bolm@oc.rwth-aachen.de
Received: January 31, 2018; Revised: March 15, 2018; Published online: &&&, &&&&
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201800161
sence of external heating,[7] and the possibility to
Abstract: Ball milling techniques have been ap-
plied in the development of a mechanosynthesis of
[Cp*Co(CO)I2], which proved highly efficient as
access different product compositions,[9a,b] to name just
a few.
With the goal to address the choice of metal we
catalyst in mechanochemical CÀH bond amidations
now investigated if mechanochemical CÀH bond
of indoles in a mixer ball mill. A wide range of
functionalizations could also be achieved by applying
amidated products is obtained in excellent yields.
widely abundant and cheap first-row cobalt com-
Compared to the solution-based methods, the
plexes, thereby substituting the previously used pre-
procedure opens a more feasible and environ-
cious metal catalysts.[12] Clearly, the success of this
mentally-friendly access to both the cobalt(III)
approach required a high mechanical stress tolerance
catalyst and 2-amidated indoles.
of the organocobalt complex.[13] Overall, we envisaged
a two-step process: First, a solvent-free mechano-
Keywords: Amidation; ball mill; cobalt; CÀH bond
synthesis of pentamethylcyclopentadienyl cobalt com-
functionalization; mechanosynthesis
plex Cp*Co(CO)I2 (4) [Cp*=h5-C5(CH3)5], and, sec-
ond, the use of this cobalt(III) complex as catalyst in
solventless CÀH bond functionalizations, specifically,
34 In the past decade, transition metal-catalyzed CÀH indol amidations with dioxazolones (Scheme 1).
35 bond activation has proven to be a powerful synthetic
36 alternative for the functionalization of organic mole-
37 cules,[1] for example, through the direct construction of
38 CÀN bonds.[2] It thereby complements classic methods
39 for the CÀN bond formation such as the Ullmann
40 reaction,[3] the Buchwald-Hartwig amination ap-
41 proach,[4] and the Chan-Lam coupling[5] amongst
42 others.
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Traditionally, solution-based protocols for CÀH
44 bond functionalizations involve activations by transi-
45 tion metal complexes containing precious metals such
46 as palladium, iridium, or rhodium. Recently, however,
47 there has been a growing interest in achieving such
48 transformations by using more abundant metals and in
49 finding milder, benign reaction conditions.[6] Focusing
50 on the latter aspect, we[7] and others[8] utilized
51 mechanochemical techniques and developed CÀH
52 bond functionalizations under solvent-free condi-
53 tions.[9] Compared with organic solvent-based proto-
54 cols, the advantages of conducting chemical trans-
55 formations by mechanochemistry include the
56 reduction of harmful organic solvents and low E-
57 factor synthesis,[10] shorter reaction times,[11] the ab-
Scheme 1. Mechanosynthesis of [Cp*Co(CO)I2] (4) and its
use in CÀH bond activation by milling.
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In solution chemistry, [Cp*Co(CO)I2] (4) is typi- ated ambient conditions (Table 1, entry 6). Lowering
cally prepared in a two-step approach starting from a the catalyst loading from 10 mol% to 2.5 mol%
mixture of Co2(CO)8 (1) and pentamethylcyclopenta- proved possible without significantly affecting the
diene (Cp*H, 2) in dichloromethane. This reaction yield of 7aa (Table 1, entry 7). Also the crude mixture
renders the intermediate [Cp*Co(CO)3] (3), which is of 4 after its mechanochemical preparation could be
further reacted with iodine in diethyl ether to yield applied, but then, the yield of 7aa was only 38%
cobalt complex 4.[14] Here, the mechanosynthesis of 4 (Table 1, entry 8).
was intended to be a one-pot two-step reaction
sequence.[15] Thus, a mixture of dicobalt octacarbonyl
Table 1. Optimization of the mechanochemical amidation.[a]
10 (1) and Cp*H (2) was milled under argon for 60 min
11 at 25 Hz to promote the formation of 3. After this
12 period of time, the milling jar was opened under argon
13 and iodine was added. Then, the grinding was
14 continued for 1 h. Gratifyingly, the analysis of the
1
15 resulting reaction mixture by H NMR spectroscopy
16 confirmed the formation of 4, which also revealed that
17 the cobalt complex was stable under the ball milling
18 conditions (Scheme 2; for details, see Supporting
19 Information).
Entry Ratio Co cat. AgSbF6
NaOAc
(mol%)
Yield of
of
(mol%) (mol%)
7aa [%][b]
(5a:6a)
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4
1:1.2
1:1.5
1.5:1
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
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2.5
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5
–
–
–
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100
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5
64
68
48
96
trace
93
95
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6[c]
7[c]
8[c]
[d]
–
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5
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[a] All reactions were conducted on a 0.5 mmol scale (of 5a or
6a). A mixture of 5a and 6a was ball-milled under argon
for 99 min at 30 Hz in a stainless steel milling jar of 10 mL
in volume with one 10 mm milling ball made of the same
material.
Scheme 2. Mechanosynthesis of [Cp*Co(CO)I2] (4).
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Motivated by the resilience of [Cp*Co(CO)I2] (4)
[b] After column chromatography.
33 in the ball mill, the screening of the conditions for the
34 mechanochemical cobalt-catalyzed CÀH amidation
35 reaction by milling was started. 1-(Pyrimidin-2-yl)-1H-
36 indole (5a) and 3-phenyl-1,4,2-dioxazol-5-one (6a)
37 were chosen as representative starting materials. First,
38 a mixture of 5a and 6a (in a ratio of 1.0:1.2) was ball-
39 milled in the presence of 10 mol% of [Cp*Co(CO)I2]
40 and 20 mol% of silver hexafluoroantimonate
[c] Air atmosphere.
[d] Use of 15 mg of the crude mixture of [Cp*Co(CO)I2] (4)
taken after its mechanochemical preparation, without
purification.
It is worth mentioning that even though the
41 (AgSbF6). To our delight, desired product 7aa was mechanochemical CÀH amidation was carried out
42 obtained in 64% yield after only 99 min of milling at without external heating, high-speed ball milling of
43 30 Hz (Table 1, entry 1). Then, the effect of the the sample can affect the temperature inside the
44 substrate ratio was investigated. Applying 1.5 equiv. of milling container. Such temperature changes have
45 6a led to a slightly increased yield (Table 1, entry 2). been demonstrated to depend not only on milling
46 In contrast, when 6a was the limiting reagent, the parameters (type of ball mill, milling media’s material,
47 reaction gave 7aa in only 48% yield (Table 1, entry 3). milling speed, time, etc.),[18] but also amorphization/
48 The presence of NaOAc (20 mol%) as additive,[16] crystallization events.[18a] Furthermore, changes in
49 exhibited a positive effect yielding indole 7aa in 96% reaction mixture composition play significant roles on
50 (Table 1, entry 4). Increasing the amount of NaOAc temperature fluctuation upon milling.[18d] Monitoring
51 from 20 mol% to 1 equiv. inhibited the amidation the changes in temperature on the outside wall of our
52 reaction (Table 1, entry 5). This result suggested that milling vessel revealed a rise in temperature from
53 NaOAc served as
a carboxylic ligand for the 238C to 358C after 99 min of milling at 30 Hz (for
54 Cp*Co(III) species and not as a base in the reaction.[17] details, see Supporting Information). It is reasonable
55 Product 7aa was also obtained (in 93% yield) when to assume that this increase in temperature during the
56 the experiment was conducted under an aerobic milling process facilitated the mechanochemical CÀH
57 atmosphere showing that the catalytic system toler- bond functionalization reaction.
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Having identified the optimal reaction conditions amidated product 7ai (93% yield). Alkyl-substituted
for the mechanochemical CÀH bond amidation as dioxazolones 7j and 7k bearing methyl and t-butyl
2.5 mol% of [Cp*Co(CO)I2], 5 mol% of AgSbF6, and groups, respectively, afforded products 7aj and 7ak in
5 mol% of NaOAc for 99 min at 30 Hz, the substrate low yields (Scheme 3), probably due to a lower
scope of indoles and dioxazolones was explored.[19] In stability of these dioxazolones under high-energy
general, 2-amidated indoles 7 were obtained with mechanical forces in the ball mill. In amidations
good tolerance of functional groups and with excellent carried out in 1,2-dichloroethane at 808C alkyl-
yields, up to 99% (Scheme 3). First, a range of substituted dioxazolones proved less active for CÀH
substituted 1-(pyrimidin-2-yl)-1H-indoles 5 was ap- bond amidations.[16b] In other cases, however, aryl- and
10 plied using dioxazolone 6a as the reaction partner. In alkyl-substituted dioxazolones have been reported to
11 these cases, indole substrates substituted with elec- exhibit comparable reactivity.[16a]
12 tron-withdrawing groups exhibited a slightly better
Subsequently, an intermolecular competition ex-
13 efficiency than those having electron-donating substi- periment with dioxazolone 6a and substituted indoles
14 tutes (Scheme 3). It is noteworthy that 5-halo-substi- 5f/5g was performed, which revealed that electron-
15 tuted indoles reacted smoothly giving the desired rich indole 5f exhibited a higher reactivity than 5g
16 products in yields ranging from 93% to 99% (7ga–ia; [Scheme 4 (a)]. The mechanochemical amidation re-
17 Scheme 3). Next, the scope of the CÀH amidation was action of indole 5a with a mixture of dioxazolones 6b
18 expanded by using aryl substituted dioxazolones 6b–h. and 6e showed a slight preference of the more
19 With 5a as coupling partner, such derivatives proved electron-rich 6b compared to 6e [Scheme 4 (b)].
20 suitable for the amidation conditions as well, affording
21 the corresponding products 7ab–ah in excellent yields
22 (up to 94%), regardless of the nature or substitution
23 pattern (Scheme 3). Similarly, indole 5a reacted with
24 thienyl-substituted dioxazolone 2i to effectively yield
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Scheme 4. Intermolecular competition experiments in ball
mills.
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An eight-fold scale-up experiment gave >1 g of
7aa (83% yield) after 99 min of milling demonstrating
the synthetic potential of the cobalt(III)-catalyzed
CÀH bond amidation (Scheme 5; top). Pleasingly,
under these conditions the catalyst loading could be
lowered to 1 mol% providing 7aa in 65% yield.
Attempts to remove the pyrimidin-2-yl directing group
in 7aa by ball milling remained unsuccessful.[20]
Neither milling of a mixture of 7aa in the presence of
NaOEt under neat nor liquid-assisted grinding con-
ditions (LAG; DMSO)[21] (99 min at 30 Hz) did afford
the free indole. In solution, removal of the same
directing group requires harsh reaction conditions
(100–1108C; 11 h to 24 h),[22] which apparently could
not be matched by ball milling.
Then, with the goal to demonstrate the generality
of the mechanochemical approach, cobalt(III)-cata-
lyzed iodination reactions of 2-arylpyridines 8 were
attempted (Scheme 5; bottom). Thus, grinding of 8 in
Scheme 3. Substrate scope of indoles and dioxazolones.
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Isolation of 4 was done by flash column chromatography (for
details, see Supporting Information).
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General procedure for the preparation of 7: A mixture of
indole (5, 0.5 mmol), dioxazolone (6, 0.75 mmol, 1.5 equiv.),
[Cp*Co(CO)I2] (6.0 mg, 0.0125 mmol, 2.5 mol%), AgSbF6
(8.6 mg, 0.025 mmol, 5 mol%), and NaOAc (2.1 mg,
0.025 mmol, 5 mol%) was loaded in a milling jar (stainless
steel, 10 mL) together with one milling ball (stainless steel,
1 cm in diameter). The milling jar was placed in the mixer
mill and shaked at 30 Hz for 99 minutes. Then, the mixture
in the jar was washed out with acetone (33 10 mL). The
solvent was removed in vacuo, and the product was purified
by flash column chromatography on silica gel (n-pentane/
EtOAc) to afford 7. To avoid the use of solvent during the
removal of the reaction mixture from the milling jar, the
mixture could alternatively be taken up by adding SiO2 (23
0.5 g) to the jar, which was milled for another 2 min each
time.
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General procedure for the preparation of 10: Under argon
atmosphere, the mixture of 2-phenylpyridine (8, 0.65 mmol),
N-iodosuccinimide (0.5 mmol, 112.5 mg), [Cp*Co(CO)I2]
(23.8 mg, 0.05 mmol, 10 mol%), AgBF4 (19.5 mg, 0.1 mmol,
20 mol%), and pivalic acid (10.2 mg, 0.1 mmol, 20 mol%)
was loaded in a milling jar (stainless steel, 10 mL) together
with one milling ball (stainless steel, 1 cm in diameter). The
milling jar was placed in the mixer mill and shaked at 25 Hz
for 99 minutes. Then, the mixture in the jar was washed out
with acetone (33 10 mL). The solvent was removed in vacuo,
and the product was purified by flash column chromatog-
raphy on silica gel (n-pentane/EtOAc) to afford 10. To avoid
the use of solvent during the removal of the reaction mixture
from the milling jar, the mixture could alternatively be taken
up by adding SiO2 (23 0.5 g) to the jar, which was milled for
another 2 min each time.
Scheme 5. Scale-up experiment and cobalt-catalyzed mecha-
nochemical iodination reactions.
28 the presence 10 mol% of cobalt complex 4, AgBF4
29 (20 mol%), pivalic acid (20 mol%) and N-iodosuccina-
30 mide (NIS) as the limiting reagent, led to mono-
31 iodinated products 10 in yields ranging from 73% to
32 83% (Scheme 5; bottom).
33
In conclusion, we demonstrated the use of
34 mechanochemical techniques in facilitating the forma-
35 tion of the first-row metal complex [Cp*Co(CO)I2]
36 (4). Subsequently, 4 was applied in CÀH bond
37 amidations of indoles with 1,4,2-dioxazol-5-ones as
Acknowledgements
H.C. thanks the China Scholarship Council (CSC) for a
38 amidating agents under neat grinding in a mixer ball predoctoral stipend. We also thank the RWTH Aachen
University for support from the Distinguished Professorship
Program funded by the Excellence Initiative of the German
Federal and State Governments.
39 mill. The resulting 2-amidated indoles were obtained
40 in excellent yields without additional heating and in
41 shorter reactions times than in solution.
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ˇˇ ´
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