Mechanochemical Solvent-Free Catalytic C?H Methylation

Article abstract of DOI:10.1002/anie.202010202

The mechanochemical, solvent-free, highly regioselective, rhodium-catalyzed C?H methylation of (hetero)arenes is reported. The reaction shows excellent functional-group compatibility and is demonstrated to work for the late-stage C?H methylation of biologically active compounds. The method requires no external heating and benefits from considerably shorter reaction times than previous solution-based C?H methylation protocols. Additionally, the mechanochemical approach is shown to enable the efficient synthesis of organometallic complexes that are difficult to generate conventionally.

Full text of DOI:10.1002/anie.202010202

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Mechanochemical Solvent-Free Catalytic C-H Methylation
Authors: Shengjun Ni, Matic Hribersek, Swarna Kumari Baddigam,
Fredric Jan Leif Ingner, Andreas Orthaber, Paul J. Gates, and
Lukasz T Pilarski
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010202
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10.1002/anie.202010202
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RESEARCH ARTICLE
Mechanochemical Solvent-Free Catalytic C—H Methylation
Shengjun Ni,[a] Matic Hribersek,[a]† Swarna K. Baddigam,[a]† Fredric J. L. Ingner,[a] Andreas Orthaber,[b]
Paul J. Gates[c] and Lukasz T. Pilarski*[a]
[a]
Dr. Shengjun Ni, Matic Hribersek, Swarna Baddigam, Fredric J. L. Ingner, Dr. L. T. Pilarski
Department of Chemistry – BMC, Uppsala University
Box 576, 75123, Uppsala (Sweden)
E-mail: lukasz.pilarski@kemi.uu.se
[b]
[c]
Dr. Andreas Orthaber
Department of Chemistry – Ångström Laboratories, Uppsala University
Box 523, 75120 Uppsala (Sweden)
Dr. Paul J. Gates
School of Chemistry, University of Bristol, Cantock’s Close
Clifton, Bristol, BS8 1TS (UK)
†
These authors contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: The mechanochemical, solvent-free, highly regioselective,
rhodium-catalyzed C–H methylation of (hetero)arenes is reported.
The reaction shows excellent functional group compatibility and is
demonstrated to work for the late-stage C–H methylation of
biologically active compounds. The method requires no external
heating and benefits from considerably shorter reaction times than
previous solution-based C–H methylation protocols. Additionally, the
mechanochemical approach is shown to enable the efficient synthesis
of organometallic complexes that are difficult to generate
conventionally.
shortened reaction times, lower operating temperatures, access
to new mechanistic pathways,[8] avoidance of solvent use and
even the option of carrying out otherwise air-sensitive reactions
under aerobic conditions.[9] For its potential to help usher in a
greener era in synthesis, IUPAC recently listed ‘reactive
extrusion’ (mechanochemistry) among the top ten “chemical
innovations that will change our world”.[10] Mechanocatalytic C–H
functionalization is a burgeoning area of research and has
delivered some impressive recent advances.[11] Here, we describe
an unprecedented mechanochemical catalytic C–H methylation
that entirely avoids solvent as a reaction medium and that can be
used even for the late-stage functionalization (LSF) of bioactive
molecules.
Introduction
The methylation of bioactive molecules can dramatically improve
their potency by enhancing lipophilicity, binding interactions,
metabolic stability and numerous other properties (benefits
collectively referred to as the “magic methyl effect”).[1]
Approximately 40% of the 200 best-selling drugs in 2019
Results and Discussion
Table 1 shows selected results from an extensive optimisation of
our C–H methylation protocol using phenylpyridine (1) as a
workhorse substrate. These reactions were performed in
stainless-steel (SS) milling vessels (14 mL internal volume)
equipped with a single SS ball (10 mm diameter) using a mixer
mill (MM) capable of oscillating at frequencies up to 36 Hz. To
avoid neurotoxic C1 reagents such as MeI or SnMe4, and to
encourage a broad substrate scope (e.g. by outcompeting
oxidative addition to aryl halides), we began our study using
MeB(OH)2 as the methyl source under oxidative conditions.[12]
[Cp*RhCl2]2 proved to be the only effective catalyst precursor[13]
amongst a variety we tested; others, including [RuCl2(p-cymene)]2
and [Cp*Co(CO)I2],[14] gave no conversion of the starting material.
Initially, 1 was milled at 36 Hz for 40 min in the presence of
[Cp*RhCl2]2 (5 mol%), MeB(OH)2 (2.0 equiv.) and Ag2CO3 (1.2
equiv), which gave 2 in 62% yield (entry 1). A lower loading of
MeB(OH)2 gave a modestly lower yield, despite a doubled
reaction time (entry 2). All other AgI salts we tested (Ag2O,
AgOAc, and AgF) proved less effective than Ag2CO3 but
contained
a
C–Me unit.[2] New synthetic C–H methylation
strategies have become highly sought after and significant recent
efforts have been devoted to their discovery.[1b] The use of
transition metal catalysis for this purpose ranks among the most
attractive of approaches[3] but its potential is far from fully
explored.
Despite their many benefits, a significant number of transition
metal-catalyzed C–H functionalizations (including C–H
methylations) rely on toxic and/or environmentally damaging
solvents, e.g. 1,2-dichloroethane (DCE), the legal regulation of
which is becoming increasingly stringent.[4] More generally,
solvent waste presents
a
formidable challenge for the
sustainability of chemical synthesis;[5] in the pharmaceutical
industry alone, an estmimated 85% of waste by mass is
attributable to solvent use.[6]
In light of these concerns, mechanochemistry offers an enticing
alternative to established, solution-based approaches.[7] The use
of mechanical action (e.g., grinding or milling) for reagent mixing
and activation can provide powerful advantages. These include
outperformed Cu(OAc)2·H2O significantly (entries 3-5 vs 6).[15]
2 h reaction time allowed us to keep the Ag2CO3 loading at 1.5
A
1
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10.1002/anie.202010202
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RESEARCH ARTICLE
equiv. and milling frequency at 30 Hz, and still obtain 2 in an
improved yield of 77% (entry 7 vs entry 1). At 36 Hz the same
conditions gave 2 in a 92% yield (entry 8).
Some notable advantages of the mechanochemical protocol
emerged from these early experiments. First, reaction times of 1-
2 h are substantially shorter than those used in related C—H
methylations, for which 16-24 h is typical. Secondly, whilst low
regioselectivity in the C—H functionalization of symmetrical
Scope: via 5-membered rhodacycles
[Cp* Rh Cl2]2
(5 mol%)
Me-B(OH)2 (2 equiv.)
(het) N
(het)
(het)
(het)
N
N
Ag2CO3 (1.5 equiv.)
Rh
Me
Me/H
H
H
(het)
X
(het)
SS vessel (14 mL)
SS ball ! = 10 mm
MM, 36 Hz, 1-4 h
R
R
4
5-membered
rhodacycles
3
5
substrates is
a
common challenge (usually, mono-
/difunctionalized product ratios fall in the range of 3-4:1),
throughout our optimisation the 2a/2b ratio remained
exceptionally high: up to 97:3 (≈32:1, entry 5). In our hands, the
corresponding reaction performed in DCE at 100 °C gave 2 in
80% yield (comparable to entry 7) but with a much lower 2a:2b
ratio of only 85:15 (<6:1; see Supporting Information for more
details).
Indole-based substrates
Me
Me
R
Me
Me
Me
Me
MeO
N
N
N
N
N
N
N
N
H
H
H
O
H
N
N
N
N
5f: 95%
5g: 99%
5h: 94%
5a: R = H, 82%
5b: R = OMe, 84%
5c: R = Br, 72%a
5d: R = I, 72%a
Other heterocyclic motifs
Table 1. Table Caption.
H
Me
N
5e: R = NO2, 76%a
N
N
Optimization: workhorse substrate
H
Me
S
S
N
[Cp* Rh Cl2]2
Me
Me
(5 mol%)
N
N
5i: 71%b,d
5k: 83%c,e (4:1)
N
5j: 70%c,d (6:1)
Me-B(OH)2 , oxidant
H
H
H
Me
Me
Me
+
ball milling
conditions
Scheme 1. Heteroarene C—H methylation via 5-membered rhodacyclic
intermediates. Conditions: 0.3 mmol scale, MeB(OH)2 (2 equiv.), [Cp*RhCl2]2 (5
mol%), Ag2CO3 (1.5 equiv.), SS vessel (14 mL internal vol.), one SS ball (10
mm diameter), 36 Hz. [a] Minor amounts of dimethylated products observed [b]
10 mol% catalyst loading. [c] Major/minor regioisomeric ratio shown in
parentheses. [d] Conditions from Scheme 2: MeBF3K (6 equiv.) [e] 1.2 equiv of
MeB(OH)2 used.
1
2a
2b
Entry[a]
MeB(OH)2
(equiv.)
Oxidant
(equiv.)
Freq. (Hz),
Time (min)
Yield (%)[b]
(2a:2b)
1
2
3
4
5
6
7
8
2.0
1.2
2.0
2.0
2.0
2.0
2.0
2.0
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2O (1.2)
36, 40
36, 80
36, 40
36, 40
36, 40
36, 60
30, 120
36, 120
62 (96:4)
54 (96:4)
54 (93:7)
17 (70:30)
53 (97:3)
5 (n.d.)
Pyrimidine-directed C2–H methylation of indoles[11g, 16] (products
5a–5h) occurred in good to quantitative yields and with generally
excellent C2—H regioselectivity. Electron-rich (e.g. product 5b),
electron-poor (5e, 5h) and potentially sterically hindered (5g)
substrates performed very well, as did those bearing C-halogen
units (5c, 5d), which leaves open the prospect of their subsequent
derivatization via coupling strategies. Our mechanochemical
protocol also proved compatible with benzothiazole- (5i) and
pyrazole-directed (5j) C–H methylation; C2–H methylation of the
thiophene ring system gave 5k in very good yield.
AgOAc (2.4)
AgF (2.4)
Cu(OAc)2·H2O (1.2)
Ag2CO3 (1.5)
77 (94:6)
92 (89:11)
Ag2CO3 (1.5)
Translating these conditions for substrates giving rise to six-
membered metallacycles (Scheme 2), whose formation is
thermodynamically less favored, required re-optimization: Me-
BF3K instead of MeB(OH)2 gave the best yields in the presence
of sub-stoichiometric AgSbF6. Unlike for the reactions in Scheme
1, Teflon™ milling vessels gave higher yields than their stainless-
steel counterparts (e.g. product 8a, Scheme 2). The influence of
milling vessel material as a parameter is not yet fully understood
in the context of mechanochemical reactions. The next part of our
study thus examined phenoxypyridine substrates, which are
useful as masked phenol surrogates[17] as well as aryl
pseudohalides,[18] and which occur in numerous biologically active
compounds (see Figure 1 below) and luminescent materials.[19]
These returned good yields for both electron-donating and
electron-withdrawing groups at ortho (8a-8g, Hl), meta (8h-i) and
para positions (8j-l). The transformation also worked well when
the ether linker was replaced with a -CH2- or -NAr- unit (products
8m-n and 8o, respectively), including as part of the carbazole
core (8p-q, cf. 8g); the pyridinoid ring of 7-azaindole also proved
[a] All reactions shown were carried out in a mixer mill (MM) using a stainless
steel (SS) milling vessel (14 mL internal volume) equipped with one SS ball (10
mm diameter). 0.3 mmol scale. [b] Determined using 1H NMR spectroscopy
against 1,3,5-trimethoxybenzene as an internal standard.
We applied our optimized protocol to the C–H methylation of
various heteroarenes expected to proceed via five-membered
rhodacyclic intermediates of type 4 (Scheme 1).
2
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10.1002/anie.202010202
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able efficiently to direct the C—H methylation of both electron-
poor and electron-rich arenes (8r-8v). These results indicate
there is some leeway in the σ-donating strength of the directing
group.[20]
energy input. Catalytic dehydrogenative aromatizations generally
require very high temperatures and long reaction times;[22] Rh-
catalyzed dehydrogenative aromatisations of indolines are rare[23]
whilst mechanochemical dehydrogenative aromatization as a
whole is without precedent.[24] Control experiments confirmed that
both Ag2CO3 and Me-BF3K are required for 11 to form. On the
basis of this and studies on Ar–H activation by Cp*RhIIIMe2L
complexes,[25] we tentatively suggest C(sp3)–H activation might
occur via s-bond metathesis (13 to 14),[26] which has been
proposed for some related processes.[27] The divergent outcomes
obtained from different milling frequencies suggest an exciting
new basis for regiocontrol in mechanochemical C–H
functionalization, the broader implications of which are under
investigation in our laboratory.
Scope: via 6-membered rhodacycles
[Cp* Rh Cl2]2
(5 mol%)
G
N
G
R
G
Rh
Ir
X
Me-BF3K
Y
N
Y
N
H
Y
additives
Me/H
Me
H
TeflonTM vessel
SS ball ! = 15 mm
R
R
7
MM, 36 Hz, 20-120 min
6
8
6-membered
rhodacycles
Phenoxypyridine substrates
ortho-
substituted
meta-
substituted
para-
substituted
Table 2. Frequency-dependent selectivity in the C–H methylation of an indoline
C7–H & C2–H activation: frequency dependent selectivity
N
O
Me
N
O
N
O
N
O
oxidative
C2–H
methylation
3
2
H
H
C7–H
methylation
H
H
R
Me
Me
Me
Me
H
R
Me
N
N
7
N
N
Bn
N
Me
N
H
TM vessel
MM, SS ball
! = 15 mm, 25 Hz
TM vessel
MM, SS ball
! = 15 mm, 36 Hz
N
N
N
Me
R
Teflon
Teflon
N
8a: R = H, 78%a,e (11%b) 8g: 70%d
8b: R = Me, 82%a
8h: R = I, 75%d,e
8i: R = CF3, 78%d
8j: R = OMe, 81%
8k: R = CO2Me, 88%
8l: R = F, 85%
9
10
11
8c: R = OMe, 71%c
8d: R = F, 85%d
en route to 10:
en route to 11:
8e: R = Cl, 86%d
‡
3
2
H
8f: R = Ph, 82%d
H
N
H
H
H
H
H
Me
Related aromatic amine substrates
N
7
N
N
Rh
Rh
N
Rh
N
N
Me
Me
with -CH2- linker
with -N-aryl- linkers
X
X
N
N
Me
R
13: σ-bond metathesis
14: β-H elimination
(proposed intermediate)
12
Me
N
N
(proposed intermediate)
(proposed transition state)
N
N
N
Me
H
Me
Me
Me
N
substrate.
H
Me
Me
H
N
N
Entry[a]
[Cp*RhCl2]2
/ AgSbF6
(mol%)
MeBF3K /
Ag2CO3
(equiv.)
Frequency,
Time
Yield (%)
(10:11)
R
R
8m: R = H, 64%f,i
8n: R = Cl, 75%e
8o: 83%
8p: R = H, 73%f
8q: R = Br, 62%f
8r: R = H, 85%e,g
8s: R = OMe, 81%e,g
8t: R = F, 74%e,g,h
8u: R = Cl, 81%e,g,h
8v: R = CO2Me,
90%e,g,h
1
2
3
4
5
6
5.0 / 20
5.0 / 20
5.0 / 20
5.0 / 20
10 / 40
10 / 40
1.5 / 1.5
1.5 / 1.5
6.0 / 3.0
6.0 / 3.0
6.0 / 3.0
6.0 / 3.0
25 Hz, 2 h
36 Hz, 2 h
25 Hz 1 h
36 Hz, 1 h
25 Hz, 1 h
36 Hz, 1 h
74 (>99:1)
90 (>99:1)[b]
38 (>99:1)
68 (59:41)
75 (>99:1)
60 (1:>99)
Scheme 2. Heteroarene C—H methylation via 6-membered rhodacyclic
intermediates. Conditions: 0.3 mmol scale, MeBF3K (6.0 equiv.) [Cp*RhCl2]2 (5
mol%), AgSbF6 (20 mol%). Ag2CO3 (3 equiv.) TeflonTM vessel, SS ball (15 mm
diameter), 36 Hz, 2 h. [a] 2.0 equiv MeBF3K and 1.5 equiv Ag2CO3. [b] Yield
using SS milling vessel under otherwise identical conditions. [c] 4.0 equiv
MeBF3K and 2.5 equiv Ag2CO3. [d] 3.0 equiv MeBF3K and 1.5 equiv Ag2CO3.
[e] Dimethylation observed as the minor product (see SI for details). [f] 4.0 equiv.
MeBF3K. [g] 1.5 equiv. MeBF3K and 1.5 equiv Ag2CO3. [h] 25 Hz. [i] [Cp*RhCl2]2
(10 mol%), AgSbF6 (40 mol%).
[a] All reactions shown were carried out at a 0.3 mmol scale using a 14 mL
TeflonTM milling vessel equipped with one SS ball (15 mm diameter). [b]
Determined using 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an
internal standard.
The new conditions also allowed the smooth C7–H methylation of
indoline 9 to give 10 in 74% yield at 25 Hz and 90% at 36 Hz
(entries 1 and 2, Table 2).[21] With increased amounts of MeBF3K
and Ag2CO3, however, we observed the formation of 11 in
significant quantities for reactions run at 36 Hz, but not at 25 Hz
(entries 3 and 4). Adjusting the catalyst loading allowed for
conditions in which the exclusive formation of either 10 or 11 could
be selected using only the milling frequency (entries 5 and 6). The
C2–H methylation (to give 11) presumably occurs via an
intermediate 2,3-dehydrogenation enabled by the additional
A hallmark advantage of C—H functionalization is its potential to
diversify bioactive molecules at a late-stage in a synthetic
sequence. This can help obviate de novo syntheses, lower costs
and expedite the exploration of chemical space.[28] To the best of
our knowledge, this study marks the first time LSF has been
conducted under mechanochemical conditions. We tested the C–
H methylation of a range of bioactive substrates, including those
based on marketed pharmaceuticals (Etoricoxib, Sulfaphenazole,
Oxaprozin and Papaverine), the herbicide Diflufenican and
3
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10.1002/anie.202010202
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RESEARCH ARTICLE
pesticide Etoxazole (Scheme 3) for all of which, reaction times
ranged from 30 min to 2.5 h. Exclusively mono-methylated
products were isolated in every case (15a, 15c-15h) with the
exception of tryptophan derivative 15b, which gave minor
amounts of the C2,C7-dimethylated product (not shown). The
mechanochemical late-stage methylation worked well with both
π-deficient and π-rich directing groups, including pyrazoles[29] and
oxazoles,[30] which are prevalent in a large number of bioactive
compounds. In total, across our entire substrate range (Schemes
1–3 and Table 2), our method was compatible with 12 different
heterocycle types and 20 different pendant functional groups.
from our C–H methylation scope (Figure 1). It is worthy of note
that solution-based rhodacycle syntheses frequently rely on toxic
solvents (e.g. DMF or DCE) and that yields for six-membered
metallacycles generated through C–H activation tend to be low.[31]
The use of mechanochemistry in organometallic synthesis is a
growing area of research and has provided routes to various
previously inaccessible species.[32] In our experiments, ball milling
at 36 Hz outperformed conventional solution-based methods for
both five- (4a) and six-membered (7a-c) rhodacycles by a yield
margin of up to 89%, and within a substantially shorter reaction
time (1 h vs 48 h). The structures of previously unreported six-
membered rhodacycles 7a-c were confirmed spectroscopically as
well as by X-ray crystallography (Figure 1).
C–H Methylation of biologically-relevant structures, including LSF
[Cp* Rh Cl2]2
(5 mol%)
Rhodacycle synthesis: Mechanochemical vs. conventional conditions
AgSbF6 (20 mol%)
Me
H
Me-BF3K, Ag2CO3
N
N
(het)
(het)
(het)
(het)
FG
FG
TeflonTM vessel (14 mL)
SS ball ! = 15mm
15
Rh
Ir
MM, 36 Hz, 0.5 - 2.5 h
N
Rh
Ir
N
N
Cl
N
N
Cl
N
A. π-Deficient directing groups; via 5-membered rhodacycles
76% (20%)a
87%
24%
4a:
7a:
SO2Me
O
51%b
Cl
O
N
H
CO2Me
N
Me
Me
N
Me
N
N
15b: 75% (4:1)a
15a: 60%
H
N
N
Rh
Ir
Rh
N
N
from Tryptophan
(amino acid)
from Etoricoxib
Cl
Cl
O
(NSAID)
B. π-Excessive directing groups; via 5-membered rhodacycles
7b
91%
2%
7c
88%
16%
Bn2N
Me
F
O
O
Mechanochemical conditions
[Cp*RhCl2]2, ligand (2.1 equiv)
KOAc (6 quiv.), MeOH (10 equiv)
Solution-based conditions
for complexes 16b-d:
[Cp*RhCl2]2, ligand (2.0 equiv)
KOAc (6 quiv.)
1,2-DCE solvent
80 °C, 48 h
O
EtO
S
N
N
N
O
N
OMe
N
Bn
H
O
TeflonTM vessel (14 mL)
SS ball ! = 15 mm, MM, 36 Hz, 1 h
H
Me
Me
F
15c: 72%
15d: 53%
15e: 75%
Figure 1. Comparison of mechanochemical (ball milling) and conventional
solution-based conditions for rhodacycle preparation. [a] Previously reported
yield using ball milling at 30 Hz.[11g] [b] Average yield from five previously
reported syntheses using solution-based conditions.[33]
from Sulfaphenazole
(anti-bacterial)
from Oxaprozin
from Etoxazole
(pesticide)
(NSAID)
C. Pyridyl directing groups; via 6-membered rhodacycles
F
F
O
MeO
MeO
We tested complexes 4a and 7c as C–H methylation catalysts in
their own right. Using conditions from Scheme 1 with 4a instead
of [Cp*RhCl2]2, product 5a was obtained in 92% yield. Similarly,
7c as the catalyst gave 8r in 78% using conditions from Scheme
2. These experiments are consistent with the putative
intermediacy of rhodacycles in our reaction and show that loss of
the chloride ligand does not necessarily precede rhodacycle
formation, at least for the first catalytic cycle.
Me
H
HN
N
H
H
O
Me
N
H
OMe
OMe
N
O
O
Me
H
Me
H
CF3
15g: 58%
15h: 78%
from Papaverine
(anti-spasmodic)
15f: 65%
from Estrone
(hormone)
from Diflufenican
(herbicide)
Several preliminary mechanistic insights may be inferred from the
mechanochemical C–H methylation catalysis. First, although
indole C2–H methylation occurs faster than does C7–H
methylation at 36 Hz (Scheme 1, products 5a-h), C7–H
methylation occurs even at 25 Hz when a C(sp2)2–H unit is
unavailable (Table 2, 9 to 10). Thus, C7–H rhodation likely occurs
reversibly at 36 Hz, prior to a more difficult transmetalation or
oxidation step at the corresponding six-membered rhodacycle.
Indeed, a C–H/D exchange experiment using 1-(pyrimidin-2-yl)-
1H-indole in the presence of 10 equiv. MeOD (Scheme 4A)
Scheme 3. Mechanocatalytic C–H methylation of bioactive motifs, including
late-stage C–H methylation. For specific conditions, see Supporting Information.
[a] Conditions from Scheme 1, 6 h. Ratio of mono- and di-methylated isomers
(major isomer shown).
En route to mechanistic experiments, we compared the efficiency
of mechanochemical and solution-based methods for the
synthesis of a range of rhodacyclic complexes based on ligands
4
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revealed extensive reversible C7–H activation, even when C2-
methylation is significantly faster. Additionally, competition
experiments (Scheme 4B) showed a strong preference for the
C2–methylation of electron-rich indoles (products 5b vs 5e) but
not for phenoxypyridines (8c vs 8d). That the more nucleophilic
position of indole[16c] undergoes faster C–H functionalization and
that electron-rich substrates outcompete their electron-poor
counterparts is suggestive of an electrophilic metalation pathway.
Studies by Bolm and co-workers on a related mechanochemical
Rh-catalyzed C–H functionalization performed under oxidative
conditions suggest that C–H rhodation is not the turnover-limiting
step.[11f] However, it is also possible reactions proceeding via 5-
and 6-membered intermediates differ somewhat in the C–H
metalation step. Presently, a CMD-type pathway cannot be ruled
out as non-rate limiting CMD-type C–H activations are possible
for both electron-rich and electron-poor substrates in Rh-
catalyzed processes.[34]
Table 3. Effect of different additives on the efficiency of transmetalation to and
reductive elimination from complex 7c.
Reductive elimination: substrate/ligand influence
additives
Me BF3K
N
N
N
(2.0 equiv.)
Rh
Ir
Me
N
N
N
Cl
R
TeflonTM vessel (14 mL)
SS ball ! = 15mm
MM, 36 Hz, 1 h
16a: R = Ph
16b: R = Me
7c
8r
Entry[a]
Additives (equiv.)
Time (min)
Yield 8r (%)
1
2
3
4
5
None
60
20
20
20
20
0
AgSbF6 (1.0)
20
9
KPF6 (1.0)
Mechanistic experiments: Regio- and chemoselectivity
AgSbF6 (1.0) + 16a (1.0)
AgSbF6 (1.0) + 16b (1.0)
33
20
A. C–H/D exchange for indole substrates:
C3: 15% D
[Cp* Rh Cl2]2
(5 mol%)
H/D
Me
N
H
(2.0 equiv.)
Me B(OH)2
In line with this, transmetalation to 7c and subsequent reductive
elimination required AgSbF6 or KPF6 to proceed at all (entry 1 vs
entries 2 & 3, Table 3). Even without Ag2CO3 present, conversion
from 7c to 8r was higher when 16a was included as an additive,
which we used to mimic the presence of additional substrates in
the reaction mixture (entry 4). By contrast, the addition of 16b did
not affect the yield (entry 2 vs entry 5). This is similar to our
findings for oxidative Ru-catalyzed C—H arylations using
organoboronates,[16b] for which we previously proposed that
unreacted substrates may play a role as ancillary/stabilizing
ligands in the cycle(s) prior to their own C–H functionalization.
N
MeOD
+
N
H/D
N
Ag2CO3 (1.5 equiv)
10 equiv.
N
N
SS vessel (14 mL)
SS ball ! = 10mm
MM, 36 Hz, 1 h
C7: 30% D
5a/5a-d
(95%)
1.0 equiv
+
11
(5%)
B. Competition experiments: electron-rich vs. electron-rich substrates
B1. Indole-based substrates
[Cp* Rh Cl2]2
R
(10 mol%)
MeO
O2N
+
Me
N
H
H
(1.0 equiv.)
Me BF3K
N
N
N
N
Ag2CO3 (1.5 equiv)
N
N
N
N
SS vessel (14 mL)
SS ball ! = 10mm
MM, 36 Hz, 1 h
Conclusion
5b: R = OMe, 40%
5e: R = NO2, 0%
1.0 equiv
1.0 equiv
We have described the first catalytic C–H methylation reaction
that proceeds under solvent-free, mechanochemical conditions.
Its benefits include high regioselectivity, short reaction times and
B2. Phenoxypyridine-based substrates
[Cp* Rh Cl2]2
(10 mol%)
O
N
O
N
H
O
N
H
a
broad functional- and directing-group tolerance that
(1.0 equiv.)
Me BF3K
R
Me
F
MeO
+
encompasses 12 important heterocycle classes and 20 different
pendant functional groups. Notably, the reaction can be used for
the late-stage methylation of more complex, biologically active
compounds – the first reported examples of late-stage C–H
functionalization carried out under mechanochemical conditions.
We have also described the considerable superiority of ball milling
for the synthesis of five- and especially six-membered rhodacyclic
species that are difficult to generate conventionally.
AgSbF6 (40 mol%)
Ag2CO3 (3.0 equiv)
8c: R = OMe, 26%
8d: R = F, 22%
TeflonTM vessel (14 mL)
1.0 equiv
1.0 equiv
SS ball ! = 15mm
MM, 36 Hz, 1 h
Scheme 4. Mechanistic experiments probing the C–H activation step. [a]
Spectroscopic yields based on 1H NMR using 1,3,5-trimethoxybenzene as a
standard.
Although C–H rhodation can occur readily without AgSbF6
present (Figure 1), the catalytic methylation reactions proceeding
via six-membered rhodacycles showed significantly improved
yields through the inclusion of AgSbF6. It is likely that AgSbF6
facilitates the transmetalation or reductive elimination step (or
both) when six-membered rhodacyclic intermediates play a part.
This, and the greater efficiency of reactions run with Me-BF3K[35]
suggests that transmetalation to the RhIII center of six-membered
rhodacyclic intermediates might be turnover-limiting.
Acknowledgements
We are grateful to Carl Tryggers Stiftelsen and the Swedish
Research Council (Vetenskapsrådet) for funding. Our thanks also
go to Dr. Johanna Larsson, Prof. Graham E. Budd and Dr.
Christine Dyrager for help with proof-reading the manuscript and
to Dr. Christopher Whiteoak for a loan of Co salts.
5
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RESEARCH ARTICLE
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
late-stage
functionalization
DG
DG
Rh
Me
12 different
heterocycle classes
source
H
Me
FG
FG
20 different
functional groups
ball milling
difficult-to-make
complexes
high selectivity
• No solvent • No heating • Short reaction times
Balls to the walls! Catalytic C–H methylation proceeds efficiently under solvent-free, mechanochemical conditions, including for the
late-stage functionalization of biologically active substrates and otherwise difficult-to-make metalacyclic complexes.
8
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