Metal-, Photocatalyst-, and Light-Free Direct C-H Acylation and Carbamoylation of Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b02679

Direct C-H acylations and carbamoylations of heterocycles can now be readily achieved without requiring any conventional metal, photocatalyst, electrocatalysis, or light activation, thus significantly improving on sustainability, costs, toxicity, waste, and simplicity of the operational procedure. These mild conditions are also suitable for gram-scale reactions and late-stage functionalizations of complex molecules, including pharmaceuticals, N,N-ligands, and light-sensitive molecules.

Full text of DOI:10.1021/acs.orglett.9b02679

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal‑, Photocatalyst‑, and Light-Free Direct C−H Acylation and
Carbamoylation of Heterocycles
Matthew T. Westwood, Claire J. C. Lamb, Daniel R. Sutherland, and Ai-Lan Lee*
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, U. K.
S
* Supporting Information
ABSTRACT: Direct C−H acylations and carbamoylations of heterocycles can now be readily achieved without requiring any
conventional metal, photocatalyst, electrocatalysis, or light activation, thus significantly improving on sustainability, costs,
toxicity, waste, and simplicity of the operational procedure. These mild conditions are also suitable for gram-scale reactions and
late-stage functionalizations of complex molecules, including pharmaceuticals, N,N-ligands, and light-sensitive molecules.
carbamoylate N-heterocycles has the potential to greatly
inisci-type direct C−H functionalizations, involving the
Maddition of carbon-centered radicals to basic hetero- expedite the synthesis of such drugs and analogues, as these
would otherwise typically be made from more inefficient,
conventional amide-coupling methodologies,4 which require
prefunctionalization of the N-heteroaryls with carboxylic acid,5
as well as waste-generating coupling reagents.
arenes, have recently seen a surge of interest due to their utility
in mild, late-stage C−H functionalizations of pharmaceuticals,
natural products, and ligand scaffolds.1 While much develop-
ment has occurred with respect to Minisci-type alkylations in
recent years,1c functionalizations with sp2-C has been relatively
less explored. Nevertheless, the ability to perform mild, late-
stage C−H acylation and carbamoylation of N-heterocycles in
a cost-effective and facile manner would be of great interest,
not least due to the many natural products2 and
pharmaceutical drugs containing these functionalities (Figure
1). Significantly, amide-functionalized N-heterocycles are
widespread among pharmaceutical drugs, for example,
antiretroviral raltegravir, local anesthetic cinchocaine, and
antimalarial candidate3 M5717. The ability to rapidly C−H
Nevertheless, the original Minisci-type decarboxylative
acylations and carbamoylations via α-keto acids and oxamic
acids required stoichiometric silver reagents6 and harsh
conditions (e.g., H2SO4 and reflux), rendering them unsuited
to late-stage functionalizations.7 For this reason, photoredox
catalysis,8 iron catalysis,9 electrocatalysis,10 and light media-
tion11 have very recently been used to render the acylation
mild and silver-free.12 For carbamoylations, few mild
procedures existed, until two photoredox-catalyzed methods
were recently reported during the course of this study.13,14 It
would therefore be a significant progress if these mild, late-
stage reactions could do away entirely with requiring metal,
photocatalyst, electrocatalysis, light irradiation, and specialist
equipment, as this would significantly improve on sustain-
ability, costs, toxicity, energy, waste, simplicity of reaction
setup, and also allow for functionalizations of light-sensitive
compounds. We herein present the first C−H acylation and
carbamoylation of basic heterocycles under metal-, photo-
catalyst-, and light-free conditions and showcase its application
in late-stage functionalization of medicinally relevant com-
pounds, ligands, and light-sensitive substrates.
Our proposed mechanism to achieve a mild yet metal-,
photocatalyst-, and light-free acylation/carbamoylation is
Figure 1. Acyl- and amide-functionalized N-heterocycles in natural
products and pharmaceutical drugs.
Received: July 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02679
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
shown in Scheme 1. We recently discovered that, contrary to
the accepted convention, metal, photocatalyst, and light are all
Table 1. Selected Optimization Studies
Scheme 1. Plausible Mechanism
b
b
temp
(°C)
2a
M
1a
(%)
3a
a
entry
equiv (mol/L)
notes
(%)
1
2
3
4
5
6
7
8
40
30
30
22
30
30
30
30
30
30
30
30
30
10
10
10
10
2
5
3
5
3
2
1
2
2
0.075
0.075
0.075
0.075
0.075
0.15
0.15
0.3
0.3
0.3
0.3
0.3
0
9
51
55
31
6
45
58
35
45
25
76
80
78
74
2 equiv of oxidant
7
6
9
10
N/A
35
82
82
c
10
11
12
13
80
64
9
MeCN solvent
0.3
MeCN/H2O 2:1
solvent
14
not necessary for mild C−H alkylations of basic heteroarenes
d
14
15
16
30
30
30
2
2
2
0.3
0.3
0.3
air atm
31
16
84
60
76
0
with alkylcarboxylic acids.15 While Minisci-type reactions
in dark
no oxidant
2−
commence via the decomposition of persulfate S2O8 to the
sulfate radical anion SO4·−, typically under metal-mediation,
photolysis, photocatalysis, or light activation,1 we unexpectedly
discovered that the use of dimethyl sulfoxide (DMSO) as
solvent under optimized conditions allows for uncatalyzed
decomposition at mild temperatures (30 °C), achievable
presumably because its rate is dependent on solvent.16
Persulfate has been reported to decompose more readily in
DMSO,16b,17 and an added benefit is that DMSO is a more
environmentally benign solvent,18 compared the more
commonly used MeCN. Thus, we postulated that, under
optimized DMSO conditions, the sulfate radical anion SO4·−
can perform hydrogen atom transfer (HAT)19,20 with readily
available α-keto acid 2 or oxamic acid 4 to form the acyl or
carbamoyl radical I, respectively,21 alongside extrusion of
CO2.22−24 Minisci-type radical addition to the N-heterocycle 1
followed by H radical abstraction by SO4·− or SET using
persulfate should then furnish the desired acylated or
carbamoylated products 3 and 5.
With this proposal in hand, we commenced our inves-
tigations using 3-methyl isoquinoline 1a and α-keto acid 2a,
using conditions originally developed for C−H alkylations.15,25
To our delight, acylated 3a was promisingly observed in
moderate 45% yield (Table 1, Entry 1). The reaction also
worked well at lower temperatures (22−30 °C, Entries 2−4),
although 30 °C seemed optimum, as does 3 equiv of oxidant
(NH4)2S2O8 (Entry 2 vs 3).
The one drawback of the aforementioned C−H alkylation
procedure is that 10 equiv of the alkylcarboxylic acid was
required;15 thus, we were keen to significantly reduce the
equivalents of α-ketoacid 2 for C−H acylation. Initially,
however, dropping the equivalents of 2a to 2 yielded poor
results (Entry 5). Nevertheless, optimization of concentration
of the reaction resulted in the largest improvement to yields
(Entries 5−11), and to our delight, a concentration of 0.3 M
allowed for a significant reduction in amount of 2a to 2 equiv,
producing our optimal conditions (Entry 10). Control
reactions in commonly used solvents for Minisci, MeCN,
and MeCN/H2O resulted in poor conversions, as expected
(Entries 12−13). The reaction can be performed in air and
a
0.15 mmol 1a in degassed solvent unless otherwise stated.
b
1
Determined by H NMR analysis with 1,3,5-trimethoxybenzene as
c
d
internal standard. Isolated yield. And nondegassed solvent.
nondegassed solvents, instead of under argon, albeit with a
reduction in yield from 80% to 60% (Entries 10 vs 14).
Acylation works just as well in the dark (Entry 15), proving
that the reaction is not light-mediated, while Entry 16 shows
that the persulfate oxidant is necessary for reaction. Note that,
unlike many Minisci-type procedures,1 no acid additive is
required to activate the heterocycle. Furthermore, the use of
cheap inorganic (NH4)2S2O8 is much more cost-effective than
recently adopted hypervalent iodine oxidants,2,11a,13a with the
added benefit that any excess (NH4)2S2O8 is readily removed
via an aqueous wash.
With optimized conditions in hand, a screen of α-keto acids
2 was performed (Scheme 2). To our delight, the phenyl in 3a
can be replaced with a heterocycle (indole) in 3b with no
detriment in yield (80%). Aryl α-keto acid containing electron-
donating p-OMe produced 3c in an excellent 98% yield. p-
NMe2 substitution yielded a moderate 42% of 3d, presumably
due to competing SET on the dimethylamino group.26 Alkyl
substitution on the aryl ring is well tolerated, yielding 3e, 3f,
and 3g in excellent 91%, 88%, and 81%, respectively. Aryl α-
keto acids with electron-withdrawing substituents on the aryl
ring reacted more sluggishly at 30 °C (33% 3h and trace 3i),
but yields improved drastically upon warming to 50 °C (48%
3h and 76% 3i). Thus, while both electron-rich and electron-
poor aromatic α-keto acids are tolerated, the electron-rich ones
react more readily, reflecting the increased nucleophilicity of
the corresponding acyl radical.
Alkyl α-keto acids are also successful acylating reagents,
albeit reacting more sluggishly at 30 °C compared to their aryl
counterparts (34% 3j, see Supporting Information). Once
again, warming to 50 °C improves the yield drastically (70% 3j,
43% 3k). In contrast, α-keto acids with tBu or Bn do not react
(<5% 3l and 3m), presumably because the corresponding
B
DOI: 10.1021/acs.orglett.9b02679
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(3q and 3r). N-Heterocycles containing two nitrogen atoms
are also tolerated, with quinazoline forming 3s in excellent 91%
yield and 2-methylquinoxaline forming 3t in 47% yield. The 2-
substituted 3u is successfully formed from quinoline (43%),
albeit 4-monosubstituted (23%) as well as the disubstituted
products (19%) are also isolated. Conversely, benzothiazole
and 2,6-lutidine reacted sluggishly even under more forcing
conditions (29% 3v, 19% 3w).
Scheme 2. α-Keto Acid Scope for C−H Acylations*
Pleasingly, acylated quinones 3x and 3y, which have been
studied as potential antimalarials,28 can also be readily accessed
(45% 3x, 53% 3y). The quinone substrates decompose under
light irradiation15 (see Supporting Information) and would
therefore not be tolerated as well under photocatalysis or light-
mediated procedures.
Following successful acylation, we turned our attention to
carbamoylations (Scheme 4). The carbamoyl radical precursor,
oxamic acids 4, are either commercially available or easily
synthesized from the corresponding amines without the need
for column chromatography (see Supporting Information).
Initial studies on model substrate 3-methyl isoquinoline 1a and
phenyl-substituted oxamic acid 4a showed that higher
temperatures and equivalents of 4 have a positive effect on
*
a
Isolated yields reported. 50 °C.
tBuOC· and BnOC· radicals decarbonylate readily to the
stabilized Bu· and Bn· radicals.
Scheme 4. Direct C−H Carbamoylations*
27
t
Next, the heteroarene scope was investigated (Scheme 3). 3-
Methyl isoquinoline, 2-methylquinoline, lepidine, and phenan-
thridine were directly acylated in good to excellent yields (81−
98%, 3c, 3n−p). Both electron-withdrawing and electron-
donating substituents are tolerated well on the quinoline ring
Scheme 3. Heteroarene ScopeC−H Acylation*
*
a
Isolated yields reported unless otherwise stated. 50 °C.
b
c
d
Approximately 90% purity. 4 equiv of oxidant. Also isolated:
e
*
a
1
23% acylation at 4-position and 19% diaddition. Determined by H
NMR analysis.
Isolated yields reported unless otherwise stated. Determined by 1H
b
NMR analysis. 50 °C.
C
DOI: 10.1021/acs.orglett.9b02679
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Letter
the yield of 5a (Scheme 4). Nevertheless, to keep the initial
general conditions as mild as possible, 40 °C and 2 equiv of 4
were chosen for the general substrate scope screen shown in
Scheme 4. In general, oxamic acids containing secondary
amides provided moderate to good yields of product (58−
75%, 5a−5d). The benzyl group (5c, 68%) is tolerated in
carbamoylations, unlike its acylation counterpart (3m).
Oxamic acids bearing tertiary amides provided up to excellent
yields of 5e−5f (96−98%), although the morpholine-
substituted 5g did not perform as well (26%). Pleasingly, the
alkene functionality is surprisingly tolerated (5h, 59%), as is
unprotected oxamic acid (5i, 95%). The furan functionality,
however, causes a drop in yield (5j, 19%).
The carbamoylation procedure is also applicable to a wide
range of heterocycles. 2-Methylquinoline, including ones with
electron-withdrawing and -donating groups, all react well (5k−
m, 55−71%) as do phenanthridine (5n, 97%), quinazoline (5o,
63%), and lepidine (5p, 76%). The light-sensitive menadione
quinone substrate also carbamoylates smoothly to form 5q in
49% yield.
solvent concentration was adjusted to account for the lower
solubility of caffeine.
In conclusion, we have developed the first direct C−H
acylation and carbamoylation of basic heterocycles under
metal-, photocatalyst-, and light-free conditions. These
sustainable conditions constitute a significant advance on
cost, toxicity, waste, and simplicity of operational procedure.
We also demonstrate that the mild protocol can be applied to
gram-scale reactions, as well as late-stage, direct C−H
functionalizations of pharmaceutically/agrochemically relevant
compounds and commonly used N−N-ligands.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02679.
Optimization studies, all experimental details, character-
ization, copies of NMR data (PDF)
Gratifyingly, a 7.5 mmol scale reaction using lepidine (5p
78%, Scheme 4) demonstrates that the reaction is scalable to
gram scale without detriment to the yield.
Finally, Scheme 5 showcases the application of this
procedure to late-stage C−H functionalization of N,N-ligands
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: A.Lee@hw.ac.uk
ORCID
Ai-Lan Lee: 0000-0001-9067-8664
Notes
Scheme 5. Late-Stage C−H Functionalization*
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Heriot-Watt Univ. (D.R.S., JWS
Scholarship) for funding. We would like to thank the
Engineering and Physical Sciences Research Council and
CRITICAT Centre for Doctoral Training for financial support
[Ph.D. studentship to C.J.C.L.; Grant No. EP/L016419/1].
Mass spectrometry data were acquired at the EPSRC UK
National Mass Spectrometry Facility at Swansea Univ.
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D
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E
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