Direct C?H Carbamoylation of Nitrogen-Containing Heterocycles

Article abstract of DOI:10.1002/chem.201806159

Nucleophilic radical additions at innately electrophilic C(sp²) centers are perfectly suited for the direct functionalization of heterocycles. Using bench stable and commercially available alkyl oxamate and oxamic acid derivatives in combination with photoredox catalysis, a direct carbamoylation of heterocycles yielding amide functionalized pharmacophores in a single step is reported. The reaction conditions reported are compatible with structurally complex heterocyclic substrates of pharmaceutical interest. Notably, derivatives containing functional groups incompatible with standard amidation reactions, such as carboxylic acids and unprotected amines, were found to be amenable to this reaction paradigm.

Full text of DOI:10.1002/chem.201806159

A Journal of
Accepted Article
Title: Direct C–H Carbamoylation of Nitrogen Containing Heterocycles
Authors: Matthieu Jouffroy and Jongrock Kong
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201806159
Link to VoR: http://dx.doi.org/10.1002/chem.201806159
Supported by

10.1002/chem.201806159
Chemistry - A European Journal
COMMUNICATION
Direct C–H Carbamoylation of Nitrogen Containing Heterocycles
Matthieu Jouffroy* and Jongrock Kong*
2
Abstract: Nucleophilic radical additions at innately electrophilic Csp
centers are perfectly suited for the direct functionalization of
Conventional Amide-bond Formation
heterocycles. Using bench stable and commercially available alkyl
R1
Conventional: C-N
oxamate and oxamic acid derivatives in combination with photoredox
catalysis, we report a direct carbamoylation of heterocycles yielding
amide functionalized pharmacophores in a single step. The reaction
conditions reported are compatible with structurally complex
heterocyclic substrates of pharmaceutical interest. Notably,
derivatives containing functional groups incompatible with standard
amidation reactions such as carboxylic acids and unprotected
amines were found to be amenable to this reaction paradigm.
R
+
HN
OH
R2
N
R1
N
O
R
N
R2
Direct Carbamoylation
R1
N
O
+
R
work:
This
C-C
R2
N
H
O
Carbamoyl
radical



No
No
reagents
pre-functionalization
coupling
Non-obvious disconnection

Mild reaction conditions
In addition to being ubiquitous in proteins,[1] amide linkages are
also crucial in their synthetic counterparts such as nylon,
hydrogels, artificial silks, and other biocompatible derivatives.[2]
Furthermore, amide bonds are not limited to polymers and are
widely present in pharmacologically active substances,[3]
estimated to be found in 25% of marketed drugs.[4] Indeed, a
recent survey found that amide formation is the most commonly
used reaction by medicinal chemists due to its suitability for
quickly performing structure–activity relationship (SAR)
studies.[5]
commercial
drugs
Heterocyclic amide
in
groups
O
O
Me
N
Me
OH
N
O
Ph
O
H
H
N
O
N
N
N
N
OMe
NH(p-F-Bn)
O
O
Vertilecanin C
Raltegravir
Figure 1. Accessing amide-functionalized N-heterocycles: classical
disconnection vs direct C–H carbamoylation.
The “natural” bond disconnection to introduce an amide
group onto a desired core involves the formation of a C–N bond
from a carboxylic acid and an amine.[6] Extensive methodology
including many novel coupling reagents have been developed to
enable the formation of challenging amide bonds under mild
reaction conditions.[7] In many cases, specifically in
pharmaceutical applications, the carboxylic acid partner may not
be readily available and will require several synthetic steps to be
prepared, rendering this approach inefficient and time-
consuming. A highly appealing but non-obvious disconnection
strategy to access amides expeditiously would be to forge the
C–C bond between a carbamoyl group and an unfunctionalized
C–H bond on a heterocycle, avoiding the steps required for the
preparation of the carboxylic acid derivative. Unfortunately,
examples of this highly desirable transformation are scarce in
the literature (Figure 1).[8]
strategies that might be used, addition-elimination of radical
nucleophiles at innately electrophilic Csp centers—also known
as the Minisci reaction —is a common reaction manifold that has
grown exponentially in recent years.[10] We therefore envisioned
performing a direct C–H functionalization of heterocycles using
2
carbamoyl
radicals,
to
generate
amide-functionalized
pharmacophores in a single step.
The Minisci group reported such transformations by using
oxamic acids as a carbamoyl radical source, together with
persulfate salts as the oxidant and a silver-based catalyst.[11]
This work, reported three decades ago, constitutes the only
example of a direct C–H carbamoylation of heterocycles yielding
N-alkyl amide-functionalized products. However, the utility of this
reaction has been limited due to the relatively harsh reaction
conditions reported (silver catalyst, excess oxidant and
carbamoyl precursor, high temperature), poor functional group
tolerance and often modest yields.[12] In recent years, several
photoredox variants of the Minisci reaction have been developed,
resulting in dramatically increased reaction yields and
robustness,[13] leading us to hypothesize that this novel
paradigm could be applied to our desired transformation. Herein,
we report a visible light promoted direct C–H carbamoylation of
nitrogen containing heterocycles.
The development of a mild and broadly applicable direct C–
H carbamoylation method would allow for the introduction of
structural diversity without the need for pre-functionalization.
These kinds of transformations are the most employed for the
acceleration of drug discovery because they obviate the need of
de novo synthesis of individual targets.[9] Among the various
Dr. M. Jouffroy, Dr. J. Kong
Process Research & Development
Merck & Co., Inc.
126 E. Lincoln Ave., Rahway, NJ 07065 USA
E-mail: matthieu.jouffroy@merck.com
jongrock_kong@merck.com
In most instances, carbamoyl radicals are generated either
from formamides via homolytic C–H bond cleavage[14] or from
15]
oxamic acids[11,
and related activated esters[16] via single
electron transfer (SET) with subsequent loss of CO2. While
formamide derivatives are the most appealing precursors in
terms of atom economy, they require in most cases harsh
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.XXXXXXXX
This article is protected by copyright. All rights reserved.

10.1002/chem.201806159
Chemistry - A European Journal
COMMUNICATION
:
Initiation
to perform a SET oxidation from oxamate 2 (or by HAT from the
conjugate acid) to generate the carbamoyl radical 3.[15d][21]
Combined with the photoredox cycle mentioned above as a
radical initiation cycle, this radical chain propagation would
afford the desired product 6 efficiently.[22][23]
R1
N
R1
N
O
R
+
R2
R2
N
H
4
H
KO
O
O
3
2
-CO2
Off
cycle
chain
propagation
We decided to investigate the direct C–H carbamoylation of
4-chloroquinoline 7 using potassium piperidine oxamate 8 as the
carbamoyl radical source (Table 1). N-alkyl and N,N’-dialkyl
oxamates could produce the corresponding carbamoyl radicals
upon oxidation, and therefore we investigated photocatalysts
possessing matching oxidation potentials. We focused on
inexpensive and metal-free organocatalysts and found that
photocatalysts of the mesityl-phenylacridinium family performed
well under our conditions, with 1 affording the best results (see
SI). Indeed, when combined with potassium persulfate (1.0
equiv) and trifluoroacetic acid (2.0 equiv) in a DMSO/H2O
mixture (1:1) under blue LED irradiation, product 9 was obtained
in excellent yield (Table 1, Entry 1).
The relative stoichiometry and nature of all reagents, as
well as other reaction parameters were investigated (see SI). In
particular, the choice of solvent mixture and reaction internal
temperature were found to be critical to ensure maximum yield
(Table 1, Entries 2 and 3). Initial reaction screens carried out
using the standard CH2Cl2/H2O and MeCN/H2O mixtures gave
only modest yields, but a dramatic increase was observed when
switching to DMSO/H2O. Crucially, it was found that maintaining
the reaction’s temperature at 30 ±2 °C using a fan allowed us to
obtain consistent results.
SET
R1
N
H
O
PC*
1*
R
PC
1
Photoredox
2-
S2O8
R2
N
Catalytic
Cycle
H
5
SET
PC
-
HAT
1
HSO4
2-
+
SO4
SO4
Blue LED
R1
Me
R
N
N
H
6
R2
Me
Me
O
Direct C-H Carbamoylation
Visible initiated



light
Unfunctionalized N-heterocycles
Solid bench-stable carbamoyl
t-Bu
N
t-Bu
BF4
Ph
1
precursor
:
Propagation
2-
2-
4
SO4
S2O8
SET
R1
R1
N
H
O
R
N
6
R2
2
SET
R2
N
H
5
O
SO4
3
-
+
SO4 HSO4
Scheme 1. Proposed Mechanism for the Direct C–H Carbamoylation of
Heterocycles.
Gratifyingly, a similar yield was obtained when using the
corresponding oxamic acid instead of potassium oxamate (with
1.0 instead of 2.0 equivalents of TFA), opening up a wider range
of commercially available reagents (Table 1, Entry 4). Control
experiments showed that the reaction failed to proceed in the
absence of light or oxidant (Table 1, Entries 5-7), and with
diminished yields without TFA (Table 1, Entry 8).Interestingly, in
the absence of photocatalyst we observed formation of product
9 and full consumption of oxamate 8 (Table 1, Entry 9). However,
the yield was low and a significant amount of side products were
generated. We rationalized that visible light could mediate
decomposition of persulfate as proposed by Ji and co-
reaction conditions to generate the desired radicals, resulting in
poor selectivity when alkyl formamides are used.[14f] Since we
aimed toward the development of a synthetic method that would
be easily implemented and compatible with the synthesis of N-
alkyl amides, we decided to focus on the use of commercially
available and bench stable oxamate salts (or the corresponding
acids) for the generation of carbamoyl radicals. In addition,
these reagents can be easily synthesized from the
corresponding amines (see SI).
We envisioned the mechanistic scenario depicted in
Scheme 1 for the visible light promoted carbamoylation of
heterocycles. Blue LED light activation of an appropriate
Table 1. Optimization of the Reaction Conditions and Control Experimentsa
1
K
TFA
mol%)
(1
photocatalyst
–
in our case 9-mesityl-3,6-di-tert-butyl-10-
Cl
Cl
2S2O
O
equiv)
8 (1.0
equiv)
phenylacridin-10-ium tetrafluoro-borate 1 - would permit the
(2.0
N
latter to reach its excited state 1* (E1/2 [PC*/PC-] = +2.08 V vs
red
XO
N
DMSO/H2O
SCE in CH3CN),[17] which is sufficiently oxidizing for SET to
N
N
O
0.1 M)
(1:1,
occur from the oxamate salt 2[18] via reductive quenching (E1/2
red
7
8
9
O
30 o 90 min
C,
equiv)
(1.0
Blue LED
= +1.76 V vs SCE in DMSO/H2O 1:1 for 8, see SI). Loss of
carbon dioxide would then generate the desired nucleophilic
carbamoyl radical 3 that should rapidly add to a protonated
heteroarene 4 to provide intermediate 5.[11, 19] Simultaneously,
b
9
Deviation from standard conditions Yield of
Entry
(%)
=
1
2
3
4
5
6
7
8
9c
None
K)
as
90
40
72
95
0
(X
MeCN/H2O
solvent mixture
oC)
control
the photocatalyst 1˙- (E1/2 [PC-/PC] = +0.59 V vs SCE in
ox
No
temperature
(~45
of TFA
CH3CN)[17] could be oxidized by persulfate (E1/2 = +1.75 V vs
ox
=
and
1.0
Acid
equiv
(X H)
SCE in MeCN)[13c] to afford the sulfate dianion and the highly
No
mixture heated to 30 o
mixture heated to 80 o
C
C
light,
oxidizing sulfate radical anion, regenerating photocatalyst 1.[13h]
No
6
light,
ox
No K2S2O8
No TFA
No
5
The latter anion (E1/2 = +2.36 V vs SCE in MeCN) is able to
18
35
oxidize 5 through hydrogen-atom transfer (HAT), yielding the
desired product 6.
photocatalyst
As often observed in photoredox catalysis,[20] off-cycle
radical chain processes may also occur in this reaction (Scheme
1, bottom).[13c] Indeed, intermediate 5 could be oxidized by the
persulfate anion, generating the sulfate radical anion that is able
a Conditions: 7 (0.10 mmol, 1.0 equiv), 8 (1.0 equiv), 1 (1 mol%), K2S2O8 (1.0
equiv), TFA (2.0 equiv), DMSO/H2O (1:1, 0.1 M). b Yields determined by HPLC
c
using a calibration curve made with pure product 9 as reference. Prolonged
reaction time allows to reach full conversion of 8, but several side products
were observed (51% yield after 16 h).
This article is protected by copyright. All rights reserved.

10.1002/chem.201806159
Chemistry - A European Journal
COMMUNICATION
was unreacted heteroarene, which could be isolated and
resubjected to the same reaction conditions. In addition to
quinoline (Table 2), other bicyclic systems such as isoquinoline,
quinoxaline, phthalazine or caffeine performed well in the
reaction (Table 3, 30-36). Of note is the Cinchona alkaloid 35
that not only shows the remarkable tolerance of the reaction
towards protic (OH) and basic (tertiary amine) functional groups,
but also the reaction’s selectivity for addition of the carbamoyl
radical to the heteroarene rather than the exogenous vinyl
functionality. The synthesis of such derivatives is of particular
interest for applications in phase transfer catalysis and the
methodology described here could be used to fine-tune a
Table 2. Direct C–H Carbamoylation of 4-Chloroquinoline with Various
Carbamoyl Moietiesa
1
K
mol%)
2S2O
(1
equiv)
2.0
K,
8 (1.0
(X
H,
Cl
Cl
N
R1
N
TFA
=
equiv)
O
R1
N
=
1.0
equiv)
(X
XO
R2
DMSO/H2O
R2
N
O
K
0.1 M)
(1:1,
O
30 o 90 min
7
C,
=
or
H
X
Blue LED
Cl
equiv)
(1.0
Cl
N
Cl
R1
N
H
H
catalyst so
as
to achieve improved
yields
and
N
N
N
R2
N
t-Bu
enantioselectivity.[27]
O
O
O
n
2
R1
R
82%
87%
80%
82%
One obvious limitation of traditional approaches to amide
formation is that the carboxylic acid precursors required are
often not accessible. This is exemplified by the preparation of
n
=
=
=
=
=
=
=
10
11,
12
13
91%
,
14
15
16
,
,
,
,
H,
1,
2,
3,
1
R
R2 Me, 91%
n
n
=
H,
2
R1
R
Me, 87%
=
,
Cl
Cl
Cl
Table 3. Scope of the Direct C–H Carbamoylation of Heterocyclesa
H
N
H
H
N
1
K
TFA
mol%)
(1
N
2S2O
N
N
N
Ad
equiv)
8 (1.0
=
2.0
equiv)
R1
N
K,
17
(X
H,
59%
18
19
,
O
81% O
92% O
Cl
,
,
O
equiv)
R1
N
=
1.0
(X
Cl
Cl
R
R
XO
R2
DMSO/H2O
R2
N
N
O
K
0.1 M)
(1:1,
H
O
30 o 90
min
N
Ph
N
N
C,
=
or
H
equiv)
N
N
N
X
Blue LED
CF3
3
(1.0
20
O
O
21
O
9
O
74%
75%
95%
,
,
,
O
Me
Me
Cl
Cl
Cl
Me
O
O
N
N
N
N
H
N
H
H
N
N
Ph
O
N
N
N
N
N
N
Cl
N
N
N
Ph
Me
O
O
47%
22
78%
23
26
24
37% O
,
,
67% O
,
28
29
34
42%
,
76%
,
,
[28]
[29]
Cl
Cl
Cl
3 steps to acid
3 steps to acid
O
(25%)
(40%)
NMe
OMe
H
N
*
N
N
Cy
N
N
N
N
N
H
25
O
80%
,
O
-(
-(
O
68%
71%
Me
79%
27
27
,
R
),
),
N
N
O
O
N
H
S
a
Isolated yields. Conditions:
7 (0.50 mmol, 1.0 equiv), potassium alkyl
30
2 steps
31
70%
72%
,
,
OH
35
acid unknown
[30]
oxamate or oxamic acid (1.0 equiv), 1 (1 mol%), K2S2O8 (1.0 equiv), TFA (X =
K: 2.0 equiv; X = H: 1.0 equiv), DMSO/H2O (1:1, 0.1 M).
(44%)
N
O
71%
,
N
N
N
N
workers,[14f] [22] generating the sulfate radical anion responsible of
oxidizing the oxamate, and consequently leading to the desired
carbamoylation reaction (see Scheme 1, propagation).[24]
N
N
O
N
O
O
Next, we explored the substrate scope of the direct C–H
carbamoylation, first focusing on the oxamate part (Table 2).
Varying the electronics of the substituents on nitrogen and were
delighted to obtain the desired products in often excellent yields.
Indeed, N-alkyl and N,N’–dialkyl carbamoyl groups were
perfectly tolerated and no activation of the C–H bonds adjacent
to nitrogen was observed.[14f, 25] Sterically encumbered amines,
which are very often problematic to couple even using the most
elaborate coupling reagents, proceeded uneventfully (Table 2,
Entries 13 and 19). Because epimerization is a common
phenomenon in standard amide bond forming reactions, we
decided to assess chiral starting materials and were pleased to
observe that no racemization occurred, affording the
corresponding product in almost identical optical purity as the
starting material (Table 2, Entry 27-(R) and (S)).[26]
32
33
58%
75%
,
,
,
CN
N
O
N
N
N
N
N
Cl
O
O
36
37
38
68%
,
34%
71%
,
in conventional amidation
H
Challenging substrates
N
H
N
Me
Me
HO
N
N
N
N
N
40
N
O
O
O
O
39
41
57%
,
61%
52%
,
,
acid unknown
acid unknown, substructure
We next turn our attention to study the scope of the
heteroaryl component (Table 3). A range of heterocycles was
found to be compatible with the developed conditions for direct
C–H carbamoylation affording the desired product in moderate
to good yields. In most cases, the mass balance of the reaction
in >10
present
patents
a
Isolated yields. Conditions: heteroarene (0.50 mmol, 1.0 equiv), potassium
alkyl oxamate or oxamic acid (1.0 equiv), 1 (1 mol%), K2S2O8 (1.0 equiv), TFA
(X = K: 2.0 equiv; X = H: 1.0 equiv), DMSO/H2O (1:1, 0.1 M).
This article is protected by copyright. All rights reserved.

10.1002/chem.201806159
Chemistry - A European Journal
COMMUNICATION
P. S. Baran, J. Am. Chem. Soc. 2010, 132, 13194; c) Y. Fujiwara, J. A.
Dixon, F. O’Hara, E. D. Funder, D. D. Dixon, R. A. Rodriguez, R. D.
Baxter, B. Herlé, N. Sach, M. R. Collins, Y. Ishihara, P. S. Baran,
Nature 2012, 492, 95; d) F. O’Hara, D. G. Blackmond, P. S. Baran, J.
Am. Chem. Soc. 2013, 135, 12122; e) G. A. Molander, V. Colombel, V.
A. Braz, Org. Lett. 2011, 13, 1852.
amides 28, 29, 37 and 38, which are easily prepared from
commercially
available
starting
materials
using
our
carbamoylation methodology, but would be harder to access via
traditional amide bond forming methods as the necessary
carboxylic acids are not readily available.
In order to challenge the method we developed, we decided
to test substrates known to be incompatible even when using
state-of-the-art amide bond forming reactions. Normally,
substrates that bear either free amines or several carboxylic
acids are particularly problematic in traditional amide couplings
and would lead to the formation of oligomers among other side-
products. However in our case, no electrophilic carboxylic acid
intermediates are formed, allowing us to isolate compounds 39-
41 without the use of protecting groups.[31] This unusual
functional group tolerance might find application in the late-stage
functionalization of drug candidates, allowing for the introduction
of amide groups to complex molecules in a single step under
mild reaction conditions.
[11] F. Coppa, F. Fontana, E. Lazzarini, F. Minisci, Heterocycles 1993, 36,
2687.
[12] Light mediated C–H carbamoylation of heterocycles has been recently
reported but is limited to the addition of non-functionalized carbamoyl
groups (Csp2-CO-NH2).[14f]
[13] a) D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M.
Tudge, Angew. Chem. Int. Ed. 2014, 53, 4802; b) G.-X. Li, C. A.
Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G. Chen, Chem. Sci.
2016, 7, 6407; c) R. A. Garza-Sanchez, A. Tlahuext-Aca, G. Tavakoli, F.
Glorius, ACS Catal. 2017, 7, 4057; d) J. K. Matsui, D. N. Primer, G. A.
Molander, Chem. Sci. 2017, 8, 3512; e) J. Jin, D. W. C. MacMillan,
Nature 2015, 525, 87; f) P. Nuhant, M. S. Oderinde, J. Genovino, A.
Juneau, Y. Gagné, C. Allais, G. M. Chinigo, C. Choi, N. W. Sach, L.
Bernier, Y. M. Fobian, M. W. Bundesmann, B. Khunte, M. Frenette, O.
O. Fadeyi, Angew. Chem. Int. Ed. 2017, 56, 15309; g) J. R. Klauck
Felix, J. James Michael, F. Glorius, Angew. Chem. Int. Ed. 2017, 56,
12336; h) J. K. Matsui, G. A. Molander, Org. Lett. 2017, 19, 950.
[14] a) D. Elad, J. Rokach, J. Org. Chem. 1964, 29, 1855; b) L. Friedman, H.
Shechter, Tetrahedron Lett. 1961, 2, 238; c) G. Pattenden, S. J.
Reynolds, J. Chem. Soc., Perkin Trans. 1 1994, 379; d) F. Minisci, F.
Recupero, C. Punta, C. Gambarotti, F. Antonietti, F. Fontana, G. F.
Pedulli, Chem. Commun. 2002, 2496; e) T. Caronna, C. Gambarotti, L.
Palmisano, C. Punta, F. Recupero, Chem. Commun. 2003, 2350; f) Y.
Zhang, K. B. Teuscher, H. Ji, Chem. Sci. 2016, 7, 2111.
In summary, we report a visible light photoredox-mediated
reaction, which enables direct C–H carbamoylation of
heterocycles by means of
a radical addition to a non-
2
functionalized Csp center. Of particular importance is the
tolerance of this reaction protocol to functional groups such as
carboxylic acids and unprotected amines that are typically
incompatible with standard amide coupling reagents. By allowing
the direct formation of N-alkyl and N,N’-dialkyl amide
functionalized heterocycles in a rapid, robust and transition
metal free manner, we believe that this non-obvious bond
disconnection should find rapid adoption in both academia and
industry.
[15] a) H. Wang, L. N. Guo, S. Wang, X.-H. Duan, Org. Lett. 2015, 17, 3054;
b) Q. Jiang, J. Jia, B. Xu, A. Zhao, C.-C. Guo, J. Org. Chem. 2015, 80,
3586; c) M. Li, C. Wang, P. Fang, H. Ge, Chem. Commun. 2011, 47,
6587; d) Q.-F. Bai, C. Jin, J.-Y. He, G. Feng, Org. Lett. 2018, 20, 2172.
[16] W. F. Petersen, R. J. K. Taylor, J. R. Donald, Org. Lett. 2017, 19, 874.
[17] A. Joshi-Pangu, F. Lévesque, H. G. Roth, S. F. Oliver, L.-C. Campeau,
D. Nicewicz, D. A. DiRocco, J. Org. Chem. 2016, 81, 7244.
Acknowledgements
[18] pH measurement shows that the reaction conditions employed are
close to be at constant pH (t = 0 min, pH 2.8, t = 90 min (end of
reaction) pH 2.6). At this pH, N-heterocycles are predominantly
protonated (pKa 4–6), whereas oxamic acids (pKa 0-2) and persulfate
(pKa -6.0; 0.2) are mostly present as salts. Sulfate generated during the
reaction act most likely as buffer (pKa –3.0, 2.0).
The authors thank Sean Bowen for NMR support. The authors
also thank A. El Marrouni, J. Balsells-Padros, E. Phillips, C.
Nawrat, A. Neel, D. Lehnherr, D. Thaisrivongs, D. DiRocco and
L.-C. Campeau for helpful discussions and critical insights.
[19] Á. Gutiérrez-Bonet, C. Remeur, J. K. Matsui, G. A. Molander, J. Am.
Chem. Soc. 2017, 139, 12251.
Keywords: carbamoylation, C-H functionalization, photoredox
[20] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426.
[21] In the absence of light or heat, no reaction between potassium
persulfate and potassium piperidine oxamate 8 was observed (Table 1,
Entry 5).
catalysis, heterocycles, alkyl oxamate.
[1]
T. Wieland, M. Bodanszky in The World of Peptides, Springer-Verlag
[22] L. Guillemard, F. Colobert, J. Wencel-Delord, Adv. Synth. Catal.,
doi:10.1002/adsc.201800692.
Berlin Heidelberg, 1991.
[2]
A. Greenberg, C. Breneman, J. Liebman in The amide linkage
:
selected structural aspects in chemistry, biochemistry, and materials
science, Wiley-Interscience, 2000.
[23] Mechanistic probes (e.g. quantum yield measurements or
luminescence quenching experiments) could not be used in our case
because reaction media is not homogeneous and these methods are
sensitive to light diffraction.
[3]
[4]
J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337.
[24] This reaction paradigm might also take place even in the presence of
photocatalyst, but the lower amount of side products obtained in the
presence of the latter suggest that this mechanism is disfavored and/or
slower.
A. K. Ghose, V. N. Viswanadhan, J. J. Wendoloski, J. Comb. Chem.
1999, 1, 55.
[5]
[6]
[7]
D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443.
A. El-Faham, F. Albericio, Chem. Rev. 2011, 111, 6557.
a) R. M. de Figueiredo, J.-S. Suppo, J.-M. Campagne, Chem. Rev.
2016, 116, 12029; b) H. Noda, M. Furutachi, Y. Asada, M. Shibasaki, N.
Kumagai, Nat. Chem. 2017, 9, 571.
[25] A. McNally, C. K. Prier, D. W. C. MacMillan, Science 2011, 334, 1114.
[26] Starting material (oxamate ester): 93% ee; 27-R: 93% ee (see SI).
[27] S.-S. Jew, H.-G. Park, Chem. Commun. 2009, 7090.
[28] M. S. S. Palanki, P. E. Erdman, L. M. Gayo-Fung, G. I. Shevlin, R W.
Sullivan, M. J. Suto, M. E. Goldman, L. J. Ransone, B. L. Bennett, A. M.
Manning, J. Med. Chem. 2000, 43, 3995.
[8]
[9]
For a recent example of an amidation reaction focusing on the C-C
bond formation, see: S. Zheng, D. N. Primer, G. A. Molander, ACS
Catal. 2017, 7, 7957.
[29] A. Golovchinskaya, Zh.Obshch. Khim. 1948, 18, 2129.
[30] B. Yao, C.-L. Deng, Y. Liu, R.-Y. Tang, X.-G. Zhang, J.-H. Li, Chem.
Commun. 2015, 51, 4097.
a) J. Wencel-Delord, F. Glorius, Nature Chem. 2013, 5, 369; b) T.
Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem.
Soc. Rev. 2016, 45, 546.
[31] Previously reported Ag-catalyzed Minisci carbamoylation conditions did
not work with free amine containing heterocycle 41.
[10] a) M. A. J. Duncton, Med. Chem. Commun. 2011, 2, 1135; b) I. B.
Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel,
This article is protected by copyright. All rights reserved.

10.1002/chem.201806159
Chemistry - A European Journal
COMMUNICATION
This article is protected by copyright. All rights reserved.