Photochemical regioselective C(sp3)-H amination of amides using N-haloimides

Article abstract of DOI:10.1021/acs.orglett.1c00831

A metal-free regioselective C(sp3)-H amination of amides using N-haloimides in the presence of lithium tert-butoxide and visible light is presented herein. This photoexcited approach is straightforward, and it aminates a wide variety of amides under mild conditions without the use of photocatalysts, external radical initiators, or oxidants. A halogen-bonded intermediate between the tert-butoxide base and the N-haloimide is proposed to be responsible for the increased photoreactivity. Calculations show that the formation of this electron donor-acceptor complex presents an exergonic energy profile.

Full text of DOI:10.1021/acs.orglett.1c00831

pubs.acs.org/OrgLett
Letter
Photochemical Regioselective C(sp3)−H Amination of Amides Using
N‑Haloimides
Lei Pan, Joseph Elmasry, Tomas Osccorima, Maria Victoria Cooke, and Sébastien Laulhé*
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ABSTRACT: A metal-free regioselective C(sp3)−H amination of
amides using N-haloimides in the presence of lithium tert-butoxide
and visible light is presented herein. This photoexcited approach is
straightforward, and it aminates a wide variety of amides under
mild conditions without the use of photocatalysts, external radical
initiators, or oxidants. A halogen-bonded intermediate between the
tert-butoxide base and the N-haloimide is proposed to be
responsible for the increased photoreactivity. Calculations show
that the formation of this electron donor−acceptor complex presents an exergonic energy profile.
We started our investigation using N-bromophthalimide
(1a) and dimethylacetamide (2a) in the presence of
stoichiometric amounts of LiOtBu under blue light (Table
1). Initial solvent screening showed that the desired amination
product 3aa could be obtained using PhCF3, PhCl, CH3CN, or
benzene (entries 1−4), but chlorobenzene provided the best
yields (entry 2). Screening of bases showed that the nature of
the counterion seems to play a major role in this chemistry.
Indeed, while lithium tert-butoxide generated the product in
67% yield, switching to sodium or potassium tert-butoxide has
a major deleterious effect, giving the desired product in only
24% or 2% yield, respectively (entries 5 and 6). The use of
bases other than tert-butoxides did not generate the product in
synthetically useful yields (see the Supporting Information for
a full table of optimization, S4). The stoichiometry of the base
was also evaluated (entries 7−10). The absence of LiOtBu in a
control reaction did not generate the desired product, and a
deviation in the number of equivalents of base from the
optimal value of 1 equiv had a deleterious effect on yield.
Thermal activation of the reaction mixture in the absence of
light showed a sharp decline in the yield (entry 11), further
demonstrating that it is light, and not the heat generated by the
lamps, that activates the reaction. Also, reducing the number of
equivalents of 2a (entries 12 and 13) leads to a reduction in
yields of the desired product. Finally, performing the reaction
open to the atmosphere leads to a decline in yield (entry 14).
mines and amides are key intermediates in many chemical
Asyntheses, as both groups are present in biologically active
natural products, synthetic intermediates, and pharmaceutical
agents.1 In particular, the amido aminal functional group is
found in various bioactive compounds such as metolazone,
fluspirilene, lymecycline, and primidone (Scheme 1A).
Traditionally, these difficult to access compounds have been
generated through condensation reactions with formaldehyde.2
Due to the importance of this amido aminal framework, the
development of C−H amination methodologies that selectively
target the amino carbon of amides has attracted some attention
in the organic community.3 Currently, two general approaches
have been employed to achieve this (Scheme 1B): (i)
transition metal-catalyzed C−H aminations3a−d and (ii)
metal-free C−H aminations.3e−h Unfortunately, both of these
approaches require the use of stoichiometric strong oxidants or
peroxides at high temperatures, increasing the risk of an
accident and the waste footprint. Consequently, the develop-
ment of metal-free and atom-economical strategies is
particularly important.
Visible light photoredox processes have recently found many
applications in organic synthesis due to the advantages of being
readily availability, sustainability, mild reaction conditions,
etc.4 Inspired by our previous C−H amination strategies using
N-haloimides,5 herein we report a metal-free C(sp3)−H
amination of amides in the presence of lithium tert-butoxide
using visible light photoexcitation. Our approach does not
require a photocatalyst or a peroxide initiator and proceeds
under mild reaction conditions, making this methodology
among the greenest approaches for selectively generating the
amido aminal functional group (Scheme 1C). Mechanistic
work proposes that a halogen-bonded electron donor−
acceptor complex between tert-butoxide and the N-haloimide
is responsible for the observed reactivity.
Received: March 12, 2021
Published: April 15, 2021
https://doi.org/10.1021/acs.orglett.1c00831
© 2021 American Chemical Society
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With the optimized conditions in hand, we initiated an
amide substrate scope study using 1a as our amine source
(Figure 1). As expected, moderate to good yields were
Scheme 1. (A) Examples of FDA-Approved Drugs
Containing the Amido Aminal Group, (B) Current Methods
for Accessing the Amido Aminal Functional Group That
Require the Use of Catalysts and Strong Oxidants at High
Temperatures, and (C) Our Photoexcited C−H Activation
under Mild Reaction Conditions
Figure 1. Amination of amides with N-bromophthalimide. Reaction
conditions: 1a (0.2 mmol), 2 (1.0 mmol), LiOtBu (0.2 mmol), 1.0
mL of PhCl, room temperature around the reaction flask of 35 °C
(heating caused by the LED lamp), overnight. Isolated yields.
obtained. Both secondary and tertiary aliphatic amides
generated the desired products 3aa, 3ab, 3ac, and 3af.
Interestingly, the use of N-chlorophthalimide leads to an
almost complete shutdown of the reaction, providing product
3aa in only 4% yield as opposed to 65% yield when 1a is used.
N-Methyl-2-pyrrolidone also generated desired product 3ad in
53% yield with a selective amination of the methylene position
over the methyl group. Finally, the presence of an aromatic
moiety is well tolerated, and amination of the methyl group is
observed predominantly (3ae). Throughout our screens, we
did not observe reaction at the α-position of the carboxyl
group; polarity-matched hydrogen atom transfer (HAT)
processes are known to favor reactions at strong hydridic
C−H bonds over weak acidic C−H bonds.4e
a
Table 1. Optimization of the Reaction and Its Conditions
b
entry
base (equiv)
solvent (mL)
yield (%)
We then investigated other possible N-haloimide sources
and found that N-halosaccharin 1b was significantly more
efficient at performing the desired amination than 1a. As
shown in Figure 2, a large variety of amides can be selectively
aminated at the amino carbon in moderate to good yields. This
is particularly important because literature precedent has
shown that N-halosaccharin reacts effectively with aromatic
compounds via C(sp2)−H activation.6 Despite our solvent
being chlorobenzene, the major product of these reactions
remains the formation of the amino aminal product, indicating
that the addition of LiOtBu plays a role in inducing
chemoselectivity. The main reactivity difference between 1a
and 1b comes from the difference in pKa between phthalimide
(8.3) and saccharin (1.6). The stronger electron-withdrawing
groups in saccharin destabilize the imidyl radical, further
increasing its reactivity. Also, stronger electron-withdrawing
groups in saccharin will increase the σ-hole of the halogen,
thereby favoring stronger halogen bonding interactions with
the tert-butoxide base.
1
2
3
4
5
6
7
8
9
10
LiOtBu (1.0)
LiOtBu (1.0)
LiOtBu (1.0)
LiOtBu (1.0)
NaOtBu (1.0)
KOtBu (1.0)
−
LiOtBu (0.75)
LiOtBu (1.25)
LiOtBu (1.5)
LiOtBu (1.0)
LiOtBu (1.0)
LiOtBu (1.0)
LiOtBu (1.0)
PhCF3 (1.0)
PhCl (1.0)
CH3CN (1.0)
PhH (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
PhCl (1.0)
42
67 (65)
c
10
49
24
2
−
45
63
35
7
44
60
16
d
11
12
13
14
e
f
g
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (1.0 mmol, 5
equiv), base (1 equiv), solvent (1 mL), room temperature around the
reaction flask of 35 °C (heating caused by the LED lamp), reaction
b
flask capped, overnight. 1H NMR yields using dibromomethane as
c
d
the internal standard. Isolated yield. Reaction performed at 60 °C
without light. With 2.5 equiv of 2a instead of 5 equiv. With 4 equiv
of 2a intead of 5 equiv. Reaction performed by adding 20 μL of H2O.
e
f
Aliphatic amide derivatives could be aminated in good to
excellent yields using both N-bromo- and N-chlorosaccharin
(3ba and 3bb, respectively). As shown for product 3ba, the
reaction does not proceed when the halogen is replaced with
hydrogen, indicating the necessity of using the N-haloimide
g
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Highly acidic α-positions such as those in product 3bh
(Figure 2) still provided the desired product in moderate yield,
and unsymmetrical N-ethyl-N-methyl amides showed regiose-
lectivity toward the methyl group over the methylene carbon
(3bi). Aromatic amides bearing electron-withdrawing groups
(-CN, -NO2, and -CF3) (3bm−3bo) presented better yields
compared with those of electron-donating groups (-OMe and
-Me) (3bl−3bt). It is also noteworthy that aromatic halogens
(F, Cl, and Br) were well tolerated and provided the desired
products in good yields (3bp−3br), enabling further
manipulations of the products through cross-coupling trans-
formations. Heteroaromatic amides were also aminated in
moderate yields (3bu and 3bv). Importantly, unlike in
previously reported aminations using 1b,8 our approach did
not seem to lead to significant reaction with the aromatic
moieties of the amides, and only small amounts of aminated
chlorobenzene were observed. Finally, as expected, sulfona-
mides tolerated the reaction conditions well, furnishing desired
product 3bw in 56% yield (Figure 2).
An additional screen important to the synthetic organic
chemistry community is the possibility of selectively aminate-
protected amines in the form of carbamates (Figure 3). Indeed,
Figure 2. Amination of amides by N-halosaccharins. Reaction
conditions: 1b (0.2 mmol), 2 (1.0 mmol), LiOtBu (0.2 mmol), 1.0
mL of PhCl, room temperature around the reaction flask of 35 °C
(heating caused by the LED lamp), overnight. Isolated yields.
Figure 3. Amination of Boc-protected amines. Reaction conditions: 1
(0.2 mmol), 4 (1.0 mmol), LiOtBu (0.2 mmol), 1.0 mL of PhCl,
room temperature around the reaction flask of 35 °C (heating caused
by the LED lamp), overnight. Isolated yields.
we hypothesized that carbamates and amides would react
similarly under our reaction conditions but would provide a
facile deprotection strategy. Much to our delight, tert-
butyloxycarbonyl (Boc)-protected amines tolerated our mild
reaction conditions and provided the desired products in
moderate to good yields (Figure 3). Boc-protected dimethyl-
amine and N-ethyl-N-methyl amine provided desired products
5ba and 5bb in excellent and good yields, respectively, when
using N-halosaccharin. Boc-protected N-methylaniline also
generated desired product 5bc, albeit in lower yields. Of
particular interest is the ability to selectively aminate Boc-
protected methamphetamine derivatives in low to moderate
yields, to give rise to potentially new bioactive compounds
such as 5bd and 5be. As expected, the use of unsymmetrical
amides favors the formation of the aminated product in the
methyl position, even in the presence of a more stable benzylic
carbon (5bb, 5bd, and 5be). This further emphasizes the
motif. An important observation is the complementary
reactivity between N-bromophthalimide 1a and N-halosacchar-
in 1b; while secondary amide 2c and N-methyl-2-pyrrolidone
provided the desired product when using 1a, this was not the
case with 1b, giving little to no products 3bc and 3bd′. In
addition, N-methyl-2-pyrrolidone reactivity seemed to switch
from the methylene position to the methyl position (3bd′).
Presumably, these observed changes are due to a difference in
the stability of the imidyl radicals of phthalimide and saccharin.
The more reactive N-centered saccharin radical reacts with the
N−H bond of secondary amides, leading to its decomposition
(3ac vs 3bc). Similarly, a less reactive phthalimide radical may
allow for equilibration to the most stable secondary radical in
the amide in 3ad (Figure 1), while the highly reactive saccharin
radical presumably reacts with the kinetic amide radical at the
methyl position [3bd′ (Figure 2)].
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possible role of steric hindrance as the driving force for the
regioselectivity of the reaction. Finally, N-halophthalimide can
also be used to aminate Boc-proteccted amines in lower yields,
as shown for product 5aa (Figure 3).
The reaction was further probed with other imide and amide
derivatives (see the Supporting Information for the full
substrate scope, S5); however, the yields obtained were often
low. The N-haloimide reagents require the presence of an
aromatic moiety to avoid decomposition of the imidyl radical.
Additionally, we presume that the aromatic moiety interacts
with the solvent (chlorobenzene) via π-stacking, which
stabilizes the reactive intermediate.
mentioned in the table of optimization, in the absence of
LiOtBu or light no product is generated, and replacing N-
haloimides with the nonhalogenated imide (such as
phthalimide) does not generate any observable product
(Scheme 2B).
To further understand the role played by LiOtBu, we
performed a series of UV−vis spectroscopic measurements on
various combinations of 1a, 1b, and lithium tert-butoxide in
PhCl (see the Supporting Information, S6). The results
indicate that LiOtBu is interacting with the N-haloimide,
possibly via halogen bonding,7 and generates a halogen-
bonded adduct A capable of absorbing blue light to initiate the
radical reaction.
To further understand the process in which the reaction
takes place, the energetic profile of the mechanism was
explored through quantum calculations (see the Supporting
Information, S7). The results show that the formation of an
electron donor−acceptor (EDA) complex presents an
exergonic energy profile (−14.6 kcal/mol), denoting that its
formation is favored. Additionally, we also calculated two
possible mechanistic pathways for the C−H activation step: (i)
a hydrogen atom transfer (HAT) step between •OtBu and the
amide and (ii) an electron transfer/proton transfer (ET/PT)
step.8 Exploration of both mechanistic pathways reveals that
the reaction seems to follow a classic HAT mechanism.
On the basis of the results presented above and previous
reports,3e−h,9 we propose a plausible reaction mechanism in
Scheme 2C. Reaction between the N-haloimide and LiOtBu
forms a halogen bond adduct A that can absorb visible blue
light and leads to a single-electron transfer yielding radical
anion B and tert-butoxide radical. Regioselective hydrogen
abstraction of the amino carbon of the amide by the tBuO•
radical generates stable radical intermediate C. Simultaneously,
radical anion B decomposes through N−Br bond cleavage to
generate phthalimidyl radical D. Fast radical−radical coupling
between C and D generates the final product (Scheme 2C).
Side reactions between D and the solvent generate aminated
byproduct 7, and trapping of intermediate C was shown using
TEMPO to give 6.
To provide some insight into the reaction mechanism, a
series of control experiments were carried out as shown in
Scheme 2. As expected, addition of a radical scavenger such as
Scheme 2. (A) Radical Trapping Experiments, (B) Control
Experiments, and (C) Proposed Reaction Mechanism
In summary, the amination of amides was developed via a
photochemical sp3 C−H bond functionalization process. This
reaction showed good functional group compatibility. As
mentioned above, the current methods suffer from external
radical initiators, oxidants, heat sources, and a relatively limited
substrate scope in many cases. Therefore, this reported process
provides a complementary and advantageous approach for
accessing amine-containing organic molecules.
ASSOCIATED CONTENT
* Supporting Information
■
sı
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) drastically
hampered the reaction. Importantly, through this experiment,
we observed the generation of compound 6 via GC-MS, which
indicates the formation of the amide radical at the amino
carbon (Scheme 2A). Additionally, throughout our reactions,
we can also observe the amination of the solvent
(chlorobenzene) to give compound 7 observed via GC-MS
as a mixture of regioisomers. This is similar to previously
published transformations,6 indicating the formation of the
imidyl radical. We presume that homolytic cleavage of the N-
haloimide prior to activation by LiOtBu is in part responsible
for this side reactivity,8 which is observed as the primary
product (7) in the absence of LiOtBu. Also as previously
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00831.
1H and 13C{1H} NMR spectra for all aminated products,
GC-MS spectra, and the substrate scope and its
limitations (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Sébastien Laulhé − Department of Chemistry and Chemical
Biology, Indiana University-Purdue University Indianapolis,
Indianapolis, Indiana 46202, United States; orcid.org/
0000-0003-4510-1916; Email: slaulhe@iupui.edu
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Authors
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Letter
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Lei Pan − Department of Chemistry and Chemical Biology,
Indiana University-Purdue University Indianapolis,
Indianapolis, Indiana 46202, United States
Joseph Elmasry − Department of Chemistry and Chemical
Biology, Indiana University-Purdue University Indianapolis,
Indianapolis, Indiana 46202, United States
Tomas Osccorima − Department of Chemistry and Chemical
Biology, Indiana University-Purdue University Indianapolis,
Indianapolis, Indiana 46202, United States
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(5) Gasonoo, M.; Thom, Z. W.; Laulhé, S. Regioselective α-
Amination of Ethers Using Stable N-Chloroimides and Lithium tert-
Butoxide. J. Org. Chem. 2019, 84, 8710−8716.
Maria Victoria Cooke − Department of Chemistry and
Chemical Biology, Indiana University-Purdue University
Indianapolis, Indianapolis, Indiana 46202, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00831
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This publication was made possible, in part, by support from
the Indiana Clinical and Translational Sciences Institute
funded, in part, by Grant UL1TR002529 from the National
Institutes of Health, National Center for Advancing Transla-
tional Sciences, Clinical and Translational Sciences Award.
Start-up funding from Indiana University-Purdue University
Indianapolis (IUPUI) was also used to support this research.
National Institute of Dental and Craniofacial Research Grant
1R21DE029156-01.
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