Generation and Reactivity of Amidyl Radicals: Manganese-Mediated Atom-Transfer Reaction

Article abstract of DOI:10.1002/anie.201913042

A simple and efficient protocol to generate amidyl radicals from amine functionalities through a manganese-mediated atom-transfer reaction has been developed. This approach employs an earth-abundant and inexpensive manganese complex, Mn₂(CO)

Full text of DOI:10.1002/anie.201913042

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Accepted Article
Title: Generation of Amidyl Radicals and Reactivity via Manganese-
Mediated Atom Transfer Reaction
Authors: Run-Zhou Liu, Jinxia Li, Jun Sun, Xian-Guan Liu, Shuanglin
Qu, Ping Li, and Bo Zhang
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10.1002/anie.201913042
Angewandte Chemie International Edition
RESEARCH ARTICLE
Generation and Reactivity of Amidyl Radicals: Manganese-
Mediated Atom-Transfer Reaction
Run-Zhou Liu, Jinxia Li, Jun Sun, Xian-Guan Liu, Shuanglin Qu,* Ping Li,* and Bo Zhang*
Abstract: A simple and efficient protocol to generate amidyl radicals
from amine functionalities through a manganese-mediated atom
transfer reaction has been developed. This approach employs an
earth-abundant and inexpensive manganese complex, Mn2(CO)10, as
the catalyst and visible light as the energy input. Using this strategy,
site-selective chlorination of unactivated C(sp3)-H bonds of aliphatic
amines and intramolecular/intermolecular chloroaminations of
unactivated alkenes were readily realized under mild reaction
conditions, thus providing efficient access to a range of synthetically
valuable alkyl chlorides, chlorinated pyrrolidines, and vicinal
chloroamine derivatives. These practical reactions exhibit a broad
substrate scope and tolerate a wide array of functional groups and
complex molecules including various marketed drug derivatives.
Introduction
As the twelfth most abundant element and the third most
abundant transition metal after iron and titanium, manganese has
been successfully exploited as a low-toxic and low-cost catalyst
for a variety of practical transformations.[1] Manganese-catalyzed
C-H oxidations,[2] halogenations,[1d] nitrogenations,[3] cross-
couplings,[4] hydrosilylations,[1h] and C-H activations[1e,g,i] have
been intensively investigated in the past decades. In stark
contrast, manganese-catalyzed atom transfer reactions for
generating radical species have received less attention.
Prominently, several important precedents in photoinduced
manganese-catalyzed/promoted atom transfer reactions have
been reported by the groups of Giese,[5] Parsons,[6] Friestad,[7]
Ryu,[8] Alexanian,[9] Fadeyi,[10] and Nagib[11]. However, all these
reactions focus on the formation of carbon-centered radicals with
alkyl halides as the C-radical precursors (Scheme 1a).
Consequently, the exploitation of atom transfer reactions
facilitated by earth-abundant manganese catalysis to generate
other radicals, especially heteroatom-centered radicals, will be of
high value to the synthetic chemistry field. In this context, Wang
and co-workers[12], as well as our group[13] have recently realized
the generation of silyl radicals from silanes through a manganese-
Scheme 1. Generation of C-, Si-, and N-radicals and reactivity modes via Mn-
mediated atom transfer reaction. LPO = dilauroyl peroxide.
catalyzed hydrogen atom transfer process, thereby enabling
efficient construction of C-Si bonds (Scheme 1b). Inspired by
these progresses and our ongoing research interest in developing
sustainable
radical
transformations
using
inexpensive
manganese as an atom transfer catalyst,[13,14] we reason that
nitrogen-centered radicals (NCRs) could be produced by an atom
transfer reaction catalyzed by manganese. NCRs are one of the
most important classes of intermediates in radical chemistry and
can be afforded by various methods.[15] However, the formation of
NCRs by using simple and mild reaction conditions remains a
challenge. To achieve our goal, a working hypothesis for
generating NCRs by manganese-mediated atom transfer strategy
is shown in Scheme 1c. We envisioned that by employing simple
manganese complexes [e.g., Mn2(CO)10] as the catalysts, in situ
formed stable N-Cl bonds from amines might be efficiently
activated through a manganese-mediated halogen atom transfer
process to furnish NCRs. Such a strategy would allow us to devise
new radical cascade reactions in a simple and mild manner.
Herein, we describe scenarios showing how this concept can be
put into practice. The significant aspects of this work include the
following: (1) This presents a novel approach to generate amidyl
radicals, a highly important class of NCRs, starting from amine
functionalities. (2) First examples for site-selective chlorination of
unactivated C(sp3)-H bonds of aliphatic amines as well as
[*] R.-Z. Liu, J. Sun, X.-G. Liu, Prof. P. Li, Prof. Dr. B. Zhang
State Key Laboratory of Natural Medicines
China Pharmaceutical University
24 Tongjia Xiang, Nanjing 210009, China
E-mail: zb3981444@cpu.edu.cn; liping2004@126.com
J. Li, Prof. Dr. S. Qu
College of Chemistry and Chemical Engineering
Hunan University
intramolecular and
intermolecular chloroaminations
of
unactivated alkenes facilitated by manganese catalyst are
reported. (3) These procedures proceed efficiently under very
mild reaction conditions and are applicable for the late-stage
modification of complex molecules.
Changsha 410082, China
E-mail: squ@hnu.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201913042
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RESEARCH ARTICLE
Results and Discussion
We first addressed remote C(sp3)-H chlorination of amine
substrates, since alkyl chlorides are very important and versatile
synthetic intermediates for organic synthesis.[16] The groups of
Studer,[17] Leonori,[18] and Yu[19] have recently achieved elegant
amidyl radical directed remote C(sp3)-H chlorinations by cleaving
N-S, N-O, and N-Cl bonds with the help of LPO radical initiator
and precious photoredox catalysts.[20,21] Obviously, developing
alternative methods that feature a cheap catalytic system and
operate under mild conditions to realize site-selective distal
C(sp3)-H chlorination would be very fascinating. Along this line,
we began our endeavor by exploring the feasibility of manganese-
catalyzed remote C(sp3)-H chlorination of the alkylamine-derived
sulfonamide 1. This in situ activation is performed by simply
reacting TCCA with 1 at room temperature. Then atom transfer
catalyst Mn2(CO)10 was added, and the reaction mixture was
irradiated with 6 W blue LEDs at room temperature for 12 h. To
our delight, δ-C(sp3)-H chlorination occurred, and the expected
product 2 was isolated in 40% yield (Table 1, entry 1). Replacing
TCCA with other electrophilic chlorinating reagents, such as NCS,
NCP, and DCDMH, resulted in poor results (Table 1, entries 2-4).
The yield was further improved by employing simple tBuOCl as
the chlorine source (Table 1, entry 5). The catalysts Mn(CO)5Br
and Fe2Cp2(CO)4 led to significantly lower yields (Table 1, entries
6 and 7). Gratifyingly, a 80% yield of 2 was obtained when the
reaction was irradiated for 1 h (Table 1, entry 8). Reducing the
catalyst loading to 5 mol% led to a slight decrease in yield (entry
9). Control experiments were carried out and revealed that no
chlorinated products were formed in the absence of Mn2(CO)10 or
visible light irradiation (Table 1, entries 10 and 11).
Table 1: Optimization of reaction conditions.[a]
Entry
[Cl+]
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
TCCA
NCS
NCP
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn(CO)5Br
Fe2Cp2(CO)4
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
none
40
0
0
trace
50
28
15
80
70
0
Scheme 2. Scope of the remote C(sp3)-H chlorination. Reaction conditions: see
entry 8, Table 1. [a] TCCA (0.5 equiv) was used instead of tBuOCl, and the
reaction was irradiated for 12 h. Yields of isolated products are given.
DCDMH
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
to furnish 7 in 70% yield. Notably, a substrate carrying a pending
alkene group also participated in this transformation to give 8 in
50% yield. In this case, no cyclized product was observed,
indicating that recombination of the translocated C-radical with Cl
is rapid. As expected, unactivated tertiary C-H bonds in cyclic and
acyclic systems could be selectively chlorinated (9, 10). Likewise,
site-specific chlorination of primary C(sp3)-H bonds is successful
(11). This method can be broadened to benzylic C-H chlorination,
as supported by the synthesis of 12. Furthermore, a range of
sulfonamides bearing electron-donating and electron-withdrawing
substituents on the aromatic ring all proceeded efficiently to afford
products 13-17 in 64-82% yields. A heteroarene such as
thiophene was compatible (18). Alkyl-substituted sulfonamides
proved to be viable substrates (19). Apart from sulfonamides, we
found that site-selective C(sp3)-H chlorination of carboxamides
could be achieved by switching to TCCA as the chlorine source
(20-23). We further interrogated the selectivity of this chlorination
8[c]
9[c,d]
10[c,e]
11[c]
0
[a] Reaction conditions: 1 (0.2 mmol) and chlorinating reagent (0.2 mmol) in
CH2Cl2 (1.0 mL) were stirred at room temperature under N2 for 3 h. After that
catalyst (10 mol%) and CH2Cl2 (1.0 mL) were added, and the reaction mixture
was irradiated with 6 W blue LEDs at room temperature under N2 for 12 h. [b]
Isolated yields. [c] The reaction was irradiated for 1 h. [d] Using 5 mol%
Mn2(CO)10. [e] The reaction was conducted in the dark. Tol = tolyl, TCCA =
trichloroisocyanuric acid, NCS
=
N-chlorosuccinimide, NCP
=
N-
chlorophthalimide, DCDMH = 1,3-dichloro-5,5-dimethylhydantoin.
Under the optimized reaction conditions, we explored the scope
of this remote C(sp3)-H chlorination (Scheme 2). Sulfonamides
bearing α or β-substituents to nitrogen were smoothly transformed
into the desired products in good yields (3, 4). Ring chlorination
can be realized, as exemplified by the efficient preparation of 5
and 6. An adamantyl substrate underwent successful chlorination
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10.1002/anie.201913042
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RESEARCH ARTICLE
when substrates have two reactive sites. As shown in 24,
chlorination of secondary C(sp3)-H bond predominated over that
of primary C(sp3)-H bond. When simultaneously presented with
aliphatic and benzylic C-H bonds, only chlorination of aliphatic C-
H bond was observed (25). With a substrate containing two
electronically similar tertiary C-H bonds, the chlorination event
occurs exclusively at the position proximal to the nitrogen (26). To
illustrate the utility of this method, a series of more complex
medicinally relevant compounds were examined. Substrates
derived from celecoxib, valdecoxib, and zonisamide were readily
converted to their corresponding products 27-29 in synthetically
useful yields with complete site selectivity.
of simple olefins, including terminal (43-45) and 1,1-disubstituted
olefins (46, 47), are suitable reaction partners that can efficiently
react with sulfonamide 42 to produce the targeted products with
yields ranging from 55% to 70%. 2,3-Dimethylbutadiene provided
product 48 in 45% yield, but with low stereoselectivity. We also
observed that a portfolio of N-alkyl sulfonamides are eligible for
this transformation with products 49-51 being formed in good
yields. It is important to note that several substrates with more
elaborate molecular architectures, such as fenofibric acid,
ibuprofen, and isoxepac, were readily functionalized, affording
products 52-54 in good yields. These results further highlight the
potential of this chloroamination reaction for the late-stage
functionalization of complex molecules.
To further explore the potential of this protocol, we attempted to
apply this manganese-mediated atom transfer strategy to the
intramolecular chloroamination of alkenes, which would create a
chlorinated pyrrolidine core that is an important substructure
present in many natural products and biological active
molecules.[22] Although great progress has been made in the
development of intramolecular alkene chloroamination,[23] these
reactions require the use of an expensive palladium catalyst or
stoichiometric strong oxidant. On the contrary, our
complementary strategy described in Scheme 3 uses inexpensive
manganese as the catalyst, and these chloroamination reactions
work well under very mild reaction conditions. Remarkably,
sulfonamides possessing diverse alkene substituent patterns,
including terminal (30-32), 1,2-disubstituted (33), and 1,1-
disubstituted alkenes (34), reacted under slightly modified
reaction conditions to afford the desired products in good yields.
We could show that formation of bicyclic and bridged ring systems
is possible using this novel method (35, 36). Intriguingly, high
diastereoselectivity was observed in both cases. Moreover, a
variety of aryl- and alkyl-substituted sulfonamides were well-
tolerated, leading to products 37-41 in good yields.
Scheme 4. Scope of the intermolecular chloroamination of alkenes. Reaction
conditions: sulfonamide (0.3 mmol) and tBuOCl (0.3 mmol) in CH2Cl2 (1.0 mL)
were stirred at room temperature under N2 for 3 h. After that Mn2(CO)10 (10
mol%), alkene (0.2 mmol), and CH2Cl2 (1.0 mL) were added, and the reaction
mixture was irradiated with 6 W blue LEDs at room temperature under N2 for 1
h. Yields of isolated products are given.
To demonstrate the practical usefulness of this methodology,
we performed one reaction at larger scale (3.0 mmol) and isolated
27 in 73% yield (1.085 g) (Scheme 5). Moreover, follow-up
chemistry on model compound 27 was investigated. Treatment of
27 with NaN3 afforded azide 55 in 83% yield. 55 underwent a Cu-
catalyzed [3+2] alkyne/azide cycloaddition to furnish triazole 56 in
95% yield. The construction of C-S bond could be implemented
through nucleophilic substitution with sodium benzenethiolate,
delivering product 57 in 42% yield. The pyrrolidine derivative 58
was readily prepared in 98% yield through intramolecular
cyclization.
Scheme 3. Scope of the intramolecular chloroamination of alkenes. Reaction
conditions: sulfonamide (0.2 mmol) and tBuOCl (0.4 mmol) in CH2Cl2 (1.0 mL)
were stirred at room temperature under N2 for 3 h. After that Mn2(CO)10 (10
mol%) and CH2Cl2 (1.0 mL) were added, and the reaction mixture was irradiated
with 6 W blue LEDs at room temperature under N2 for 1 h. Yields of isolated
products are given. The relative configuration of 35 and 36 was determined by
ROESY analysis.
To gain insights into the mechanism, we performed several
mechanistic experiments with the model substrate 1. When 1 was
treated with tBuOCl in CH2Cl2 at room temperature for 3 h, N-
chlorosulfonamide 59 was obtained in 97% yield. Further, 59 was
used as the starting material and underwent smooth
photochemical reaction to produce 2 in 90% yield (Scheme 6a).
Encouraged by these results, we next evaluated the viability of
this strategy for intermolecular chloroamination of unactivated
alkenes (Scheme 4).[24] We are pleased to find that a diverse set
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10.1002/anie.201913042
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RESEARCH ARTICLE
representative radical initiator. Under these radical conditions, 2
could be obtained in low yields, suggesting that Mn2(CO)10 might
serve as both an atom transfer catalyst and a radical initiator.
Density functional theory (DFT) calculations were carried out to
further understand the mechanism of this reaction.[25] A plausible
reaction mechanism is depicted in Scheme 7a [with the remote
C(sp3)-H chlorination of aliphatic amines as an example], and the
DFT-calculated free energy profile is shown in Scheme 7b. First,
.
Mn2(CO)10 is converted to Mn(CO)5 by visible-light-induced Mn-
Mn bond homolysis (bond dissociation energy, BDE of Mn-Mn
.
bond = 15 kcal/mol).[13,14,26] The resulting Mn(CO)5 abstracts the
Cl atom from N-Cl bond of in situ formed N-chlorosulfonamide A
via TS1 (with a free energy activation barrier of 8.6 kcal/mol),
generating the amidyl radical B and ClMn(CO)5 with energy
decreased by 27.3 kcal/mol. Then, the 1,5-hydrogen atom
transfer (HAT) occurs through TS2, crossing a free energy
activation barrier of 12.6 kcal/mol, leading to the C-radical C. Next,
the Cl atom transfer could proceed through two possible pathways.
Along Path a, C accepts the Cl atom from A to produce B and
product D. Interestingly, the Cl atom is directly transferred from A
to C without an energetic barrier. The potential energy surface
(PES) scanning also supports that this process is barrierless (see
Figure S3 in SI). Following Path b, ClMn(CO)5 provides the Cl
atom via TSa with a free energy activation barrier of 13 kcal/mol
(TSa relative to C). Overall, A is more effective than ClMn(CO)5
to provide the Cl atom. We determined the quantum yield of the
reaction of 59 to be 22 (λ = 420 nm). The barrierless process for
radical chain propagation (of A to B) also explains the observed
high quantum yield [see the Supporting Information (SI) for
details].[27] Although Path a is more favorable than Path b, we
could not completely exclude Path b because the corresponding
activation barrier is not high (13.0 kcal/mol), which is accessible
Scheme 5. Gram-scale reaction and diversification of 27.
These observations indicate that the N-chlorinated species is a
competent intermediate in this reaction. Next, radical trapping
experiment and radical clock experiment were performed. When
2.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added, this reaction was completely suppressed. Meanwhile, the
TEMPO-trapped product 60 could be identified by high-resolution
mass spectrometry (HRMS) (Scheme 6b). Subjecting of 1 and
radical clock substrate 61 to our standard reaction conditions
afforded the ring-opened product 62 in 23% yield (Scheme 6c).
When sulfonamide 63 was subjected to the optimized reaction
conditions, 1,4-aryl migration product 64 was isolated in 50% yield
(Scheme 6d). These results suggest that a C-radical and N-
radical are generated in this transformation. To probe whether a
cationic intermediate is involved in chlorine atom transfer process,
some nucleophiles such as MeOH and H2O were added to the
reaction. As anticipated, the addition of MeOH or H2O resulted in
no adduct product. These experiments along with the lack of
pyrrolidine formation show that chlorine atom transfer to a C-
radical intermediate rather than carbocation is operative. Finally,
we studied the remote C(sp3)-H chlorination of 59 in the absence
of manganese using azobisisobutyronitrile (AIBN) or Et3B as a
Scheme 7. a) Proposed reaction mechanism. b) Calculated free energy profile
for the formation of product.
Scheme 6. Mechanistic studies.
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RESEARCH ARTICLE
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[4]
Conclusion
In summary, we have presented a novel strategy for generation
of amidyl radicals from amines through an atom transfer reaction
facilitated by an inexpensive earth-abundant manganese complex,
Mn2(CO)10. This procedure enables site-selective chlorination of
unactivated C(sp3)-H bonds of aliphatic amines and
intramolecular/intermolecular chloroaminations of unactivated
alkenes, thereby providing a mild and efficient approach to a wide
array of synthetically versatile alkyl chlorides, chlorinated
pyrrolidines, and vicinal chloroamine derivatives. These reactions
operate under visible-light irradiation and display good functional-
group compatibility and wide substrate scope and are amenable
to gram-scale preparation. Additionally, the practicality of this
chemistry is demonstrated on the late-stage functionalization of
complex drug derivatives. Efforts to extend this methodology to
other NCR-mediated radical cascade reactions are currently
underway in our laboratory.
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Acknowledgements
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This work is financially supported by the National Natural Science
Foundation of China (21702230), the Program for Jiangsu
Province Innovative Research Team, and "Double First-Class"
Project of China Pharmaceutical University (CPU2018GY35,
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Keywords: radicals • chlorination • manganese • visible light •
synthetic methods
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DFT calculations were performed by Gaussian program under the level
of M06-L/6-311++G(d,p)-SMD(CH2Cl2)//M06-L/6-31G(d,p)-SMD (CH2Cl2)
and SDD for Mn atom. See SI for computational details.
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RESEARCH ARTICLE
R.-Z. Liu, J. Li, J. Sun, X.-G. Liu, S. Qu,*
P. Li,* B. Zhang*
Page No. – Page No.
Generation and Reactivity of Amidyl
Radicals: Manganese-Mediated Atom-
Transfer Reaction
A visible-light-driven manganese-mediated protocol for generation of amidyl radicals
from amines is described. This novel strategy enables site-selective chlorination of
unactivated C(sp3)-H bonds of aliphatic amines and intramolecular/intermolecular
chloroaminations of unactivated alkenes. These reactions feature a broad substrate
scope, good functional-group tolerance, scalability, and excellent practicality.
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