Site-Specific C(sp3)–H Aminations of Imidates and Amidines Enabled by Covalently Tethered Distonic Radical Anions

Article abstract of DOI:10.1002/anie.202008806

The utilization of N-centered radicals to synthesize nitrogen-containing compounds has attracted considerable attention recently, due to their powerful reactivities and the concomitant construction of C?N bonds. However, the generation and control of N-centered radicals remain particularly challenging. We report a tethering strategy using SOMO-HOMO-converted distonic radical anions for the site-specific aminations of imidates and amidines with aid of the non-covalent interaction. This reaction features a remarkably broad substrate scope and also enables the late-stage functionalization of bioactive molecules. Furthermore, the reaction mechanism is thoroughly investigated through kinetic studies, Raman spectroscopy, electron paramagnetic resonance spectroscopy, and density functional theory calculations, revealing that the aminations likely involve direct homolytic cleavage of N?H bonds and subsequently controllable 1,5 or 1,6 hydrogen atom transfer.

Full text of DOI:10.1002/anie.202008806

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Accepted Article
Title: Site-Specific C(sp3)−H Aminations of Imidates and Amidines
Enabled by Covalently Tethered Distonic Radical Anions
Authors: Rong Zhao, Kang Fu, Yuanding Fang, Jia Zhou, and Lei Shi
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10.1002/anie.202008806
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RESEARCH ARTICLE
Site-Specific C(sp3)−H Aminations of Imidates and Amidines
Enabled by Covalently Tethered Distonic Radical Anions
Rong Zhao,[a] Kang Fu,[a] Yuanding Fang,[a] Jia Zhou,*[a] and Lei Shi*[a,b]
Dedication ((optional))
[a]
[b]
R. Zhao, K. Fu, Y. Fang, Prof. Dr. J. Zhou, Prof. Dr. L. Shi
School of Science
Harbin Institute of Technology (Shenzhen)
Shenzhen 518055 (China)
E-mail: jiazhou@hit.edu.cn; lshi@hit.edu.cn
Prof. Dr. L. Shi
Beijing National Laboratory for Molecular Sciences
Beijing 100190 (China)
Supporting information for this article is given via a link at the end of the document.
Abstract: The utilization of N-centered radicals to synthesize
nitrogen-containing compounds has attracted considerable attention
recently, due to their powerful reactivities and the concomitant
construction of C−N bonds. However, the generation and control of N-
centered radicals remain particularly challenging. Herein we report a
tethering strategy using SOMO-HOMO converted distonic radical
anions for the site-specific aminations of imidates and amidines with
aid of the non-covalent interaction, which features a remarkably broad
substrate scope including the late-stage functionalizations of bioactive
molecules. Furthermore, after the kinetic studies, Raman
spectroscopy, electron paramagnetic resonance spectroscopy, and
density functional theory calculations, the reaction mechanism is
thoroughly investigated, revealing the aminations likely involve the
directly homolytic cleavage of N−H bonds and subsequently
controllable 1,5- or 1,6-hydrogen atom transfer.
Introduction
In the enzyme-substrate complex, the proximity effect is
achieved via interactions of the substrate and the active sites,
which partly contributes to the catalytic effectiveness of the
enzymes.[1] Enlightened by the enzyme catalysis, the analogous
proximity between two functional centers connected by covalent
bonds plays a highly significant role in synthetic chemistry. The
introduction of covalent tethers transforms an intermolecular
reaction into the corresponding intramolecular variant, which
brings a considerable rate increase (reactivity) and greater regio-
and stereoselectivity (selectivity) due to the innate benefits of the
intramolecularity[2] and the effective molarity.[3] As one of the
pioneers of using the tethering strategy, Breslow etc. attached the
chlorinating agent to the steroid, and adjusted the distance
between two reacting sites by choosing an appropriate length of
the ester linkage to perform a site-selective chlorination (Figure
1a, left).[4] Besides connecting the reacting species, structurally
tethered modifications on Noyori’s catalysts have been made by
Wills etc. to provide additional constraints on the conformation of
the transition states, and led to the significant improvements on
yields and enantioselectivities than the analogous non-tethered
catalysts (Figure 1a, right).[5] In addition, linking an extra activating
group on catalysts for cooperative activation, with the “side arm”
Figure 1. Different tethering strategies and the distonic radical anions.
strategy as the representative by Tang etc.,[6] has been an
inspiring idea for designing new catalysts and reagents (Figure 1a,
middle. More examples of the tethering strategies are shown in
Scheme S1 and S2).
Our group has recently become interested in utilizing
cooperative activation of the tethering approach.[7] In previous
reports, the tethering strategies generally involve additional steps
for the preassociation and dissociation.[8] By contrast, the ring
opening of the cyclic diacyl peroxides in the presence of halide
1
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salts could avoid the assembling step of the covalent linkage, and
in situ produce the distonic radical anion B, in which charge and
radical locate on different atoms acting as two significant binding
sites unlike the regular radical ions (Figure 1b). To our knowledge,
the independent acyloxy radical A has been employed as an
efficient hydrogen atom transfer (HAT) catalyst.[9] Intuitively, B as
the base-linked variant of A might further facilitate the challenging
H-abstraction processes with the additionally proximity-
dependent assistance of the intramolecular base. Compared with
other traditional radical anions, such as C generated from 2,3-
dichloro-5,6-dicyanoquinone (DDQ), the radical anion B could
cooperatively activate and affect nearby sections in a specific
substrate due to the flexible linking structures between the
negative charges and radical sites, offering increased reactivity
and spatial control with the assistance of tethered carboxylate
anion.
Recent theoretical studies suggested that, in a great range of
distonic radical anions, the radicals can be significantly stabilized
by the presence of negatively-charged functional groups, when
compared with their corresponding neutral species.[10] In order to
investigate the improved stabilities of carbonyloxyl radicals, O−I
bond dissociation enthalpies (BDEs) were estimated for a series
of neutral or anionic acyl hypoiodites as radical precursors (Figure
1c). As we can see, the O−I BDEs for distonic radical anions F
and I manifest in 12-13 kcal mol−1 decrease as compared with the
protonated (E and H) or nonsubstituted forms (D and G), which
confirms the temporal regulation brought by tethered carboxylate
anion. Apart from the improved stabilities, the dicarboxylate
radical anions in our studies also display that the singly occupied
molecular orbital (SOMO) of the unpaired electron of the radical
lies at a lower energy than the doubly occupied molecular orbital
(HOMO) of the lone pair electrons of the anion[10] (Figure 1d,
Figure S2, S3, and Table S4), which seems to represent a
violation of the aufbau or building-up principle. It’s worth noting
that the SOMO-HOMO converted distonic radical anions are all
too infrequently applied in practical organic synthesis.
of a few researchers, and have been successfully used in β C−H
amination protocols of alcohols by photochemistry,[13a]
thermochemistry,[13b] and electrochemistry,[13c] even the
installation to the sugar templates.[13d] Recently, the
enantioselective radical C–H amination was also achieved by
Nagib group.[13e] However, the γ-selective C−H aminations of
alcohols have not been well solved yet,[13f] because a seven-
membered-ring transition state for 1,6-HAT is often kinetically less
favored than six-membered transition states for 1,5-HAT.[14] On
the other hand, the similar β C−H aminations of amidines have
only rarely been carried out by using transition metal catalyst,[15]
which is applicable to the synthesis of diverse dihydroimidazole
and diamine derivatives. Based on our previous work on the
homolysis of O−H bonds,[7] we attempt to offer an alternative
appealing approach to imidate radicals and amidine radicals from
the directly homolytic cleavage of N−H bonds by the tether-
tunable distonic radical anions, and enable β or γ-selective
C(sp3)−H aminations relative to the oxygen/nitrogen of imidates
and amidines (Figure 2).
Results and Discussion
Optimization of the reaction conditions. Initial efforts were
focused on the optimization of β C−H amination of imidate 1
(Figure 3), and we found that using the combination of phthaloyl
peroxides (PPO) and CsI in MeCN under the blue LED irradiation,
the β amino alcohol 3 was obtained in 91% yield in 2 h (entry 1).
Control experiments (entries 1-3) confirmed that visible light is
required, and even more generally power-saving sunlight is also
quite efficient for conducting the corresponding C−H aminations.
In consideration of extensive applications of carbonyloxyl radicals
•
(RCO2 ) in polymerization,[16a] hydrogen abstraction,[16b] and the
addition to carbon-carbon double[16c,16d] and triple bonds,[16e] we
began with a critical assessment of acyclic diacyl peroxides as
carbonyloxyl radical precursor (entry 4) and different cyclic diacyl
peroxides as dicarboxylate radical anion precursors (entries 2 and
5, and the detailed information in Table S1), respectively.
Excellent yields were obtained by cyclic diacyl peroxides
Figure 2. The β- or γ- aminations of imidates and amidines.
Nitrogen-centered radicals (NCRs) are powerful synthetic
intermediates due to the polarity regulation of usually nucleophilic
nitrogen centers and the direct involvement of the nitrogen atom
in bond-forming.[11] Furthermore, a suitably in situ-generated
nitrogen-centered radicals can trigger the subsequent C(sp3)−H
bond cleavage, and ultimately lead to remote functionalizations
through HAT processes.[12] Recently, trichloroacetimidates as the
promising imidate radical precursors have aroused the attention
Figure 3. Optimization of the β C(sp3)−H aminations of imidates. [a] Reaction
conditions: 1 (0.3 mmol), oxidant (0.9 mmol), CsI (0.9 mmol), MeCN (3 mL), rt,
2 h. NR, not recorded. [b] Isolated yields. [c] Reaction time: 8 h. [d] Reaction
conditions: 1 (0.3 mmol), MPO (0.9 mmol), CsI (0.12 mmol), MeCN (3 mL), rt, 2
h. PPO, phthaloyl peroxide; BPO, benzoyl peroxide; MPO, malonoyl peroxide.
See also Tables S1, S2, S3.
2
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Figure 4. Scope of β-aminations of imidates. Isolated yields are shown. [a] Reactions were performed on 0.3 mmol scale. MPO (0.9 mmol) and CsI (0.9 mmol) were
used. C.P., complex products; N.D., not detected; Ts, tosyl; Cbz, carboxybenzyl; Boc, tert-butyloxycarbonyl; TBS, tert-butyldimethylsilyl.
compared with acyclic benzoyl peroxide (BPO), indicating the
cooperation of intramolecular base brought by the cyclic structure
of peroxides played a key role in this transformation. Noteworthily,
a partially iodine-catalyzed example was also obtained (85%,
entry 6), when 0.4 equiv. of CsI was employed (the detailed
information in Table S2). Besides, the effectivities of both PPO
and malonoyl peroxides (MPO) brought alternative oxidants for
other substrates (the detailed information in Table S3).
Furthermore, the distinctly different yields of corresponding
oxazolines by altering the R group in imidate 1 suggest −CCl3
serving as the optimal functional group (entries 5, 7, and 8).
Substrate scope. With these optimized conditions in hand,
we investigated the substrate scope of β C−H aminations of
imidates using MPO as the oxidant (Figure 4). A wide range of
trichloroacetimidates bearing sterically and electronically diverse
functional groups smoothly underwent the intramolecular
aminations and the subsequent hydrolysis to generate β amino
alcohols. Ortho-, meta-, and para-substitutions of either
electronically rich or deficient groups were tolerated (3-17).
Additionally, naphthalenes (18 and 19) and heteroarenes such as
thiophene (20) were also tolerant with good yields (>81%), but
indole-derived β amino alcohol 22 was isolated with a low yield
probably due to the undesirable overoxidation. In the further
investigation, alcohols with the tertiary β C−H bonds (23-25) and
secondary alcohols (26, 27, both trans, > 20:1 dr; and 28, cis, >
20:1
dr)
were
β-aminated
efficiently.
The
trans-
diastereoselectivity of β amino alcohol 26 was confirmed by the
X-ray crystallographic analysis.[32] Notably, the products with
3
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Figure 5. Scope of γ-aminations of imidates and β-aminations of amidines. Isolated yields are shown. [a] Reactions were performed on 0.6 mmol scale. PPO (1.8
mmol) and CsI (1.8 mmol) were used. [b] Reaction was performed on 0.15 mmol scale. [c] Reaction was performed on 0.17 mmol scale. [d] Reactions were
performed on 0.3 mmol scale. MPO (0.9 mmol) and CsI (0.9 mmol) were used.
hydrolysis-sensitive substituents (29 and 30) were isolated as the
oxazolines. Furthermore, the late-stage aminations of the small-
molecule drug derivatives, carbohydrate analogue, and steroid-
derived substrates were also successful in moderate to excellent
yields (31-35, up to 99%).[32] It was found that the introduction of
the N atom to substrates bearing both 1,5-HAT and benzylic 1,6-
HAT sites realized the selectively β-aminations (39-41) due to that
the generated radicals can be stabilized by the orbital overlap of
a lone pair on an adjacent heteroatom.[17] As a unique bioisostere
for the phenyl ring,[18] o-carborane was investigated which
replaced phenyl groups with the three-dimensional aromaticity.
The successful β-amination and the following aromatization
generate product 44 with a phenyl group rather than −CCl3.
Subsequntly, we examined the imidates bearing an activated
benzylic γ site and a β site relative to the oxygen without the α-
effect from heteroatoms (Figure 5, top row). The desired dihydro-
1,3-oxazine 45 was generated after the γ-selective amination (via
1,6-HAT) under the similar oxidizing conditions of PPO and CsI.
After the hydrolysis, no β amination product (via 1,5-HAT) was
detected in 1H NMR (Figure S4). Compared with only one
published case describing an unsuccessful γ-selective amination
via 1,6-HAT (reaction conditions: 0.05 equiv. of I2 and 1.2 equiv.
of PhI(OAc)2),[13f] the preferred site selectivity of the amino alcohol
products was obviously reversed from β to γ position (γ:β ratio
from 1:2 to over 20:1), thereby confirming the wider applicability
of our proximity-dependent tethering strategy. These benzylic γ-
aminations were amenable to both electronically donating and
withdrawing groups (47-52) as well as the heteroarene (53) in
4
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moderate yields. To impact the formations of the key six-
membered dihydro-1,3-oxazine by the Thorpe-Ingold effect,
modifications of substitutions in alkyl backbones of the imidates
were conducted (54 and 55), while the yields were slightly lower
(43% for 54 and 48% for 55) compared to the similar product (46:
60%). Ultimately, the benzocyclic structure was found to be
optimal for the intramolecular amination (56, 76%, >20:1 dr), and
the cis-diastereoselectivity of 56 was also confirmed by the X-ray
crystallographic analysis.[32] Furthermore, the late-stage
functionalizations of the derivatives from the dehydrocholesterol
and carbohydrate were performed successfully as well (57 and
58). Having successfully achieved the synthesis of the oxazoline
and dihydro-1,3-oxazine derivatives (Figure 4 and Figure 5 top
row), we further developed a strategy for the synthesis of
dihydroimidazole derivatives, and evaluated the
β
C−H
aminations of amidines under the MPO-oxidative conditions
(Figure 5, bottom). Different electron-rich, electron-deficient, and
heteroarene substituted amidines were converted into the
corresponding dihydroimidazoles (59-65). The N-centered radical
generated from substrate 66 did not abstract the benzylic
hydrogen, but underwent a faster 5-exo-trig cyclization with the
C=C double bond.
200
400
600
800
Mechanistic studies. On the basis of the previously
reported radical amination reactions,[13,19] which proposed
–
possible triiodide (I3 ) intermediate and putative N−I bond
Figure 7. Raman spectra and control experiments to exclude path II. TBAI =
tetrabutylammonium iodide, TBHP = tert-butyl hydroperoxide.
cleavage pathway, several conjectures about the possible
pathways were provided for the further detailed evaluation, in
which three pivotal issues were involved: 1) the generation of
imidate radicals via directly homolytic cleavage of N−H bonds
(path I) or homolytic cleavage of in situ-generated N−I bonds
(path II or path III); 2) the control of the selectivities in 1,5- versus
1,6-HAT processes driven by NCRs; 3) complete exclusion of the
direct benzylic oxidation pathway (Figure 6).
conditions (Exclude path II in Figure 6). The cyclic voltammetry
experiments about intermediates were also conducted (Figure
S7-S10).
Subsequently, we conducted the amination in the presence
of the radical traps TEMPO and BHT (Figure 8a). The addition of
0.1 equiv. of TEMPO completely inhibited the reaction. Whereas
the presence of 0.1 equiv. of BHT led to a decrease in yield of 2a,
0.5 equiv. of BHT completely suppressed the reactivity (Table S7).
Fortunately, an acyloxy radical adduct with BHT was isolated
(Figure 8a and Table S6). This inhibition by radical traps could be
the result of their interaction with cyclic diacyl peroxides or
distonic radical anions. To further validate the radical
intermediates, we performed the electron paramagnetic
resonance (EPR) experiments of MPO/PPO in the presence or
absence of CsI with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). In
agreement with the above quenching experiments, EPR spectra
also suggested that there is the generation of paramagnetic
organic radicals before the incorporation of substrates (Figure 8b
and detailed information in Figure S11). Based on the above
observations involving the origin of initial radicals, the BDEs were
calculated for N-iodoimidates and acyl hypoiodites (R−CO2I)
tailed with the carboxylate (Figure 8c). In the previous report,[13f]
the cleavage of N−I bonds in N-iodoimidates, which were
synthesized from acetoxyl iodine and imidates, was suggested to
be responsible for the generation of NCRs. Although the BDEs of
N−I bonds in N-iodoimidates are fairly low (< 40 kcal/mol),[21] the
indeed lower BDEs of O−I bonds in our geminal or vicinal acyl
hypoiodites (< 28 kcal/mol, or < 33 kcal/mol in the presence of
Cs+) suggested that the homolytic cleavage of O−I bonds
occurred earlier than the proposed formation of N-iodoimidates,
and the generated distonic radical anions spontaneously
promoted the subsequent generation of NCRs by the homolytic
cleavage of N−H bonds (Exclude path III in Figure 6).
Figure 6. Some suppositions about the pathways of the reaction mechanism.
To explore the possibility of the triiodide pathway, evaluations
of Raman spectroscopy were performed (Figure 7a). The band at
–
110 cm–1 in the TBAI/TBHP system was assigned to triiodide (I3 )
referring to the published report[20] (spectrum I). Obviously, there
was also I3– in other four spectra II to V of the combination of the
iodine source and various oxidants. In addition, the higher peaks
in spectra II to V were supposed to be due to the corresponding
acyl hypoiodite (R−CO2I) (Table S8). The regeneration of acyl
hypoiodite from triiodide was confirmed with control experiments
(Figure 7b) and Raman spectra (spectrum VI and Figure S6). The
β C−H amination of 1 did not occur with the use of cesium triiodide
but proceeded in the presence of MPO under identical conditions,
revealing that the acyl hypoiodite (R−CO2I) was the key active
intermediate and the triiodide was a stable inert species under our
5
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3450
3500
3550
3600
Field(Gauss)
Figure 9. Scope of di-iodinations, aminations and kinetic isotope effect
experiments to exclude path IV. Isolated yields are shown. [a] Reactions were
performed on 0.3 mmol scale. MPO (0.9 mmol) and CsI (0.9 mmol) were used.
[b] Reaction was performed under blue LED. [c] PPO as the oxidant.
Figure 8. Experiments and calculations related to radical intermediates to
exclude path III. TEMPO = 2,2,6,6-tetramethylpiperidin-1-yloxy, BHT = 2,6-di-
tert-butyl-4-methylphenol. BDEs of O−I and N−I bonds calculated by M06L-
D3/6-311G(d,p).
intermolecular KIE and the large intramolecular KIE imply that
imidate radical formation is reversible and occurs prior to benzylic
C−H cleavage. In contrast, approximate KIE values of inter- and
intramolecular reactions were observed in a direct benzylic
oxidation condition[26] (intermolecular kH/kD = 2.6, intramolecular
kH/kD = 2.7). The inconsistency of the differences between inter-
and intramolecular KIE indicates the direct benzylic oxidation
pathway could be excluded in our mechanism. We also calculated
the intramolecular KIE by DFT method, and the Wigner tunnelling
correction[27] is included in the KIE calculation. The calculated
values 8.5 and 8.9 listed in Figure 9d are in reasonable agreement
with the experimental values (Exclude path IV in Figure 6).
After precluding the possibilities of paths II to IV in Figure 6,
the potential energy profiles about path I were calculated by DFT
method to thoroughly examine the generation of NCRs and the
subsequent HAT process (Figure 10). In the first half part of the
β- and γ-amination processes of imidates (the generation of
NCRs), the calculated O···Cl distances in the intermediates INT1
and INT5 (2.85 and 2.86 Å, respectively) were shorter than the
sum of the van der Waals radii of O and Cl atoms (3.27 Å),[28]
which indicated that the tethered carboxylate interacted with
−CCl3 group by the halogen bonding[29] as a Lewis base and
effectively assisted the homolytic cleavage of the strong N−H
bond (95.6 kcal/mol) driven by the acyloxy radical in the presence
of weaker C−H bonds (84.4 kcal/mol) (Figure 10a). In the latter
half part of the β- and γ-aminations of imidates (the HAT process
To preclude the possibility of the common benzylic oxidation,
the following experiments were conducted. On the one hand, a
double β C−H di-iodination in non-benzylic positions was
achieved (Figure 9a, 69-71),[22] suggesting a non-benzylic 1,5-
HAT process even in the presence of electronically activated
benzylic C−H bonds. Additionally, the β- and γ-amination of the
inert aliphatic C−H in benzimidates in acceptable yields further
broadened the substrate scope and reaction type (Figure 9b, 1,5-
HAT: 72 and 73; 1,6-HAT: 75), due to the generation of a more
reactive NCR and more nucleophilic N.[13a] The density functional
theory (DFT) calculation results supported the anion-π interaction
between π-electron-deficient phenyl group and the carboxylate
anion (centre⸱⸱⸱O 3.83 Å, Figure S13).[23] Noteworthily, the
structure of 75 is very particular and can be found in the core
skeleton of natural products such as haouamine A and B (Figure
S1).[24]
On the other hand, the kinetic isotope effect (KIE) studies
about 1,5- and 1,6-HAT provided the intermolecular KIE of 2.38
and 2.65 (Figure 9c), and the intramolecular KIE of 8.1 and 6.2
(Figure 9d), respectively, suggesting HAT as the product-
determining step. The observed difference between inter- and
intramolecular KIE implies that the benzylic C−H abstraction is not
the only contributor to product selectivity in the intermolecular
competition KIE experiments.[25] Specifically, the relatively small
6
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RESEARCH ARTICLE
Figure 10. Potential energy profiles and BDEs of N−H and C−H bonds by DFT calculations.
of NCRs), the activation energy of TS2 and TS5 were calculated
to be 13.1 kcal/mol and 9.3 kcal/mol higher than that of INT1 and
INT6, respectively (Figure 10b), therefore the 1,5- or 1,6-HAT is
the rate-determining step. In the calculated potential energy
surface of imidate (n = 2), the energy barrier ∆G‡ of TS5 (9.3
kcal/mol vs. INT6) was 5 kcal/mol lower than TS6 (14.3 kcal/mol
vs. INT6), which suggested the 1,6-HAT process was kinetically
favorable. This result was qualitatively consistent with the
10c, middle R2 = Cbz). Moreover, the unsuccessful case (Figure
10c, left R1 = Me) resulted from the lacking of suitable non-
covalent interaction suggests the importance of assistance by
tethered carboxylate anion once again.
With the β- and γ-aminations of imidates as representative, a
proposed mechanism was described in Figure 11, based on the
above experimental results and the DFT calculations. After the
combination of cyclic diacyl peroxides and iodide ion, the in situ-
experimental observation of γ site selectivity. In both TS5 and TS6, generated intermediates L[7, 31] proceed the homolytic cleavage of
NCRs abstract hydrogen atom from −CH2− group. In TS5, the O−I bonds under the visible light illumination, producing the
N···H distance is 1.37 Å, and C···H distance is 1.26 Å. By contrast, distonic radical anions M and the iodine radical. With the extra
in TS6 the N···H distance is 1.29 Å, while C···H distance is 1.33
Å. The longer distance of N···H in TS5 indicates TS5 is much
closer to the reactant, thus requiring less energy to overcome the
barrier.
With regard to the 1,5- and 1,6-HAT processes triggered by
imidate radicals and amidine radicals (Figure 10c, more analysis
in Table S9), the increasing BDE differences between C−H and
N−H bonds generally implies a thermodynamically more favorable
exchange from weak C−H to strong N−H,[30] which coincide with
the experimental results (Figure 10c, left, right, and middle R2 =
H). However, the α-effect from the heteroatoms may be
responsible for an exceptional site-selectivity in imidate 37 (Figure
halogen bonding assistance of the tethered intramolecular base,
the acyloxy radicals of the intermediates M effectively conduct the
directly homolytic cleavage of N−H bonds in imidates N,
generating the pivotal imidate radicals P and the byproduct O. The
NCRs P undergo regioselective 1,5- or 1,6-HAT to transpose the
open shell to a carbon-centered radical Q. The resulting alkyl
radicals Q subsequently lead to the rapid iodine radical trapping
to produce alkyl iodides R. The β or γ amino alcohols T are
eventually obtained after the attack of nucleophilic N atom and the
hydrolysis process. However, a direct cyclization pathway or even
other possible pathways from Q to S cannot be completely ruled
out at this stage.
7
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2018A030313038), Shenzhen Fundamental Research Projects
(Grant No. JCYJ20180306171838187), the Open Project
Program of Beijing National Laboratory for Molecular Sciences
(BNLMS201819), and Harbin Institute of Technology (Shenzhen)
(Talent Development Starting Fund from Shenzhen Government).
Computer time made available by the National Supercomputing
Center of China in Shenzhen (Shenzhen Cloud Computing
Center) is gratefully acknowledged. We deeply thank Prof.
Herbert Mayr (Ludwig-Maximilians-Universitꢀt Mꢁnchen) for
proofreading the manuscript, Prof. Ping Xu (Harbin Institute of
Technology) and Prof. Huarui Sun (Harbin Institute of Technology,
Shenzhen) for the assistance on the measurement of Raman
spectroscopy.
Keywords: visible light • tethering • distonic radical anion •
amination • cyclic diacyl peroxides
[1]
a) W. P. Jencks, Catalysis in Chemistry and Enzymology, eds.; McGraw-
Hill, 1969; b) J. R. Knowles, C. A. Parsons, Nature 1969, 221, 53–54; c)
T. C. Bruice, Proximity Effects and Enzyme Catalysis; Enzymes, 3rd ed.;
Academic Press, 1970; pp 217–279.
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Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (Grant No.21871067), the Natural
Science Foundation of Guangdong Province (Grant No.
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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9
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RESEARCH ARTICLE
Entry for the Table of Contents
A SOMO-HOMO converted dicarboxylate radical anion mediated tethering strategy for site-specific aminations of imidates and
amidines is presented. A variety of β and γ amino alcohols and dihydroimidazoles are efficiently prepared in good to excellent yields
with high functional group tolerance under visible light irradiation, and late-stage functionalizations of bioactive molecules are also
achieved in non-covalent interaction pattern.
10
This article is protected by copyright. All rights reserved.