Practical and Selective sp3 C?H Bond Chlorination via Aminium Radicals

Article abstract of DOI:10.1002/anie.202100030

The introduction of chlorine atoms into organic molecules is fundamental to the manufacture of industrial chemicals, the elaboration of advanced synthetic intermediates and also the fine-tuning of physicochemical and biological properties of drugs, agrochemicals and polymers. We report here a general and practical photochemical strategy enabling the site-selective chlorination of sp³ C?H bonds. This process exploits the ability of protonated N-chloroamines to serve as aminium radical precursors and also radical chlorinating agents. Upon photochemical initiation, an efficient radical-chain propagation is established allowing the functionalization of a broad range of substrates due to the large number of compatible functionalities. The ability to synergistically maximize both polar and steric effects in the H-atom transfer transition state through appropriate selection of the aminium radical has provided the highest known selectivity in radical sp³ C?H chlorination.

Full text of DOI:10.1002/anie.202100030

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7132–7139
International Edition:
German Edition:
doi.org/10.1002/anie.202100030
doi.org/10.1002/ange.202100030
À
C H Functionalization Very Important Paper
3
À
Practical and Selective sp C H Bond Chlorination via Aminium
Radicals
´
Alastair J. McMillan, Martyna Sienkowska, Piero Di Lorenzo, Gemma K. Gransbury,
Nicholas F. Chilton, Michela Salamone, Alessandro Ruffoni,* Massimo Bietti,* and
Daniele Leonori*
Abstract: The introduction of chlorine atoms into organic
molecules is fundamental to the manufacture of industrial
chemicals, the elaboration of advanced synthetic intermediates
and also the fine-tuning of physicochemical and biological
properties of drugs, agrochemicals and polymers. We report
of high importance to enable further elaboration of key
synthetic intermediates[3] and also to aid the modulation of
physical and biological properties of high-value final prod-
ucts.[4]
3
À
Radical sp C H chlorination via hydrogen-atom transfer
here a general and practical photochemical strategy enabling
(HAT) would be an ideal approach to access these building
blocks and indeed it is widely used in the industrial valor-
isation of light alkanes.[2] However, as these processes are
based on the radical chain reactivity of chlorine radicals (ClC),
they require harsh conditions, are difficult to control and
deliver complex mixtures of all possible constitutional
3
À
the site-selective chlorination of sp C H bonds. This process
exploits the ability of protonated N-chloroamines to serve as
aminium radical precursors and also radical chlorinating
agents. Upon photochemical initiation, an efficient radical-
chain propagation is established allowing the functionalization
of a broad range of substrates due to the large number of
compatible functionalities. The ability to synergistically max-
imize both polar and steric effects in the H-atom transfer
transition state through appropriate selection of the aminium
radical has provided the highest known selectivity in radical sp3
isomers (Scheme 1B).[5] Overall, achieving high selectivity
3
À
in radical sp C H chlorination is still challenging because it
requires fine control of the interplay between multiple factors
(e.g. enthalpic, polar, steric and stereoelectronic, conjugative
and hyperconjugative, torsional and strain) that determine
3
[6]
À
À
C H chlorination.
the reactivity of each individual sp C H bond.
The state-of-the-art in radical sp3 C H chlorination is
summarised in Scheme 1C using trans-decalin 1 and methyl-
hexanoate 2, two substrates whose HAT-chlorination is
mainly affected by steric and polar factors, respectively.
While methodologies based on ClC radicals are unselective
and also lead to poly-chlorination (Scheme 1C, box a),
systems displaying strong bias for specific positions and
leading selectively to 3[7] and 4[8] have been reported. Groves
À
Introduction
Chlorine-containing molecules are integral to all chemical
disciplines (Scheme 1A).[1] It has been estimated that the
manufacture of > 50% of industrial chemicals and > 20% of
pharmaceutical products requires at some point the introduc-
tion of a chlorine atom into a feedstock or an advanced
building block, respectively.[2] Methodologies able to target
the selective chlorination of organic compounds are therefore
developed a bioinspired MnIII-porphyrin catalyst able, upon
oxidation to MnV O, to sterically differentiate between sp
3
=
À
C H bonds. This biphasic system uses NaOCl as both the
oxidant and the Cl-source and often requires an excess of the
hydrocarbon substrate (Scheme 1C, box b).[9] Following the
´
[*] A. J. McMillan, M. Sienkowska, P. Di Lorenzo, Dr. G. K. Gransbury,
Dr. N. F. Chilton, Dr. A. Ruffoni, Prof. D. Leonori
Department of Chemistry, University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: alessandro.ruffoni@manchester.ac.uk
daniele.leonori@manchester.ac.uk
À
pioneering work of Greene on C H chlorination using N-t-
Bu,N-chloroamide,[10] Alexanian has identified two bench-
stable N-t-Bu,N-chlorobenzamide reagents that, depending
on the aromatic substitution pattern, target specific sp C H
bonds on the basis of either electronic or steric factors
(Scheme 1C, box c).[11] In both cases, photochemical or
thermal conditions generate an amidyl radical that partic-
ipates in a HAT-based radical-chain chlorination.
Despite these powerful advances, a methodology able to
selectively discriminate between very similar sp C H bonds
in organic molecules is still a challenge, especially when broad
functional group compatibility is required. Here, we describe
3
À
Homepage: https://leonorigroup.com
Prof. M. Salamone, Prof. M. Bietti
Dipartimento di Scienze e Tecnologie Chimiche, Università “Tor
Vergata”
Via della Ricerca Scientifica, 00133 Rome (Italy)
E-mail: bietti@uniroma2.it
3
À
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.202100030.
3
À
a practical process for site-selective sp C H chlorination via
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
aminium radicals (Scheme 1C, box d). This strategy does not
require the preparation of bespoke catalysts/reagents and
uses simple cyclic amines in combination with N-chlorosucci-
nimide (NCS). The large structural modularity of commer-
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3
À
Scheme 1. A) Examples of high-value chlorinated molecules. B) Classical approaches to sp C H chlorination via ClC lead to isomeric mixtures.
3
À
C) Achieving selectivity in sp C H chlorination. D) Reactivity patterns of protonated N-chloroamines: ionic vs. radical processes. E) Proposed
mechanistic analysis for HAT chlorination with aminium radicals. SET=single-electron transfer; SH2=bimolecular homolytic substitution;
SEAr=electrophilic aromatic substitution.
mode for sp3 C H functionalization, the harsh reaction
conditions combined with the known difficulties in preparing
and isolating N-chloroamines, have thwarted its adoption and
exploitation by the synthetic community.
À
cially available amines facilitates easy tuning of the steric
properties of the aminium radicals which, combined with their
intrinsic high electrophilicity, has provided the highest known
3
À
selectivity in radical sp C H chlorination.
We recently questioned if our mild activation protocol for
aminium radical generation could be adapted for the realiza-
Design Plan
tion of a synthetic HAT-functionalization platform enabling
3
À
site-selective sp C H chlorination. As shown in Scheme 1E,
We have recently developed photoinduced protocols for
our strategy is based on amine activation (chlorination and
protonation, A ! B), followed by photoinduced initiation to
start a radical-chain propagation centred on aminium radical
C. We were hopeful that C would enable site-selective HAT
À
aromatic C H amination and olefin diamination exploiting
the generation of aminium radicals from both 18 and 28
alkylamines (Scheme 1D).[12] These processes rely on in situ
amine activation by chlorination followed by protonation (A
! B). The corresponding N-Cl-ammonium salts B are
powerful electrophiles in classical ionic chemistry,[13] but
upon judicious choice of the reaction conditions their
reactivity can be diverted into radical manifolds based on
aminium radicals C. These species are isoelectronic with alkyl
radicals but carry a formal positive charge which dramatically
enhances their reactivity towards electron rich p-systems [see
Scheme 1D, paths (a) and (b)].[14] Pioneering work from
Minisci[15] and Deno[16] has also demonstrated that these
open-shell intermediates can be used in radical HAT-chlori-
nation but required preformed N-chloroamines, H2SO4 as
solvent and either high-energy UV-irradiation (l = 254 nm)
or an excess of FeSO4. Despite the potential of this reactivity
À
from the aliphatic C H bond of an organic molecule D and
give the corresponding radical E and the protonated amine G.
Chlorine-transfer (SH2) between B and E would provide the
chlorinated product F, and, crucially, would regenerate the
chain-carrying aminium radical C. There are four intrinsic
features that should synergistically maximise “reactivity &
selectivity” aspects in this manifold. (1) The N–H BDE in G is
ꢀ 103 kcalmolÀ1,[17] which is larger than the BDEs of most sp3
À
À
C H bonds (e.g. BDE for C H in cyclohexane = 99 kcal
molÀ1)[18] and should provide the enthalpic driving force for
the HAT step. (2) The strong electrophilic character of
aminium radicals [calculated local electrophilicity index
[19]
(w+
)
rc
for piperidinium radical ꢀ 4.2 eV][20] is expected to
provide extensive charge-transfer character to the HAT
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transition state H. This kinetic polar effect should impart
significant stabilisation and critically amplify the innate
3
[21]
À
electronic differentiation of the sp C H bonds. (3) The
ability to prepare the HAT-chlorination reagents B in situ
from simple amines ought to enable the fine tuning of the
chemical environment around the aminium radical thus
À
maximising C H discrimination in the HAT step based
3
À
mostly on sterics. (4) A common drawback in radical sp C H
chlorination is the formation of polychlorinated materials. In
our case, the great sensitivity of aminium radicals to polar
inductive effects means that the Cl substituent in product F
acts as a sp3 C H deactivating group thus insulating the
À
product from further and unwanted functionalization.[22]
Regarding the initiation process, we initially considered
the use of a photoredox catalyst [for example, Ru(bpy)3Cl2]
but we quickly realised that simple blue light irradiation was
sufficient to sustain chain propagation and achieve high
chemical yields. Our current working hypothesis for this step
involves the adventitious photochemical generation of ClC
that would perform the very first HAT (low selectivity) and
then enable the generation of the key aminium radical C.
Reaction Optimization
3
À
We started the optimization of the sp C H chlorination
process using trans-decalin 1 in order to focus on HAT
discrimination based on steric effects. Following the proce-
dure reported in Scheme 2A, 21 secondary amines A (cyclic
and acyclic) were screened and all provided preferentially the
C-2 chlorinated product 3 in moderate to high yields.[23] The
selectivity of the process depended on the amine structure
3
À
and in no case abstraction of the weaker tertiary sp C H
À1 [24]
3
À
bond (C H BDE = 91 kcalmol )
was observed. This
demonstrates the difference in HAT site-selectivity of this
approach vs. other aminium radicals like quinuclidinium or
À
Scheme 2. A) Optimization of the sp C H chlorination on 1. B) Opti-
3
À
mization of the sp C H chlorination on 2.
+
+
triethylenediammonium bis(tetrafluoroborate)C (TEDAC )
which have been shown to functionalize both 28 and 38 sites.[25]
To evaluate the steric hinderance at the aminium radical
centre, we employed a simple line-of-sight methodology in
our AtomAccess code[26] and determined the percentage
visible solid angle (%VSA) of the N-atom.[20] Pleasingly,
a trend between the C-2 selectivity and the %VSA for all
amines was observed despite their large structural differ-
ence,[20] and a clear correlation was identified in the case of
the piperidine-based derivatives A1–5 (Scheme 2A). In this
case, the sequential introduction of substituents at C-2 and C-
6 of the piperidine core resulted in increased steric hinderance
that translated into higher selectivity for chlorination at C-2.
In particular, the use of 2,2,6,6-tetramethylpiperidine (TMP,
A4) enabled to reach a ratio C-2:C-1 > 13:1, which represent
an overall 93% selectivity. To the best of our knowledge, this
is the highest reported selectivity for the chlorination of this
the methylene units, making the w–1 position the least
deactivated towards HAT by electrophilic radicals. In this
case, as all aminium radicals tested have similar electro-
philicity [based on their calculated local electrophilicity
indices (w+rc)], a less dramatic variation in the reaction
selectivity was observed. However, the amines A1 and A3
that lead to some of the slightly more electrophilic radicals,
gave 4 in 84% and 83% wÀ1 selectivity, respectively.
It is worth pointing out that during the optimization
process (as well as the substrate scope) we encountered
a significant challenge in the accurate determination of the
reaction selectivity, especially in the case of volatile or
unfunctionalized hydrocarbons. Analysis of crude mixtures
by 1H NMR spectroscopy or gas chromatography, as done by
others, proved not accurate in our hands. We therefore used
a different approach and employed quantitative 13C NMR
spectroscopy. The sensitivity of this analytical tool enabled
the identification and full assignment of all reaction compo-
nents even when present in very small amounts.[28]
substrate.[27]
3
À
We then used related conditions to evaluate the sp C H
chlorination of methylhexanoate 2, which should mostly
respond to polar factors as steric discrimination between the
methylene positions is less pronounced. In general, the
electron withdrawing ester group progressively deactivates
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Radical Initiation
yield (5: 28% vs. 3: 90%) is probably due to the cis-decalin
concave shape that can sterically hamper the HAT process
without affecting too much the innate selectivity (5: 87% vs.
3: 93%). Also in this case, the tertiary position remained
untouched. A similar trend of reactivity for programmable
chlorination at the more accessible methylene site was
As direct photolysis of N-chloroammoniums is not
possible under blue light irradiation,[29] we believe this radical
reactivity is initiated by the adventitious generation of Cl2
during the N-chloroamine formation step (Scheme 1E). As
Cl2 displays a slight absorption in the visible region,[30] under
observed for trans- and cis-1,2-dimethylcyclohexane (6 and
[31]
3
À
À
our conditions Cl Cl bond homolysis can take place thus
7). The lack of chlorination of tertiary sp C H bonds in these
starting the aminium radical-based chain propagation.
examples is mechanistically relevant as it confirms that the
overall selectivity is controlled by sterics. Indeed, these
Due to difficulties to spectroscopically detect small
amounts of Cl2 in our reactions, we performed indirect
experiments using amine A1 and hydrocarbon 1 to support
this mechanistic hypothesis (Scheme 3). (1) When the reac-
tion was performed in the presence of the Cl2-scavenger 2-
methyl-2-butene[32] (10 mol%), functionalization of 1 was
suppressed (entry 2). (2) Blue light irradiation of the N-
chloroamine prior to the addition of HClO4 and 1 also
thwarted reactivity most likely because the adventitious Cl2
was immediately consumed in unproductive pathways (en-
try 3). These two experiments are in agreement with the key
role of ClC to initiate the radical chain process. (3) However,
chlorination was restored by simply adding Cl2-saturated
CH2Cl2,[33] which lead to formation of 3 in similar yield and
selectivity (entry 4). (4) Finally, Bu4NCl can generate Cl2 by
reaction with N-chloroamines[34] and this is also an effective
way of re-initiating our reactions. Indeed, blue light irradi-
ation of the N-chloroamine (to destroy any adventitious Cl2),
À
substrates are known mechanistic probes in HAT-based C
H functionalization due to the operation of torsional effects.
Interestingly, our approach does not target the activated
À
tertiary equatorial C H bond of 7 and this is in contrast with
previous studies based on the reactivity of nitrogen radical-
s,[11a] as well as dioxiranes[35] and Fe/Mn-oxo species.[36]
A
minor functionalization of the tertiary position was observed
in trans-1,4-dimethylcyclohexane (8) potentially owing to the
more sterically encumbered nature of its methylene sites
which required the use of the less hindered A3 to improve the
chemical yield. In the case of adamantane,[37] the tertiary C H
À
bond has low steric hindrance which lead to its quantitative
chlorination (9). This selectivity is interesting as other
electrophilic radicals like t-BuOC and ClC usually give ꢀ 1:1
mixture of 38 vs. 28.[38] High selectivity could also be obtained
in the case of bicyclic norbornane that led to the selective
formation of 10.
followed by the addition of HClO4, 1 and Bu4NCl (10 mol%)
Next, we explored the second set of reactions conditions
identified during the optimization of 2 (see Scheme 2B).
Using a linear 5-carbon framework, we have been able to
evaluate the electronic effect of a broad range of commonly
used functionalities. In all cases, high selectivity for the more
reactive wÀ1 position was observed even in the case of n-
hexane (11) where no electronic bias is present.
A N,N-dimethylamide provided 12 with slightly higher
selectivity compared to ester 2. Ketone (13) and nitrile (14)
functionalities were tolerated but a small decrease in the
selectivity was observed. 1-Cl-, Br- and F-pentane afforded
15–17 which are interesting building blocks for further
functionalization[39] but still represent a remarkable synthetic
challenge to other methodologies.
3
À
resulted in sp C H chlorination again in similar yield and
selectivity (entry 5). During the evaluation of the substrate
scope, we have found the addition of Bu4NCl to be beneficial
to improve the outcome of low yielding examples. We believe
this additive aids the radical chlorination in the case of
challenging substrates where chain initiation and/or propa-
gation is not efficient. Overall, these results support the role
of Cl2 as chain initiator and also highlight the importance in
following the reaction set-up procedure to obtain reprodu-
cible results.
We then evaluated other heteroatom-based functionali-
ties starting with various O- and N-groups of different Lewis
basicity and inductive power. Electron withdrawing OSO2Ph,
OAc and NPhth (NPhth = phthalimide) groups provided the
desired products (18–20) in good yield and high wÀ1
selectivity [comparable (18) or higher (19, 20) than what
previously reported using other systems].[11a]
Substrates containing free alcohol, ether and alkylamine
substituents are a known challenge in methodologies that
employ electrophilic HAT reagents. Bar the free acid, these
functionalities enhance reactivity at the a-position due to
hyperconjugation between the heteroatom lone-pair and the
Scheme 3. Supporting the involvement of ClC.
Scope of the Process
À
With a set of three optimum amines, A1, A3 and A4, we
moved to evaluate the scope of the process (Scheme 4). The
chlorination of unfunctionalized hydrocarbons was evaluated
using bulky A4 with the intention of maximising steric
discrimination. In analogy to trans-decalin 1, cis-decalin was
also preferentially chlorinated at C-2 (5). The decrease in
C H s* orbital (Scheme 4, box A). This increases the hydridic
nature of the a-C hydrogens (BDE ꢀ 91–95 kcalmolÀ1) and
leads to preferential functionalization at this position result-
ing in a-chloro-alcohols and -amines that are unstable. As our
reactions are run under acidic conditions, protonation (or H-
bonding) switches via polarity reversal the innate reactivity of
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À
Scheme 4. Substrate scope for the photoinduced sp C H chlorination strategy. a) amine=A4; b) solvent=CH2Cl2; c amine=A3; d) solvent=H-
FIP; e) the amount of amine, NCS and acid was doubled; f) amine=A1; g) the reaction was performed using preformed N-chlorotetramethylpi-
peridine;[20] h) reaction run adding Bu4NCl (10 mol%). Phth=phthalimide.
3
À
the sp C H bonds thus deactivating the a-methylene units
towards HAT.[40] This strong through-bond effect enabled
selective targeting of the wÀ1 site providing 21–24 which
cannot be achieved by previous strategies. Another manifes-
tation of the acid-mediated switch in the HAT site-selectivity
was observed for the functionalization of 1-arylpentanes. In
the case of 1-phenylpentane, benzylic chlorination took place
À1
À
(25) owing to its weaker C H bond (BDE = 89 kcalmol )
and the stabilization of the incipient radical. However, in the
case of the corresponding 2-, 3- and 4-pyridyl derivatives,
protonation converts the aromatic group into a strong
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deactivating substituent thus enabling selective targeting of
Surprisingly when the bulkier A4 was tested the unexpected
the distal wÀ1 site (26–28).
and fully site-selective chlorination at C-7 took place (41),
which was confirmed by X-Ray analysis.[46] To the best of our
knowledge no chemical transformation has allowed the direct
targeting of this position and only de novo multistep syn-
thesis[47] or microbial hydroxylation using Cunninghamella
eschinulata[48] have been reported for the preparation of C-7-
functionalised (+)-sclareolide. In general, C-2 functionaliza-
tion is favored due to the planarization of an incipient radical
in the HAT transition state that releases the unfavorable 1,3-
diaxial interactions with the angular Me-groups.[6b] We
propose that increasing the steric hinderance of the HAT
reagent diverts the site-selectivity of the process to the less
activated but more accessible C-7 methylene unit.[49] While
unexpected this result represent an outstanding example of
reagent-dictated site-selectivity and suggests that by screen-
ing structurally different aminium radicals, the complex
topology of natural products might open up for novel and
selective functionalization paradigms.
A Ph substituent is a strong activating group also in the
presence of other deactivating functionalities like a free
carboxylic acid as demonstrated by the successful formation
of 29 and 30.
It is important to note that in none of these examples we
2
À
observed radical sp C H amination as previously reported by
us and others.[12a,41] The reaction of aminium radicals with
aromatics displays strong solvent dependence and can be
achieved using polar media like CH3CN and/or HFIP.[12a,42] In
this case, the use of CH2Cl2 as the solvent and, crucially, the
absence of a photocatalyst, enabled to divert the aminium
radical reactivity from p-addition to HAT. We believe this
control over chemoselectivity to be noteworthy, since pio-
neering laser-flash photolysis studies by Chow,[43] demon-
strated how HAT reactivity is several orders of magnitudes
slower than addition to p-systems.
We were also interested in evaluating longer and shorter
alkyl chain derivatives. In the case of octanoic acid, selective
wÀ1 chlorination was achieved (31), however, the remote
position of the carboxylic acid leads to attenuation of the Conclusion
polar discrimination between the remote methylene units.
3
À
Nevertheless, 31 was obtained in overall 66% wÀ1 selectivity.
Shorter chain derivatives might suffer from the opposite
effect as the deactivating functional group is now closer to the
terminal methylene group. Despite this potential negative
kinetic polar effect, chlorination of four derivatives bearing
a butyl chain (32–35) was achieved in ꢁ 75% wÀ1 selectivity
and moderate to good chemical yield.
We then decided to evaluate the methodology in the late
stage modification of more complex and high-value materials.
g-Undecalactone is an aroma compound with an intense
peach flavour and its seven-C chain was chlorinated (36) in
overall 68% wÀ1 selectivity and good yield.
Achieving selectivity in radical sp C H chlorination is
still a synthetic challenge especially when broad functional
group compatibility is required. In this article we have
reported the development of a photochemical protocol for
the efficient and site-selective assembly of chlorinated build-
ing blocks. This strategy harnesses the conversion of secon-
dary amines into aminium radicals that are powerful inter-
mediates in HAT processes. The high-electrophilicity of these
species, combined with the ease of modulating the steric
hinderance around their N-centre has allowed to synergisti-
cally maximise polar and steric factors in the HAT-chlorina-
tion manifold.
NCS 60591 is a surface-active agent so the introduction of
a Cl-atom might infer interesting physicochemical proper-
ties.[44] Pleasingly, when exposed to our reaction conditions,
selective chlorination was achieved in 86% selectivity (37).
We believe this high wÀ1 selectivity is the result of two
synergistic effects, an inductive contribution from the free C-
4-OH group and a steric one from the branching at C-7, that
progressively deactivate most of the methylene units towards
HAT. A manifestation of steric deactivation of CH2 groups
was observed in the chlorination of 5a-cholestane, a bench-
Overall, this reactivity has enabled the direct introduction
3
À
of chlorine atoms in place of sp C H bonds with often the
highest known site-selectivity. The process tolerates a broad
range of functionalities that are frequently elusive in other
radical approaches thus providing access to high-value build-
ing blocks for further chemical diversification. The possibility
À
to override the innate selectivity for C H functionalization by
changing the steric environment around the aminium radical
might enable the exploration of currently elusive chemical
space.
À
mark substrate for C H functionalization methodologies,
containing 48 different sp3 C H bonds and no heteroato-
À
m.[11a,45] Our chlorination process enabled selective targeting
of C-2 and C-3 methylene units over the other 11 possible CH2
groups with an overall 58% yield (38) which is similar to what
reported by MnIII-porphyrin systems.[45a]
Acknowledgements
We thank Dr Ralph Adams, Prof David A. Leigh and Dean
Thomas for help with the quantitative 13C NMR analysis. D.L.
thanks EPSRC for a Fellowship (EP/P004997/1), and the
European Research Council for a research grant (758427).
The AtomAccess code was developed by G.K.G. and N.F.C.
for research activities on ERC CoG-816268 (PI: Dr David P.
Mills, University of Manchester).
The cytotoxic sesquiterpene (+)-sclareolide (39) is an-
À
other benchmark substrate commonly evaluated in C H
functionalization methodologies.[11a,45b] In general, this sub-
strate can be modified at C-11 using enolate chemistry or at
C-2 by HAT-based methodologies.[36a] Under our optimized
condition using A3, we obtained site-selective chlorination at
C-2 to give 2-chlorosclareolide (40) with good diastereose-
lectivity (dr 6.9:1) and good chemical yield on gram-scale.
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[13] J. R. L. Smith, L. C. McKeer, J. M. Taylor, J. Chem. Soc. Perkin
Trans. 2 1989, 1537 –1543.
Conflict of interest
[14] J. M. Ganley, P. R. D. Murray, R. R. Knowles, ACS Catal. 2020,
10, 11712 –11738.
The authors declare no conflict of interest.
[15] F. Minisci, R. Galli, A. Galli, R. Bernardi, Tetrahedron Lett.
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À
Keywords: aminium radical ·C H functionalization ·
chlorination ·H-atom transfer ·late-stage functionalization
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À
À
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Manuscript received: January 2, 2021
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ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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