Microtubing-Reactor-Assisted Aliphatic C?H Functionalization with HCl as a Hydrogen-Atom-Transfer Catalyst Precursor in Conjunction with an Organic Photoredox Catalyst

Article abstract of DOI:10.1002/anie.201804844

Chlorine radical, which is classically generated by the homolysis of Cl₂ under UV irradiation, can abstract a hydrogen atom from an unactivated C(sp³)?H bond. We herein demonstrate the use of HCl as an effective hydrogen-atom-transfer catalyst precursor activated by an organic acridinium photoredox catalyst under visible-light irradiation for C?H alkylation and allylation. The key to success relied on the utilization of microtubing reactors to maintain the volatile HCl catalyst. This photomediated chlorine-based C?H activation protocol is effective for a variety of unactivated C(sp³)?H bond patterns, even with primary C(sp³)?H bonds, as in ethane. The merit of this strategy is illustrated by rapid access to several pharmaceutical drugs from abundant unfunctionalized alkane feedstocks.

Full text of DOI:10.1002/anie.201804844

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Accepted Article
Title: Micro-Tubing Reactor-Assisted Aliphatic C-H Functionalization
Utilizing HCl as the Hydrogen Atom Transfer Catalyst Precursor
in Conjunction with an Organo Photoredox Catalyst
Authors: Hong-Ping Deng, Quan Zhou, and Jie Wu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804844
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Micro-Tubing Reactor-Assisted Aliphatic CH Functionalization
Utilizing HCl as the Hydrogen Atom Transfer Catalyst Precursor
in Conjunction with an Organo Photoredox Catalyst
Hong-Ping Deng, Quan Zhou, and Jie Wu*
Abstract: Chlorine radical, classically being generated from
homolysis of Cl2 under UV irradiation, can abstract hydrogen atom
from an unactivated C(sp3)H bond. We herein demonstrate the
use of HCl as an effective hydrogen atom transfer catalyst
precursor activated by an organo acridinium photoredox catalyst
under visible-light irradiation for CH alkylation and allylation. The
key to success relied on the utilization of micro-tubing reactors to
maintain the volatile HCl catalyst. This photo-mediated chlorine-
based CH activation protocol is effective for a variety of
unactivated C(sp3)H bond patterns, even with primary C(sp3)H
bonds such as ethane. The merit of this strategy is illustrated by
the rapid access of several pharmaceutical drugs from abundant
unfunctionalized alkane feedstocks.
Scheme 1. Synergistic merger of photoredox and HAT catalysis.
substrates (≥ 10 equiv) to achieve effective transformations.
We envisioned that HCl would be produced in any chlorine
radical-based HAT process, and the generation of chlorine radical
from HCl (BDE = 103 kcal/mol) would realize a chlorine-based
CH activation strategy in a catalytic fashion. A literature survey
Dramatic developments in photocatalysis over the past decade
have enabled previously inaccessible transformations.[1] In
particular, the synergistic combination of photoredox catalysts
and hydrogen atom transfer (HAT) catalysts has offered
enormous opportunities for C(sp3)H activations.[2] In general,
upon light irradiation, the activated photocatalyst can oxidize the
HAT catalyst via single-electron transfer (SET) to form a hydrogen
abstractor, either in the presence or absence of a base, which will
abstract a hydrogen atom to deliver a carbon radical to enable
CH activation (Scheme 1a). In this context, a variety of HAT
catalysts based on S (thiols),[3] N (quinuclidines, sulfonamides),[4]
and
O
(benzoates, N-hydroxides)[5] have been developed
(Scheme 1b). However, the development of readily available and
highly efficient catalytic systems that accommodate a wide range
of CH patterns without the requirement of stoichiometric
amounts of additives is still highly desirable.
Chlorine radical, classically being generated from homolysis of
Cl2 under UV irradiation, represents another heteroatom-centered
radical capable of abstracting hydrogen atoms from unactivated
aliphatic CH bonds. However, it has not been widely recognized
as a HAT catalyst under visible-light mediation. In this regards,
Doyle and our group have recently demonstrated the generation
of chlorine radical by photolysis of a Ni(III) chloride intermediate
generated from photoredox-mediated single-electron oxidation of
a Ni(II) precursor, that could activate C(sp3)H bonds for
arylation[6] and hydroalkylation of alkynes[7] respectively (Scheme
2a).[8] However, the former reaction uses stoichiometric amounts
of chloride compounds, and the latter suffered from a limited CH
substrate scope. Both methods required excess amounts of CH
Scheme 2. Photoredox-induced chlorine radical as the HAT catalyst.
[*]
Dr. H.-P. Deng, Q. Zhou, Dr. J. Wu
disclosed that the Fukuzumi group had attempted to develop such
a catalytic process for the oxygenation of cyclohexane.[9,10] 9-
Mesityl-10-methylacridinium ion (MesAcr+) was employed as the
photocatalyst owing to its strong oxidizing ability (E1/2(cat*/cat) =
+2.06 V vs SCE), which was capable of oxidizing Cl anion to Cl
Department of Chemistry, National University of Singapore
3 Science Drive 3, Republic of Singapore, 117543
E-mail: chmjie@nus.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201804844
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radical (Eox(Cl-/Cl) = +2.03 V vs SCE).[11] However, the reaction
suffered from low conversion (16% of cyclohexane) and product
selectivity (cyclohexanol:cyclohexanone~3:5) (Scheme 2b).[9]
The continuous micro-flow technologies have provided effective
platforms for photo-synthesis due to the improved light
penetration associated with micro-tubing reactors.[12] Our group
has recently developed a “stop-flow” micro-tubing (SFMT) reactor
for efficient screening of gas-involved photo-mediated
transformations in a convenient and effective manner.[13] As part
of our ongoing interests in developing visible-light-promoted
transformations using readily available C(sp3)H bonds as the
latent nucleophilic handles,[7,14] we herein report a metal-free CH
alkylation and allylation using HCl as the HAT catalyst precursor
in conjunction with MesAcr+ photoredox catalyst assisted by
micro-tubing reactors (Scheme 2c). The high efficiency relied on
the unique advantages provided by the micro-tubing reactors.
favouring the functionalization of secondary CH bonds over
primary CH bonds (9). Selective alkylation proceeded at more
hydridic CH bonds in cyclopentanone and cycloheptanone (10
and 11) because of the electrophilic nature of chlorine radicals.[15]
Alkyl bromide delivered product 12 in 42% yield with good
selectivity for the tertiary CH bond over several secondary and
primary CH bonds presented in the molecule.[5d] Other than
unactivated C(sp3)H bonds, benzylic CH bonds could also
participate effectively to give 13. Ethers and phenyl ethers
afforded coupling products (14 to 16) in good yields. The reactions
of alcohols or aliphatic amides proceeded smoothly to afford
products 17-21 in moderate to excellent yields, with alkylation
occurring exclusively at the carbon adjacent to the heteroatom.
Aldehydes could be applied as latent nucleophilic handles to
achieve umpolung reactivity, accessing hydroacylation-type
product 22. Notably, the primary C(sp3)H bonds of alkyl boronate
ester was more reactive than the secondary C(sp3)H bonds (23),
probably due to the more hydridic character of the CH bonds.
Scheme 3. C(sp3)H alkylation via the merger of phoredox and HCl catalysts.
As demonstrated in our previous report on benzylic/allylic
alkylation, the radical adduct formed from radical addition with
benzylidenemalononitrile 2 could oxidize the reduced form of
acridinium catalyst (E1/2ox = -0.57 V vs SCE in MeCN) to turn over
the photoredox cycle.[14a] This study was initiated by evaluating
the CH alkylation of cyclohexane (10 equiv) using 2 in the
-
presence of catalytic MesArc+ClO4 and HCl under blue LED
irradiation. Various reaction parameters was evaluated in batch
reactors (see Supplementary Information), and the coupling
product 3 could be obtained with very poor reproducibility
(Scheme 3). Mild heating was required as the amount of product
3 generated at room temperature was significantly lower. We
speculated that the low reproducibility was caused by the
evaporation of volatile HCl in batch reactors. SFMT reactor (PFA,
ID = 0.03’’, V = 3.0 mL) was thus employed to prevent the escape
of HCl from the reaction solution. Different from continuous-flow
technology, the reaction time was not constrained by the volume
of the SFMT reactor, which provided a convenient and effective
platform to incorporate volatile reagents for long-term reactions.
Gratifyingly, the transformation indeed became more effective in
SFMT reactors than in batch reactors, delivering complete
conversion with excellent reproducibility with lesser amounts of
cyclohexane (2 vs 10 equiv) and HCl (5 vs 20 mol%) (Scheme 3).
No product was detected in the absence of photocatalyst, HCl, or
light, demonstrating the need for these components.
Scheme 4. Scope of CH substrates. [a] Combined isolated yields. [b]
Diastereoselectivity and regioselectivity, where relevant, were determined by
analysis of crude 1H NMR spectra. [c] CH substrates (5.0 equiv) were used.
It is important to note that this chlorine-based photoredox
protocol represents a rare catalytic system that can functionalize
unactivated primary C(sp3)H bonds (e.g., CH3 in pentane BDE =
100.2 kcal/mol).[16] We then attempted to extend this dual catalyst
system to activate more challenging molecules like methane
(BDE = 104 kcal/mol) and ethane (BDE = 101.1 kcal/mol), which
With a robust alkylation protocol in hand, we explored the
generality of CH substrates under blue LED irradiation in SFMT
o
reactors at 50 C. As shown in Scheme 4, cyclic hydrocarbons
with different ring sizes provided alkylation products 4-8 in good
to excellent yields. Acyclic substrates bearing multiple reactive
sites like pentane could participate in the coupling efficiently,
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has stood as one of the fundamentally intriguing challenges in
organic synthesis.[17] Even though methane turned out to be
problematic, which afforded a complex mixture of unidentified
products, ethane proved to be an effective substrate as coupling
product 24 was selectively generated in excellent yield in SFMT
reactors (PFA, ID = 0.03’’, V = 3.0 mL, 20 bar). Notably, product
24 could not be generated in conventional batch reactors, where
ethane might escape the reaction solution at 50 oC at 1 atm
pressure with a very low concentration remained. The scope of
Michael acceptors was then evaluated by using ethane as the
model CH partner (Scheme 5). A variety of electron-poor (25-30)
and electron-rich (31-33) arenes on the methylene-malononitriles
were well tolerated, bearing functional groups such as nitrile (25),
trifluoromethyl (26), acid (27), halides (28-30), and phthalimide
(33). Naphthalene (34) and heterocycles such as benzothiazole
(35) were readily accommodated. The substrate with an alkyl
instead of an aryl substituent on the methylene-malononitrile
participated efficiently in the coupling reaction (36). The change
of nitrile to ester groups in malononitrile moiety was feasible (37
and 38). However, the alkylation proceeded effectively only with
strong Michael acceptors (bearing two electron-withdrawing
groups). Reactions with other alkenes such as unsaturated
ketones or esters gave sluggish reactivity, probably because that
the radical adducts formed were not oxidizing enough to turn over
the photoredox catalytic cycle (Scheme S1).[14a]
carbonitriles (39), which are important synthons for constructing
complex bioactive heterocycles.[18] Methylphenidate 40, used in
the treatment of attention deficit hyperactivity disorder (ADHD)
and narcolepsy, could be easily produced from 20.[19] Indobufen,
a platelet aggregation inhibitor, was synthesized in three steps
from ethane alkylation product 29.[20] The cyclohexane alkylation
products (4 and 3) could be directly transformed into cetiedil, a
vasodilatator substance with reported anticholinergic properties,
and its most potent analogue MR 16728, respectively.[21]
Scheme 5. Scope of electron-deficient olefins. [a] Isolated yields.
Scheme 6. Synthetic applications of alkylation products. [a] TFA (0.5 M), 0 o
C
Synthetic applicability of this methodology was illustrated
through the gram-scale alkylation reaction, which was easily
achieved using a single SFMT reactor (PFA, ID = 0.062’’, V = 27.2
mL), even with gas/liquid biphasic reactions (Scheme 6a).
Furthermore, the developed alkylation could also be scaled-up by
converting SFMT reactors to continuous-flow micro-tubing
reactors (Scheme 6b). This method represents a practical
protocol for metal- and additive-free intermolecular alkylation of
unactivated CH bonds under visible-light mediation.
to r.t., 1 h. [b] 1) MeOH (10.0 equiv), Cs2CO3 (2 equiv), O2, in MeCN, 50 oC, 12
h; 2) HCl (6 M), H2O, reflux, 24 h; 3) MeOH/SOCl2 (4:1), reflux, 12 h. [c] 1) MeOH
(10.0 equiv), Cs2CO3 (2 equiv), O2, in MeCN, 50 oC, 12 h; 2) 1-Isoindolinone
(1.5 equiv), Pd2(dba)3 (5 mol%), Xantphos (12 mol%), Cs2CO3 (1.5 equiv),
dioxane, 120 oC, 12 h; 3) LiOH (3.0 equiv), THF/H2O, 12 h. [d] 2-(Azepan-1-
yl)ethanol (2 equiv), Cs2CO3 (2 equiv), O2, in MeCN, 50 oC, 24 h. [e] 3-(Azepan-
1-yl)propan-1-amine (2 equiv), Cs2CO3 (2 equiv), O2, in MeCN, 50 oC, 24 h.
The synthetic value of this chlorine radical-based photo
C(sp3)H alkylation strategy was further illustrated in the facile
synthesis of several biologically active compounds (Scheme 6c).
The aldehyde alkylation product (22) could undergo an acid-
triggered cyclization to generate fully substituted 2-aminofuran-3-
The synthetic utility of this photo-mediated chlorine radical-
based HAT process can be extended beyond alkylation of
unactivated C(sp3)H bonds. Our preliminary results illustrated
that the CH activation protocol could be extended to allylation
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using allyl phenyl sulfones as allyl sources to generate allylated
transient radical I will undergo a radical substitution with 44 to
deliver the allylation product. The benzenesulfinyl radical IV acts
as an oxidant to regenerate the MesAcr+ catalyst.[24]
products 45 to 52 in moderate to good yields (Scheme 7).
In summary, we have accomplished effective and reliable
metal-free CH alkylation and allylation via the synergistic
combination of an acridinium photocatalyst and HCl as the HAT
catalyst precursor assisted by micro-tubing reactors, which were
unreproducible or even inaccessible in conventional batch
reactors. The alkylation accommodated a broad range of CH
patterns, even with unactivated primary C(sp3)H bonds (e.g.,
ethane), and was metal- and additive-free, and amenable to large-
scale synthesis. The synthetic utility was highlighted by the rapid
access to several pharmaceutical drug molecules using abundant
alkanes in an atom- and step-economic fashion.
Scheme 7. Unactivated C(sp3)H allylation via the merger of photoredox and
HCl catalysts. [a] Isolated yields.
Acknowledgements
We are grateful for the financial support provided by the National
University of Singapore and the Ministry of Education (MOE) of
Singapore (R-143-000-665-114, R-143-000-696-114, R-143-000-
A30-112), GSK-EDB (R-143-000-687-592), and A*STAR
RIE2020 AME (R-143-000-690-305).
Keywords: hydrogen chloride • photocatalysis • stop-flow micro-
tubing reactor • CH functionalization • hydrogen atom transfer
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catalyst to reset the catalytic cycle.[14a] Protonation of intermediate
III produces the alkylation product. In the allylation process, the
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Entry for the Table of Contents (Please choose one layout)
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Hong-Ping Deng, Quan Zhou, and Jie
Wu*
Page No. – Page No.
Micro-Tubing Reactor-Assisted
Aliphatic CH Functionalization
Utilizing HCl as the Hydrogen Atom
Transfer Catalyst Precursor in
Conjunction with an Organo
Photoredox Catalyst
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