One-Pot Photomediated Giese Reaction/Friedel-Crafts Hydroxyalkylation/Oxidative Aromatization to Access Naphthalene Derivatives from Toluenes and Enones

Article abstract of DOI:10.1021/acscatal.8b00481

Value-added chemicals, γ-aryl ketones and naphthalenes, were conveniently synthesized from readily available toluenes and enones through the synergistic combination of photoredox and Lewis acid catalysis. The direct synthesis of γ-aryl ketones represents a rare example of Giese reactions between benzylic C(sp³)-H and enones that avoids the use of prefunctionalized metallic nucleophiles. Naphthalene derivatives were accessed through a one-pot Giese reaction/Friedel-Crafts hydroxyalkylation/oxidative aromatization sequential transformation.

Full text of DOI:10.1021/acscatal.8b00481

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Article
One-Pot Photo-Mediated Giese Reaction/Friedel-Crafts
Hydroxyalkylation/Oxidative Aromatization to Access
Naphthalene Derivatives from Toluenes and Enones
Haiwang Liu, Lishuang Ma, Rong Zhou, Xuebo Chen, Weihai Fang, and Jie Wu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00481 • Publication Date (Web): 29 May 2018
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One-Pot Photo-Mediated Giese Reaction/Friedel-Crafts
Hydroxyalkylation/Oxidative Aromatization to Access
Naphthalene Derivatives from Toluenes and Enones
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Haiwang Liu,† Lishuang Ma,‡ Rong Zhou,†,§ Xuebo Chen‡*, Weihai Fang,‡ and Jie Wu†*
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543,
Republic of Singapore
‡College of Chemistry, Beijing Normal University, Beijing, 100875, People’s Republic of China
§College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan,
030024, People’s Republic of China
Corresponding email for Jie Wu: chmjie@nus.edu.sg
Corresponding email for Xuebo Chen: xuebochen@bnu.edu.cn
ABSTRACT: Valueꢀadded chemicals,
synthesized from readily available toluenes and enones through the synergistic combination of
photoredox and Lewis acid catalysis. The direct synthesis of ꢀaryl ketones represents a rare
γꢀaryl ketones and naphthalenes, were conveniently
γ
example of Giese reactions between benzylic C(sp3)−H and enones that avoids the use of
prefunctionalized metallic nucleophiles. Naphthalene derivatives were accessed through a oneꢀ
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pot Giese reaction/FriedelꢀCrafts hydroxyalkylation/oxidative aromatization sequential
transformation.
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KEYWORDS: C−H activation; photocatalysis; Lewis acid catalysis; γꢀaryl ketone; naphthalene
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Introduction
Naphthalenes are important and ubiquitous structural motifs in many important
pharmaceutical drugs (Scheme 1), and have also received much attention in material science.1
However, most of the naphthalene building blocks for complex molecule synthesis were
introduced by preꢀfunctionalized naphthalene moieties (e.g. halogenated naphthalene,
naphthalenol, etc). Synthetic methodologies towards the preparation of naphthalene scaffolds
from readily available and inexpensive chemical feedstocks have been less explored and are
highly desirable. Current strategies for the synthesis of naphthalene derivatives are mainly
limited to annulation or cycloaddition of benzene derivatives.2
Scheme 1. Drugs Containing the Naphthalene Core
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Visibleꢀlightꢀmediated photoredox catalysis has attracted increasing attention over the past
decade because of its unique reactivity patterns, high efficiency, and mild reaction conditions.3
Our group has recently disclosed a direct benzylic C(sp3)−H alkylation using only acridinium
organoꢀcatalyst 1 under visibleꢀlight mediation via a radical cation deprotonation pathway
without using any base additive (Scheme 2).4 However, an efficient transformation requires the
use of very strong Michael acceptor methyleneꢀmalononitriles, to generate a radical adduct that
is oxidative enough to oxidize the reduced photoredox catalyst 1’ to regenerate catalyst 1. Mild
electronꢀdeficient alkenes such as unsaturated ketones, that deliver important synthetic building
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blocks, γꢀaryl ketones, gave sluggish reactivity in the presence of only photocatalyst 1 (less than
2% conversion after 24 hours, Table 1, entry 1). Conventional methods for the benzylic
conjugate addition to unsaturated ketones involve the use of various benzyl metallic species,
which will introduce undesired byꢀproducts as waste. The catalytic activation of benzylic
C(sp3)−H bonds as latent nucleophilic handles thus represents a green and sustainable process.
However, efficient conjugate additions of benzylic C(sp3)−H to electron deficient alkenes via
benzyl radical intermediates, falling into Giese reactions,5 are normally limited to strong
electronꢀdeficient alkenes (bearing two electronꢀwithdrawing substituents).6 To the best of our
knowledge, there is only a single report on the addition of tolueneꢀtype compounds to enones via
a radical process, which proceeded with poor reactivity (27% yield, 87% conversion).6c We
envisioned that adding a Lewis acid catalyst might significantly enhance the electrophilicity of
the unsaturated ketone for an efficient radical addition,7 and also increase the oxidative ability of
the radical adduct to turn over the catalytic cycle. We herein disclosed an efficient synthesis of
γ
ꢀaryl ketones from benzylic C(sp3)−H and unsaturated ketones through the synergistic
combination of photoredox and Lewis acid catalysis,3d,8 which can further undergo FriedelꢀCrafts
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hydroxyalkylation and oxidative aromatization to access useful naphthalene derivatives in a oneꢀ
pot fashion (Scheme 2). The addition of Lewis acid catalyst was essential in enone activation to
achieve an efficient Giese reaction as well as to promote the subsequent FriedelꢀCrafts
hydroxyalkylation.
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Scheme 2. Benzylic Conjugate Addition
Results and Discussion
pꢀXylene 2 and benzylideneacetone 3 were chosen as model substrates to investigate the
effectiveness of a variety of Lewis acid catalysts (20 mol%) on the Giese reaction in the presence
of photocatalyst 1 (Table 1). Some common Lewis acids including AlCl3, BF3·OEt2, SnCl4, CuI,
and CuI2 were ineffective (entries 2 to 6). Gratifyingly, the use of cationic transitionꢀmetal
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triflates (entries 7 to 10) produced desired product 4 at ambient conditions, among which,
Cu(OTf)2 was dramatically effective, giving 4 in 77% isolated yield (entry 10). The catalyst
loading of Cu(OTf)2 can be decreased to 10 mol% with similar efficiency (entry 11). However,
further reducing catalyst loading to 5 mol% resulted in decreased conversion (entry 12).
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Table 1. Evaluation of Various Lewis Acid Catalysts
Adopting the optimal conditions (Table 1, entry 11), we sought to evaluate the generality of
enone substrates for benzylic conjugate addition using pꢀxylene as the benzylic substrate
(Scheme 3). Experiments probing the scope of benzylideneacetone revealed that substrates
possessing either electronꢀrich (5-7) or electronꢀdeficient arenes (8-14) proceeded well to afford
1,4ꢀaddition products in moderate to good yields. Functional groups such as acetate (7), halogen
(8-11), trifluoromethyl (12), cyanide (13), ester (14), and boronate ester (15) were well tolerated.
The βꢀalkylated enone participated in the Giese reaction to afford product 16 in moderate yield.
Moreover, simple vinyl ketones such as methyl and ethyl vinyl ketones could be employed to
obtain the benzylic addition products 17 and 18. Trisubstituted benzylideneacetones were readily
accommodated to deliver the desired products (19 and 20). The change of methyl ketone to
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sterically demanding tertꢀbutyl ketone was feasible (21). Chalconeꢀtype substrates could also
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participate efficiently in this coupling (22-30). Notably, when employing enone bearing a
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substituted pyridine moiety, both and ꢀaddition products (24 and 25) were isolated in similar
β
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yields. Importantly, aryl ketone substrates with an additional Lewis basic atom that can bind to
the Lewis acid catalyst more effectively as bidentate substrates, such as phenol (27), furan (28),
thiofuran (29) and imidazole (30), were suitable candidates. This provides an opportunity to
develop a chiral Lewis acid catalyst system using chiral ligand to achieve an asymmetric
conjugate addition starting with readily available benzylic C(sp3)−H bonds, considering that the
racemic transformation is diminished in the absence of the Lewis acid catalyst.8,9 The 2ꢀoxoester
substrate which could be another type of bidentate substrates for Lewis acid, proceeded well to
afford product 31 in good yield. Furthermore, the coupling reactions proceeded quite efficiently
with various cyclic enones bearing different ring sizes (32 to 34). In addition to enones,
unsaturated esters such as ethyl acrylate could be employed in this protocol to deliver the
benzylic conjugate addition product 35 in moderate yield.
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Me
O
Cu(OTf)2 (10 mol%)
R2
Me
R2
1 (1.25 mol%)
R1
+
R3
O
R1
Me
DCE, RT, 24 to 40 h, Blue LED
Me
(1 mmol)
R3
(0.2 mmol)
Me
Me
Me
9
O
O
O
O
O
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Me
Me
Me
Me
Ph
Me
4
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50%
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53%
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51%
Me
Me
tBu
Me
AcO
Me
78%
Me
O
O
O
Me
Me
Me
F
Cl
Br
F
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9
10
70%
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80%
72 %
63%
Me
Me
Me
Me
O
O
O
O
Me
Me
Me
Me
F3C
NC
Me
Me
MeOOC
PinB
Me
12
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72%
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77%
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66%
75%
Me
Me
Et
O
O
Me
Me
O
O
Me
Me
16
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44%
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43%
19
52% (d.r. = 1:1)d
47%
Me
Me
Me
O
O
O
O
Me
Ph
tBu
Ph
MeO
Me
21
43%
22
70%
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62%
20
Br
41% (d.r. = 1:1)d
Me
Me
O
N
Ph
O
O
O
OH
N
Ph
Me
Br
27b
61%
24
25
38%
26
65%
39%
Me
Me
Me
Me
O
O
O
O
O
OEt
N
S
N
O
30c
58%
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29
58%
31
73%
57%
O
O
O
O
Et
Me
O
Me
Me
Me
32
77%
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85%
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74%
35
53%
aIsolated yields, diastereoselectivity based on the analysis of 1H NMR spectra of the crude reaction
mixture. bReaction conducted at 80 oC. cReaction conducted at 60 oC. dDiastereomeric ratios were
determined by analysis of 1H NMR spectra of the crude mixture.
Scheme 3. Scope of Enones for the Benzylic Conjugate Additiona
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The scope of benzylic substrates for the Giese reaction was subsequently explored. As shown
in Scheme 4, all electronꢀneutral (36), electronꢀrich (37-40), and electronꢀpoor (41 and 42)
toluene moieties underwent effective coupling in the presence of the dual catalysts under blue
LED irradiation. The steric orthoꢀmethyl substituent did not hinder the reaction process (38).
Incorporation of a boronate ester (43) or a pyridine (44) substituent on toluene was also feasible.
In addition to toluene, ethylbenzene and indane were all suitable candidates and the reactions
proceeded smoothly to deliver the desired products in good yields (45 and 46). This photoredox
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induced coupling represents a rare case of effective Giese reactions between benzylic C(sp3)
−H
bonds and enone substrates.
Scheme 4. Scope of Benzylic C−H Partners for the Giese Reactiona
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In the midst of Giese reaction optimization, naphthalene 47 was detected when reaction
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temperature was elevated to 70 C. We proposed that this compound may be derived from
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Cu(OTf)2ꢀcatalyzed FriedelꢀCrafts hydroxyalkylation of coupling product 4 followed by
oxidative aromatization. The cascade transformation was thus investigated attempting to access
naphthalene products in high yields. Pleasingly, naphthalene 47 was cleanly generated from
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o
methyl ketone 4 in the presence of a catalytic amount of Cu(OTf)2 at 100 C under O2
o
atmosphere (Table 2, entry 1). At 70 C the conversion was significantly lower (entry 2). No
reaction occurred without Lewis acid catalyst Cu(OTf)2 (entry 3). O2 was essential for this
transformation, as a significant amount of tetralin byꢀproduct 48 was generated in the absence of
O2 (entry 4). Previous reports have demonstrated that the FriedelꢀCrafts hydroxyalkylation
product 1,2ꢀdihydronaphthalene would undergo disproportionation to produce tetraline and
naphthalene at elevated temperature in the absence of external oxidants.10 Other oxidant such as
K2S2O8 was inferior to O2 which resulted in lower yield of naphthalene 47 together with a small
amount of byꢀproduct 48 (entry 5).
Table 2. Evaluation of Lewis Acid-Promoted Friedel-Crafts Hydroxyalkylation/Oxidative
Aromatization Cascade
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With both optimized conditions for the Giese reaction and cascade FriedelꢀCrafts
hydroxyalkylation/oxidative aromatization in hand, we then attempted the oneꢀpot generation of
naphthalene compounds directly from readily available toluenes and enones (Scheme 5). We
were pleased to isolate the desired naphthalene 47 in 58% yield in a oneꢀpot process using pꢀ
xylene 2 and benzylideneacetone 3 as the starting compounds. The impact of substitution on the
enone was evaluated with various aryl rings with para, meta, or ortho substituents (49-51),
exhibiting electronꢀwithdrawing (49-55) or electronꢀdonating properties (56), which were well
tolerated to deliver the naphthalenes in good yields. The alkyl substituted enone could participate
well in the oneꢀpot naphthalene synthesis (57). Introduction of additional alkyl or aryl substituent
on the alkene moiety of enones yielded naphthalene products in moderate yield (58 and 59).
Chalcones could be applied to this oneꢀport threeꢀstep transformation as well (60). Notably, the
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sequential transformations proceeded smoothly using
α,βꢀunsaturated aldehydes to deliver
naphthalene product 61 in moderate yield. The scope for the toluene moiety was subsequently
investigated. Derivatives with para, meta, or ortho methyl substituents proceeded well (47, 62
and 63). Changing paraꢀderivative to steric demanding tertꢀbutyl group was feasible (64).
Ethylbenzene was also a suitable candidate (65). In summary, this oneꢀpot protocol demonstrated
that selective functionalization of naphthalene at any desired position C1ꢀC8 is possible with the
proper choice of starting toluenes and enones.
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Scheme 5. One-Pot Three-Step Synthesis of Naphthalenesa
Several control experiments were performed to gain further insights of the dual catalystꢀ
promoted Giese reaction.11 First, no alkylation products were detected in the presence of radical
scavenger TEMPO, suggesting that a radical process was involved. Moreover, as indicated by
the luminescence quenching experiments, pꢀxylene could quench the excited state of acridinium
1*, whereas enones gave negligible quenching. The energy barrier for benzylic radical addition
to enones was significantly lower in the presence of Cu(OTf)2 Lewis acid as demonstrated by
DFT calculations (4.0 kcal/mol vs 8.8 kcal/mol, Scheme 6). In addition, the reductive potential
changes drastically upon the formation of Lewis acid adduct. As estimated by DFT calculation,
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radical adducts without Lewis acid (Ered = ꢀ1.18 V vs SCE) and with Cu(OTf)2 Lewis acid (Ered
=
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+0.74 V vs SCE) suggest that only the Lewis acid adduct can oxidize the reduced catalyst 1’
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(Eox = ꢀ0.57 V vs SCE in MeCN). Deuteriumꢀlabelling experiments (Supporting Information,
1/2
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Figure S4) revealed that the proton source could be derived from either the toluene substrate or
active protons in the solvent. The intermolecular competition experiment established that the
magnitude of the kinetic isotopic effect (KIE) given by kH/kD was 2.8 (Supporting Information, Figure
S7), indicating that the deprotonation might be involved in the rateꢀlimiting step. A tentative
mechanistic pathway was proposed in light of all the experimental data (Scheme 7). As
supported by the luminescence study, visibleꢀlight irradiation of the [Acr+ꢀMes]ClO4
photocatalyst 1 to its excited state 1* (Ered*1/2 = +2.06 V vs SCE in MeCN) oxidizes the tolueneꢀ
type substrate to its radical cation I. Then subsequent deprotonation of I delivers radical II,
which is in equilibrium with the more stable benzylic radical III. Nucleophilic addition of radical
III to the Cu(II) Lewis acidꢀactivated enone will furnish Lewis acid alkyl radical adduct IV,
which is capable of oxidizing the reduced form of acridinium catalyst 1’ to regenerate ground
state catalyst 1. Protonation of intermediate V produces the Giese reaction product VI. The
deuteriumꢀlabeling experiments shown that the anion intermediate V would abstract a proton
from the reaction mixture. Upon heating, compound VI can further undergo an intramolecular
FriedelꢀCrafts hydroxyalkylation assisted by Cu(OTf)2 catalyst to afford VIII. The final
oxidative aromatization in the presence of O2 will accomplish the synthesis of naphthalene
product.
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Scheme 6. Calculated Energy Barriers of Radical Addition and Reductive Potentials of
Radical Adducts (a) without Lewis Acid; (b) in the Presence of Cu(OTf)2 Lewis Acid.
Atomic Distances Denoted in Ångström
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Scheme 7. Plausible Mechanism for the One-Pot Synthesis of Naphthalenes
Conclusion
Overall, we have developed a convenient direct synthesis of γꢀaryl ketones and naphthalenes
from readily available toluenes and enones by the synergistic combination of photoredox and
Lewis acidꢀcatalysis, featuring atomꢀ and stepꢀeconomical synthesis. The effective radical
addition represents a rare successful example of Giese reactions between toluenes and enones,
without the need of strong Michael acceptors. The unprecedented oneꢀpot photoꢀinduced Giese
reaction/FriedelꢀCrafts hydroxyalkylation/oxidative aromatization provides an easy method to
access naphthalenes with selective functionalization at any desired position from inexpensive
feedstocks. The Cu(OTf)2 Lewis acid catalyst plays a dual role in this sequential transformation
to enable an efficient Giese reaction and to promote the subsequent FriedelꢀCrafts
hydroxyalkylation.
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Supporting information
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Detailed experimental procedures, characterization data, copies of H NMR and 13C NMR
spectra of final products are reported in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org/.
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Acknowledgements
We are grateful for the financial support provided by the National University of Singapore and
the Ministry of Education (MOE) of Singapore (Rꢀ143ꢀ000ꢀ645ꢀ112, Rꢀ143ꢀ000ꢀ665ꢀ114),
GSKꢀEDB (Rꢀ143ꢀ000ꢀ687ꢀ592), A*STAR AME (Rꢀ143ꢀ000ꢀ690ꢀ305), and National Natural
Science Foundation of China (21702142).
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[11] See the Supporting Information for details on the control experiments, luminescence
quenching studies, CV tests, and DFT calculations.
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Table of Contents Graphic
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