Iridium catalyzed alkylation of 2′-hydroxyacetophenone with alcohols under thermal or microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2017.10.024

2′-Hydroxyacetophenone was alkylated with a range of substituted benzyl and heteroaryl alcohols to afford the corresponding C-alkylated products in good yields under microwave irradiation. The C-alkylated products were reacted with bromoacetonitrile to afford 2-amino-3-benzyl 1,4-naphthoquinone derivatives in moderate yields.

Full text of DOI:10.1016/j.tetlet.2017.10.024

Tetrahedron Letters 58 (2017) 4400–4402
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iridium catalyzed alkylation of 20-hydroxyacetophenone with alcohols
under thermal or microwave conditions
⇑
Jamie Hunter, Scott Rice, Robert Lowe, Christopher M. Pask, Stuart Warriner, Visuvanathar Sridharan
School of Chemistry, University of Leeds, LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
20-Hydroxyacetophenone was alkylated with a range of substituted benzyl and heteroaryl alcohols to
afford the corresponding C-alkylated products in good yields under microwave irradiation. The C-alky-
lated products were reacted with bromoacetonitrile to afford 2-amino-3-benzyl 1,4-naphthoquinone
derivatives in moderate yields.
Article history:
Received 20 September 2017
Revised 4 October 2017
Accepted 9 October 2017
Available online 13 October 2017
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Iridium
Alkylation
Catalysis
Microwave
Amino naphthoquinone
20-Hydroxyphenyl ketones are important structural motifs
which possess a wide range of applications, including as anti-oxi-
dants,1 flavors and fragrances2 (Fig. 1).
sponding 2-amino 3-benzyl 1,4-naphthoquinone derivatives
(Scheme 2b) under microwave irradiation.
Previously, we identified the iridium chloro-bridged compound
1 [X = Cl, M = Ir (III)] as an effective catalyst for the alkylation of
ketones with alcohols (Fig. 2).9
Metal catalyzed reactions can often be accelerated by micro-
wave irradiation.10 Optimization showed that the reaction could
be carried out under microwave conditions (300 W) with the use
of KOH as the base (Scheme 2a). The use of catalytic KOH (20
mol%) failed to give the C-alkylated product, due to the presence
of the phenolic OH group.5,9
Conventional methods for the alkylation of ketones typically
utilise toxic/corrosive alkyl halides; this can be overcome by the
use of alcohols as alkylating agents in combination with an appro-
priate metal catalyst. These latter processes are essentially atom
economical with water formed as the only by-product.3 The
a-
alkylation of ketones with alcohols has been achieved using hydro-
gen borrowing methodology under ruthenium,4 iridium,5 palla-
dium,6 and other transition metal catalysts.7
These metal ions usually require ligands such as phosphines, N-
heterocyclic carbenes, and N-donors to stabilize the metal ion.
Recently Donohoe and co-workers reported an iridium catalyzed
Initially, we carried out the alkylation reaction of 20-hydroxy-
acetophenone (1 mmol) with para-methoxybenzyl alcohol (1.1
mmol), KOH (1.2 mmol), and [Cp*IrCl2]2 (2.5 mol%) in tert-amyl
alcohol (5 mL) at 120 °C for 2 h under microwave irradiation,
which cleanly afforded the corresponding C-alkylated product 2
in 75% yield (Table 1, entry 1).
redox-neutral reaction to afford
a-branched ketones with higher
alcohols. However the above reaction was restricted to either
ortho-disubstituted phenyl or cyclopropyl ketones.8
Previously, we reported the iridium catalyzed chemoselective
alkylation of 20-aminoacetophenone with alcohols to form either
CAC or CAN bonds under microwave irradiation (Scheme 1).9
Herein, we report (i) an iridium catalyzed alkylation of 20-
hydroxyacetophenone with alcohols to form a new CAC bond
under microwave irradiation (Scheme 2a) and (ii) treatment of
the alkylated products with bromoacetonitrile to afford the corre-
In the above process the dialkylated product was not detected.
No reaction took place in the presence of KOH alone, indicating
that the combination of the iridium complex and a base was nec-
essary for the reaction. To the best of our knowledge this repre-
sents the first reported example of CAC bond formation using 20-
hydroxyacetophenone (a potential chelator for Ir) with an alcohol.
Benzyl alcohols substituted with electron-withdrawing or
donating groups were readily alkylated to afford the corresponding
C-alkylated products 3–9 in good yields (40–90%; Entries 2–8).
Thermal reactions were also carried out at 110 °C for 24 h, which
⇑
Corresponding author.
E-mail address: V.Sridharan@leeds.ac.uk (V. Sridharan).
https://doi.org/10.1016/j.tetlet.2017.10.024
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

J. Hunter et al. / Tetrahedron Letters 58 (2017) 4400–4402
4401
Table 1
Iridium catalyzed redox-neutral reactions of 20-hydroxyacetophenone.a
Entry Alcohol
Product
Yield
(%)b,c
1
66 (75)
2
60 (91)
Fig. 1. Selected 20-hydroxyphenyl ketone motif properties.
3
4
5
6
7
40 (50)
82 (96)
51
Scheme 1. Ir Catalysed chemoselective alkylation reactions.
41
90
8
(75)
58
9
10
31
Scheme 2. Examined Ir catalyzed redox-neutral processes.
a
Reagents and conditions: 20-Hydroxyacetophenone (1 mmol), alcohol (1.1
mmol), [IrCp*Cl2]2 (2.5 mol%), KOH (1.2 mmol), tert-amyl alcohol (5 mL), 120 °C,
120 min, microwave irradiation.
b
Isolated yield.
c
Yields in brackets refers to isolated yields under thermal conditions. Reagents
and conditions: 20-hydroxyacetophenone (1 mmol), KOH (1.2 mmol), [IrCp*Cl2]2
(2.5 mol%), tert-amyl alcohol (5 mL), 110 °C, 24 h.
tube under microwave irradiation at 60 °C for 1 h, then for 2 h at
140 °C to afford naphthoquinone derivative 12a (path a) in 47%
yield as an orange solid (Scheme 3). In the above reaction none
of the benzofuran derivative (path B) was observed. The structure
of naphthoquinone derivative 12a was confirmed by single crystal
X-ray diffraction (Fig. 3).11
Fig. 2. Examined catalysts.
afforded the C-alkylated products in slightly better yields (50–96%;
Entries 1–4).
Next the ketone component was varied. Thus, the reaction of 20-
hydroxy-60-methoxyacetophenone (1 mmol) with benzylalcohol
(1.1 mmol), KOH (1.2 mmol), and [Cp*IrCl2]2 (2.5 mol%) in tert-
amyl alcohol (5 mL) at 110 °C for 24 h, afforded the corresponding
C-alkylated product in 58% yield (Entry 9). The use of 2-phenyl
ethyl alcohol in the above reaction resulted in a low yield (31%;
Entry 10).
Next we briefly studied the reaction illustrated in Scheme 2b.
The initial reaction was performed using 1-(2-hydroxyphenyl)-3-
(4-bromophenyl) propan-1-one 5 (1 mmol), 2-bromoacetonitrile
(2 mmol), and Cs2CO3 (4 mmol) in 1,4-dioxane (5 mL) in a sealed
Scheme 3. Synthesis of naphthoquinone derivatives. Reagents and conditions:
Cs2CO3 (4.0 eq.), bromoacetonitrile (2.0 eq.), microwave irradiation, 60 °C, 1 h, then
2 h, 140 °C.

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J. Hunter et al. / Tetrahedron Letters 58 (2017) 4400–4402
At this stage it must be emphasized that the proposed mecha-
nism (Scheme 4) for naphthoquinone derivative formation is tenta-
tive and the subject of ongoing research. Thus in the presence of
cesium carbonate, compound A is in equilibrium with enolate B,
which undergoes nucleophilic addition to give compound C. Com-
pound C is in equilibrium with enolate D, which then undergoes a
thermal 6p electron pericyclization reaction to afford intermediate
F. Finally intermediate F undergoes aromatization followed by oxi-
dation in air to give the 2-amino-3-benzyl 1,4-naphthoquinone.
In summary, we have successfully carried out the iridium cat-
alyzed alkylation of 20-hydroxyacetophenone with a range of sub-
stituted benzyl and heteroaryl alcohols under microwave
irradiation to afford the corresponding C-alkylated products in
good yields. The C-alkylated products were further reacted with
bromoacetonitrile to afford 2-amino-3-benzyl 1,4-naphthoquinone
derivatives in moderate yields.
Fig. 3. Molecular structure of compound 12a.
Acknowledgments
We thank Leeds University for support.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.10.024.
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