α-Arylation of aryl ketones: Expanding the scope of the Truce-Smiles rearrangement

Article abstract of DOI:10.1055/s-0028-1083523

The Truce-Smiles rearrangement has been applied to the synthesis of substituted a-aryl aryl ketones and the synthetic utility of the products has been demonstrated by the conversion of one of them to the substituted indole 2-(1H-indol-2-yl)phenol.

Full text of DOI:10.1055/s-0028-1083523

LETTER
2689
a-Arylation of Aryl Ketones: Expanding the Scope of the Truce–Smiles
Rearrangement
Expanding the
T
i
ruce–S
m
miles
R
earrangeme
o
nt thy J. Snape*,1
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
E-mail: TJSnape@uclan.ac.uk
Received 4 July 2008
we outline our initial results in this area and demonstrate
Abstract: The Truce–Smiles rearrangement has been applied to the
the potential synthetic utility of the products with the syn-
thesis of 2-(1H-indol-2-yl)phenol.
Our preliminary results are shown in Table 1,8 which
synthesis of substituted a-aryl aryl ketones and the synthetic utility
of the products has been demonstrated by the conversion of one of
them to the substituted indole 2-(1H-indol-2-yl)phenol.
Key words: arylation, ketone, rearrangement, indole, Truce– summarises the generality of the rearrangement and high-
Smiles
lights the extremely mild conditions used to prepare the a-
arylated products directly from commercially available
material. The reactions were performed using equimolar
amounts of both the phenol derivative 1 and the 1-fluoro-
2-nitrobenzene derivative 2 along with potassium carbon-
ate (2.5 equiv) in dimethyl sulfoxide at room temperature.
a-Arylated ketones are structural features of a large num-
ber of biologically interesting molecules,2 however, the
synthesis of such compounds is synthetically challeng-
ing.3 Equally, the indole framework is considered to be a
privileged structure in drug discovery and developing
novel routes to such compounds will help with their con-
tinued exploitation in medicinal chemistry.4 These re-
quirements inspired us to consider whether the Truce–
Smiles rearrangement could be developed to meet these
needs.
Recently, Mitchell5 and Erickson6 discovered, unexpect-
edly, that certain diaryl ethers spontaneously rearrange via
the Truce–Smiles rearrangement (see Scheme 1, X = O),
under defined experimental conditions, to generate the
isomeric a-arylated products.5,6
The unoptimised reactions proceed in good yield
(Table 1, entries 1–5). Whilst the reason for the poor yield
of 10 (entry 6) is unclear, it is believed that optimum con-
ditions for individual rearrangements are substrate depen-
dent.5 This is further evidenced by entry 7, where in this
case the low yield is thought to be due to the difficulty in
generating, in situ, the corresponding enolate of diaryl
ether 3 (R1 = OMe, R2–R5 = H) as the result of the elec-
tronic effects of the p-methoxy group;9 exposure to our
standard reaction conditions yielded the unrearranged
SNAr diaryl ether product 14 in 65% yield (Scheme 2).
NO2
XH
X
1
4
OH
O
F
K2CO3
DMSO, r.t.
O
O
NO2
4
–
+
1
+ 11
R
R
< 10%
MeO
MeO
Scheme 1 An example of the Truce–Smiles rearrangement
12
13
14 65%
Scheme 2
With the exception of these two examples, there have
been very few instances where the Truce–Smiles rear-
rangement has been applied to provide a general and flex-
ible route to functionalised a-arylated carbonyl
compounds, especially those which are suitably function-
alised to be synthetically useful.7 By exploiting this dearth
of examples, we hoped to develop the Truce–Smiles rear-
rangement into a synthetically useful reaction and thus we
set out to answer two questions: a) does Scheme 1 depict
a general process which is applicable to more substituted
diaryl ethers; and b) if so, can the products possess suit-
ably functionality so as to be subsequently manipulated
into other useful building blocks and structures? Herein
We were able to demonstrate that the reaction does in fact
proceed via the Truce–Smiles rearrangement as depicted
in Table 1 and not by a direct intermolecular arylation of
the ketone enolate, since the corresponding reaction of ac-
etophenone (15) with 1-fluoro-2-nitrobenzene (13) recov-
ered unreacted starting material only (Scheme 3).
O
F
K2CO3
DMSO, r.t.
NO2
no reaction
+
15
13
SYNLETT 2008, No. 17, pp 2689–2691
Advanced online publication: 01.10.2008
x
x
.x
x
.2
0
0
8
Scheme 3
DOI: 10.1055/s-0028-1083523; Art ID: D25308ST
© Georg Thieme Verlag Stuttgart · New York

2690
T. J. Snape
LETTER
Table 1 Expanding the Truce–Smiles Rearrangementa
R4
R5
R4
NO2
O
OH
O
F
R5
R3
NO2
OH
R2
O
Truce–
Smiles
K2CO3
O
+
rearrangement
DMSO, r.t.
R1
R4
–
NO2
R3
R1
R2
R5
R3
R1
2
1
R2
4
3
Entry
Product
R1
R2
H
H
Br
H
H
H
H
R3
H
R4
H
R5
Isolated yield (%)
1
2
3
4
5
6
7
5
6
H
H
H
H
65
74
H
Me
Me
Me
H
H
7
H
H
65
8
H
H
CO2Me
NO2
H
52
9
H
H
73
10
11
H
Me
H
Br
H
24
OMe
H
<10b
a Reagents and conditions: 1 (1 equiv), 2 (1 equiv), K2CO3 (2.5 equiv), DMSO (0.1 M), r.t.
b The diaryl ether 3 was isolated in 65% yield.
Similarly, the proposed intermediate diaryl ether 17 was mild conditions and the utility of these compounds was
prepared (Scheme 4) and was found to smoothly rear- demonstrated with the conversion of 5 into 2-(1H-indol-2-
range to the a-aryl compound 6 in 93% yield.
yl)phenol (18).
Having established conditions for the successful synthesis Developing an asymmetric variant as well as applying the
of substituted a-aryl aryl ketones 5–10 (Table 1) via the reaction to biologically active compounds is currently un-
Truce–Smiles rearrangement, we were able to show that der way and will be reported in due course.
these products also provide a short synthesis to substituted
indoles in good yield (Scheme 5).10
Acknowledgment
In summary, the scope of the Truce–Smiles rearrange-
ment has been extended to allow synthetically useful sub-
stituted a-arylated aryl ketones to be prepared under very
TJS would like to thank the Centre of Excellence for Biocatalysis,
Biotransformations and Biocatalytic Manufacture (CoEBio3) for
funding and Professor Nick Turner for continued support.
F
i) K2CO3
HO
NO2
References and Notes
O
O
DMSO, r.t., 85%
+
ii) PTSA
acetone, H2O
50 °C, 98%
(1) New Address: T. J. Snape, School of Pharmacy, Maudland
Building, University of Central Lancashire, Preston, PR1
2HE, UK.
13
16
(2) Millard, A.; Rathke, M. J. Am. Chem. Soc. 1977, 99, 4833.
(3) Bella, M.; Kobbelgaard, S.; Jørgensen, K. J. Am. Chem. Soc.
2005, 127, 3670.
(4) Horton, D.; Bourne, G.; Smythe, M. Chem. Rev. 2003, 103,
893.
NO2
O
K2CO3
DMSO, r.t.
O
6
93%
(5) Mitchell, L.; Barvian, N. Tetrahedron Lett. 2004, 45, 5669.
(6) Erickson, W.; McKennon, M. Tetrahedron Lett. 2000, 41,
4541.
(7) Snape, T. Chem. Soc. Rev. 2008, in press; DOI:10.1039/
B808960D.
17
Scheme 4 Proving the two-step mechanism
(8) Representative Example – Synthesis of 5
2¢-Hydroxyacetophenone (0.5 g, 3.67 mmol), and 1-fluoro-
2-nitrobenzene (0.39 mL, 3.67 mmol) were dissolved in
DMSO (37 mL). Potassium carbonate (1.27 g, 9.18 mmol)
was added and the reaction stirred at r.t. for 17 h. Upon
consumption of the starting material (TLC) H2O (30 mL)
was added and the mixture acidified with 1 M HCl (to pH ca. 3).
O2N
O
OH HN
OH
Pd/C, H2
MeOH
72%
5
18
Scheme 5 Indole synthesis
Synlett 2008, No. 17, 2689–2691 © Thieme Stuttgart · New York

LETTER
The product was extracted with EtOAc (2 × 30 mL) and the
Expanding the Truce–Smiles Rearrangement
2691
0.41 mmol) was dissolved in MeOH (4.1 mL). Then,
combined organic layers were washed with H2O (2 × 30 mL)
and brine (30 mL), dried (MgSO4), and the solvent removed
in vacuo. The crude product was purified by column
chromatography on silica gel (3% EtOAc in toluene) to give
the title compound as a yellow solid (614 mg, 65%). Rf =
0.18 (10% EtOAc in PE); mp 111–113 °C (EtOAc–toluene).
IR: nmax = 3070 (br OH), 1644 (C=O) cm–1. 1H NMR (300
MHz, CDCl3): d = 11.84 (1 H, s, OH), 8.18 (1 H, dd, J = 1.6,
10.8 Hz, Ar), 7.91 (1 H, dd, J = 2.2, 10.6 Hz, Ar), 7.64 (1 H,
td, J = 1.6, 10.0 Hz, Ar), 7.52 (2 H, td, J = 2.0, 10.0 Hz, Ar),
7.32 (1 H, dd, J = 1.6, 10.0 Hz, Ar), 7.02–6.94 (2 H, m, Ar),
4.79 (2 H, s, CH2). 13C NMR (75 MHz, CDCl3): d = 201.2,
162.5, 148.9, 140.4 (C), 136.7, 133.7, 133.6, 129.7, 128.7,
125.3, 119.1 (CH), 119.0 (C), 118.7 (CH), 43.7 CH2). MS
(ES+): m/z (%) = 258 (50) [M + H]+. HRMS: m/z calcd for
C14H12NO4 [M+H+]: 258.0766; found: 258.0786.
Pd/C (10 mg, 10 wt%) was added, and the flask evacuated
and backfilled with hydrogen (3 cycles). The reaction was
then stirred under an atmosphere of hydrogen for 18 h. The
reaction was filtered through Celite and eluted with MeOH
(10 mL) and the solvent removed in vacuo. The crude
product was purified by column chromatography on silica
gel (10% EtOAc in PE) to give the title compound as a pale
yellow solid (62 mg, 72%). Rf = 0.39 (30% EtOAc in PE);
mp 170–172 °C (EtOAc–PE). IR: nmax 3500 (OH), 3425
(NH) cm–1. 1H NMR (300 MHz, CDCl3): d = 9.22 (1 H, br
s), 7.70 (1 H, dd, J = 1.6, 7.8 Hz, Ar), 7.66 (1 H, d, J = 7.8
Hz, Ar), 7.42 (1 H, d, J = 8.1 Hz, Ar), 7.26–7.11 (3 H, m,
Ar), 7.04 (1 H, td, J = 1.1, 7.6 Hz, Ar), 6.91 (1 H, dd, J = 0.9,
8.1 Hz, Ar), 6.87 (1 H, m, Ar), 6.00–5.00 (1 H, br s).
13C NMR (75 MHz, CDCl3): d = 152.0, 136.4, 134.8 (C),
128.9 (CH), 128.4 (C), 128.3, 122.2, 121.5, 120.4, 120.1
(CH), 119.1 (C), 116.6, 111.0, 100.2 (CH). MS (ES+): m/z
(%) = 210 [M + H]+. HRMS: m/z calcd for C14H12NO [M +
H+]: 210.0919; found: 210.0920.
(9) Bordwell, F.; Cornforth, F. J. Org. Chem. 1978, 43, 1763.
(10) Synthesis of 18
1-(2-Hydroxyphenyl)-2-(2-nitrophenyl)ethanone (5, 105 mg,
Synlett 2008, No. 17, 2689–2691 © Thieme Stuttgart · New York

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