α-Halogenation as a Strategy to Functionalize Cyclohexa-2,4-dienones

Article abstract of DOI:10.1055/s-0036-1588359

A facile pyridine-mediated α-halogenation approach to functionalize cyclohexa-2,4-dienones is developed. A range of reactions, including organometallic coupling protocols, have been applied on these newly obtained halogenated cyclohexa-2,4-dienones, and the results are presented herein.

Full text of DOI:10.1055/s-0036-1588359

SYNLETT
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9
3
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2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
S. K. Chittimalla et al.
Letter
Synlett
α-Halogenation as a Strategy to Functionalize Cyclohexa-2,4-
dienones
Santhosh Kumar Chittimalla*
O
H3CO
H3CO
Manikandan Koodalingam
Vinod Kumar Gadi
Ar
O
O
H3CO
H3CO
H3CO
'halogen source' H3CO
X
R
'Pd'
Prasad Anaspure
Suzuki coupling
pyridine, CH2Cl2
r.t. or reflux
O
Ph
R
R
Medicinal Chemistry Department, AMRI Singapore
Research Centre, 61 Science Park Road, #05-01, The
Galen, Science Park II, Singapore 117525, Singapore
santhosh.chittimalla@amriglobal.com
H3CO
H3CO
X = I; Br; Cl
26 examples
up to 96% yield
5 examples
R
Sonogashira coupling
chemcsk@gmail.com
Received: 22.09.2016
Accepted after revision: 30.10.2016
Published online: 17.11.2016
specifically, the presence of a halogen allows for organome-
tallic cross-coupling reactions thus permitting functional-
ization of the MOB without disturbing its core structure.
It is well known that MOBs substituted at the 5-position
are stable and isolable,1j,3–5 therefore for our initial studies,
such substrates were chosen.
DOI: 10.1055/s-0036-1588359; Art ID: st-2016-d0626-l
Abstract A facile pyridine-mediated α-halogenation approach to func-
tionalize cyclohexa-2,4-dienones is developed. A range of reactions, in-
cluding organometallic coupling protocols, have been applied on these
newly obtained halogenated cyclohexa-2,4-dienones, and the results
are presented herein.
Initially, we investigated α-iodination8 and chose MOB 1
as a substrate. Thus, to a methylene chloride solution of
MOB 1 (1.0 equiv) and pyridine (1.5 equiv) at room tem-
perature, was added I2 (1.5 equiv), and the mixture was al-
lowed to stir.9 Within 15 minutes, TLC analysis indicated
complete consumption of MOB 1. Subsequently, workup
followed by chromatographic purification furnished mono-
iodinated product 1a in 96% yield (Scheme 1). However,
when the reaction was attempted in the absence of pyri-
dine, MOB 1 was recovered unreacted signifying that the re-
action was indeed pyridine catalyzed. A proposed mecha-
nism for the formation of product 1a is shown in Scheme 1.
Key words cyclohexa-2,4-dienones, α-halogenation, nucleophilic
chlorination, Michael addition, dearomatization, palladium hydride,
conjugate reduction
Cyclohexa-2,4-dienones are valuable synthetic precur-
sors in the preparation of numerous structurally diverse
molecules.1 The significance of these versatile intermedi-
ates has been demonstrated by exploiting them in the total
synthesis of several biologically important natural prod-
ucts.2 For the past few years our group has been involved in
expanding the scope of masked o-benzoquinones (MOB), a
class of cyclohexa-2,4-dienones in organic synthesis.3 Inci-
dentally, detour protocols to attain meta-functionalized
phenols have been established employing these linearly
conjugated dienones as substrates.4 In these reactions the
core cyclohexa-2,4-dienone unit may be transformed to a
completely new structure, but less work has been carried
out to functionalize the cyclohexa-2,4-dienone moiety
without disrupting its central structure. Towards this objec-
tive, recently we have shown that MOBs can participate in a
Baylis–Hillman reaction with aryl-aldehydes and activated
ketones furnishing α-substituted MOBs.5 These results
prompted us to investigate further strategies to functional-
ize MOBs. At the outset, we were interested in α-halogena-
tion of these versatile building blocks. These halogenated
cyclohexadienones could then be utilized as substrates to
deliver structurally diverse halogen-containing products,6,7
1
In the H NMR spectrum, peaks at δ = 5.27 and 7.68 ppm
representing H2 and H1, respectively, with JH1–H2 of 7.6 Hz
(ortho coupling) helped to establish the assigned structure
1a.
O
O
H3CO
H3CO
H3CO
H3CO
I
I2, pyridine
CH2Cl2
r.t., 15 min
7.68 ppm
H3CO
H3CO
1a 96%
H1
H2
5.27 ppm
1
JH1–H2 = 7.6 Hz
I
I
:B
O
O
O
H
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
I
I
R
Py
R
Py
R
Py
Scheme 1 α-Iodination of MOB 1. Proposed mechanism for the forma-
tion of α-iodocyclohexa-2,4-dienone 1a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
S. K. Chittimalla et al.
Letter
Synlett
Next, the above conversion was performed in dichloro-
methane using 20 mol% pyridine along with K2CO3 (2.0
equiv).8c,d The reaction took 16 hours for complete con-
sumption of MOB 1. However, under these conditions, along
with desired product 1a (57%), di-iodo MOB 1a′ was pro-
duced in 35% yield (Scheme 2). We presume that the longer
reaction time and the presence of the enol-ether moiety in
compound 1a is the reason for the formation of unexpected
product 1a′.10 With optimized reaction conditions in hand,
we sought to explore the generality of this α-iodination re-
action. Gratifyingly, MOBs 2–6 participated in the pyridine-
mediated α-iodination under the optimized reaction condi-
tions (1.5 equiv of pyridine, 1.5 equiv of I2, CH2Cl2, r.t.)9 pro-
viding the corresponding α-iodo-dienones 2a–6a in good
yields (Table 1,X = I). Among these, we noted that α-iodina-
tion reaction of MOB 6 was slow, requiring six hours to give
O
O
O
H3CO
H3CO
H3CO
H3CO
I
Br
H3CO
H3CO
X
H3CO
H3CO
H3C
O
X
X
I
Br
1b'
1a or 1b
1a'
O
O
OH
H3CO
H3CO
H3CO
X
Br
H3CO
H3CO
Br
H3CO
H3C
H1
H3CO
H2
Br
Br
X = I (2a), Br (2b), Cl (2c),
(11)
1b
1b''
Ph
Scheme 2 Structures of unexpected products 1a′, 1b′ and observed
2D NOESY cross peaks in compounds 2a,b,c and 11
1
α-iododienone 6a in an acceptable yield of 70%. In the H
as for iodination, to a dichloromethane solution of MOB 1
and pyridine at room temperature, a solution of bromine, in
dichloromethane, was added dropwise (Table 1,X = Br).9 Af-
ter one hour, TLC analysis indicated complete consumption
of starting material to give product 1b in 95% yield.11 Con-
sequently, this general α-bromination procedure9 was ap-
plied to MOBs 2–6. We were pleased to obtain the corre-
sponding α-bromo-MOBs 2b–6b in acceptable yields (Table
1,X = Br). However, in some cases (MOBs 2, 4, 5) 15–20% of
unreacted MOB was recovered. Attempts to improve the
yield by prolonging the reaction time were detrimental
leading to the formation of complex mixtures. Furthermore,
several literature-reported protocols for the α-bromination
of these conjugated enones were unsuccessful. For example,
NMR spectrum of α-iodo-dienone 2a, an allylic coupling of
1.6 Hz was observed for the methyl group; further evidence
for the structural assignment of 2a was given by the pres-
ence of 2D NOESY cross peaks between the methyl protons
and ‘H2’; ‘H1’, and ‘H2’ (Scheme 2). In the 1H NMR spectra of
compounds 1a–6a, the resonances for H1 and H2 appeared
between δ = 7.51–7.70 ppm and 5.27–7.00 ppm, respective-
ly, and the coupling constant JH1–H2 was between 6.4–7.6 Hz
(Table 1,X = I).
Encouraged by the above results, we then investigated
α-bromination of MOBs 1–6. Following a similar procedure
Table 1 α-Iodination, α-Βromination, and α-Chlorination of MOBs 1–6a
O
O
H3CO
X
H3CO
H3CO
'X' source
O
O
H3CO
ketal =
conditionsb
R
H1
R
H2
2a–6a; 1b–6b; 1c–6c
1–6
α-Iodination
α-Bromination
α-Chlorination
R
Time Product H1
H2 δ
(ppm) (Hz)
JH1–H2
Time Product
H1
H2 δ
(ppm)
JH1–H2
(Hz)
Time
(h)
Product
/yield (%)
H1
H2 δ
(ppm)
JH1–H2
(Hz)
(h)
/Yield (%)
(h)
/Yield (%)
1 OCH3
2 CH3
3 CO2CH3
4 Br
–
2
2
2
2
6
–
–
–
–
1
1
1
1
1
1
1b 95
2bc 52
3b 67
4bc 64
5bc 64
6bd 54
7.39
5.31
6.03
7.16
6.67
6.41
6.67
8.0
6.8
6.8
7.2
7.2
6.8
2
16
16
16
16
16
1ce 93
2cf 48
3cf 45
4cf 41
5cf 40
6cf 42
7.14
5.33
6.09
7.15
6.73
6.47
6.74
7.6
6.8
6.8
7.6
7.2
7.2
2a 82
3a 75
4a 80
5a 78
6a 70
7.57
7.75
7.51
7.61
7.70
5.93
7.00
6.55
6.31
6.53
6.8
6.8
7.2
7.2
6.8
7.27
7.42
7.23
7.32
7.39
7.02
7.25
6.98
7.06
7.13
5 Cl
6 ketal
a Reaction conditions: α-iodination (X = I): I2 (1.5 equiv), pyridine (1.5 equiv), CH2Cl2, r.t.; α-Bromination (X = Br): Br2 (1.5 equiv), pyridine (1.5 equiv), CH2Cl2, r.t.;
α-Chlorination (X = Cl): NCS (3.5 equiv), pyridine (3.5 equiv), CH2Cl2, reflux.
b All the reactions were performed on 1.0 mmol scale.
c 15–20% of unreacted MOB was recovered.
d ~8% of uncharacterized product was also obtained.
e NCS (2.5 equiv), pyridine (2.5 equiv).
f 35–40% of unreacted MOB was recovered.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
S. K. Chittimalla et al.
Letter
Synlett
changing the brominating agent to NBS, n-Bu4NBr3,12a
py·HBr-NBS, Et3N·HBr-NBS12b did not improve the yield.
When a very common α-bromination method of conjugat-
ed enones was applied to MOB 1;12c (tretment with Br2 for
15 min at 0 °C followed by addition of Et3N), three products
1b (21%), 1b′ (19%), and 1b′′ (22%) were obtained (Scheme
2). We presume that the presence of an enol-ether moiety
in compound 1b is the reason for the formation of dibromo-
MOB 1b′.10 Dibromophenol 1b′′ could be formed by nucleo-
philic bromination of bromo-MOB 1b (Scheme 2).
We wished to extend the protocol to obtain α-chloro-
MOBs. For this purpose, we utilized N-chlorosuccinimide
(NCS) as the electrophilic chlorine source. MOB 1, in the
presence of 2.5 equivalents of pyridine and 2.5 equivalents
of NCS in refluxing dichloromethane provided the corre-
sponding α-chloro-dienone 1c in 93% yield after two hours
(Table 1,X = Cl). However, the conversion did not proceed
cleanly with other MOBs. After much experimentation we
found that, in the case of MOBs 2–6, 3.5 equivalents of pyri-
dine, 3.5 equivalents of NCS in dichloromethane at reflux
were the optimum conditions to produce acceptable yields
of the corresponding α-chloro-dienones 2c–6c; although,
none of the reactions had reached completion after 16
hours. Our attempts to improve the yield or drive the reac-
tion to completion by increasing the amount of NCS or pyri-
dine or changing solvent (1,2-DCE, THF, DMF) either at
room temperature or at reflux were not successful.
en to completion. In the case of α-bromination, the reaction
had to be stopped after one hour as prolonging the reaction
time led to formation of a complex mixture and a reduction
in yield. As before, in the α-chlorination reaction protocol,
around 40% of starting naphthoquinone monoketals 7 and 8
were recovered.
Subsequently, selected α-halo-dienones were subjected
to organometallic coupling reactions (Scheme
4 and
Scheme 5). Compound 1b participated in a Sonagashira re-
action13 with phenylacetylene providing the corresponding
adduct 9 in 74% yield. To our surprise, under the same reac-
tion conditions compound 2a and phenylacetylene fur-
nished diarylacetylene 10 in 80% isolated yield (Scheme 4).
We speculate that the hydrido-palladium intermediate14
formed from palladium(0) and DIPEA could reduce the con-
jugated double bond to give intermediate I and this in turn
might aromatize to yield the observed diarylacetylene de-
rivative 10.15 Consequently, in an effort to establish if either
Sonagashira coupling followed by aromatization reaction
was occurring or aromatization followed by Sonagashira
coupling had taken place to furnish diarylacetylene 10, we
repeated the reaction at –10 °C. After 30 minutes reaction
1
time, TLC and H NMR analysis of the crude reaction mix-
ture indicated three products; MOB 2a and 11 along with
aromatized product 10 indicating that, in this conversion,
Sonagashira coupling had occurred first followed by aroma-
tization. To avoid generating the hydrido-palladium spe-
cies, we investigated an alternative Sonagashira coupling
procedure.16 In this protocol, Pd(PPh3)4 was used as catalyst,
pre-synthesized copper(I) phenylethyne17 as reactant, and
for iodination
I2 (1.5 equiv), pyridine (1.5 equiv),
CH2Cl2, r.t., 16 h
O
O
H3CO
H3CO
H3CO
H3CO
X
for bromination
Br2 (1.5 equiv), pyridine (1.5 equiv),
CH2Cl2, r.t., 1 h
H3CO
O
for chlorination
NCS (3.5 equiv), pyridine (3.5 equiv),
CH2Cl2, reflux, 16 h
H3CO
PdCl2(PPh3)2
H3CO
1b
R
R
CuI, DIPEA
7: R = H; 8: R = Br
7a–c,8a–c
THF
r.t., 1 h
9 74%
X = I
7a: R = H (86%)
8a: R = Br (75%)
X = Br
X = Cl
7cb: R = H (48%)
8cb: R = Br (38%)
7ba: R = H (61%)
8ba: R = Br (68%)
H3CO
H3CO
O
Scheme 3 α-Iodination, α-bromination, and α-chlorination of naph-
thoquinone monoketals 7 and 8. a 10–15% of unreacted naphthoqui-
none monoketal was recovered. b ca. 40% of unreacted
naphthoquinone monoketal was recovered.
PdCl2(PPh3)2
CuI, DIPEA
THF
r.t., 1 h
H3C
2a
11
DIPEA
N
Pd(0)
H
Pd
With these results in hand, to broaden the scope of this
work, we chose 1,2-naphthoquinone monoketals 7 and 8 as
substrates to ascertain if these could also participate in α-
halogenation. To our satisfaction, both substrates 7 and 8
underwent α-iodination under the optimized conditions9
to furnish the corresponding α-iodo-derivatives 7a (86%)
and 8a (75%) (Scheme 3) after 16 hours. It is worth noting
that the reaction time was longer compared to the MOBs
(Table 1). However, although the α-bromination and α-
chlorination protocols provided the corresponding α-halo-
genated 1,2-naphthoquinone monoketals 7b (61%), 7c
(48%), 8b (68%), 8c (38%), the conversion could not be driv-
Pd(PPh3)4
py, MeCN
r.t., 1 h
H3C
H3CO
H3CO
conjugate addition !
O
I
Cu
aromatization
H3CO
H3CO
H3CO
H3C
OH
O
H3C
11 93%
10 80%
Scheme 4 Sonagashira coupling procedure applied to α-halo-MOBs
1b and 2a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
S. K. Chittimalla et al.
Letter
Synlett
pyridine as base. Under these conditions, we were able to
obtain the Sonogashira-coupled product 11 in 93% yield
(Scheme 4).
O
H
OH
H3CO
H3CO
Br
Cl
H3CO
H3CO
Br
Cl
PhI(OAc)2
4 N HCl
1b
1,4-dioxane
r.t., 5 h
MeOH
r.t., 30 min
H3CO
6.67 ppm
H
5.56 ppm
CH3
16 98%
17 95%
CH3
O
OH
H3CO
H3CO
O
Cl
H3CO
Cl
Cl
(HO)2B
H3CO
PhI(OAc)2
4 N HCl
Pd(PPh3)4, LiCl
5c
13
2a
H3CO
Cl
Cl
1,4-dioxane
r.t., 5 h
Cl
MeOH
Na2CO3, 1,2-DME
80 °C, 16 h
r.t., 30 min
H
7.08 ppm
18 97%
6.63 ppm
H
H3C
12 38%
19 85%
O
O
O
OH
H3CO
H3CO
Pd(PPh3)4, LiCl
Na2CO3, 1,2-DME
80 °C, 1 h
I
H3CO
H3CO
I2, py
H3CO
H3CO
Cl
H3CO
Cl
Cl
NCS, py
4 N HCl
CH2Cl2
r.t., 1 h
H3C
H3C
CH2Cl2
reflux, 16 h
1,4-dioxane
r.t., 5 h
NO2
H3C
H3C
CH3
CH3
CH3
13c 44%
CH3
20 97%
13
13a / 72%
B(OH)2
N3
O
Pd(PPh3)2Cl2
NaHCO3 (aq)
THF
H3CO
H3CO
Cl
O
PhI(OAc)2
B
reflux, 1 h
O
MeOH
r.t., 30 min
H3C
Cl
21 95%
CH3
O
O
H3CO
H3CO
H3CO
H3CO
Scheme 6 Nucleophilic chlorination on α-halo-MOBs 1b, 5c, 13c fol-
lowed by oxidation of 2-methoxyphenols 16, 18, 20 to halo-MOBs 17,
19, 21
N3
NO2
H3C
H3C
14 87%
15 80%
CH3
CH3
Scheme 5 Suzuki coupling procedure applied to α-halo-MOBs 1b and
13a
cated by 1H NMR integration of the crude reaction mixture).
We propose that the initially formed Michael adduct II un-
dergoes facile SN2 reaction with ‘Cl–’ present in the reaction
mixture to give intermediate III which eventually aromatiz-
es to product 20. In an attempt to separate the products, the
mixture of compounds 20 and 22 was dearomatized to give
a mixture of 21 and 23, but these were also inseparable.
Subsequently, Suzuki reaction18a between α-iododien-
one 2a and p-tolylboronic acid gave the corresponding α-
aryl MOB 12 albeit in low yield (38%). Suzuki reactions
were also performed on α-iododienone 13a with 2-azido-
arylboronic acid pinacolate ester18b and 2-nitrophenylbo-
ronic acid to give Suzuki coupling products 14 (87%) and 15
(80%), respectively (Scheme 5).
In order to explore the reactivity of theses substrates
further, nucleophilic chlorination on the halogenated MOBs
was performed (Scheme 6).4a Thus, α-halodienones 1b, 5c,
13c were treated with 4 N HCl in 1,4-dioxane at room tem-
perature. After five hours dihalophenols 16, 20 and trihalo-
phenol 18 were produced in near quantitative yields (no
column chromatographic purification was required). These
penta- and hexa-substituted benzenes 16, 18, and 20 upon
PhI(OAc)2-mediated oxidation furnished halogenated MOBs
17, 19, and 21, respectively, in high yield. Consequently, the
regioselectivity in nucleophilic chloroaddition products
was confirmed by comparing the 1H NMR δ values of H2 in
1b, 5c with those of 17 and 19, respectively.
O
O
possible pathway
for the formation of
products 20 and 21
H3CO
H3CO
H3CO
H3CO
I
Cl
Cl
Cl
H3C
Cl
H3C
CH3
CH3
II
III
Cl
5.99 ppm
OH
5.70 ppm
OH
O
3.79 ppm
H3CO
3.76 ppm
H3CO
H3CO
I
Cl
I
H3CO
4 N HCl
+
1,4-dioxane
r.t., 5 h
90%
H3C
Cl
CH3
H3C
Cl
H3C
CH3
CH3
13a
22
20
0.25 : 1.0
r.t., 30 min
90%
PhI(OAc)2
MeOH
O
O
H3CO
H3CO
H3CO
However, nucleophilic chlorination was not straightfor-
ward with substrate 13a. To our surprise, upon treating α-
iododienone 13a with HCl in 1,4-dioxane, an inseparable
mixture of two products was obtained (Scheme 7). On close
observation it became clear that these were expected phe-
nol 22 and unexpected phenol 20 (in 0.25:1.0 ratio as indi-
I
Cl
Cl
H3CO
+
H3C
Cl
H3C
CH3
23
CH3
21
Scheme 7 Nucleophilic chlorination on α-halo-MOB 13a followed by
oxidation to halo-MOBs 21 and 23
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
S. K. Chittimalla et al.
Letter
Synlett
In conclusion, we have demonstrated α-halogenation as
a strategy to functionalize cyclohexa-2,4-dienone monoke-
tals 1–6 and 1,2-naphthoquinone monoketals 7 and 8. No-
tably, the present method is compatible with a wide range
of functional groups such as methoxy, alkyl (methyl), halo-
gen, ester, and ketal groups. The methoxy group at C-5 of
MOB 1 provides additional activation in these reactions, as
is evident from reaction times and yields of the correspond-
ing α-halodienones 1a–c. The halogenation processes in
this study show the trend, iodination > bromination > chlo-
rination. These products may serve as important precursors
for the synthesis of novel cyclohexa-2,4-dienones. The α-
bromination and α-chlorination protocols still require opti-
mization and work towards this end is in progress.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588359.
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33, 917. (b) Bovonsombat, P.; Angara, G. J.; McNelis, E. Tetrahe-
dron Lett. 1994, 35, 6787. (c) Li, K.; Alexakis, A. Angew. Chem.
Int. Ed. 2006, 45, 7600. (d) Djuardi, E.; Bovonsombat, P.;
McNelis, E. Synth. Commun. 1997, 27, 2497.
(9) General Procedure for α-Halogenation Reaction
To a stirred solution of MOB 1 (100 mg, 0.54 mmol) and pyri-
dine (0.81 mmol for α-iodination and α-bromination; 1.89
mmol for α-chlorination) in CH2Cl2 (4 mL) at r.t. was added
iodine (0.81 mmol) or bromine (0.81 mmol as a solution in 1 mL
CH2Cl2 or neat Br2 in the case of naphthoquinone monoketals 7
and 8) or NCS (1.89 mmol). The resulting mixture was allowed
to stir at r.t. or at reflux as indicated in the Schemes, for 15 min
to 16 h before quenching with sat. Na2S2O3. The layers were sep-
arated, and the organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give a residue, which was
purified by column chromatography (EtOAc in hexanes, 0–15%)
to afford α-iododienone 1a (96%), α-bromodienone 1b (95%), or
α-chlorodienone 1c (93%).
References and Notes
(1) For selected recent examples, see: (a) Wang, C.-C.; Ku, Y.-C.;
Chuang, G. J. J. Org. Chem. 2015, 80, 10979. (b) Suzuki, T.;
Okuyama, H.; Takano, A.; Suzuki, S.; Shimizu, I.; Kobayashi, S.
J. Org. Chem. 2014, 79, 2903. (c) Tsao, K.-W.; Devendar, B.; Liao,
C.-C. Tetrahedron Lett. 2013, 54, 3055. (d) Nair, V.; Menon, R. S.;
Biju, A. T.; Abhilash, K. G. Chem. Soc. Rev. 2012, 41, 1050.
(e) Singh, V.; Sahu, P. K.; Sahu, B. C.; Mobin, S. M. J. Org. Chem.
2009, 74, 6092. (f) Gao, S.-Y.; Chittimalla, S. K.; Liao, C.-C. J. Org.
Chem. 2009, 74, 1632. (g) Chang, C.-P.; Chen, C.-H.; Chuang, G. J.;
Liao, C.-C. Tetrahedron Lett. 2009, 50, 3414. For some reviews,
see: (h) Gagnepain, J.; Mereau, R.; Dejugnac, D.; Leger, J.-M.;
Castet, F.; Deffieux, D.; Pouysegu, L.; Quideau, S. Tetrahedron
2007, 63, 6493. (i) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem.
Rev. 2004, 104, 1383. (j) Liao, C.-C.; Peddinti, R. K. Acc. Chem.
Res. 2002, 35, 856. (k) Singh, V. Acc. Chem. Res. 1999, 32, 324.
(2) For some recent examples, see: (a) Coffinier, R.; El Assal, M.;
Peixoto, P. A.; Bosset, C.; Miqueu, K.; Sotiropoulos, J.-M.;
Pouysegu, L.; Quideau, S. Org. Lett. 2016, 18, 1120.
(b) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2014, 136, 6598. (c) Suzuki, T.; Miyajima, Y.; Suzuki,
K.; Iwakiri, K.; Koshimizu, M.; Hirai, G.; Sodeoka, M.; Kobayashi,
S. Org. Lett. 2013, 15, 1748. (d) Chou, Y.-Y.; Liao, C.-C. Org. Lett.
2013, 15, 1584. (e) Yu, M.; Snider, B. B. Org. Lett. 2011, 13, 4224.
(f) Roche, S. P.; Porco, J. A. Jr. Angew. Chem. Int. Ed. 2011, 50,
4068. (g) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron
2010, 66, 2235. (h) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org.
Lett. 2009, 11, 4774. (i) Lu, P.-H.; Yang, C.-S.; Devendar, B.; Liao,
C.-C. Org. Lett. 2010, 12, 2642. (j) Shiao, H.-Y.; Hsieh, H.-P.; Liao,
C.-C. Org. Lett. 2008, 10, 449. (k) Kao, T.-C.; Chuang, G. J.; Liao,
C.-C. Angew. Chem. Int. Ed. 2008, 47, 7325. (l) Hsu, D.-S.; Liao, C.-
C. Org. Lett. 2007, 9, 4563. (m) Liao, C.-C. Pure Appl. Chem. 2005,
77, 1221.
α-Iododienone 1a
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 7.6 Hz, 1 H), 5.27 (d,
J = 7.6 Hz, 1 H), 3.81 (s, 3 H), 3.31 (s, 6 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 188.9 (C), 164.9 (C), 151.1 (CH), 98.1 (CH), 94.4
(C), 90.5 (C), 56.5 (CH3), 51.8 (2 × CH3) ppm.
α-Bromodienone 1b
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.0 Hz, 1 H), 5.31 (d,
J = 8.0 Hz, 1 H), 3.81 (s, 3 H), 3.32 (s, 6 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 187.6 (C), 163.8 (C), 143.8 (CH), 113.7 (C), 96.3
(CH), 95.3 (CH), 56.4 (CH3), 51.7 (2 × CH3) ppm.
α-Chlorodienone 1c
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 7.6 Hz, 1 H), 5.33 (d,
J = 7.6 Hz, 1 H), 3.80 (s, 3 H), 3.31 (s, 6 H). 13C NMR (100 MHz,
CDCl3): δ = 187.5 ( C), 162.9 (C), 139.8 (CH ), 123.2( C), 95.4 (C),
95.2 (CH ), 56.3 (CH3 ), 51.6 (2 × CH3).
(10) O’Brien, M.; Cooper, D. Synlett 2016, 27, 164.
(3) (a) Chittimalla, S. K.; Bandi, C. RSC Adv. 2013, 3, 13663.
(b) Chittimalla, S. K.; Kuppusamy, R.; Thiyagarajan, K.; Bandi, C.
Eur. J. Org. Chem. 2013, 2715. (c) Chittimalla, S. K.; Kuppusamy,
R.; Chakrabarti, A. Synlett 2012, 23, 1901.
(11) In the absence of pyridine, α-bromination did not proceed.
(12) (a) Bose, G.; Barua, P. M. B.; Chaudhuri, M. K.; Kalita, D.; Khan,
A. T. Chem. Lett. 2001, 290. (b) Jyothi, D.; HariPrasad, S. Synlett
2009, 2309. (c) Nicolaou, K. C.; Ding, H.; Richard, J.-A.; Chen, D.
Y.-K. J. Am. Chem. Soc. 2010, 132, 3815.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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S. K. Chittimalla et al.
Letter
Synlett
(13) (a) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
(b) Buszek, K. R.; Yeong, J. Synth. Commun. 1994, 24, 2461.
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(15) To confirm the aromatization process, we subjected MOB 2
(nonhalogenated MOB) to exactly same reaction conditions
[phenyl acetylene, PdCl2(PPh3)2, CuI, DIPEA]. After 1 h, 2-
methoxy-3-methylphenol was obtained in 85% yield.
(16) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F