Iodine-Catalyzed Oxidative Aromatization: A Metal-Free Concise Approach to meta-Substituted Phenols from Cyclohex-2-enones

Article abstract of DOI:10.1002/adsc.201600930

A metal-free approach to meta-substituted phenols from cyclohex-2-enone via catalytic oxidative aromatization has been developed. The transformations are initiated with a catalytic amount of molecular iodine as the direct oxidant, while dimethyl sulfoxide is employed as the terminal oxidant. This practical approach is capable of avoiding the use of metal promoters and costly reagents, the lengthy synthesis, and overoxidation of products, and thus facilitates the efficient construction of meta-substituted phenol derivatives from inexpensive commercial chemicals under mild conditions. The synthetic utility of this approach is evident in the de novo syntheses of two bioactive molecules with good total yields, in which easily available chemicals were employed, protective groups were not utilized, and no unwanted carbon atoms were removed in each step. (Figure presented.).

Full text of DOI:10.1002/adsc.201600930

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DOI: 10.1002/adsc.201600930
Iodine-Catalyzed Oxidative Aromatization: A Metal-Free Concise
Approach to meta-Substituted Phenols from Cyclohex-2-enones
Shi-Ke Wang,a Ming-Tao Chen,a Da-Yuan Zhao,a Xia You,a and Qun-Li Luoa,*
a
Key Laboratory of Applied Chemistry of Chongqing Municipality, College of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, Peopleꢀs Republic of China
Fax : (+86)-23–6825-4000; phone: (+86)-23–6825-2360; e-mail: qlluo@swu.edu.cn
Received: August 22, 2016; Revised: October 10, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600930.
Abstract: A metal-free approach to meta-substituted phenol derivatives from inexpensive commercial
phenols from cyclohex-2-enone via catalytic oxida- chemicals under mild conditions. The synthetic utility
tive aromatization has been developed. The transfor- of this approach is evident in the de novo syntheses
mations are initiated with a catalytic amount of mo- of two bioactive molecules with good total yields, in
lecular iodine as the direct oxidant, while dimethyl which easily available chemicals were employed, pro-
sulfoxide is employed as the terminal oxidant. This tective groups were not utilized, and no unwanted
practical approach is capable of avoiding the use of carbon atoms were removed in each step.
metal promoters and costly reagents, the lengthy syn-
thesis, and overoxidation of products, and thus facili- Keywords: enones; iodine; oxidative aromatization;
tates the efficient construction of meta-substituted phenols; synthetic methods
Introduction
idation of products, a competitive reaction with oxida-
tive aromatization because of the susceptibility of
Phenols are ubiquitous in nature and have a variety phenols under the oxidative conditions. In order to
of applications in synthetic organic chemistry as val- bypass the problem, the existing examples employed
uable precursors in the construction of natural prod- indirect protocols by the installation of groups in ad-
ucts, bioactive compounds, fine chemicals, and func- vance at the susceptible positions of phenols to pre-
tional materials.[1] Conventional strategies for the syn- vent overoxidation or by the use of preoxidized sub-
theses of substituted phenols relied on functionaliza- strates through eliminative aromatization to keep the
tions and functional group transformations around oxidants away from phenols.[7] Therefore, it would be
the periphery of a preexisting aromatic ring such as of significant importance to develop a direct protocol
selective hydroxylations of benzenes, nucleophilic and
electrophilic aromatic substitutions, and metal-cata-
lyzed cross-coupling reactions.[2] These strategies en-
riched straightforward routes to ortho- and para-sub-
stituted phenols. By contrast, the regiospecific synthe-
sis of meta-substituted phenols through such strategies
frequently suffered from tedious multistep synthesis
or pre-installation of directing groups due to the fact
that regioselectivities strongly depend on electronic
effects in aromatic substitution chemistry.[3,4] Accord-
ingly, oxidative aromatization of non-aromatic precur-
sors provides an alternative choice.[5] Very recently,
several research groups have made extensive progress
in the metal-catalyzed oxidative aromatization of cy-
clohexenones to phenols (Scheme 1A).[6] However,
the advances on related metal-free approaches have
been frustrating, particularly in relation to the overox- cyclohex-2-enones to phenols.
Scheme 1. Catalytic oxidative aromatization of substituted
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Table 1. Optimization of the reaction conditions.[a]
so that meta-substituted phenols can be regiospecifi-
cally and facilely achieved in the absence of metal
promoters, but would not be overoxidized.
Molecular iodine has been a catalyst with substan-
tial applications in various organic reactions.[8] It is
widely available, relatively inexpensive, stable toward
air and moisture, and of low toxicity. Nevertheless,
there are no synthetic methodologies to substituted
phenols involving iodine-catalyzed oxidative aromati-
zation.[7j] Here we report an unprecedented approach
to phenols catalyzed by molecular iodine
(Scheme 1B). This finding provides a general access
to meta-substituted phenols in which metal catalysts
are unnecessary while the lengthy synthesis and over-
oxidation of products can be avoided.
En-
try
R
Solvent
T
t
Yield
(equiv.)
[oC] [h] [%]
1
2
3
4
5
6
7
8
I2 (1)/t-BuOK (2) DCM
I2 (2)
I2 (1)/CuO (1)
I2 (1)/t-BuOK (2) t-BuOH
I2 (1)/t-BuOK (3) t-BuOH/DCM 25
I2 (1)/t-BuOK (3) Et2O
I2 (1)/t-BuOK (3) MeCN
I2 (4)
I2 (0.2)
I2 (1)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
–
10
85
80
25
12 N.R.
t-BuOH
t-BuOH
8
8
8
N.R.
N.R.
0[b]
24 0[c]
24 0[c]
24 0[c]
25
25
85
60
60
60
60
r.t.
50
80
DME
DME
4
0[b]
9
12 0[c]
8 96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
toluene
THF
DMSO
DMSO
DMSO
DMSO
DMSO
Results and Discussion
20 95
24 96
12 trace
12 78
20 94
At the outset of the investigation, we chose 3,5-diaryl-
ACHTUNGTRENNUNGcyclohex-2-enone 1a as the substrate in the model re-
action (Table 1) since it could be prepared readily
from easily available starting materials (p-methoxy-
100 20 92
ACHTUNGTRENNUNGacetophenone, benzaldehyde, and acetone). It was
60
60
60
60
60
60
60
60
12 N.R.
12 N.R.
12 N.R.
12 N.R.
24 94
12 N.R.
12 N.R.
12 N.R.
disclosed in previous research that the dehydrogena-
tive oxidation of alcohol was achieved with molecular
iodine in the presence of potassium tert-butoxide at
108C.[9] However, 1a could not be oxidized under sim-
ilar conditions (Table 1, entry 1). The use of tert-butyl
alcohol as solvent led to the consumption of 1a, but
no desired product was isolated (entries 4 and 5).
Meanwhile, we noticed that molecular iodine itself
was capable of oxidizing cyclohex-2-enones in an ap-
propriate solvent (entries 8 and 9).[10] Therefore, di-
methyl sulfoxide (DMSO) was tested as solvent at
a moderate temperature, and the desired phenol was
obtained in 96% yield by the use of a stoichiometric
amount of iodine (entry 10). This promising result en-
couraged us to conduct the reaction with a catalytic
amount of iodine. Fortunately, 2a was obtained in ex-
cellent yield with extension of the reaction time by
the use of 20 mol% of iodine (entries 11 and 12). Sig-
NIS (0.2)
NCS (0.2)
NBS (0.2)
KI (0.2)
[a]
Reaction conditions: 1a (0.2 mmol), solvent (1 mL) under
air. Yield of isolated product. NIS=N-iodosuccinimide,
NBS=N-bromosuccinimide, NCS=N-chlorosuccinimide,
N.R. =no reaction.
Thin-layer chromatography (TLC) indicated that 1a was
completely transformed into a complicated mixture, and
no confirmed compound was identified.
TLC indicated that 1a was partially transformed into
a complicated mixture, but no confirmed compound was
identified.
[b]
[c]
nificantly, the transformation worked well at a wide erally, the substrates containing electron-donating
range of temperature (60–1008C). When the tempera- substituted aryl groups at the 5-position were less
ture was lower than 608C, the reaction was slow (en- active than those containing electron-withdrawing
tries 13–16). Thus, 608C was the optimal temperature groups (entries 1–6 vs. 7 and 8). Nevertheless, the con-
for the transformation. The experiments on halogen versions of sluggish substrates, especially those con-
source screening showed that NIS was slightly less ef- taining an electron-rich aryl at 5-position, such as 1g
ficient than molecular iodine, whereas NCS, NBS and and 1h (entries 7 and 8), could be realized in good
KI failed to produce 2a at 608C (entries 20–24).
yields through extension of the reaction time.
To assess the scope of the present approach, various
On the other hand, the aryls at the 3-position of cy-
3,5-disubstituted cyclohex-2-enones were prepared, clohex-2-enones had insignificant impacts on the reac-
and they were examined under the optimized reaction tivity. The substrates bearing either an electron-rich
conditions (Table 2). An array of 3,5-disubstituted or electron-poor phenyl at the 3-position of the cyclo-
phenols 2a–r was obtained in mostly excellent yields hex-2-enone ring were smoothly transformed into the
from readily available starting materials. No overoxi- desired phenols under the standard conditions (en-
dized products were observed in all the cases.[11] Gen- tries 1–6 and 9–12).
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Table 2. Substrate scope of the catalytic oxidative aromatiza-
that are often incapable of tolerating the conditions
of Pd- or Cu-mediated reactions at an elevated tem-
perature, such as chloroaryl (entry 2) and bromoaryl
(entries 5, 9, 14), some that are sensitive to strong
acids, such as acetal (entry 7), furanyl (entry 10) and
NHBoc (entry 11), and some that are intolerable to
strong reducers or oxidizers, such as nitro (entry 6),
furanyl (entry 10), and phenol (entry 12). They all de-
livered the products in excellent yields (88–96%).
This broad functional group compatibility and mild
conditions would provide an enormous potential to
further functionalize the aromatization products.
tion of 3,5-disubstitued cyclohex-2-enones.[a]
Entry
R1
R2
1/2
Yield
1
2
Ph
Ph
1a/2a
1b/2b
96%
94%
To gain some insights into the reaction mechanism,
several control experiments were performed
(Table 3). The oxidative aromatization could be initi-
ated by iodation of the C–H bond at the 2-, 4- or 6-
position of the cyclohex-2-enone ring. The substrate
having a substituent at the 2-position of the ring was
transformed into phenol 2s in 89% yield (Table 3,
entry 1), whereas those containing a group at the 4-
or 6-position resulted in only moderate to poor yields
(entries 2–6). These results suggested that iodation of
the cyclohex-2-enone ring at the 4- or 6-position was
more reasonable than that at the 2-position. Mean-
while, the substrates free of a substituent at the 6-po-
sition were transformed faster than those free at the
4-position (entries 2–3 vs. 4–6), which was consistent
with the fact that deprotonation of cyclohex-2-enone
3
4
5
Ph
Ph
Ph
1c/2c
1d/2d
1e/2e
94%
92%
92%
Ph
6
7
1f/2f
1g/2g
96%
Ph
Ph
88%[b]
8
1h/2h
74%[c]
9
1i/2i
1j/2j
96%
89%[d]
10
2-furanyl
Ph
Ph
11
1k/2k
92%
Table 3. Control experiments.[a]
12
13
14
Ph
1l/2l
91%
97%
96%
Ph
CO2H
CO2H
1m/2m
1n/2n
15
16
17
18
Ph
Ph
Ph
Ph
CO2Et
CONHBn
CONHPh
R3
1o/2o
1p/2p
1q/2q
1r/2r
97%[d]
82%[e]
95%[d,e]
97%[d,e]
Entry
Ar
R1
R2
R3
1/2
Yield
[a]
Reaction conditions: 1 (0.2 mmol), I2 (20 mol%), DMSO
(1 mL), under air for 24 h unless otherwise stated. Isolat-
ed yields are given. R3 =4-methoxyanilinocarbonyl.
The reaction time was 48 h.
The reaction time was 72 h.
The reaction time was 36 h.
1
2
3
4
5
6
7
8
Ar1
Ph
Me
H
H
H
H
H
H
CO2Et
Me
CO2Me
H
1s/2s
1t/2t
89%
58%
21%
10%
11%
trace
trace
92%
Me
CO2Et
H
H
H
Ph
1u/2u
1v/2v
1w/2w
1x/2x
1y/2y
1k/2k
[b]
[c]
[d]
[e]
Ar1
Ar1
Ar1
Ar2
Ar3
H
Me
Me
H
With 50 mol% of I2.
H
H
H
H
Fascinatingly, several meta-hydroxybenzoic acid de-
9
N.R.
31%
24%
rivatives were prepared effectively (entries 13–18).
Substituted meta-hydroxybenzoic acids are highly val-
uable building blocks for organic synthesis, but the ex-
isting methods are indirect or use harsh conditions,
and normally give benzoates rather than the free
acids.[4,5c] The present approach flexibly provides
a direct and facile access to meta-substituted benzoic
acid derivatives as well as the related carboxylic acid.
Remarkably, many susceptible functional groups
could survive the reaction conditions, including some
10
11
[a]
Reaction conditions: 1 (0.2 mmol), I2 (20 mol%), DMSO
(1 mL), under air for 24 h unless otherwise stated. Isolat-
ed yields are given. Ar1 =4-methoxyphenyl; Ar2 =
4-aminopthenyl; Ar3 =4-t-butoxycarbonylaminophenyl;
TEMPO=2,2,6,6-tetramethylpiperidine 1-oxyl.
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took place at the 6-position more easily than at the 4-
position and subsequently afforded cyclohexa-1,5-di-
enolate rather than cyclohexa-1,3-dienolate.[12] We
presume that the steric hindrance of the substituent
obstructed the iodation of cyclohexa-1,5-dienolate
when 6-substituted substrates were employed, and
thereby retarded such substrates from the oxidative
aromatization. Therefore, the oxidative aromatization
was possibly initiated by iodation at the 6-position of
the cyclohex-2-enone ring.
To elucidate the role of molecular iodine, control
experiments of entries 7–11 were conducted. For the
substrate containing an alkaline amino group, the
transformation was difficult to proceed (entry 7). But
for the amino-protected substrate, the reaction
worked well (entry 8). In addition, KI failed to ac-
complish the reactions (entry 9), which supported that
(i) it was not DMSO but molecular iodine that acted
as the direct oxidizer under the standard conditions,
and (ii) iodide ion was difficult to be oxidized into
molecular iodine by DMSO in a neutral or alkaline
environment.[11a,b] However, if the acidity of the reac-
tion system was increased, the aromatic ring of the
products could be further iodated.[11c] Thus, external
acid or base was unnecessary for the catalytically oxi-
dative aromatization since HI produced in situ was ca-
pable of transmitting the catalytic cycle fluently.
When the reactions were performed in a dark envi-
ronment, in the presence or absence of 2,2,6,6-tetra-
methylpiperidine 1-oxyl (TEMPO, a radical scaveng-
Scheme 3. De novo synthesis of BRD4(1) inhibitor 5. Reac-
tion conditions: (a) (i) EtOH, room temperature 4 h, then
458C 4 h; (ii) NaBH4, 08C, 4 h, then room temperature, 4 h.
(b) HOAc, HCl (conc.), reflux, 18 h. (c) acetone, pyrrolidine
(50 mol%), 408C, 24 h. (d) (i) oxalyl dichloride, CH2Cl2,
DMF (cat.), 08C to room temperature, 2 h; (ii) 3, THF,
K2CO3, 08C to room temperature, 8 h. (e) I2 (50 mol%),
DMSO, 608C, 60 h. (f) (i) oxalyl dichloride, CH2Cl2, room
temperature: (ii) 3, THF, TEA, 08C to room temperature,
see: ref.[15b]
The synthetic utility of our methodology is demon-
er),[13] and at room temperature, the phenols were strated by the preparation of the bioactive molecules
slowly produced (entries 10 and 11), which supported shown in Scheme 3 and Scheme 4.
the process of catalytically oxidative aromatization
combined with an ionic mechanism rather than a radi-
cal one.
On the basis of the above studies and reported lit-
erature,[11,14] a catalytic cycle of iodine-mediated oxi-
dative aromatization is illustrated in Scheme 2. The
iodation of cyclohex-2-enone A produces iodo ketone
B and hydrogen iodide. The elimination of another
molecule of hydrogen iodide from B generates cyclo-
hexadienone C. The tautomerization of C furnishes
the intended phenol D. The oxidation of hydrogen
iodide by DMSO leads to the regeneration of molecu-
lar iodine that is needed in the next catalytic
cycle.[11,14]
Scheme 4. De novo synthesis of bioactive LUF5771. Reac-
tion conditions: (a) NaOH, EtOH, room temperature, 6 h.
(b) acetone, NaOMe, 508C, 2 h. (c) I2 (20 mol%), DMSO,
608C, 24 h. (d) isocyanatocyclopentane, TEA, CH2Cl2, room
Scheme 2. Proposed mechanism.
temperature, 12 h.
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Dihyroquinoxalinone 5 was recently identified as ized meta-substituted phenols are under investigation
a novel inhibitor of BRD4(1), one of the particularly in our lab.
important members of the bromodomains (BRDs)
which have been thought to be possible drug targets
for cancer, inflammation, diabetes and cardiovascular Experimental Section
therapeutics.[15] By the use of oxidative aromatization
strategy, the first de novo synthesis of 5 was achieved General Methods
in 5 steps from inexpensive commercial chemicals
with good yields in each step (Scheme 3). The frag-
were used as received. All solvents for chromatographic sep-
Unless otherwise noted, commercially available reagents
ment of quinoxalinone (3) was synthesized in a one-
pot procedure from o-phenylenediamine and glyoxylic
acid by sequential dehydration condensation, cycliza-
tion and in situ reduction, while the fragment of keto
acid (1m) was prepared from acetophenone, glyoxylic
acid, and acetone via sequential aldol condensation
and Robinson annulation. The amidation of 1m with
3 furnished amide 4. The iodine-catalyzed oxidative
aromatization of 4 afforded BRD4(1) inhibitor 5. By
the use of this route, metal reagents and protective
groups were not utilized, no unwanted carbon atoms
were removed in each step, and the coupling of phe-
nolic acid 2m and amine 3 was avoided. Comparative-
ly, the direct coupling of 2m and 3 resulted in poor
yield.[15b,16]
arations were distilled before use. Solvents for the water-
free reactions were dried with standard procedures and
stored in Schlenk flasks over molecular sieves. Column chro-
matography was carried out with 200–300 mesh silica gel.
Thin-layer chromatography (TLC) was performed on glass-
backed silica plates. UV light, I2, and solutions of 2,4-dini-
trophenylhydrazine and potassium permanganate were used
to visualize products. Concentrating a solution under re-
duced pressure refers to distillation using a rotary evapora-
tor attached to a vacuum pump (3–10 mmHg). Products ob-
tained as solids or high boiling oils were dried under
1
vacuum (1–3 mmHg). H and 13C NMR spectra were record-
ed on a 600 MHz spectrometer (Bruker) at 293 K and the
chemical shifts (d) were internally referenced by the residu-
al solvent signals relative to tetramethylsilane (CDCl3 at
7.26 ppm for 1H, and at 77.00 ppm for 13C; DMSO-d6 at
1
2.50 ppm for H, and at 39.50 ppm for 13C). Data are report-
The application of this approach was further exem-
plified in the efficient synthesis of LUF5771,[17]
a meta-substituted phenol-derived antagonist of the
ed as s=singlet, d=doublet, t=triplet, q=quartet, m=mul-
tiplet, b=broad; coupling constant(s) in Hz; integration.
High-resolution mass spectrometry (HR-MS) for accurate
mass measurements was performed on a Waters Synapt-G2
mass spectrometer unless otherwise noted. All the known
products were confirmed by comparison with spectroscopic
analysis of the authentic samples. The yields in the text refer
to isolated yields of compounds (average of two runs).
human
luteinizing
hormone
(LH)
receptor
(Scheme 4). We accomplished the de novo synthesis
of this compound in 4 steps with more than 70% total
yield from easily available starting materials (p-meth-
ylacetophenone, benzaldehyde, acetone, and isocyana-
tocyclopentane). The reported syntheses of LUF5771
required the use of either fluorinating reagents or
noble metal catalysts.[6c,7i,17] By contrast, the present
synthesis totally avoided the requirements of rigorous
reaction conditions and special or expensive reagents.
General Procedure for the Iodine-Catalyzed
Oxidative Aromatization
In a typical run, a 10-mL Schlenk tube was charged with
a solution of 1 (0.2 mmol) and I2 (10 mg, 0.04 mmol) in
DMSO (1 mL), then covered with a rubber stopper under
ambient atmosphere. The mixture was continually stirred at
608C until 1 had disappeared as monitored by TLC (typical-
ly, for 24 h). After being cooled to the ambient temperature,
the reaction was quenched with 3 mL of saturated aqueous
solution of Na2S2O3 and then extracted 3 times with EtOAc.
The combined organic extracts were sequentially washed
with deionized water and brine, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. The
crude product was purified by column chromatography
(silica, petroleum ether/EtOAc mixture as eluent). The iso-
lated products were confirmed by 1H and 13C NMR. The
exact time for each reaction is shown in Table 2.
Conclusions
In conclusion, we have developed the first metal-free
approach to substituted phenols from cyclohex-2-
enone via catalytic oxidative aromatization, which in-
tegrates several advantages of an ideal methodology,
such as the substrates could be facilely prepared, the
reagents are of low cost, the optimized temperature
range is wide, the operations are safe, convenient and
easily controllable, and the transformations are highly
atom-economic with broad functional group compati-
bility and excellent efficiency. The oxidative condi-
tions are so mild that the overoxidation of products
has not been observed. Our approach provided a gen-
eral access to meta-substituted phenols, facilitated the
de novo syntheses of meta-substituted phenol deriva-
tives, and therefore efficiently afforded two examples
De novo Synthesis of BRD4(1) Inhibitor 5
Aldol condensation to form S1m: Acetophenone (360 mg,
3 mmol) and glyoxylic acid monohydrate (414 mg,
4.5 mmol) were added in sequence to a solution of concen-
trated HCl (0.5 mL) in AcOH (10 mL). The mixture was
of bioactive molecules. The applications of functional- heated to reflux for 18 h. After the reaction was complete as
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1
monitored by TLC, the mixture was cooled to the ambient
temperature, and dried under vacuum. The crude product,
(E)-4-oxo-4-phenylbut-2-enoic acid (S1m) was used directly
for next step.
Robinson annulation to form 1m: To a mixed solvent of
methanol (4 mL) and acetone (1.5 mL, 20 mmol) were se-
quentially added S1m (176 mg, 1 mmol) and pyrrolidine
(42 mL, 0.5 mmol). The solution was heated to 408C for
24 h. After the reaction was complete, the solvent was re-
moved under vacuumn, and then EtOAc (10 mL) and water
(10 mL) were added. The product was extracted with
EtOAc (3 times). The combined organic phase was dried
over anhydrous Na2SO4. The crude product was purified by
(81%). H NMR (600 MHz, CDCl3): d=9.53 (s, 1H), 7.47
(d, J=6.1 Hz, 2H), 7.39 (dd, J=10.4, 5.2 Hz, 4H), 7.24 (d,
J=7.7 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.8 Hz,
1H), 6.41 (s, 1H), 4.64 (s, 1H), 4.43 (d, J=16.4 Hz, 1H),
3.83 (s, 1H), 3.19 (ddd, J=17.7, 10.7, 2.1 Hz, 1H), 2.81 (dd,
J=16.5, 13.1 Hz, 2H), 2.58 (d, J=15.5 Hz, 1H); 13C NMR
(151 MHz, CDCl3): d=197.3, 172.9, 169.2, 157.6, 138.0,
131.7, 130.4, 128.9, 127.6, 126.5, 126.1, 124.6, 123.7, 123.5,
117.3, 46.6, 39.8, 37.9, 31.1; HR-MS (ESI-TOF): m/z=
369.1219, calcd. for C21H18N2NaO3 [M+Na]+: 369.1210.
Catalytic oxidative aromatization of 4 to form 5: The re-
action was performed according to the general procedure. A
mixture of 4 (70 mg, 0.2 mmol) and I2 (25 mg, 0.1 mmol) in
DMSO (1 mL) was stirred at 608C for 60 h. After the reac-
tion was completed, the reaction mixture was quenched with
a saturated aqueous solution of Na2S2O3 and then extracted
3 times with EtOAc. The combined organic extracts were
sequentially washed with deionized water and brine, dried
over anhydrous Na2SO4, filtered, and concentrated under
vacuum. The crude product was purified by silica gel chro-
matography to provide compound 5[15b] as a yellow solid;
yield: 60 mg (87%). 1H NMR (600 MHz, DMSO-d6): d=
10.80 (s, 1H), 9.86 (s, 1H), 7.48–7.39 (m, 4H), 7.35 (t, J=
7.1 Hz, 1H), 7.13–7.08 (m, 2H), 7.05 (d, J=7.9 Hz, 1H),
6.98 (s, 1H), 6.82–7.78 (m, 3H), 4.41 (s, 2H); 13C NMR
(151 MHz, DMSO-d6): d=168.6, 167.4, 158.2, 142.0, 139.9,
136.8, 131.7, 129.4, 128.3, 127.5, 127.0, 126.3, 124.8, 122.2,
118.0, 116.7, 116.3, 114.6, 41.0.
silica gel chromatography to provide 5-oxo-3-phenylcyclo-
[18]
hex-3-enecarboxylic acid (1m)
as a white solid; yield:
177 mg (82%). 1H NMR (600 MHz, CDCl3): d=9.93 (s,
1H), 7.59–7.53 (m, 2H), 7.46–7.40 (m, 3H), 6.47 (s, 1H),
3.31–3.23 (m, 1H), 3.09 (t, J=8.1 Hz, 2H), 2.82 (dd, J=16.8,
4.6 Hz, 1H), 2.74 (dd, J=16.8, 10.6 Hz, 1H); 13C NMR
(151 MHz, CDCl3): d=197.4, 178.4, 157.8, 137.9, 130.5,
128.9, 126.3, 125.2, 125.2, 39.7, 38.6, 30.1.
Sequential dehydration cyclization and reduction to form
3: Glyoxylic acid monohydrate (184 mg, 2 mmol) was added
to a solution of o-phenylenediamine (218 mg, 2 mmol) in
EtOH (10 mL). The mixture was stirred at room tempera-
ture for 4 h, then at 458C for 4 h. After the reaction was
complete as monitored by TLC, the mixture was cooled in
an ice-water bath, and sodium borohydride (530 mg,
14 mmol) was added with stirring in one portion. The solu-
tion was stirred in the cooling bath for 4 h, then at room
temperature for 4 h, quenched with a saturated aqueous so-
lution of NH4Cl, and extracted with EtOAc (3 times). The
combined organic extracts were washed with water and
brine, dried over anhydrous Na2SO4. The crude product was
Acknowledgements
The authors are grateful for the financial support from the
National Natural Science Foundation of China (20971105)
and the Experimental Technology Foundation of Southwest
University (SYJ2016019).
purified by silica gel chromatography to provide 3,4-dihy-
[19]
droquinoxalin-2(1H)-one (3)
as a white solid; yield:
222 mg (75%). 1H NMR (600 MHz, CDCl3): d=8.62 (br.s,
1H), 6.92–6.84 (m, 1H), 6.78–6.70 (m, 2H), 6.67 (d, J=
7.8 Hz, 1H), 3.99 (s, 2H), 3.86 (br.s, 1H); 13C NMR
(151 MHz, CDCl3): d=167.0, 133.8, 125.5, 124.0, 119.6,
115.7, 114.1, 47.2.
References
Amidation of 1m to form cyclohex-2-enone 4: (a) In situ
preparation of the acyl chloride of 1m before use. To a solu-
tion of carboxylic acid 1m (108 mg, 0.5 mmol) in dry CH2Cl2
(5 mL) were added oxalyl chloride (64 mL, 0.75 mmol) and
DMF (one drop) at 08C. The resulting mixture was stirred
at room temperature for 2 h. Then the solvents were re-
moved under vacuum, and the residue was diluted with dry
dichloromethane (2 mL), and then concentrated under
vacuum. The residue was dissolved in dry THF (2 mL) for
immediate use. (b) Amidation with amine 3. To a solution
of amine 3 (75 mg, 0.5 mmol) in dry THF (3 mL) was added
K2CO3 power (138 mg, 1 mmol). The suspension was cooled
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were washed with water and brine, dried over anhydrous
Na2SO4. The crude product was purified by silica gel chro-
matography to provide 4 as a white solid ꢀ; yield: 141 mg
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These are not the final page numbers!

FULL PAPERS
8 Iodine-Catalyzed Oxidative Aromatization: A Metal-Free
Concise Approach to meta-Substituted Phenols from
Cyclohex-2-enones
Adv. Synth. Catal. 2016, 358, 1 – 8
Shi-Ke Wang, Ming-Tao Chen, Da-Yuan Zhao, Xia You,
Qun-Li Luo*
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!