Potassium Persulfate Mediated Conjugation of β-Ketosulfones with TEMPO

Article abstract of DOI:10.1055/s-0036-1588317

We report a simple route for the preparation of α-aminoxy-β-ketosulfones in high yields by a potassium persulfate mediated α-aminoxylation of β-ketosulfones with TEMPO in acetonitrile at room temperature for 12 hours.

Full text of DOI:10.1055/s-0036-1588317

SYNLETT
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0
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
C.-K. Chan, M.-Y. Chang
Letter
Synlett
Potassium Persulfate Mediated Conjugation of β-Ketosulfones
with TEMPO
C.-K. Chan
O
O
S
K2S2O8, MeCN
r.t., 12 h
M.-Y. Chang*
O
O
S
Ar
R
O
O
N
(50–88%)
Ar
R
O
Department of Medicinal and Applied Chemistry,
Kaohsiung Medical University, Kaohsiung 807,
Taiwan
O
14 examples
Me
Me
Me
Me
Me
Me
Me
Me
N
mychang@kmu.edu.tw
Y
Y
Ar = Ph, 4-Tol, 4-FC6H4, 4-MeOC6H4, 4-O2NC6H4, 2-naphthyl, 4-biphenyl
R = Me, Ph, 4-Tol, 4-FC6H4, 4-MeOC6H4
Y = H, OH
Received: 13.07.2016
O
O
Accepted after revision: 28.08.2016
Published online: 09.09.2016
DOI: 10.1055/s-0036-1588317; Art ID: st-2016-w0454-l
O
O
O
Ar/H
R
Me
Me
Me
Me
N
reagents (1)–(4)
O
N
+
R
Ar/H
α
Me
Me
Me
Me
Abstract We report a simple route for the preparation of α-aminoxy-
β-ketosulfones in high yields by a potassium persulfate mediated α-
aminoxylation of β-ketosulfones with TEMPO in acetonitrile at room
temperature for 12 hours.
(1) Oxidants: CAN, Cu(I), Cu(II)
(2) Organocatalysts: proline, imidazolidinone, pyrrolidine, peptide
(3) Bases: LDA, iPr2NEt
(4) Photocatalysts: Ru(II), Ir(III), rose bengal
Key words ketosulfones, alkoxyamines, aminoxylation, potassium
persulfate, TEMPO, quinoxalines
Scheme 1 Synthetic routes to alkoxyamines
α-Alkoxyamination (α-aminoxylation) can serve as a di-
rect method for the activation of carbon atoms in the posi-
tions α to a functional group and subsequent coupling with
an oxyamino radical to generate a new carbon–oxyamino
bond under oxidative conditions.1 This is not only a key step
in the preparation of functionalized materials such as fire-
proofing agents or rheology modifiers, but it can also be
employed as a valuable route for the formation of useful
building blocks or carbon-radical precursors in organic
chemistry. Over the past decade, tremendous progress has
been made in the oxidative radical α-alkoxyamination of
carbonyl compounds (aldehydes and ketones) and 1,3-di-
carbonyl synthons (β-keto esters and β-diketones) with
TEMPO. Generally, these reactions are induced by oxidant-
mediated direct conjugation,2,3 organocatalyst-promoted
cross-coupling of enamine intermediates,4 base-promoted
alkylation of enolate intermediates,5 or by a photoinduced
route (Scheme 1).6 Although many efforts have been devot-
ed to synthesizing alkoxyamines, there is still a continuing
need to provide a new and efficient oxidative reagent for
the conjugation of 1,3-dicarbonyl synthons with TEMPO.
In continuation of our investigations on synthetic appli-
cations of β-ketosulfones,7 we developed the K2S2O8 (2a)-
mediated α-alkoxyamination of the β-ketosulfone 1a with
TEMPO (3a) in MeCN at room temperature for 12 hours. Re-
cently, Luo and Deng reported a synthetic route to vicinal
tricarbonyl compounds through DDQ-mediated C–H acti-
vated α-oxidation of β-keto esters with TEMPO; however,
they only examined one case of a β-ketosulfone skeleton
under these conditions (Scheme 2).8 Although DDQ is a
common oxidant and is often used in various oxidations,
the reported isolated yield was low (49%). On the basis of
our work, potassium persulfate (K2S2O8) provides a better
yield (80%). Taking into account the yield of the conjugated
Luo and Deng's work
O
O
S
O
O
S
Ph
Me
DDQ, TEMPO
O
O
N
Ph
Me
MeCN, r.t., 12 h
(49%)
O
Me
Me
Me
Me
1a
O
O
S
4a
Our work
O
O
S
Ph
Me
K2S2O8 (2a), TEMPO (3a)
O
O
N
Ph
Me
O
MeCN, r.t., 12 h
(80%)
Me
Me
Me
Me
1a
4a
Scheme 2 α-Alkoxyamination of a β-ketosulfone with TEMPO
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
C.-K. Chan, M.-Y. Chang
Letter
Synlett
adducts and the costs of the reagents DDQ and K2S2O8, we
believe that K2S2O8 is the optimal reagent for the overall
process.
served (entry 10). When MeCN was replaced by CH2Cl2 or
EtOAc, the yields were 37% and 45%, respectively (entries 11
and 12). A reduction in the reaction time from 12 to 5
hours, gave only a 36% yield of 4a, with 48% recovery of 1a
(entry 13) whereas increasing the reaction time to 40 h
gave a slightly reduced yield of 4a of 52% (entry 14). In-
creasing the temperature from room temperature to the re-
flux temperature gave a better yield (65%) after five hours,
whereas the yield fell to 35% after 12 hours (entries 15 and
16). Interestingly, traces of 4a (8%) were isolated at room
temperature after 40 hours in the absence of K2S2O8 (2a) in
open-vessel conditions (entry 17). On the basis of a higher
yield, we believe that K2S2O8 (1.1 equiv) and MeCN are an
optimal combination for the conjugation of β-ketosulfones
with TEMPO.
Having determined the optimal reaction conditions (Ta-
ble 1, entry 1), we explored the conversion of other sub-
strates (Table 2).9 The K2S2O8 (2a)-mediated α-aminoxyl-
ation of β-ketosulfones 1a–k with TEMPO analogues 3a and
3b in MeCN at room temperature for 12 h provided the cor-
responding α-aminoxy-β-ketosulfones 4a–n in yields of
50–88%. A diversity of electron-withdrawing and electron-
Initially, the reaction of β-ketosulfone 1a with 1.1 equiv-
alents of K2S2O8 (2a) and 1.2 equivalents of TEMPO (3a) in
MeCN at room temperature for 12 hours gave the alkoxy-
amine 4a in 80% yield (Table 1, entry 1). When we per-
formed the same reaction with 1.1 equivalents of DDQ (2b),
t-BuOOH (2c), H2O2 (2d), Oxone (2e), i-BuONO (2f), NaOCl
(2g), or (diacetoxyiodo)benzene (DIB; 2h), we did not ob-
tain better yields of the desired alkoxyamine 4a (entries 2–
8). When CAN (2i) was used as the oxidant, we obtained a
39% yield of alkoxyamine 4a along with a 21% yield of ben-
zoic acid (entry 9). These studies confirmed that K2S2O8
(2a) is an appropriate oxidant for the formation of alkoxy-
amine 4a. On increasing the amount of TEMPO from 1.1 to
2.0 equivalents, no obvious increase in the yield was ob-
Table 1 . Optimization of the Reaction Conditionsa
O
O
S
O
O
S
Ph
Me
oxidant 2, TEMPO (3a)
O
O
N
Ph
Me
O
conditions
Me
Me
Me
Me
Table 2 Synthesis of Alkoxyamines 4a–na
1a
O
O
S
4a
Ar
R
K2S2O8 (2a)
MeCN, r.t., 12 h
O
O
S
O
Entry Oxidant
(equiv)
Solvent
Temp
(°C)
Time
(h)
Yieldb (%)
of 4a
O
N
Ar
R
O
Me
Me
Me
Me
O
1
Me
Me
N
Me
Me
1
2
K2S2O8 (2a) (1.1)
DDQ (2b) (1.1)
tBuOOH (2c) (1.1)
H2O2 (2d) (1.1)
Oxone (2e) (1.1),
i-BuONO (2f) (1.1),
NaOCl (2g) (1.1),
DIB (2h) (1.1),
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
25
25
25
25
25
25
25
25
25
25
25
25
25
25
82
82
25
12
12
12
12
12
12
12
12
12
12
12
12
5
80
45
Y
4
3
<5c
<5c
<5c
<5c
<5c
<5c
39d
75
3
Y
4
Entry
Ar
R
Y
Product Yieldb
(%)
5
6
1
1a
1b
1c
1d
1e
1f
Ph
Me
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
H
4a
4b
4c
4d
4e
4f
80
83
83
85
80
56
80
85
81
52
81
88
50
80
7
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
H
H
H
H
H
H
H
H
H
8
Ph
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
9
CAN (2i) (1.1)
4-Tol
10
11
12
13
14
15
16
17
K2S2O8 (2a) (2.0)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (1.1)
K2S2O8 (2a) (0)
4-FC6H4
4-MeOC6H4
4-O2NC6H4
2-naphthyl
Ph
37
45
1g
1h
1i
4g
4h
4i
36e
52
40
5
4-FC6H4
65
1j
Ph
4-MeOC6H4
4-Tol
4j
12
40
35
1a
1e
1f
Ph
OH
OH
OH
OH
4k
4l
8f
4-FC6H4
4-MeOC6H4
4-biphenyl
4-Tol
a Reaction conditions: 1a (1.0 mmol), TEMPO (1.2 equiv), solvent (5 mL),
open vessel.
4-Tol
4m
4n
b Isolated yields.
1k
4-Tol
c 1a was recovered (85–92%).
d 21% of benzoic acid was isolated.
e 48% of 1a was recovered.
a Reaction conditions: 1 (1.0 mmol), 2a (1.1 mmol), 3 (1.2 mmol), MeCN (5
mL), 12 h, r.t.
f 81% of 1a was recovered.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
C.-K. Chan, M.-Y. Chang
Letter
Synlett
neutral groups Ar and R on the sulfone 1 were well tolerat-
ed; however, when Ar or R was an electron-donating group,
the corresponding products 4f, 4j, and 4m were obtained in
slightly lower yields (56, 52, and 50%, respectively; Table 2,
entries 6, 10, and 13).
scaffold present in useful synthetic intermediates11 and
bioactive molecules.12 The most popular reported proce-
dures for syntheses of quinoxalines involve the condensa-
tion of 1,2-diaminobenzenes with various polar ortho-car-
bon units, such as α-methylene aldehydes or ketones, 1,2-
diketones, epoxides, vicinal diols, diazoketones, alkenes, or
alkynes.13 Among these starting substrates, no examples of
an α-aminoxy-β-ketosulfone has been reported for the for-
mation of a quinoxaline. Condensation of α-aminoxy-β-ke-
tosulfone 4c, 4d, or 4f with benzene-1,2-diamine in reflux-
ing 1,4-dioxane for 10 hours gave the corresponding qui-
One the basis of these results, we propose a mechanism
in which the reaction proceeds by a single-electron transfer
(SET) process (Scheme 3).10 Initially, an SO4–∙ anion radical is
formed by hemolytic cleavage of K2S2O8. 1a′, the enol form
of 1a formed by keto–enol tautomerization, undergoes SET
–∙
with the SO4 to give radical A1. Resonance of the delocal-
ized electron in the radical A1 then gives the secondary car-
bon radical A2. Finally, coupling of A2 and TEMPO (3a) af-
fords 4a.2a During the process, O–O bond-forming and
bond-cleavage reactions of TEMPO and KSO4–∙ also occur.
noxaline 7a–c (62–71%)14 through
a tandem process
involving condensation of 4c, 4d, or 4f with benzene-1,2-
diamine and sequential intramolecular desulfonylation of
intermediate I and aromatization of intermediate II.
O
O
O
S
NH2
KO
S
O
K2S2O8 (2a)
2
Ar
Tol
O
O
NH2
N
N
Ar
O
N
O
O
S
O
O
S
OH
O
Me
Me
Me
Me
1,4-dioxane, reflux, 10 h
S
Ph
Me
Ph
Me
Ph
Me
O
O
O
A1
1a
1a'
TEMPO OSO3K
KSO H
+
4
4c, Ar = Ph
4d, Ar = 4-Tol
4f, Ar = 4-MeOC6H4
7a, Ar = Ph (69%)
7b, Ar = 4-Tol (62%)
7c, Ar = 4-MeOC6H4 (71%)
KSO4
+
TEMPO (3a)
O
O
S
condensation
aromatization
O
O
Ph
Me
Ar
O
O
S
N
N
Ar
O
O
N
Ph
Me
O
Me
Me
Me
Me
Me
Me
S
Tol
desulfonylation
A2
NH2
N
H
O
O
N
N
Me
Me
Me
Me
Me
Me
4a
II
I
Scheme 3 Plausible mechanism
Scheme 5 . Synthesis of 7a–c
By changing the α-substituent from a sulfonyl group to
a carbonyl group (β-diketones 5a and 5b) or an ethyl ester
group (β-keto ester 5c), we obtained the alkoxyamines 6a–c
in 47, 53, and 31% yield, respectively (Scheme 4). The α-
aminoxy-β-ketosulfones 4a–n provided better yields (50–
88%) than did the α-aminoxy-β-diketones 6a and 6b6d or
the α-aminoxy-β-keto ester 6c.2d
In summary, we have developed a simple route to α-
aminoxy-β-ketosulfones by K2S2O8-mediated α-aminoxyl-
ation of β-ketosulfones 1 with TEMPO 3 in MeCN at room
temperature for 12 hours. The products 4 were obtained in
good to high yields. The K2S2O8-mediated α-aminoxylation
of 1,3-dicarbonyl synthons 5 (β-diketones and β-keto ester)
gave the corresponding products 6 in moderate yields.
Moreover, quinoxalines 7 were synthesized by condensa-
tion of the α-aminoxy-β-ketosulfone products 4 with 1,2-
diaminobenzene. Further investigations on synthetic appli-
cations of β-ketosulfones will be conducted and published
in due course.
O
O
Ph
R1
O
O
K2S2O8 (2a), TEMPO (3a)
O
N
Ph
R1
MeCN, r.t., 12 h
Me
Me
Me
Me
5a, R1 = Me
5b, R1 = Ph
5c, R1 = OEt
6a, R1 = Me (47%)
6b, R1 = Ph (53%)
6c, R1 = OEt (31%)
Acknowledgment
The authors would like to thank the Ministry of Science and Technol-
ogy of the Republic of China for its financial support (MOST 105-
2113-M-037-001).
Scheme 4 Synthesis of alkoxyamines 6a–c
As an extension of our K2S2O8-mediated α-alkoxyamina-
tion of β-ketosulfones with TEMPO, we prepared a series of
quinoxalines 7a–c (Scheme 5). Quinoxaline is a versatile
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
C.-K. Chan, M.-Y. Chang
Letter
Synlett
Supporting Information
diketones, see: (d) Schroll, P.; König, B. Eur. J. Org. Chem. 2015,
309. For Ru(II)/β-keto esters, see: (e) Daniel, M.; Fensterbank, L.;
Goddard, J.-P.; Ollivier, C. Org. Chem. Front. 2014, 1, 551.
(7) Synthetic applications on β-ketosulfones. For styrylsulfones,
see: (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Synlett 2014, 25,
1739. For vinylcyclopropanes, see: (b) Chang, M.-Y.; Chen, Y.-C.;
Chan, C.-K. Tetrahedron 2014, 70, 8908. For tetrahydrofurans,
see: (c) Chang, M.-Y.; Cheng, Y.-C. Synlett 2016, 27, 854. For tet-
rahydropyrans, see: (d) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tet-
rahedron 2015, 71, 1192. For dihydropyrans, see: (e) Chang, M.-
Y.; Chen, Y.-H.; Cheng, Y.-C. Tetrahedron 2016, 72, 518. For pyr-
roles, see: (f) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2014,
16, 6252. For vinylfurans, see: (g) Chan, C.-K.; Lu, Y.-J.; Chang,
M.-Y. Tetrahedron 2015, 71, 9544. For arylfurans, see: (h) Chang,
M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 1264. For arenes,
see: (i) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17,
3142. For arylpyridazines, see: (j) Chang, M.-Y.; Lu, Y.-J.; Cheng,
Y.-C. Tetrahedron 2015, 71, 6840. For tetralins and benzosuber-
ans, see: (k) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2016, 18, 608.
For aryltetralins, see: (l) Chang, M.-Y.; Cheng, Y.-C. Org. Lett.
2016, 18, 1682. For arylnaphthalenes, see: (m) Chang, M.-Y.;
Huang, Y.-H.; Wang, H.-S. Tetrahedron 2016, 72, 1888. For
phenanthrenes, see: (n) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K.
Tetrahedron 2015, 71, 782. For phenanthrofurans, see: (o) Chan,
C.-K.; Chen, Y.-C.; Chen, Y.-L.; Chang, M.-Y. Tetrahedron 2015,
71, 9187.
Supporting information (experimental procedures and scanned pho-
tocopies of NMR (CDCl3) spectral data) for this article is available on-
line at http://dx.doi.org/10.1055/s-0036-1588317.
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References and Notes
(1) For reviews on α-alkoxyamination (α-aminoxylation), see:
(a) Hawker, C. J. Acc. Chem. Res. 1997, 30, 373. (b) Korolev, G. V.;
Marchenko, A. P. Russ. Chem. Rev. 2000, 69, 409. (c) Studer, A.
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Chem. Rev. 2008, 108, 1104. (f) Vogler, T.; Studer, A. Synthesis
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(h) Merino, P.; Tejero, T.; Delso, I.; Matute, R. Synthesis 2016, 48,
653. (i) Tebben, L.; Studer, A. Angew. Chem. Int. Ed. 2011, 50,
5034.
(2) Oxidant-mediated conjugation of 1,3-dicarbonyl synthons with
TEMPO. For CuCl2/β-keto esters, see: (a) Luo, X.; Wang, Z.-L.; Jin,
J.-H.; An, X.-L.; Shen, Z.; Deng, W.-P. Tetrahedron 2014, 70, 8226.
For alkenes/β-diesters, see: (b) Wetter, C.; Jantos, K.; Woithe, K.;
Studer, A. Org. Lett. 2003, 5, 2899. For CAN/β-keto esters, see:
(c) Feng, P.; Sun, X.; Su, Y.; Li, X.; Zhang, L.-H.; Shi, X.; Jiao, N.
Org. Lett. 2014, 16, 3388. (d) Feng, P.; Song, S.; Zhang, L.-H.; Jiao,
N. Synlett 2014, 25, 2717.
(8) For DDQ-mediated oxidation of β-keto esters, see: Wang, Z.-L.;
An, X.-L.; Ge, L.-S.; Jin, J.-H.; Luo, X.; Deng, W.-P. Tetrahedron
2014, 70, 3788.
(3) Oxidant-mediated conjugation of carbonyl synthons with
TEMPO. For CuCl/aldehydes, see: (a) Schoening, K.-U.; Fischer,
W.; Hauck, S.; Dichtl, A.; Kuepfert, M. J. Org. Chem. 2009, 74,
1567. For Cu/Fe/α-alkoxyketones, see: (b) Xie, Y.-X.; Song, R.-J.;
Liu, Y.; Liu, Y.-Y.; Xiang, J.-N.; Li, J.-H. Adv. Synth. Catal. 2013,
355, 3387.
(9) Alkoxyamines 4; General Procedure
K2S2O8 (2a, 300 mg, 1.1 mmol) was added to a solution of the
appropriate β-keto sulfone 1 (1.0 mmol) and TEMPO analogue 3
(1.2 mmol) in MeCN (5 mL) at r.t., and the mixture was stirred at
r.t. for 12 h. The solvent was evaporated and the residue was
diluted with H2O (10 mL). The mixture was extracted with
EtOAc (3 × 20 mL) and the organic layers were combined,
washed with brine, dried, filtered, and concentrated to afford
the crude product, which was purified by chromatography
[silica gel, hexanes–EtOAc (10:1 to 6:1)]
(4) Organocatalyst-mediated α-alkoxyamination of aldehydes via
enamine intermediates. For proline, see: (a) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293. (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2003, 125, 10808. For imidazolidinone, see:
(c) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124.
For pyrrolidine/electrolysis, see: (d) Bui, N.-N.; Ho, X.-H.; Mho,
S.-i.; Jang, H.-Y. Eur. J. Org. Chem. 2009, 5309. For imidazolidi-
none/CuCl2, see: (e) Simonovich, S. P.; Van Humbeck, J. F.;
MacMillan, D. W. C. Chem. Sci. 2012, 3, 58. (f) Abeykoon, G. A.;
Chatterjee, S.; Chen, J. S. Org. Lett. 2014, 16, 3248. For pyrroli-
dine/FeCl3, see: (g) Van Humbeck, J. F.; Simonovich, S. P.;
Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
10012. For peptide/FeCl2, see: (h) Akagawa, K.; Fujiwara, T.;
Sakamoto, S.; Kudo, K. Org. Lett. 2010, 12, 1804.
2-(Methylsulfonyl)-1-phenyl-2-[(2,2,6,6-tetramethylpiperi-
din-1-yl)oxy]ethanone (4a)
Colorless gum; yield: 282 mg (80%); 1H NMR (400 MHz, CDCl3):
δ = 8.03 (d, J = 7.2 Hz, 2 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.6
Hz, 2 H), 6.22 (s, 1 H), 3.11 (s, 3 H), 1.57 (br s, 6 H), 1.43 (br s, 2
H), 1.31 (br s, 4 H), 1.18 (br s, 3 H), 0.86 (br s, 3 H); 13C NMR (100
MHz, CDCl3): δ = 194.15, 136.34, 133.71 (2 C), 128.65 (2 C),
128.43 (2 C), 94.78, 61.70, 60.26, 40.46, 40.25, 37.16, 33.52,
32.57, 19.81, 16.25. HRMS (ESI): m/z [M + 1]+ calcd for C18H28
-
(5) Base-mediated α-alkoxyamination of carbonyl synthons via
enolate intermediates. For pyridine/ketones, see: (a) Li, Y.;
Pouliot, M.; Vogler, T.; Renaud, P.; Studer, A. Org. Lett. 2012, 14,
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E
C.-K. Chan, M.-Y. Chang
Letter
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E