Dithiolane-directed tandem oxidation/1,2-benzyl migration of tetramic acids under ambient conditions

Article abstract of DOI:10.1002/adsc.201200096

Reactions directly involving triplet oxygen are an important issue in organic and biological chemistry. We now report that exposure of tetramic acids in the open air (molecular oxygen) at room temperature can lead to the formation of succinimide derivatives in high to excellent yields via tandem oxidation/1,2-benzyl migration. In this reaction, the dithiolane moiety plays a crucial role and succinimides are produced either in the presence or absence of dibutyl sulfide as reductant. Copyright

Full text of DOI:10.1002/adsc.201200096

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DOI: 10.1002/adsc.201200096
Dithiolane-Directed Tandem Oxidation/1,2-Benzyl Migration of
Tetramic Acids under Ambient Conditions
Yifei Li,a Xianxiu Xu,a,* Chunyu Xia,a Ling Pan,a and Qun Liua,*
a
Department of Chemistry, Northeast Normal University, Changchun 130024, Peopleꢀs Republic of China
Fax : (+86)-431-8509-9759; e-mail: xuxx677@nenu.edu.cn or liuqun@nenu.edu.cn
Received: February 5, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200096.
Abstract: Reactions directly involving triplet
oxygen are an important issue in organic and bio-
logical chemistry. We now report that exposure of
tetramic acids in the open air (molecular oxygen) at
room temperature can lead to the formation of suc-
cinimide derivatives in high to excellent yields via
tandem oxidation/1,2-benzyl migration. In this reac-
tion, the dithiolane moiety plays a crucial role and
succinimides are produced either in the presence or
absence of dibutyl sulfide as reductant.
(Figure 1).[4,5] In comparison, the reaction of D, a non-
pyrrolic cyclic amino acid derivative, could not give
the corresponding hydroperoxide product E, indicat-
ing the crucial role of the electron-donating pyrrole
moiety
in
the
aerobic
oxidation
reaction
(Scheme 1).[3]
During efforts to develop the synthetic utility of al-
kenoyl ketene dithioacetals,[8–10] recently, succinimide
derivative 3a was isolated as a by-product of the
transformation of cinnamoyl ketene dithioacetal 1a
into tetramic acid 2a (via intramolecular aza-anti-Mi-
chael addition) under basic conditions in open air
(Scheme 2).[10a,11] To the best of our knowledge, the
transformation of 2a into 3a not only provides a new
approach to the synthesis of succinimide derivatives[12]
and a mild method for the oxidative rearrangement of
tetramic acids,[13] but also represents a new reaction
Keywords: 1,2-benzyl migration; dithiolanes; oxida-
tion; triplet oxygen
The utilization of environmentally friendly molecular
oxygen is a highly attractive topic in organic and bio-
logical chemistry.[1–7] In this context, the selective oxi-
dation of organic compounds using molecular oxygen,
instead of metal salts, peroxides and other more so-
phisticated oxidants, has attracted increasing attention
in recent years.[1,2] However, examples of the incorpo-
ration of molecular oxygen into organic compounds
under metal-free conditions or without photoexcita-
tion are still scarce. In a series of reports, Al-Moura-
bit and co-workers[3] showed that cyclic amino acid
derivatives having a pyrrole unit could be converted
easily to hydroperoxides and the corresponding re-
duced derivatives under mild conditions using molec-
ular oxygen as oxidant. For example, treatment of A
with O2 in DMF solvent at room temperature in the Scheme 1. Pyrrole-assisted oxidation.
absence of a base for 0.5 h, gave hydroperoxide B in
quantitative yield. Under identical conditions but with
the addition of four equivalents of dibutyl sulfide as
reductant for 3 h, compound C was produced in 93%
yield (Scheme 1).[3a] These properties are similar to
those of flavins, for example, 5-ethyl-3-methyllumifla-
vin, which can catalyze oxidations of sulfides and
amines with molecular oxygen via its hydroperoxide Figure 1. 5-Ethyl-3-methyllumiflavin and its hydroperoxide.
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Dithiolane-Directed Tandem Oxidation/1,2-Benzyl Migration of Tetramic Acids
Scheme 2.
Table 1. Reactions of 2a under various conditions.[a]
(Table 1, entry 6) or under a nitrogen atmosphere
(Table 1, entry 7). It is noteworthy that, under similar
conditions as in Table 1, entry 2, the oxidative rear-
rangement reaction proceeded smoothly to afford 3a
in excellent yield when the reaction was carried out in
the dark (Table 1, entry 8).
Furthermore, it was found that tetramic acid 4[10b]
was inert to the oxidation conditions. After treatment
under the optimal conditions (Table 1, entry 2) for
48 h, 4 was completely recovered (Scheme 3). This
Entry
Base (equiv.)
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
KOH (1.0)
KOH (2.0)
NaOH (2.0)
K2CO3 (2.0)
Et3N (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
48
90
93
91
3.0
3.5
48
48
48
nd[c]
nd[c]
nd[c]
nd[c,d]
91[e]
CH3CN
CH3CN
3.0
3.0
[a]
Reaction conditions: 2a (1.0 mmol), solvent (5 mL).
Yield of isolated product.
Not detected.
The reaction was carried out under a nitrogen atmos-
phere.
The reaction was performed in the dark.
[b]
[c]
[d]
Scheme 3.
[e]
result indicates the crucial role of the 1,3-dithiolan-2-
ylidene moiety of 2 in the aerobic oxidation reaction
involving tandem C H oxidation/1,2-benzyl migration due to its stronger electron-releasing ability to the tet-
ꢀ
[14]
ꢀ
(1,2-C C migration)
in which molecular oxygen ramic acid (pyrrolidine-2,4-dione) ring system (p-p
serves as the sole oxidant in the absence of transition conjugation)[16] which is consistent with related re-
metal catalysts and photoexcitation.[1–7,13,15] In addi- ports on the direct oxidation of cyclic a-amino acid-
tion, different from the oxidation reactions of flavins derived diketopiperazines[3] with molecular oxygen
and cyclic amino acid derivatives,[3,4] tetramic acids 2 under metal-free systems (also see Scheme 1).
show a strong tendency to form oxidative rearrange-
Next, under optimal conditions as in Table 1,
ment products. In this communication, the prelimina- entry 2, a series of experiments aimed to investigate
ry results on this new oxidative rearrangement reac- the influence of the Ar and R groups of tetramic
tion are described.
acids 2 for the dithiolane-directed tandem oxidation/
In the present study, at first, the reaction of tetra- 1,2-benzyl migration was performed and the results
mic acid derivative 2a was investigated (Table 1). It are summarized in Table 2. It was proved that the oxi-
was found that succinimide 3a could be obtained in dative rearrangement of 2 having phenyl (Table 2, en-
excellent yield (93%) by treatment of 2a (1.0 mmol) tries 1–4), electron-rich (Table 2, entries 5, 9, 10 and
with KOH (2.0 equiv.) in acetonitrile (5 mL) at room 15), or electron-deficient (Table 2, entries 6–8, 11–14
temperature in the open air for 3 h (Table 1, entry 2). and 16) aryl/heteroaryl groups can afford the corre-
A similar result was obtained by using NaOH (2.0 sponding succinimide derivatives 3 in high to excel-
equiv.) as the base (Table 1, entry 3). In comparison, lent yields where R=benzyl (Table 2, entries 1 and 5–
K2CO3 and Et3N were ineffective under otherwise 9), 4-methylbenzyl (Table 2, entries 11–14), 4-chloro-
identical conditions (Table 1, entries 4 and 5). Howev- benzyl (Table 1, entry 16), or various alkyl groups
er, no reaction was observed either in ethanol solvent (Table 2, entries 2, 3, 10 and 15).
Adv. Synth. Catal. 2012, 354, 1712 – 1716
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Yifei Li et al.
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Table 2. Synthesis of succinimides 3.[a]
Entry 3
Ar
R
Time [h] Yield [%][b]
1
2
3
4
5
6
7
8
3a Ph
3b Ph
3c Ph
3d Ph
Bn
Me
t-Bu
2-Br-Bn
3
91
90
90
95
91
91
93
90
94
91
90
88
79
91
92
89
90[c]
24
24
3
2.5
12
12
18
8
3e 4-Me-C6H4 Bn
3f 4-Cl-C6H4
3g 3-Cl-C6H4
3h 4-Br-C6H4
3i 2-furyl
Bn
Bn
Bn
Bn
allyl
4-Me-C6H4 48
4-Me-C6H4 48
4-Me-C6H4 40
9
10
11
12
13
14
15
16
17
3j 2-furyl
24
3k 2-pyridyl
3l 3-pyridyl
3m 4-pyridyl
3n 3-NO2-C6H4 4-Me-C6H4 36
3o 2-furyl
3p 2-pyridyl
3k 2-pyridyl
Scheme 4. Proposed mechanism for the transformation of 2
into 3.
n-Pr
4-Cl-C6H4 48
4-Me-C6H4
24
2
[2f]
ꢀ
the diradical intermediate V via O O homolysis
[a]
Reaction conditions: 2 (1.0 mmol), KOH (2.0 equiv.),
CH3CN (5 mL), room temperature in open air.
Yield of isolated product.
The reaction was carried out under an oxygen atmos-
phere (oxygen was bubbled into the stirred solution).
and subsequent intramolecular 1,2-migration of the
benzyl group to give succinimides 3. In this mecha-
nism, a 1,4-type non-bonded sulfur-oxygen interaction
in intermediate II/IIꢀ may play an important role for
the introduction of triplet oxygen (Table 2 vs.
Scheme 3) although it is not clear at this stage.[18]
Different from the oxidation of cyclic a-amino
[b]
[c]
The above results show that tetramic acids 2 with acid-derived diketopiperazines and flavins with mo-
electron-rich aryl substituents (Ar) react at a faster lecular oxygen, in which the corresponding hydroper-
rate (Table 2, entry 5 vs. entries 6–8). In addition, the oxide products can be reduced by sulfides (for exam-
reaction rate significantly increases under an oxygen ple, dibutyl sulfide, see Scheme 1).[3a,4,5] In our experi-
atmosphere (Table 2, entry 11 vs. entry 17). In addi- ments, however, none the corresponding hydroperox-
tion, it was found that a stoichiometric amount of ide product could be detected by performing the reac-
oxygen (0.5 equiv. of O2) was required for the tandem tion of 2a under optimal conditions (Table 1, entry 2)
oxidation/1,2-benzyl migration reaction. For example, in the presence of 4.0 equiv. of (n-Bu)2S or PPh3 as re-
succinimide 3a was obtained in 90% yield from the ductant. In these cases, similar with the reactions of 2
reaction of 2a (1.0 mmol) in acetonitrile (5 mL) in the in the absence of reductants (Table 2), succinimide 3a
presence of KOH (2.0 equiv.) and molecular oxygen was obtained in excellent yields. These results may in-
(0.6 equiv.) at room temperature for 3 h.[17] On the dicate that the intramolecular nucleophilic attack of
basis of the above experimental results and related re- the peroxy anion on the adjacent carbonyl carbon
ports,[3–5,15] the proposed mechanism for the transfor- (III!IV) is faster than the reduction of the hydroper-
mation of 2 into 3 is outlined in Scheme 4.
oxide intermediate and thus drives the reaction to un-
The process may involve: (i) deprotonation of 2 dergo further rearrangement (Scheme 4, III!IV!
into enolate anion I followed by a single-electron V!3).
transfer (SET) process between I and triplet oxygen
The construction of distinct types of complex mole-
to form the superoxide anion radical and the radical cules from identical starting materials is an attractive
intermediate II/II’; (ii) reaction of IIꢀ with superoxide and challenging task in organic synthesis.[19] Thus, the
anion radical to produce the anion intermediate possibility of a single-step transformation of cinnamo-
III;[3,4] (iii) intramolecular nucleophilic attack of the yl ketene dithioacetals 1 into succinimides 3 was fur-
peroxy anion on the adjacent carbonyl carbon[3c,15] ther examined. As the result, 3a was obtained in 70%
through a 4-exo-trig cyclization to yield the 1,2-dioxe- yield by treating 1a with NaH (2.0 equiv.) in DMSO
tane intermediate IV,[3] and finally (iv) formation of (5 mL) at room temperature in open air for 20 h via
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Adv. Synth. Catal. 2012, 354, 1712 – 1716

Dithiolane-Directed Tandem Oxidation/1,2-Benzyl Migration of Tetramic Acids
Zhu, Angew. Chem. 2011, 123, 5796; Angew. Chem. Int.
Ed. 2011, 50, 5678; c) Y.-H. Zhang, J.-Q. Yu, J. Am.
Chem. Soc. 2009, 131, 14654; d) J. W. Kim, K. Yamagu-
chi, N. Mizuno, Angew. Chem. 2008, 120, 9389; Angew.
Chem. Int. Ed. 2008, 47, 9249; e) A. M. Khenkin, L.
Weiner, R. Neumann, J. Am. Chem. Soc. 2005, 127,
9988; f) A. Wang, H. Jiang, H. Chen, J. Am. Chem.
Soc. 2009, 131, 3846.
Scheme 5. One-step synthesis of 3a.
[3] a) H. Tian, L. Ermolenko, M. Gabant, G. Vergne, C.
Moriou, P. Retailleau, A. Al-Mourabit, Adv. Synth.
Catal. 2011, 353, 1525; b) N. Travert, A. Al-Mourabit, J.
Am. Chem. Soc. 2004, 126, 10252; c) C. Vergne, J. Ap-
penzeller, C. Ratinaud, M.-T. Martin, C. Debitus, A.
Zaparucha, A. Al-Mourabit, Org. Lett. 2008, 10, 493.
[4] For reviews on flavin-catalyzed oxidations, see: a) F. G.
Gelalcha, Chem. Rev. 2007, 107, 3338; b) Y. Imada, T.
Naota, Chem. Rec. 2007, 7, 354.
a tandem intramolecular aza-anti-Michael addition/
oxidation/1,2-benzyl migration process (Scheme 5).
In conclusion, succinimide derivatives 3 were syn-
thesized in high to excellent yields under very mild
conditions via oxidative rearrangement of tetramic
acids 2. This new oxidative rearrangement reaction is
unique in several respects including the use of triplet
oxygen as oxidant without activation (metal-free sys-
tems without photoexcitation). Particularly, it reveals
that the appended dithiolane moiety in tetramic acids
2 can play a key role in the aerobic oxidation by in-
corporating molecular oxygen into organic substrates.
Further investigation of the reaction scope, and on
the mechanisms is currently underway.
[5] Y. Imada, H. Iida, S. Ono, S.-I. Murahashi, J. Am.
Chem. Soc. 2003, 125, 2868.
[6] J. Kaizer, E. Balogh-Hergovich, M. Czaun, T. Casy, G.
Speier, Corrd. Chem. Rev. 2006, 250, 2222.
[7] a) J. Zhao, Y. Zhao, H. Fu, Angew. Chem. 2011, 123,
3853; Angew. Chem. Int. Ed. 2011, 50, 3769; b) V. A.
Schmidt, E. J. Alexanian, Angew. Chem. 2010, 122,
4593; Angew. Chem. Int. Ed. 2010, 49, 4491; c) B. C.
Giglio, V. A. Schmidt, E. J. Alexanian, J. Am. Chem.
Soc. 2011, 133, 13320; d) M. Wang, Z. Fu, H. Feng, Y.
Dong, J. Liu, Q. Liu, Chem. Commun. 2010, 46, 9061.
[8] For a review, see: L. Pan, Q. Liu, Synlett 2011, 1073.
[9] a) Y. Li, X. Xu, J. Tan, C. Xia, D. Zhang, Q. Liu, J.
Am. Chem. Soc. 2011, 133, 1775; b) J. Tan, X. Xu, L.
Zhang, Y. Li, Q. Liu, Angew. Chem. 2009, 121, 2912;
Angew. Chem. Int. Ed. 2009, 48, 2868.
[10] a) Y. Li, X. Xu, J. Tan, P. Liao, J. Zhang, Q. Liu, Org.
Lett. 2010, 12, 244; b) X. Bi, J. Zhang, Q. Liu, J. Tan, B.
Li, Adv. Synth. Catal. 2007, 349, 2301.
[11] CCDC 832246 (3a) and CCDC 833018 (3k) contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Experimental Section
General Procedure for the Synthesis of 3 (Taking 3a
as an Example)
To the stirred mixture of 2a (383 mg, 1.0 mmol) in CH3CN
(5 mL) was added KOH (112 mg, 2.0 mmol) in one portion
at room temperature. After stirred for 3.0 h, the substrate 2a
was consumed as indicated by TLC. Then the resulting mix-
ture was poured into ice-water (50 mL) under stirring. The
precipitated solid was collected by filtration, the solid
washed with water (3ꢂ10 mL), and dried under vacuum to
afford the crude product 3a, which was purified by flash
chromatography (silica gel, petroleum ether:diethyl ether=
1:2, v/v) to give 3a; yield: 370 mg (93%).
Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[12] For recent reports on the synthesis of succinimide de-
rivatives, see: a) K. M. Driller, H. Klein, R. Jackstell,
M. Beller, Angew. Chem. 2009, 121, 6157; Angew.
Chem. Int. Ed. 2009, 48, 6041; b) G.-Q. Li, Y. Li, L.-X.
Dai, S.-L. You, Org. Lett. 2007, 9, 3519; c) M. Adib, S.
Ansari, H. R. Bijanzadeh, Synlett 2011, 619; d) S. Pra-
teeptongkum, K. M. Driller, R. Jackstell, A. Spannen-
berg, M. Beller, Chem. Eur. J. 2010, 16, 9606; e) D. Ba-
savaiah, B. Devendar, K. Aravindu, A. Veerendhar,
Chem. Eur. J. 2010, 16, 2031; f) T.; Kondo, M. Nomura,
Y.; Ura, K. Wada, T.-a. Mitsudo, J. Am. Chem. Soc.
2006, 128, 14816.
Acknowledgements
Financial support of this research provided by the NNSFC
(21072027 and 21172030), and the Fundamental Research
Funds for the Central Universities (09 QNJJ017) is greatly
acknowledged.
[13] For enzymatically mediated oxidative rearrangement of
tetramic acids to pyridone alkaloids, see: a) L. M. Halo,
M. N. Heneghan, A. A. Yakasai, Z. Song, K. Williams,
A. M. Bailey, R. J. Cox, C. M. Lazarus, T. J. Simpson, J.
Am. Chem. Soc. 2008, 130, 17988; b) M. Isaka, P. Chin-
thanom, S. Supothina, P. Tobwor, N. L. Hywel-Jones, J.
Nat. Prod. 2010, 73, 2057.
References
[1] For reviews, see: a) E. L. Clennana, A. Pace, Tetrahe-
dron 2005, 61, 6665; b) P. R. Ogilby, Chem. Soc. Rev.
2010, 39, 3181; c) A. E. Wendlandt, A. M. Suess, S. S.
Stahl, Angew. Chem. 2011, 123, 11256; Angew. Chem.
Int. Ed. 2011, 50, 11062.
[2] a) C. Zhang, N. Jiao, J. Am. Chem. Soc. 2010, 132, 28;
b) H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang, Q.
[14] a) K. Suzuki, H. Takikawa, Y. Hachisu, J. W. Bode,
Angew. Chem. 2007, 119, 3316; Angew. Chem. Int. Ed.
Adv. Synth. Catal. 2012, 354, 1712 – 1716
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1715

Yifei Li et al.
COMMUNICATIONS
2007, 46, 3252; b) M. M. Hussain, H. Li, N. Hussain, M.
UreÇa, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc.
2009, 131, 6516; c) K. C. Guꢃrard, A. Guꢃrinot, C. Bou-
chard-Aubin, M.-A. Mꢃnard, M. Lepage, M. A. Beau-
lieu, S. Canesi, J. Org. Chem. 2012, 77, 2121.
[18] a) F. V. Gonzalez, A. Jain, S. Rodriguez, J. A. Saez, C.
Vicent, G. Peris, J. Org. Chem. 2010, 75, 5888; b) R. K.
Dieter, Tetrahedron 1986, 42, 3029.
[19] For recent reports, see: a) B. Alcaide, P. Almendros, T.
Martınez del Campo, Angew. Chem. 2007, 119, 6804;
Angew. Chem. Int. Ed. 2007, 46, 6684; b) X. Jiang, X.
Ma, Z. Zheng, S. Ma, Chem. Eur. J. 2008, 14, 8572;
c) L. Liu, J. Zhang, Angew. Chem. 2009, 121, 6209;
Angew. Chem. Int. Ed. 2009, 48, 6093; d) A. S. Dudnik,
Y. Xia, Y. Li, V. Gevorgyan, J. Am. Chem. Soc. 2010,
132, 7645; e) P. A. Evans, J. R. Sawyer, P. A. Inglesby,
Angew. Chem. 2010, 122, 5882; Angew. Chem. Int. Ed.
2010, 49, 5746; f) P. Panne, J. M. Fox, J. Am. Chem.
Soc. 2007, 129, 22.
[15] a) D. Sheng, D. P. Ballou, V. Massey, Biochemistry
2001, 40, 11156. For recent reviews on the Baeyer–Vil-
liger reaction, see: b) H. Leisch, K. Morley, P. C. K.
Lau, Chem. Rev. 2011, 111, 4165; c) G.-J. ten Brink,
I. W. C. E. Arends, R. A. Sheldon, Chem. Rev. 2004,
104, 4105.
[16] T. Okuyama, Acc. Chem. Res. 1986, 19, 370.
[17] Three parallel experiments gave similar results.
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