Efficient selective formation of C-C single bonds and C=C double bonds by NBS-promoted oxidative coupling of β-keto esters

Article abstract of DOI:10.1080/00397910701578123

A new application of NBS, which results in the oxidative coupling of β-keto esters to selectively form C-C single and C=C double bonds, can be controlled by the amount of NBS and t-BuOK employed. This methodology adds a new entry to C-C single and C=C double-bond formation between active methylene groups under mild conditions with high selectivity. Copyright Taylor & Francis Group, LLC.

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Efficient Selective Formation of C‐C
Single Bonds and C˭C Double Bonds by
NBS‐Promoted Oxidative Coupling of β‐Keto
Esters
Zhiguo Wang a , Guodong Yin a , Aihua Chen a , Shengli Hu a & Anxin Wu a
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan, China
Version of record first published: 14 Dec 2007.
To cite this article: Zhiguo Wang , Guodong Yin , Aihua Chen , Shengli Hu & Anxin Wu (2007): Efficient
Selective Formation of C‐C Single Bonds and C˭C Double Bonds by NBS‐Promoted Oxidative Coupling of β‐Keto
Esters, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:24, 4399-4405
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Synthetic Communicationsw, 37: 4399–4405, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701578123
Efficient Selective Formation of C-C Single
Bonds and C55C Double Bonds by NBS-
Promoted Oxidative Coupling of b-Keto
Esters
Zhiguo Wang, Guodong Yin, Aihua Chen, Shengli Hu, and
Anxin Wu
Key Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
Wuhan, China
Abstract: A new application of NBS, which results in the oxidative coupling of b-keto
esters to selectively form C-C single and C55C double bonds, can be controlled by the
amount of NBS and t-BuOK employed. This methodology adds a new entry to C-C
single and C55C double-bond formation between active methylene groups under
mild conditions with high selectivity.
Keywords: active methylene groups, b-keto esters, NBS, oxidative coupling
Saturated and unsaturated 1,4-diketones are important precursors for synthesis
of some natural and synthetic products containing furan, pyrrole, thiophene,
and pyridazine derivative systems. To date, a variety of synthetic methods
for the preparation of 1,4-diketones via homocoupling procedures have been
developed.[1–8] In addition, in terms of availability and ease of handling,
N-bromosuccinimide (NBS) is a superior brominating reagent, and lots
of 1,3-dicarbonyl compounds, such as b-keto esters, b-diketones, and
Received January 26, 2007
Address correspondence to Zhiguo Wang, Key Laboratory of Pesticide and
Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, China. E-mail: chwangzg@yahoo.com.cn
4399

4400
Z. Wang et al.
b-sulfonyl ketones, may be reacted with NBS to afford the corresponding
a-brominated products in good yields.[9,10]
In this article, we report a novel application of NBS, namely the
oxidative coupling of b-keto esters to selectively synthesize saturated or
unsaturated 1,4-diketones, which is efficiently controlled by the amount of
NBS and t-BuOK employed. For example, 2.1 molar equivalents of NBS
and an equimolar amount t-BuOK delivered only saturated 1,4-diketones
(Scheme 1, left). When the amounts of NBS and t-BuOK were in the range
of 2.1–4.0 molar, a mixture of saturated and unsaturated 1,4-diketones was
obtained. When the amount was continually increased to 5.0 molar, exper-
imental results indicated that only unsaturated 1,4-diketones were produced
(Scheme 1, right). To the best of our knowledge, this is a previously
unknown method for the formation of C-C single and C55C double bonds.
To begin our study, several base systems (K2CO3, CsCO3, Na-EtOH,
NaH, and t-BuOK) were tested, and t-BuOK was proven to be more
effective for the reaction. The typical procedure for synthesis of compound
5b is as follows: To a stirred solution of ethyl benzoylacetate 5a (236 mg,
1 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere, t-BuOK
(235 mg, 2.1 mmol) was added. To this mixture, a solution of NBS
(372 mg, 2.1 mmol) in anhydrous THF (15 mL) was added dropwise, and
the mixture was stirred overnight at room temperature. The solvent was
removed under reduced pressure; the residue was quenched with water
(40 mL), followed by extraction with dichloromethane (3 ꢀ 10 mL). Then
the solvent was evaporated, and the residue was purified by column chrom-
atography with hexane–EtOAc (5:1), which delivered the saturated product
5b (223 mg) in 95% yield. To establish the generality of the procedure,
under these optimized reaction conditions, other substrates, as shown in
Table 1, were examined. The corresponding saturated 1,4-diketones
were obtained in excellent yields (90–96%, Table 1, product b) except
for ethyl 4-nitrobenzoylacetate 7a as substrate (entry 7). Probably, the
a-brominated b-keto esters intermediate was readily converted to other
Scheme 1.

Oxidative Coupling of b-Keto Esters
4401
Table 1. Selective preparation of C-C single and C55C double bonds
Entry
Substrates a
Products ba
Products ca
1
2
R ¼ C6H5
1b (95)
2b (96)
3b (92)
4b (90)
5b (95)
6b (90)
—
1c (80, E:Z ¼ 3:2)
2c (80, E-isomer)b
3c (68, E-isomer)b
4c (65, E-isomer)b
5c (90, E-isomer)b
6c (82, E:Z ¼ 4:1)
7c (55, E-isomer)b
—
R ¼ 4-MeOC6H4
3
R ¼ 3,4-(MeO)2C6H3
R ¼3,4,5,-(MeO)3C6H2
R ¼ 3,4-(OCH2O)C6H3
R ¼ 3-MeO-4-PhCH2O-C6H3
R ¼ 4-NO2C6H4
4
5
6
7
8
Ethyl acetoacetate
8b (95)
9b (94)
10b (92)
9
10
Acetylacetone
Diethyl malonate
—
10b (82)
aIsolated yields in parentheses.
bE-isomers were the exclusive isolated products.
products in the presence of the strong electron-withdrawing (NO2) on the
aromatic ring.
Interestingly, when 5.0 molar equivalents of NBS and an equivmolar
amount t-BuOK were employed, the only unsaturated olefinic product
1
(E)-5c was obtained in 90% yield (entry 5). In contrast to the H NMR
spectrum recorded for 5b, the spectrum for (E)-5c did not show the CH
methine resonance at d ¼ 5.43 ppm. To further confirm the presence of a
C55C double bond and to determine precise structural features of (E)-5c, an
X-ray structure determination (Fig. 1) was performed.[11] Specifically, the
˚
bond length between C9–C9a was found to be 1.334 A, confirming the
presence of a double bond. E-Isomer was the exclusive isolated product,
1
and only a trace amount of the Z-isomer was detected by H NMR analysis
of the crude reaction mixture. Similar reactions with substrates 2a–4a
Figure 1. X-ray structure of compound (E) 5c.

4402
Z. Wang et al.
yielded the corresponding major olefinic products, E-isomers of 2c–4c in
moderate to good yields (65–80%), respectively (entries 2–4). When ethyl
benzoylacetate 1a (entry 1) was reacted under the same conditions, an insepar-
able mixture of regioisomeric products, (E)- and (Z)-1c, in an approximate
1
ratio of 3:2 (estimated from H NMR analysis of crude product mixtures)
was produced. Similarly, employing substrate 6a afforded (E)-and (Z)-6c in
a ratio of 4:1 (entry 6). It was notable that 7a gave (E)-7c in moderate yield
(55%) even though the corresponding saturated product was not obtained in
that case.
To extend the scope of this novel reaction, we further investigated the use
of aliphatic 1,3-dicarbonyl compounds, ethyl acetoacetate 8a, acetylacetone
9a, and diethyl malonate 10a under identical reaction conditions. Most
notably, when the acetyl group was present in the substrates (entries 8 and
9), oxidation to the C55C double-bond level was not observed even when
the reaction time was prolonged to three days or the reaction temperature
was elevated to 508C. We hypothesize that the presumed keto-enol tautomer-
ization precludes further oxidation.[12] X-ray crystal structure confirms the
1
structure of 9b as the double enol tautomer.[13] In addition, the H NMR
spectrum recorded for 9b displays a resonance at d ¼ 16.8 ppm, which corre-
sponds to the H-atom involved in the intramolecular hydrogen-bonding
interaction.
In summary, we have described the novel use of NBS/t-BuOK mixtures
to selectively form C-C single bonds or C55C double bonds during the
oxidative coupling of b-keto esters. This research represents a new
approach to C-C single and C55C double-bond formation, which should be
broadly applicable to active methylene compounds. The reaction possesses
several advantageous features including good yields and easily accessible
starting materials, which suggest that this synthetic approach should be
widely applicable in organic synthesis of natural and synthetic products.
EXPERIMENTAL
NBS was recrystallized from AcOH and dried in vacuo before use. THF was
absolutely dried before use. Column chromatography was performed using
200- to 300-mesh silica gel. The melting point was determined with an
XT4A micromelting-point apparatus and was uncorrected. Infrared spectra
were recorded on a Perkin-Elmer PE-983 spectrometer as KBr film with
absorption in centimeters21. NMR spectra were recorded in CDCl3 on a
Varian Mercury 400 spectrometer, and resonances are given in parts per
million (d) relative to TMS. Mass spectra were measured on a Finnigan
Trace MS spectrometer. Elemental analyses were performed on a Vario EL
III elementary analysis instrument. The general experimental procedure for
synthesis of compounds b and c are analogous as given in the text. Selected
new compounds are characterized and listed.

Oxidative Coupling of b-Keto Esters
4403
(E)-2c: White crystals, mp 137–1388C. 1H NMR (400 MHz, CDCl3):
d ¼ 7.97 (d, 4H, J ¼ 8.8 Hz), 6.99 (d, 4H, J ¼ 8.8 Hz), 4.03 (q, 4H,
J ¼ 7.2 Hz), 3.89 (s, 6H), 0.97 (t, 6H, J ¼ 7.2 Hz). 13C NMR (100 MHz,
CDCl3): d ¼ 189.6, 164.1, 162.7, 141.8, 131.2, 128.9, 114.1, 62.5, 55.5,
13.4. IR (KBr): 1721 (s), 1665 (s) cm21. EI-MS: m/z (%) ¼ 441 (14)
[M þ 1]þ, 135 (100). Anal. calcd. for C24H24O8: C, 65.45; H, 5.49. Found:
C, 65.34; H, 5.56.
1
(E)-3c: White crystals, mp 142–1438C. H NMR (400 MHz, CDCl3):d¼
7.57–7.53 (m, 4H), 6.90 (d, 2H, J ¼ 8.4 Hz), 4.21 (q, 4H, J ¼ 7.2 Hz), 3.96
(s, 6H), 3.94 (s, 6H), 1.27 (t, 6H, J ¼ 7.2 Hz). 13C NMR (100 MHz,
CDCl3): d ¼ 198.0, 167.5, 153.6, 148.9, 129.0, 123.3, 110.0, 109.8, 61.1,
55.8, 55.7, 13.8 (only 12 of the 13 expected resonances were observed). IþR
(KBr): 1738 (s), 1675 (s) cm21. EI-MS: m/z (%) ¼ 501 (7) [M þ 1]
,
165 (100). Anal. calcd. for C26H28O10: C, 62.39; H, 5.64. Found: C, 62.48;
H, 5.58.
(E)-4c: White crystals, mp 151–1528C. 1H NMR (400 MHz, CDCl3):
d ¼ 7.31 (s, 4H), 4.38 (t, 4H, J ¼ 7.2 Hz), 3.92–3.90 (m, 18H), 1.40 (t, 6H,
J ¼ 7.2 Hz). 13C NMR (100 MHz, CDCl3): d ¼ 166.2, 152.9, 142.1, 125.5,
107.2, 106.7, 61.1, 60.9, 56.2, 14.4 (only 10 of the 11 expected resonances
were observed). IR (KBr): 1718 (s), 1638 (s) cm21. EI-MS: m/z (%) ¼ 561
(9) [M þ 1]þ, 195 (100). Anal. calcd. for C28H32O12: C, 59.99; H, 5.75.
Found: C, 60.08; H, 5.71.
1
(E)-5c: Green crystals, mp 145–1468C. H NMR (400 MHz, CDCl3): d¼
7.54–7.51 (m, 4H), 6.89 (d, 2H, J ¼ 8.0 Hz), 6.09 (s, 4H), 4.07 (q, 4 H,
J ¼ 7.2 Hz), 1.01 (t, 6H, J ¼ 7.2 Hz). 13C NMR (100 MHz, CDCl3):
d ¼ 189.0, 162.5, 152.6, 148.4, 141.7, 130.6, 126.0, 108.2, 107.7, 102.0,
62.6, 13.4. IR (KBr): 1721 (s), 1668 (s) cm21. EI-MS: m/z (%) ¼ 469 (39)
[M þ 1]þ, 148 (100). Anal. calcd. for C24H20O10: C, 61.54; H, 4.30. Found:
C, 61.50; H, 4.37.
(E)-7c: White crystals, mp 147–1488C. 1H NMR (400 MHz, CDCl3):
d ¼ 8.28 (d, 4H, J ¼ 2.4 Hz), 8.22 (d, 4H, J ¼ 2.4 Hz), 4.44 (q, 4H, J
¼7.2 Hz), 1.43 (t, 6H, J ¼ 7.2 Hz). 13C NMR (100 MHz, CDCl3):
d ¼ 164.7, 150.5, 135.8, 130.6, 123.5, 61.9, 14.2 (only 7 of the 9 expected res-
onances were observed). IR (KBr): 1733 (s), 1674 (s). EI-MS: m/z (%) ¼ 471
(14) [M þ 1]þ, 150 (100). Anal. calcd. for C22H18N2O10: C, 56.17; H, 3.86; N,
5.96. Found: C, 56.21; H, 3.80; N, 6.02.
ACKNOWLEDGMENT
This work was supported by Central China Normal University, the Scientific
Research Foundation for the Returned Overseas Chinese Scholars, and State
Education Ministry (No. [2005] 383).

4404
Z. Wang et al.
REFERENCES
1. Linker, T.; Linker, U. Simple synthesis of tetra-Acceptor-substituted alkenes by
the formal dehydrodimerization of malonates. Angew. Chem. Int. Ed. 2000, 39,
902.
2. Quast, H.; Seefelder, M.; Ivanova, S.; Heubes, M.; Peters, E. M.; Peters, K. Tetra-
acylethenes as dienophiles and hetero dienes in two-step Diels-Alder reactions.
Eur. J. Org. Chem. 1999, 3343.
3. Wu, A.; Zhao, Y.; Chen, N.; Pan, X. A Modification of the knorr oxidative
coupling method for preparation of 1,4-diketones. Synth. Commun. 1997, 27, 331.
4. Skarzewski, J.; Zon, J. Tetramethyl ethene-1,1,2,2-tetracarboxylate: oxidative
homocoupling of dimethyl malonate in the presence of magnesium oxide. Synth.
Commun. 1995, 25, 2953.
5. Liu, Y.-C.; Romero, J. R. Chemical and electrochemical oxidative dimerization of
carbonyl compounds by cerium(IV) salts. a comparative Study. Tetrahedron Lett.
1995, 36, 8757.
6. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Reactions of arylazosulfones with
the conjugate bases of active-methylene compounds. Tetrahedron 1995, 51, 3905.
7. Villemin, D.; Alloum, A. B. Potassium fluoride on alumina: oxidative coupling of
acidic carbon compounds with diiodine. Synth. Commun. 1992, 22, 3169.
8. Aidhen, I. S.; Narasimhan, N. S. Intramolecular arylation of soft carbon centre or
enolate using Mn(III) acetate: studies towards spirostructure of fredericamycin A.
Tetrahedron Lett. 1989, 30, 5323.
9. (a) Yang, D.; Yan, Y.-L.; Lui, B. Mild a-halogenation reactions of 1,3-dicarbonyl
compounds catalyzed by lewis acids. J. Org. Chem. 2002, 67, 7429;
(b) Misra, A. P.; Raj, K.; Bhaduri, A. P. In Search of Imidazo [1,2-a] pyridine
derivatives exhibiting resistance for catalytic hydrogenation. Synth. Commun.
1999, 29, 3227; (c) Coats, S. J.; Wasserman, H. H. The conversion of a-bromo-
b-dicarbonyls to vicinal tricarbonyls using dimethyldioxirane and base. Tetrahe-
dron Lett. 1995, 36, 7735; (d) Endo, M.; Droghini, R. 1-b-Methylcarbapenem
intermediates Stereoselective synthesis of (3S,4R)-3-[(1R)-1-tert-butyldimethyl-
silyloxyethyl]-4-[(1R)-3-methoxycarbonyl-1-methyl-2-oxopropyl]azetidin-2-one
and its related chemistry. Can. J. Chem. 1988, 66, 1400; (e) Hlavka, J.; Bitha, P.;
Lin, Y.; Strohmeyer, T. Reactions of 2,3-diamino-4(3H)-pyrimidinones. II.
J. Heterocycl. Chem. 1985, 22, 1317; (f) Yoshida, J.; Yano, S.; Ozawa, T.;
Kawabata, N. Regioselective synthesis of dihydrofurans from 2,2-dibromo-1,3-
diketone and olefin using copper. Tetrahedron Lett. 1984, 25, 2817;
(g) Kaye, P. T.; Meakins, G. D.; Smith, A. K.; Tirel, M. D. N,N-disubstituted 2-
aminothiazole-5-carboxylates: preparation and rotation of functional groups.
J. Chem. Soc., Perkin Trans. 1 1983, 1677.
10. (a) Boyd, R. E.; Rasmussen, C. R.; Press, J. B. Regiospecific synthesis of unsym-
metrical a-bromoketones. Synth. Commun. 1995, 25, 1045; (b) Karimi, S.;
Grohmann, K. G. Intramolecular ring-opening of cyclopropanones by enolate
anions. J. Org. Chem. 1995, 60, 554; (c) Curran, D. P.; Bosch, E.; Kaplan, J.;
Newcomb, M. Rate constants for halogen atom transfer from representative
a-halo carbonyl compounds to primary alkyl radicals. J. Org. Chem. 1989, 54,
1826; (d) Curran, D. P.; Chang, C. T. Atom transfer cyclization reactions of
a-iodo esters, ketones, and malonates: examples of selective 5-exo, 6-endo, 6-
exo, and 7-endo ring closures. J. Org. Chem. 1989, 54, 3140.
11. Wang, Z.; Chen, A.; Yin, G.; Wu, A. Diethyl 2,3-bis(benzo[1,3]dioxole-5-
carbonyl)-but-2-enedioate. Acta Cryst. 2005, E61, o2320.

Oxidative Coupling of b-Keto Esters
4405
12. Burdett, J. L.; Rogers, M. T. Keto-Enol tautomerism in b-dicarbonyls studied by
nuclear magnetic resonance spectroscopy.1 I. Proton chemical shifts and equili-
brium constants of pure compounds. J. Am. Chem. Soc. 1964, 86, 2105.
13. (a) Schaefer, J. P.; Wheatley, P. J. The crystal and molecular structure of tetra-acet-
ylethane. J. Chem. Soc. A 1966, 528; (b) Power, L. F.; Turner, K. E.;
Moore, F. H. J. Refinement of the crystal and molecular structure of tetraacety-
lethane by neutron diffraction. Cryst. Mol. Struct. 1975, 5, 59;
(c) Lyssenko, K. A.; Lyubetsky, D. V.; Antipin, M. Y. Intramolecular H-bonds
in the crystal of tetraacetylethane: 3c-4e interaction or a dynamic disorder?.
Mendeleev Commun. 2003, 13, 60.