Preparation of β-keto esters and β-diketones by C-acylation/deacetylation of acetoacetic esters and acetonyl ketones with 1-acylbenzotriazoles

Article abstract of DOI:10.1021/jo049274l

Acyl-, aroyl-, and heteroaroyl-acetic esters 6a-f and 8a-1 are prepared by reactions of 1-acylbenzotriazoles 1a-k with acetoacetic esters 5 or 7a,b in the presence of sodium hydride followed by regioselective deacetylation. Similar C-acylation/deacetylati

Full text of DOI:10.1021/jo049274l

P r ep a r a tion of â-Keto Ester s a n d â-Dik eton es by C-Acyla tion /
Dea cetyla tion of Acetoa cetic Ester s a n d Aceton yl Keton es w ith
1-Acylben zotr ia zoles
Alan R. Katritzky,* Zuoquan Wang, Mingyi Wang, Chavon R. Wilkerson, C. Dennis Hall, and
Novruz G. Akhmedov
Center for Heterocyclic Compounds, University of Florida, Department of Chemistry,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received April 29, 2004
Acyl-, aroyl-, and heteroaroyl-acetic esters 6a -f and 8a -l are prepared by reactions of 1-acylbenzo-
triazoles 1a -k with acetoacetic esters 5 or 7a ,b in the presence of sodium hydride followed by
regioselective deacetylation. Similar C-acylation/deacetylation of acetylacetone and benzoylacetone
affords â-diketones 10a -d and 13a -c, respectively.
SCHEME 1
In tr od u ction
â-Keto esters and â-diketones have been important
intermediates in organic synthesis since the discovery of
the Claisen condensation more than a century ago.1a-i
Familiar general syntheses of â-diketones and â-keto
esters include (i) acylation of ketones or carboxylic esters
by acyl halides or esters2a-d and (ii) acylation of acety-
lacetone or ethyl acetoacetate and their substituted
derivatives by acyl halides or esters followed by base-
promoted cleavage of a carbonyl group.3a-c The above
methods offer many useful synthetic procedures, but
some acyl halides, such as 3-phenyl-2-propynoyl chloride
and 2-pyridoyl chloride, are quite tedious to synthesize,
store, and handle and therefore are often prepared in
situ. Moreover, â-keto ester and â-diketone anions are
ambident; thus, when acetylacetone or ethyl acetoacetate
are reacted with electrophiles such as acyl chlorides in
the presence of base, both C- and/or O-acylation can
occur. For example, under phase-transfer conditions,
acylation of acetylacetone and of ethyl acetoacetate with
acetyl chloride and benzoyl chloride yielded O-acylated
enol esters in 83-98% yields.4a-c The nature of the
solvent, electrophile, metal counterion, reaction temper-
ature, and structure of the substrate influence the
chemoselectivity of such acylations.5
Benzotriazole is a good leaving group and has been
used extensively as a novel synthetic auxiliary.6a-c Gen-
erally, 1-acylbenzotriazoles 1 are more stable than acid
chlorides and can be used in many N-,7a-d C-,8a-c and
O-acylation reactions9a,b (Scheme 1).
We now show that C-acylations of acetoacetic esters
by 1-acylbenzotriazoles, followed by spontaneous deacety-
lation, lead to useful preparative methods for acyl-, aroyl-,
(4) (a) March, J . March’s Advanced Organic Chemistry, 3rd ed.; J ohn
Wiley & Sons: New York, 1985; pp 436-436. (b) J ones, R. A.; Nokkeo,
S.; Singh, S. Synth. Commun. 1977, 7, 195-199. (c) Taylor, E. C.;
Hawks, G. H., III; Mckillop, A. J . Am. Chem. Soc. 1968, 90, 2421-
2422.
(5) Black, T. H. Org. Prep. Proced. Int. 1989, 21, 179-217.
(6) (a) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron
1991, 47, 2683-2732. (b) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko,
O. V. Chem. Rev. 1998, 98, 409-548. (c) Katritzky, A. R.; Lan, X.; Fan,
W.-Q. Synthesis 1994, 445-456.
(7) (a) Katritzky, A. R.; Levell, J . R.; Pleynet D. P. M. Synthesis 1998,
153-156. (b) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J . Org. Chem. 2000,
65, 8210-8213. (c) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.;
Akhmedov, N. G. Arkivoc 2002, viii, 134-142. (d) Katritzky, A. R.;
Rogovoy, B. V.; Kirichenko, N.; Vvedensky, V. Bioorg. Med. Chem. Lett.
2002, 12, 1809-1811.
(8) (a) Katritzky, A. R.; Pastor, A.; J . Org. Chem. 2000, 65, 3679-
3682. (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J . Org.
Chem. 2003, 68, 1443-1446. (c) Katritzky, A. R.; Abdel-Fattah, A. A.
A.; Wang, M. J . Org. Chem. 2003, 68, 4932-4934.
(9) (a) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J . Heterocycl.
Chem. 1999, 36, 777-781. (b) Wedler, C.; Kleiner, K.; Kunath, A.;
Schick, H. Liebigs Ann. 1996, 881-885.
* Corresponding author.
(1) (a) Claisen, L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20,
651-654. (b) Claisen, L. Liebigs Ann. Chem. 1896, 291, 100-111. (c)
Yoshida, M.; Fujikawa, K.; Sato, S.; Hara, S. Arkivoc 2003, vi, 36-42.
(d) Cristau, H.-J .; Marat, X.; Vors, J .-P.; Pirat, J .-L. Tetrahedron Lett.
2003, 44, 3179-3181. (e) Christoffers J .; Oertling, H.; Fisher, P.; Frey,
W. Tetrahedron 2003, 59, 3769-2778. (f) Kotha, S.; Manivannan, E.
Arkivoc 2003, iii, 67-76. (g) Kollenz, G.; Dalvi, T. S.; Kappe, C. O.;
Wentrup, C. Arkivoc 2000, 1 (1), 74-79. (h) Katritzky, A. R.; Silina,
A.; Tymoshenko, D. O.; Qiu, G.; Nair, S. K.; Steel, P. J . Arkivoc 2001,
vii, 138-144. (i) Falsone, F. S.; Kappe, C. O. Arkivoc 2001, ii, 122-
134.
(2) (a) Movchan, T. I.; Voloshanovskii, I. S. J . Appl. Chem. USSR
(Engl. Transl.) 1992, 65, 1973-1976. (b) Linn, B. O.; Hauser, C. R. J .
Am. Chem. Soc. 1956, 78, 6066-6070. (c) Hauser, C. R.; Hudson, B.
E., J r. In Org. React.; Adams, R., Bachmann, W. E., J ohnson, J . R.,
Fieser, L. F., Snyder, H. R., Eds.; J ohn Wiley & Sons: New York, 1942;
Vol. 1, pp 266-289. (d) Casey, M.; Donnelly, J . A.; Ryan, J . C.; Ushioda,
S. Arkivoc 2003, vii, 310-327.
(3) (a) Berend, L.; Heymann, F. J . Prakt. Chem. 1902, 290-294. (b)
Duff, J . C. J . Chem. Soc. 1914, 105, 2182-2186. (c) McElvain, S. M.;
Weber, K. H. J . Am. Chem. Soc. 1941, 63, 2192-2197.
10.1021/jo049274l CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004
J . Org. Chem. 2004, 69, 6617-6622
6617

Katritzky et al.
SCHEME 2
a
Products were recovered as mixtures of keto/enol tautomers as evidenced by 1H NMR in CDCl3. b Determined by 1H NMR of products
6. c Products were recovered almost entirely in keto form with the exception of 8b and 8k , where the percentage of the enol form was 7%
for 8b and 100% for 8k as determined by 1H NMR in CDCl3. Quenched with silica gel.
d
and heteroaroyl-acetic esters. Similar treatment of ac-
etonyl ketones affords a variety of â-diketones.
together with microanalyses. The 1H NMR spectra of
6a -f show new sets of singlets at δ 3.43-4.86 assigned
to the R-methylene protons, and the 13C NMR spectra
show signals at δ 45.3-49.2 corresponding to the R-me-
Resu lts a n d Discu ssion
1
thylene carbons. While some H and 13C signals for enol
1-Acylbenzotriazoles 1a -n were readily prepared by
treating carboxylic acids either (i) in THF with 1-(meth-
ylsulfonyl)-1H-1,2,3-benzotriazole in the presence of tri-
ethylamine under reflux overnight7bor (ii) with thionyl
chloride and benzotriazole at 25 °C.10
Condensation of the corresponding enolates of ethyl
acetoacetate 5 (Scheme 2, A) with 1-acylbenzotriazoles
1a -f at rt for 14 h, followed by cleavage of the acetyl
group in situ with an aqueous solution of ammonium
chloride and ammonium hydroxide under reflux and in
the presence of benzotriazole moiety gave â-keto esters
6a -f in 58-85% yields. No O-acylation or other byprod-
ucts were detected.
forms in the tautomeric mixtures 6a -f are not visible or
overlap with those of their keto forms, singlets at δ 4.98-
6.61 in 1H NMR spectra and signals at δ 86.6-89.9 in
13C NMR spectra are assigned to the olefinic hydrogens
and their respective carbons and clearly indicate the
presence and relative quantity of the corresponding enol
forms. An exception is 6d , for which the 13C signal of the
R-methine carbon was not observed. In nearly all cases,
the keto forms of the â-keto esters 6 predominate in the
keto-enol tautomeric mixtures in CDCl3 solution. An
exception, however, is 6e, where at 20 °C in CDCl3
solution the enol:keto ratio is 3:2, probably due to the
strong electron-withdrawing effect of the pyridyl group
(Scheme 2,A). This assignment and tautomeric preference
The structures of the known â-keto esters 6a ,11 6b,12
6c,13 6d ,14 6e,15 and 6f 6 are supported by comparison of
their melting points and spectroscopic data with litera-
ture reports and, in some cases, by 1H/13C NMR data
(13) Karnik, A. V.; Rane, J . P. Indian J . Chem. Sect. B 1998, 37,
1191-1193.
(14) Taylor, E. C.; Turchi, I. J . Org. Prep. Proced. Int. 1978, 10, 221-
224.
(10) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795-
(15) Carabateas, P. M.; Brundage, R. P.; Gelotte, K. O.; Gruett, M.
D.; Lorenz, R. R.; Opalka, C. J ., J r.; Singh, B.; Thielking, W. H.;
Williams, G. L.; Lesher, G. Y. J . Heterocycl. Chem. 1984, 21, 1849-
1856.
2798.
(11) Balaji, B. S.; Chanda, B. M. Tetrahedron 1998, 54, 13237-
13252.
(12) Lee, L. F.; Schleppnik, F. M.; Howe, R. K. J . Heterocycl. Chem.
1985, 22, 1621-1630.
(16) Matsuo, K.; Kimura, M.; Kimuta, T.; Takai, N.; Tanata, K.
Chem. Parm. Bull. 1984, 32, 4197-4204.
6618 J . Org. Chem., Vol. 69, No. 20, 2004

SCHEME 3
a
1
Products were recovered in mixtures of enol/keto tautomers as evidenced by 1H NMR in CDCl3. b Determined by H NMR of products
10a -d . c Byproduct 11 was isolated in 18% yield. Byproducts 10b and 12 were isolated in 23 and 24% yields, respectively.
d
is in accord with the results of previously reported
theoretical and experimental studies.17
in which both acetyl groups were replaced by benzoyl.
Reaction of 9 with 2 equiv of either 1c or 1g gave
symmetrical â-diketones 10b and 10c in almost quanti-
tative yields. Reaction of 9 with a mixture of 1 equiv of
1c and 1 equiv of 1d yielded unsymmetrical â-diketone
10d in 52% yield and two byproducts 10b and 1224 in 23
and 24% yields, respectively.
Transformations analogous to those described above
also succeeded with other R-acetyl carboxylic esters.
Thus, â-keto esters 7a and 7b were similarly converted
into 8a -g and 8h -k , respectively in 51-76% isolated
yields (Scheme 2B).
The keto structures of the known 8a ,18 8c,19 8f,20 8j,21
The enol structures of the known â-diketones 10a ,25a,b
and novel 8b,d ,e,g-i,l are confirmed by their 1H/13C
10b,26 and 10c27 and the novel 10d are supported by H/
1
1
NMR data. The H NMR spectra for each of 8a -g show
13C NMR spectra, which show a set of singlets at δ 6.18-
6.81 corresponding to the R-olefinic protons and signals
at δ 92.1-96.7 assigned to the R-olefinic carbons.28 All
the â-diketones 10a -d contained the corresponding keto
forms as minor tautomers. The minor keto structures
were characterized by 1H singlets between δ 4.1 and 4.57
and 13C NMR signals between δ 50 and 54.7, and the
two sets of quartets between δ 3.51 and 4.71 assigned to
R-methine protons and OCH2 protons and for 8h -j,l
triplets between δ 4.41 and 4.62 corresponding to R-me-
thine protons. The 13C NMR signals for 8a -j,l at δ 47.3-
57.4 correspond to tertiary carbons of the keto forms. The
only enol form detected as a minor tautomer among 8a -
j,l was in 8b (7% enol in CDCl3 solution), for which δH )
12.80 (OH) and δC ) 94.6 (the disubstituted olefinic
carbon) were found. Unlike 8a -j,l ethyl (Z)-2-benzyl-3-
hydroxy-5-phenyl-2-penten-4-ynoate 8k exists entirely in
the enol form in CDCl3 solution. Thus, the 1H NMR
spectrum of 8k shows two singlets at δ 3.80 and 12.40,
corresponding to the two methylene protons in the benzyl
group and hydroxy group in the enol form, respectively,
and 13C NMR shows a signal at δ 108.4, assigned to the
disubstituted olefinic carbon. This assignment is in
accord with previously reported experimental studies.22
Analogous transformations also worked smoothly with
acetylacetone 9 (Scheme 3). Thus, reaction of 9 with 1a
produced both the expected â-diketone 10a (55%) pre-
dominately in the enol form (in CDCl3) and dibenzoyl-
methane 1123 (18%) as a byproduct of a double reaction
1
relative amounts were estimated by H NMR.
An analogous transformation was successful with
1-benzoylacetone 10a which, on reaction with 1-acylben-
zotriazole 1l produced the expected â-diketone 13a in
62% yield almost entirely in the enol form. Reaction with
1d gave 13b in 61% yield and two byproducts 11 and 12
in 17 and 15% yields, respectively. Similarly, reaction
with 1g produced 13c (61%) (Scheme 4).
The structures of the known products 13a ,29 13b,30 and
1
13c31a,b are supported by microanalyses and H/13C NMR
1
data, which show H singlets between δ 6.37 and 6.77
and 13C signals at δ 92.7-96.2 corresponding to enol
forms.28 Compounds 13a and 13b contained the corre-
(24) Barluenga, J .; del Pozo, C.; Olano, B. Synthesis 1996, 133-
140.
(25) (a) Ukai, K.; Oshima, K.; Matsubara, S. J . Am. Chem. Soc. 2000,
122, 12047-12048. (b) Muir, W. M.; Ritchie, P. D.; Lyman, D. J . J .
Org. Chem. 1966, 31, 3790-3793.
(17) Burdett, J . L.; Rogers, M. T. J . Am. Chem. Soc. 1964, 86, 2105-
2109.
(26) Hao, W.; Zhang, Y.; Ying, T.; Lu, P. Synth. Commun. 1996, 26,
2421-2427.
(18) Emelina, E. E.; Semenova, N. A.; Ershov, B. A. J . Org. Chem.
USSR (Engl. Transl.) 1974, 10, 1044-1048.
(27) Ishii, A.; Nakuyama, J .; Kazami, J .-i.; Ida, Y.; Nakamura, T.;
Hoshino, M. J . Org. Chem. 1991, 56, 78-82.
(19) Lukesˇ, R.; Sˇrogl, J . Collection Czechoslov. Chem. Commun.
1961, 26, 2238-2243.
(28) Hayamizu, K.; Yanagisawa, M.; Yamamoto, O. J apanese Inte-
grated Spectral Data Base System for Organic Compounds; National
Institute of Advanced Industrial Science and Technology: Tsukuba,
J apan, 2001; SDBS No. 874.
(20) Turner, J . A.; J acks, W. S. J . Org. Chem. 1989, 54, 4229-4235.
(21) Queignec, R.; Kirschleger, B.; Lambert, F.; Aboutaj, M. Synth.
Commun. 1988, 18, 1213-1223.
(22) Zaugg, H. E.; Michaels, R. J .; Baker, E. J . J . Am. Chem. Soc.
1968, 90, 3800-3808.
(29) Tolkunov, S. V. Chem. Heterocycl. Compd. (Engl. Transl.) 1998,
34, 1132-1136.
(23) Allen, C. F. H.; Abell, R. D.; Normington, J . B. In Organic
Syntheses; Gilman, H., Adams, R., Marvel, C. S., Clarke, H. T., Noller,
C. R., Conant, J . B., Whitmore, F. C., Eds.; J ohn Wiley & Sons: New
York, 1941; Coll. Vol. 1, pp 205-206.
(30) Okuzumi, T. Nippon Kagaku Zasshi 1961, 82, 1235-1240.
(31) (a) Mitchell, A. D.; Nonhebel, D. C. Tetrahedron 1976, 32, 2437-
2438. (b) Harris, S. R.; Levine, R. J . Am. Chem. Soc. 1948, 70, 3360-
3361.
J . Org. Chem, Vol. 69, No. 20, 2004 6619

Katritzky et al.
SCHEME 4
a
1
Products were recovered in mixtures of enol/keto tautomers as evidenced by 1H NMR in CDCl3. b Determined by H NMR of products
13a -c. c Byproducts 11 and 12 were isolated in 17 and 15% yields respectively. Byproducts 11 and 10c were isolated in 16 and 15%
yields, respectively.
d
SCHEME 5
sponding keto forms as the minor tautomers in CDCl3
solution, but no keto form was detected in 13c. The keto
structures of 13a and 13b were characterized by 1H
singlets between δ 4.28 and 4.48 and 13C signals between
δ 51 and 50.0.
When the reaction of 9 with 1a was quenched with
dilute hydrochloric acid, 10a (57%) and 11 (16%) were
again obtained in yields similar to those showed in
Scheme 3, together with 1-(1H-1,2,3-benzotriazol-1-yl)-
1-ethanone 149a (21%, Scheme 5), but no 1-(2H-1,2,3-
benzotriazol-2-yl)-1-ethanone was detected. Formation
and isolation of 1-(1H-1,2,3-benzotriazol-1-yl)-1-ethanone
14 suggests an intermolecular benzotriazole-mediated
acylation/deacetylation process to give 10a , 11, and 14,
which is similar to one previously reported13 (path 1 of
Scheme 5). Presumably, formation of 11 in reactions of
10a with 1d or 1g (Scheme 4) followed path 2 of Scheme
5 and formation of 12 and 10c followed path 3 of Scheme
6620 J . Org. Chem., Vol. 69, No. 20, 2004

SCHEME 6
a
b
1-Phenylcyclopropyl. 2-(2-Phenylethyl)phenyl.
5. In these cases, however, debenzoylation took place,
instead of deacetylation.
of this method includes the following: (i) most acylben-
zotriazoles are stable to storage over months; (ii) the use
of acylbenzotriazoles offers mild reaction conditions and
operational ease and, more importantly, O-acylation is
greatly reduced; and (iii) acetoacetic esters and R-acetyl
ketones are obtained in good to excellent yields. The
approach offers efficient, one-pot methodology for func-
tional group interchange by acylation, aroylation, or
heteroaroylation of R-acetyl ketones or acetoacetic esters
followed by deacetylation. The method is probably most
valuable when it is desirable to avoid using the corre-
sponding acid chlorides.
Attempts to capture the postulated C-acylated inter-
mediates 16 (Scheme 6) by shortening the reaction time
to 2-3.5 h and avoiding the hydrolysis step by quenching
with silica gel failed. Under these conditions, the main
isolated intermediates were O-acylated (E)-enol esters
15a -e in 27-36% yields.
A possible explanation for the formation of 15a -e, but
not the C-acylated intermediates 16, is that formation
of the O-acylated (E)-enol esters is less sterically hindered
than formation of C-acylated intermediates. This is
supported by formation of C-acylated products 8c-g and
8k ,l, which have relatively small acyl groups when the
reactions were also quenched with silica gel (Scheme 2B).
Presumably, in some cases, e.g., (E)-enol ester 15c and
keto ester 8j, kinetically favored O-acylation products 15
gradually convert to their corresponding C-acylation
intermediates 16, which in the presence of benzotriazole
moiety form the thermodynamically stable C-acylation
products 8. Similarly, during the preparation of keto ester
8l, the corresponding O-acylation product 15 was isolated
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. Melting points were
determined on a hot-stage apparatus and are uncorrected.
NMR spectra were recorded in CDCl3 with TMS as the internal
standard for 1H (300 MHz) or CDCl3 as the internal standard
for 13C (75 MHz), unless otherwise specified. Elemental and
mass spectrometry analyses were performed by Analytical
Laboratories, Department of Chemistry, University of Florida.
All reactions were carried out under an atmosphere of nitro-
gen. Anhydrous THF was obtained by distillation immediately
prior to use, from sodium/benzophenone ketyl. Column chro-
matography was performed with S733-1 silica gel (200-425
mesh).
1
and characterized by H NMR with a reaction time of 3
h; however, with a reaction time of 14 h, only 8l was
isolated.
The spectral and analytical data of the novel 15a -e
Gen er a l P r oced u r e for th e P r ep a r a tion of â-Keto
Ester s 6a -f. To a stirred solution of ethyl acetoacetate 5 (0.66
g, 5 mmol) in THF (30 mL) was added NaH (60%, 0.27 g, 5.5
mmol) at rt, and stirring was continued for 40 min under
nitrogen. Each 1-acylbenzotriazole (1a -f: 5 mmol) in THF (30
mL) was then added by syringe at room temperature, and the
resulting mixture was stirred at room temperature for 14 h
under nitrogen. Water (22 mL), ammonium chloride (0.88 g,
16.5 mmol), and ammonium hydroxide (28.8%, 0.21 mL) were
added to the mixture, which was then heated under reflux for
1 h. The mixture was acidified to pH 5 with 0.05 N HCl (∼50
mL) and then extracted with AcOEt (3 × 50 mL). The
combined organic phase was washed with water (2 × 50 mL)
and dried over anhydrous MgSO4. Removal of solvents under
reduced pressure and purification of the residue by column
chromatography on silica gel gave the corresponding pure
â-keto esters 6.
1
confirm their (E)-enol ester structures. Thus, H NMR
for 15a ,b show typical homoallylic coupling constants of
1.5 Hz for two olefinic methyl groups. Each 1H NMR
spectrum of the remaining three enol esters 15c-e
displays a triplet between δ 2.29 and 2.46 and a slightly
broadened singlet between δ 3.48 and 3.66 corresponding
to the olefinic methyl and the methylene of benzyl groups,
respectively. The (E)-configuration of 15a -e is supported
by the fact that no NOE enhancement was found between
the two olefinic methyl groups of 15a ,b or the methyl
and the benzyl groups of 15c-e. Olefinic carbons were
also detected in the 13C spectra of 15a -e at δ 117.0-
121.8 and 156.7-157.6, consistent with previously re-
ported experimental studies32
Gen er al P r ocedu r e for th e P r epar ation of r-Mon oalkyl-
Su bstitu ted â-Keto Ester s 8a ,b,h -j. To a stirred solution
of ethyl R-monosubstituted acetoacetate 7a or 7b (5 mmol) in
THF (30 mL) was added NaH (60%, 0.20 g, 5 mmol for 8a ,b,h ,i;
0.27 g, 6.6 mmol for 8j) at room temperature, and stirring was
continued for 40 min under nitrogen. Each 1-acylbenzotriazole
(1c,f,d ,g,a : 5 mmol) in THF (30 mL) was added by syringe at
room temperature, and the resulting mixture was stirred for
In summary, a simple procedure for the preparation
of acetoacetic esters and R-acetyl ketones has been
developed by treatment of starting acetoacetic esters or
R-acetyl ketones with 1-acylbenzotriazoles in the presence
of sodium hydride, followed by hydrolysis. The advantage
(32) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903-3906.
J . Org. Chem, Vol. 69, No. 20, 2004 6621

Katritzky et al.
14 h under nitrogen. Water (22 mL), ammonium chloride (0.88
g, 16.5 mmol), and ammonium hydroxide (28.8%, 0.21 mL)
were added to the mixture, which was then heated under
reflux for 1 h. The mixture was worked up in the same method
as for 6 to give the corresponding pure â-keto ester 8.
Gen er al P r ocedu r e for th e P r epar ation of r-Mon oalkyl-
Su bstitu ted â-Keto Ester s 8c-g,l a n d r-Ben zyl-â-en ol
Ester 8k . To a stirred solution of ethyl R-monosubstituted
acetoacetate 7a or 7b (5 mmol) in THF (30 mL) was added
NaH (60%, 0.20 g, 5 mmol) at room temperature, and stirring
was continued for 40 min under nitrogen. Each 1-acylbenzo-
triazole (1d ,g,h ,a ,j,i,k : 5 mmol) in THF (30 mL) was added
by syringe at room temperature, and the resulting mixture
was stirred for 3-14 h. A small amount of silica gel was added
to the reaction mixture and THF was removed under reduced
pressure. The residue was purified by column chromatography
on silica gel to give the corresponding R-monoalkyl-substituted
â-keto esters 8c-g,l and R-benzyl-â-enol ester 8k .
Gen er a l P r oced u r e for th e P r ep a r a tion of â-Dik eton es
10a -d . To a stirred solution of the acetylacetone 9 (0.51 g, 5
mmol) in THF (30 mL) was added NaH (60%, 0.2 g, 5 mmol
for 10a ; 0.4 g, 10 mmol for 10b-d ) at room temperature, and
stirring was continued for 40 min under nitrogen. Each
1-acylbenzotriazole (1a , 5 mmol; 1c, 10 mmol; 1g, 10 mmol;
1c, 5 mmol, + 1d , 5 mmol) in THF (30 mL) was added by
syringe at room temperature, and the resulting mixture was
stirred for 14 h under nitrogen. Water (22 mL), ammonium
chloride (0.88 g, 16.5 mmol), and ammonium hydroxide (28.8%,
0.21 mL) were added to the mixture, which was then heated
under reflux for 1 h. The same workup was followed as for 6
to give the corresponding products 10.
mmol) at rt, and stirring was continued for 40 min under
nitrogen. Each 1-acylbenzotriazole (1k ,d ,g: 5 mmol) in THF
(30 mL) was added by syringe at room temperature, and the
resulting mixture was stirred at room temperature for 14 h
under nitrogen. Water (22 mL), ammonium chloride (0.88 g,
16.5 mmol), and ammonium hydroxide (28.8%, 0.21 mL) were
added to the mixture, which was then heated under reflux for
1 h. The same workup was followed as for 6 to give the
corresponding products 13a -c.
Gen er a l P r oced u r e for th e P r ep a r a tion of O-Acyla ted
En ola tes 15a -e. To a stirred solution of ethyl R-monosub-
stituted acetoacetate 7a or 7b (5 mmol) in THF (30 mL) was
added NaH (60%, 0.20 g, 5 mmol) at room temperature, and
stirring was continued for 40 min under nitrogen. Each
1-acylbenzotriazole (1m ,n ,a ,c: 5 mmol) in THF (30 mL) was
added to the yellow suspension by syringe at room tempera-
ture, and the resulting mixture was stirred for 2-3.5 h. A
small amount of silica gel was added to the reaction mixture,
and THF was removed under reduced pressure. The residue
was purified by column chromatography on silica gel using a
mixture of hexanes/chloroform (3/1 f 1/1, v/v) as an eluant to
give the corresponding product 15 as a colorless oil.
Ack n ow led gm en t. We thank National Institute of
Advanced Industrial Science and Technology, J apan, for
online Integrated Spectral Data Base System for Or-
ganic Compounds.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 6a -f; 8a ,b,h ,i,j; 8c-g,k ,l; 11, 10a -d , 12;
13a -c; and 15a -e. This material is available free of charge
via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of â-Dik eton s
13a -c. To a stirred solution of 1-benzoylacetone 10a (0.81 g,
5 mmol) in THF (30 mL) was added NaH (60%, 0.27 g, 6.6
J O049274L
6622 J . Org. Chem., Vol. 69, No. 20, 2004