Reactions of glycidyl derivatives with ambident nucleophiles. Part 1: Ethyl acetoacetate

Article abstract of DOI:10.1016/S0040-4020(00)00788-2

The formation of functionalized furans and pyrans from the title reactants is analyzed with regard to the reaction conditions and to the nature of the leaving group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00788-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8669±8672
Reactions of Glycidyl Derivatives with Ambident Nucleophiles.
Part 1: Ethyl Acetoacetate
*
Gerald Dyker and Andreas Thone
È
È È
Institut fur Synthesechemie, Fachbereich 6, Gerhard-Mercator-Universitat Duisburg, Lotharstraûe 1, D-47048 Duisburg, Germany
Received 10 August 2000; accepted 30 August 2000
AbstractÐThe formation of functionalized furans and pyrans from the title reactants is analyzed with regard to the reaction conditions and
to the nature of the leaving group. q 2000 Elsevier Science Ltd. All rights reserved.
Ethyl acetoacetate (1) as well as glycidyl derivatives 2 such
as epichlorohydrin (2a)1a and glycidyl tosylate (2d)1b are
important industrial chemicals available and regularly
applied in bulk quantities. We were surprised to notice
that exclusively a furanoid cyclization product of these
compounds has been described in literature2 and no
pyranoid product, which we could isolate for the ®rst
time. Clearly, a thorough investigation of cyclization reac-
tions of 1 with 2 is missing, a gap we wish to ®ll with this
article.
X we could isolate and identify four types of products
(Scheme 1). With epichlorohydrin (2a) exclusively
lactone 5a with the chloromethyl side chain was found
(Table 1, entry 1: NaOEt as base in ethanol at 508C), a
product already known from an `Organic Synthesis'
procedure.2 In contrast, applying epibromohydrin (2b),
epiiodohydrin (2c) or glycidyl tosylate (2d) let to the
formation of a mixture of dihydrofuran 33 and tetrahydro-
pyran 4 (Table 1, entries 2±4). Surprisingly, 4 has never
been described before and became the main product when
starting from tosylate 2d. In the case of epibromohydrin
(2b) changing the base from NaOEt to K2CO3 had a
minor in¯uence on the yield but no in¯uence on the product
ratio (entry 6), whereas the nature of the solvent in¯uenced
both yield and product ratio: in the case of the tosylate 2d
applied in DMF the O-alkylation product 64 was identi®ed
as the main product.
1 and 2 are both multifunctionalized compounds, which
have several opportunities for interaction: up to four
nucleophilic and two electrophilic centers can be active in
the case of 1, in the case of 2 one can localize one
nucleophilic and three electrophilic centers. Depending on
the reaction conditions and especially on the leaving group
Scheme 1. Types of products derived from reactions of ethyl acetoacetate (1) with glycidyl derivatives 2.
Keywords: ambident nucleophiles; cyclization; nucleophilic substitution; pyrans.
* Corresponding author. Tel.: 1208-379-2831; fax: 1208-379-4192; e-mail: dyker@uni-duisburg.de
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00788-2

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G. Dyker, A. Thone / Tetrahedron 56 (2000) 8669±8672
8670
Table 1. Base induced coupling reactions of ethyl acetoacetate (1) with glycidyl derivatives 2 (the ratio of 3:4 was determined by 1H NMR (500 MHz, CDCl3)
of the crude product; diagnostic signals: for 3: dˆ2.20 (t, Jˆ1.6 Hz, 3H, vinyl-CH3); for 4: dˆ2.26 (t, Jˆ1.5 Hz, 3H, vinyl-CH3); yield of the puri®ed product
after Kugelrohr distillation is given)
Entry
X
Solvent
Base
T [8C]
t [d]
Yield [%]: 314 (ratio)
5
6
1
2
3
4
5
6
7
8
9
10
Cl
Br
I
OTos
Br
Br
Br
Br
EtOH
EtOH
EtOH
EtOH
DMF
EtOH
DMF
DMF
DMF
DMF
NaOEt
NaOEt
NaOEt
NaOEt
Li2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
50
50
50
50
50
50
50
20
50
20
1
1
1
1
2
2
2
2
2
1
±
42
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
30
54 (64:36)
43 (81:19)
60 (25:75)
44 (100:0)
60 (63:37)
19 (100:0)
33 (100:0)
13 (88:12)
4 (57:43)
Br
OTos
Formally, the formation of the heterocycles 3, 4 and 5 is
easily understood by appropriate combinations of the
synthons 1.1 and 1.2 corresponding to ethyl acetoacetate 1
with the synthons 2.1, 2.2 and 2.3 corresponding to the
glycidyl derivatives 2; pyran 4 for instance derives from a
combination of 1.1 with 2.3. Obviously, these synthons are
useful for classifying cyclization reactions of glycidyl
derivatives 2 with various reagents.5 A mechanistic inter-
pretation, of course, requires a more detailed study: as
expected, the O-alkylation product 6 did not cyclize under
treatment with NaOEt in ethanol. Therefore it is clear that
the formation of the heterocycles 3, 4 and 5 starts with a
C-alkylation, either by nucleophilic attack of the enolate of
1 at the C±X group of 2 directly leading to intermediate 7,
or by attack at the terminal epoxide to give 8. This key
intermediate has several opportunities to cyclize: 1. intra-
molecular nucleophilic substitution under epoxide forma-
tion is an alternative route to 7; 2. lactone formation gives
5; 3. enolate formation to 10 and subsequent 6-exo-tet-
cyclization is the most feasible pathway to tetrahydropyran
4. Since the quota of pyran formation is strongly in¯uenced
by the nature of the leaving group X, this leaving group
should be present in the key intermediates leading to 4.
The structures 8 and 10 ful®l this requirement, but not 7.
Therefore only a minor portion of 4 if at all could be formed
via 7, and indeed, a sample of 7,6 independently synthesized
by alkylation of 1 with allyl bromide and subsequent epoxi-
dation with dimethyldioxirane, exclusively cyclized to 3
under various reaction conditions (in ethanol at 508C and
also in the presence of NaOEt) (Scheme 2).
In conclusion, we have proven that not only furanoid hetero-
cycles but also the equally interesting tetrahydropyran
moiety is accessible by simple cyclization reactions of
ethyl acetoacetate 1 with glycidyl derivatives 2.
Experimental
General
Mp (uncorrected): Reichert Thermovar. IR: Perkin±Elmer
983. UV: Perkin±Elmer 554. NMR: Bruker DRX 500; H
1
NMR spectra (500 MHz) were recorded in CDCl3 (if not
mentioned otherwise) with TMS as the internal standard.
13C NMR spectra (126 MHz) were measured by using
CDCl3 as the solvent and the internal standard. MS: MAT
311A (70 eV). For analytical TLC precoated plastic sheets
Scheme 2. Mechanistic considerations for heterocyclizations of 1 with 2.

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G. Dyker, A. Thone / Tetrahedron 56 (2000) 8669±8672
8671
`POLYGRAM SIL G/UV254' from `Macherey-Nagel'
were used. Epiiodohydrin (2c)7 and glycidyl tosylate (2d)8
were synthesized according to literature procedures.
430 mg (30%) of enol ether 6 were obtained as a colorless
oil, identi®ed by comparison of the NMR spectra with
published data4 of the corresponding methyl ester. IR
(®lm):nˆ2983 cm21 (m), 2932 (m), 2403 (w), 2243 (w),
1706 (s), 1624 (s), 1446 (m), 1367 (m), 1342 (m), 1277
(s), 1145 (s), 1054 (s), 963 (m), 915 (m), 947 (m), 819
(m), 773 (m), 665 (m). 1H NMR: dˆ1.27 ppm (t,
Jˆ7.2 Hz, 3H), 2.33 (s, 3H), 2.69 (dd, Jˆ4.9, 2.6 Hz, 1H),
2.89 (dd, Jˆ4.9, 4.2 Hz, 1H), 3.29 (m, 1H), 3.70 (dd,
Jˆ11.1, 6.1 Hz, 1H), 4.05 (dd, Jˆ11.1, 2.9 Hz, 1H), 4.13
(q, Jˆ7.2 Hz, 2H), 5.00 (d, Jˆ0.4 Hz, 1H). 13C NMR:
dˆ14.38 ppm (q), 18.84 (q), 44.54 (t), 49.37 (d), 59.45
(t), 68.74 (t), 91.96 (d), 167.61 (s), 171.71 (s). MS (70 eV,
758C); m/z (%): 187 (6), 186 (49, M1), 141 (75), 140 (11),
130 (15), 115 (10), 103 (10), 102 (15), 87 (11), 85 (66), 84
(28), 83 (17), 69 (20), 58 (10), 57 (100), 43 (59). C9H14O4
(186.2): calcd C 58.05, H 7.58; found C 57.97, H 7.55.
Ethyl 4,5-dihydro-5-hydroxymethyl-2-methylfuran-3-
carboxylate (3) and ethyl 5,6-dihydro-5-hydroxy-2-
methyl-4H-pyran-3-carboxylate (4). A solution of sodium
ethoxide in ethanol was prepared from 575 mg (25.0 mmol)
of sodium and 40 ml of ethanol. 3.25 g (25.0 mmol) of ethyl
acetoacetate (1) and 5.71 g (25.0 mmol) of glycidyl tosylate
(2d) were added and the resulting reaction mixture was
stirred at 508C for 1 d. After hydrolyzation with 80 ml of
water the solution was extracted three times with 30 ml of
diethyl ether. The combined organic layers were concen-
trated and the residue was distilled in the Kugelrohr oven
at 1508C/0.02 mbar to give 2.79 g (60%) of a mixture of the
1
regioisomers 3 and 4 in the ratio 1:3 according to the H
NMR spectrum (the same ratio was determined for the crude
product before distillation). TLC (silica, petroleum ether/
methy tert-butyl ether 1:1): Rfˆ0.23 (4), 0.21 (3). Analyti-
cally pure samples of the regioisomers were obtained by
¯ash chromatography. First fraction: dihydropyran 4 as a
colorless oil. IR (®lm):nˆ3437 cm21 (m, br, OH), 2979
(w), 2934 (w), 1701 (s), 1687 (s), 1624 (s), 1380 (m),
Ethyl 2-acetyl-4,5-epoxypentanoate (7). To a solution of
100 mg (0.587 mmol) of ethyl 2-acetyl-4-pentenoate9 in
10 ml of acetone 17.6 ml (1.76 mmol) of a 0.1 M solution
of dimethyldioxirane in acetone was added within 10 min.
The solvent was removed at room temperature under
reduced pressure (at ®rst 16 mbar, ®nally 0.25 mbar) to
give 98 mg (90%) of epoxide 7 as a mixture of diastero-
1
1258 (s), 1227 (m), 1106 (s), 1066 (m), 1047 (m). H
1
NMR: dˆ1.28 ppm (t, Jˆ7.1 Hz, 3H), 2.26 (t, Jˆ1.5 Hz,
3H), 2.37 (s, br, 1H, OH), 2.38 (m, 1H), 2.59 (m, 1H), 3.94
(m, 2H), 4.13 (m, 1H), 4.16 (q, Jˆ7.1 Hz, 2H). 13C NMR:
dˆ14.38 ppm (q), 19.92 (q), 30.36 (t), 59.90 (t), 62.43 (d),
69.68 (t), 98.87 (s), 164.40 (s), 168.30 (s). MS (70 eV,
1208C); m/z (%): 187 (4), 186 (33, M1), 168 (16), 143
(22), 141 (42), 140 (9), 139 (27), 115 (17), 97 (100), 71
(10), 69 (12), 55 (37), 44 (11), 40 (13). C9H14O4 (186.2):
calcd C 58.05, H 7.58; found C 58.22, H 7.56.
isomers in the ratio 53:47 according to the H NMR spec-
1
trum. ± H NMR: dˆ1.29 ppm (m, 3H), 1.88 (m, 1H), 2.28
(m, 1H), 2.28 and 2.30 (s, 3H of diasteroisomers A and B),
2.51 (m, 1H), 2.77 (m, 1H), 2.97 (m, 1H), 3.67 (`q', 1H),
4.16 (q, Jˆ7.1 Hz, 2H). 13C NMR: dˆ13.88 ppm (q), 29.31
(q), 30.42 (t), 47.03 (t), 49.71 (d), 55.87 (d), 61.54 (t),
169.05 (s), 202.04 (s).
Heating epoxide 7 in ethanol in the presence of potassium
carbonate at 508C let exclusively to the formation of
dihydrofuran 3; its regioisomer 4 was not detected.
Second fraction: dihydrofuran 3 as a colorless oil, whose
spectroscopic data are in accord with literature.3a IR
(®lm):nˆ3438 cm21 (m, br, OH), 2981 (m), 2936 (m),
2875 (m), 1692 (s), 1641 (s), 1444 (m), 1384 (s), 1328
(m), 1264 (s), 1228 (s), 1146 (s), 1091 (s), 1056 (m), 1020
Acknowledgements
1
(m), 967 (m), 825 (m), 765 (m). H NMR: dˆ1.27 ppm (t,
Financial support of the Fonds der Chemischen Industrie is
gratefully acknowledged.
Jˆ7.1 Hz, 3H), 1.99 (s, br, 1H, OH), 2.20 (t, Jˆ1.6 Hz, 3H),
2.62 (m, 1H), 2.92 (m, 1H), 3.68 (dd, Jˆ12.1, 6.6 Hz, 1H),
3.72 (dd, Jˆ12.1, 3.6 Hz, 1H), 4.16 (q, Jˆ7.1 Hz, 2H), 4.73
(m, 1H). 13C NMR: dˆ14.08 ppm (q), 14.44 ppm (q), 31.38
(t), 59.59 (t), 64.99 (t), 82.39 (d), 102.26 (s), 166.11 (s),
167.47 (s). MS (70 eV, 1208C); m/z (%): 186 (24, M1),
155 (9), 141 (26), 140 (9), 139 (16), 126 (12), 108 (9), 97
(21), 95 (10), 85 (8), 83 (28), 69 (9), 57 (9), 55 (12), 42
(100), 41 (8), 38 (8).
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