Aryl γ-ketoesters as precursors for γ-butyrolactones in samarium(II) iodide-mediated reactions

Article abstract of DOI:10.1081/SCC-100000200

Various aryl γ-ketoesters were transformed into the corresponding substituted γ-lactones in good yield upon reaction with SmI₂.

Full text of DOI:10.1081/SCC-100000200

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ARYL γ-KETOESTERS AS PRECURSORS FOR γ-
BUTYROLACTONES IN SAMARIUM(II) IODIDE-MEDIATED
REACTIONS
D. Bradley G. Williams a , Kevin Blann a & Cedric W. Holzapfel a
a Department of Chemistry and Biochemistry , Rand Afrikaans University , P.O. Box 524,
Auckland Park, 2006, South Africa
Published online: 16 Aug 2006.
To cite this article: D. Bradley G. Williams , Kevin Blann & Cedric W. Holzapfel (2001) ARYL γ-KETOESTERS AS
PRECURSORS FOR γ-BUTYROLACTONES IN SAMARIUM(II) IODIDE-MEDIATED REACTIONS, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:2, 203-209, DOI: 10.1081/
SCC-100000200
To link to this article: http://dx.doi.org/10.1081/SCC-100000200
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SYNTHETIC COMMUNICATIONS, 31(2), 203–209 (2001)
ARYL γ-KETOESTERS AS PRECURSORS
FOR γ-BUTYROLACTONES IN
SAMARIUM(II) IODIDE-MEDIATED
REACTIONS
D. Bradley G. Williams,∗ Kevin Blann,
and Cedric W. Holzapfel
Department of Chemistry and Biochemistry, Rand
Afrikaans University, P.O. Box 524, Auckland Park,
2006, South Africa
ABSTRACT
Various aryl γ -ketoesters were transformed into the corre-
sponding substituted γ -lactones in good yield upon reaction with
SmI2.
Butyrolactones and butenolides are important intermediates and end prod-
ucts in organic synthesis (1–3). This being the case, many procedures directed at
the synthesis of substituted butyrolactones have been devised. These include rad-
ical cyclization reactions (4), ring-expansion methodology (5), and various other
protocols (6–8). The conversion of γ -ketoesters into the corresponding alcohols
followed by acidic cyclisation has been published some time ago (9). Similar, but
isolated, reduction-cyclization reactions have been observed in relation to other
work when using SmI2 as the reductant (10–13). In all of these latter cases, the
lactone was formed as part of a sequence of reactions, almost invariably involving
∗ To whom correspondence should be addressed. E-mail: dbgw@na.rau.ac.za
203
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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WILLIAMS, BLANN, AND HOLZAPFEL
Scheme 1. 3a: R = H, Rꢁ = Et, Rꢁꢁ = H; 3b: R = H, Rꢁ = Bu, Rꢁꢁ = H; 3c: R = Cl,
Rꢁ = Et, Rꢁꢁ = H; 3d: R = Cl, Rꢁ = Bu, Rꢁꢁ = H, 3e: R = Cl, Rꢁ = Me, Rꢁꢁ = 2-Me; 3f:
R = Cl, Rꢁ = Me, Rꢁꢁ = 3-Me; 3g: R = OMe, Rꢁ = OEt, Rꢁꢁ = H.
a samarium-Barbier coupling reaction or a ketyl radical anion-olefin coupling as
the first step.
Our previous work in the area of SmI2-mediated reactions (14–16) suggested
to us that a variety of substituted butyrolactones could be prepared by a directed
approach to such compounds when making use of readily available starting ma-
terials in conjunction with SmI2. To this end, we anticipated that γ -ketoesters
would be ideal substrates: reduction of the keto function would provide an inter-
mediate Sm-alkoxide, which could cyclize onto the ester function to generate the
corresponding butyrolactone.
The γ -ketoesters 3 were readily available via the Stetter reaction (17) of a
variety of aryl aldehydes 1 with some α,β-unsaturated esters 2 (Scheme 1).
The various γ -ketoesters 3 were smoothly converted into the corresponding
lactones 4 once they had been subjected to reaction with SmI2 in the presence of
a proton source (Scheme 2). The identities of all starting materials and products
were established on the basis of original data or by comparison with published data.
The following compounds have been prepared previously: 3a(17); 3b(18); 3c(17);
3f(17); 3g(19); 4a(9); 4b(20); trans-4d(21). The full results are summarized in
Table 1.
The results detailed in Table 1 clearly indicate the facility with which the
substrates 3 may be converted into the analogous lactones 4 in good yield. In some
cases (Entries 7 and 9), the reduced (uncyclized) alcohol 5a was isolated in low
yield (transesterification had occurred in the case of Entry 9). It is also evident that
para substitution on the arene (Entries 6 to 14) did not significantly influence the
yield of the reaction, nor did simple substitution on the pendant chain (Entries 10
to 13). In the latter cases, diastereomeric lactones were obtained in approximately
Scheme 2. 4a: R = H, Rꢁꢁ = H, 4b: R = Cl, Rꢁꢁ = H; 4c: R = Cl, Rꢁꢁ = 3-Me; 4d: R = Cl,
Rꢁꢁ 4-Me; 4e: R = OMe, Rꢁꢁ = H.

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205
Table 1. Reaction of γ -Ketoesters with SmI2
Entry No. Substrate Proton Source (equivalents)a
Product (%)
1
2
3
4
5
6
7
3a
3a
3a
3b
3b
3c
3c
5
4a (70)
4a (31)
4a (76)
4a (68)
4a (69)
5 eq. phenol
50
5
50
5
4b (56)
4b (70)
50
5a (8)
8
9
3d
3d
5
50
4b (59)
4b (68)
5a (9)
10
11
12
13
14
3e
3e
3f
5
trans 4c (33)b
cis 4c (25)
trans 4c (41)b
cis 4c (31)
trans 4d (44)b
cis 4d (15)
trans 4d (60)b
cis 4d (20)
4e (44)
50
5
50
3f
3g
5 eq. phenol
a Unless otherwise stated, the proton source was ethanol.
b The trans- or cis-relative stereochemistry was established on the basis
of nOe experiments.
1:1 to 3:1 (trans to cis) ratios, with the bias being towards the trans products in
each case. There was also no significant difference in the yields of the products as
a function of changes in the type of ester employed (ethyl vs. n-butyl vs. methyl).
It was interesting to note, however, that the presence of the p-Cl substituent
required the addition of a vast excess of proton source (EtOH) before good yields
of the desired lactone were obtained. It was also necessary to dilute the substrates
3c–3f in THF (five times dilution compared to other substrates) prior to their
addition to the SmI2/THF/EtOH mixture. When less of the proton source was
added, or when the substrate was added in a more concentrated solution to the
SmI2, dimeric lactones 6 were isolated. This pinacol dimerization-lactonization
sequencewasfoundtobeageneralphenomenon, dependingonconditions, andwill
be the subject of a disclosure elsewhere. The presence of the p-methoxy substituent
in the substrate rendered the compound highly reactive under reflux conditions:
only intractable material was obtained from that reaction. This high degree of
reactivity could be tempered by carrying out the reaction at room temperature in

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WILLIAMS, BLANN, AND HOLZAPFEL
the presence of ethanol as the proton source. However, this led to the isolation of a
1:1 mixture of the alcohol and the lactone (4e and 5b). This problem was overcome
by the addition of phenol as a proton source, in which case the desired lactone was
isolated in a yield of 44% (Entry 14). We have previously observed similar changes
in reactivity when making use of phenol as the proton source in Sm(II)-mediated
reactions.7a
In summary, we have developed a rapid preparative technique for the synthe-
sis of some substituted γ -butyrolactones via a reduction-lactonization sequence.
Some substitution on the aryl and aliphatic moieties of the γ -ketoester substrates
is tolerated well under these conditions.
EXPERIMENTAL
Solvents were distilled under nitrogen from the appropriate drying agent
directly before use. All experimental work was carried out under an atmosphere
of argon in flamed out glassware. Chromatography was carried out using Merck
Kieselgel 60 (230–400 mesh). NMR spectra were recorded on a Varian Gem-
ini 300 spectrometer in CDCl3, mass spectra were recorded on a Finnigan-Matt
8200 spectrometer, and IR spectra were recorded on a Perkin-Elmer 881 spec-
trometer in CHCl3. Keto-ester starting materials were prepared as previously
described.8
Butyl 4-(4-Chlorophenyl)-4-oxobutanoate (3d)
43%; mp. 32◦–34◦C; TLC: Rf 0.44 (5:1 hexanes-EtOAc); IR: νmax(CHCl3)/
cm−1 3039, 1737, 1694, 1600; 1HNMR: (300 MHz, CDCl3) δH 7.92–7.88 (dm, 2H,
J = 8.7 Hz), 7.44–7.40 (dm, 2H, J = 8.7 Hz), 4.08 (t, 2H, J = 7.1 Hz), 3.26
(t, 2H, J = 6.6 Hz), 2.74 (t, 2H, J = 6.6 Hz), 1.58 (pentet, 2H, J = 7.1 Hz), 1.36
(sextet, 2H, J = 7.1 Hz), 0.91 (t, 3H, J = 7.1 Hz); 13C NMR: (75 MHz, CDCl3)
δC 196.8, 172.7, 139.6, 134.8, 129.4, 128.9, 64.7, 33.4, 30.7, 28.2, 19.2, 13.8;
EIMS m/z: 271 (M+, 8), 269 (22), 213 (53), 195 (78), 167 (21), 139 (100), 111
(30); HRMS: calcd for C14H1735ClO3: 268.0866, found: 268.0859.

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Methyl 4-(4-Chlorophenyl)-4-oxo-2-methylbutanoate (3e)
207
17%; oil; TLC: Rf 0.20 (10:1 hexanes-EtOAc); IR: νmax(CHCl3)/cm−1 3040,
1742, 1703, 1601; 1H NMR: (300 MHz, CDCl3) δH 7.91–7.86 (dm, 2H,
J = 8.7 Hz), 7.44–7.39 (dm, 2H, J = 8.7 Hz), 3.68 (s, 3H), 3.44 (dd, 1H, J = 17.6
and J = 8.1 Hz), 3.17–3.06 (m, 1H), 2.96 (dd, 1H, J = 17.6 and J = 5.1 Hz), 1.26
(d, 3H, J = 7.2 Hz); 13C NMR: (75 MHz, CDCl3) δC 196.7, 176.2, 139.6, 134.9,
129.4, 128.9, 52.0, 41.9, 34.9, 17.4; EIMS m/z: 242 (M+, 4), 240 (10), 209 (8),
166 (11), 139 (93), 111 (100); HRMS: calcd for C12H1335ClO3: 240.0553, found:
240.0550.
Representative Procedure for the Reduction and Lactonization
of γ-Ketoesters with SmI2
To a solution of SmI2 (2.4 eq., 0.09 M) in THF (10 mL) and EtOH (50 eq.)
under reflux (oil bath temperature 75◦C) was added the γ -ketoester 3 (0.39 mmol)
in THF (10 mL). The resulting solution was heated under reflux for 5 h, after which
it was quenched with 0.2 mL of a 25% aqueous solution of NH4Cl. The volatile
component of the mixture was removed in vacuo and the residue was passed
through a short filter column of silica. The crude product was finally purified by
column chromatography.
Trans-5-(4-Chlorophenyl)-3-methyl-2(3H)-dihydrofuranone (4c)
41%; oil; TLC: Rf 0.30 (3:1 hexanes-EtOAc); IR: νmax (CHCl3)/cm−1 3024,
2984, 2943, 1781, 1500; 1H NMR: (300 MHz, CDCl3) δH 7.34 (d, 2H, J = 8.4 Hz),
7.23 (d, 2H, J = 8.4 Hz), 5.52 (t, 1H, J = 6.3 Hz), 2.70 (app. sx, 1H, J = 7.7 Hz),
2.44–2.29 (m, 2H), 1.32 (d, 3H, J = 7.7 Hz); 13C NMR: (75 MHz, CDCl3)
δC 179.4, 138.2, 134.0, 128.9, 126.3, 77.6, 38.3, 33.6, 15.5; EIMS m/z: 212
(M+, 19), 210 (56), 175 (29), 139 (61), 42 (100); HRMS: calcd for C11H1135ClO2:
210.0448, found: 210.0455.
Cis-5-(4-Chlorophenyl)-3-methyl-2(3H)-dihydrofuranone (4c)
31%; oil; TLC: Rf 0.24 (3:1 hexanes-EtOAc); IR: νmax (CHCl3)/cm−1 3030,
2987, 2943, 1782, 1499; 1H NMR: (300 MHz, CDCl3) δH 7.36–7.32
(dm, 2H, J = 8.7 Hz), 7.28–7.25 (dm, 2H, J = 8.7 Hz), 5.31 (dd, 1H, J = 10.6
and 5.4 Hz), 2.84–2.74 (m, 2H), 1.84–1.71 (m, 1H), 1.32 (d, 3H, J = 6.6 Hz); 13
C
NMR: (75 MHz, CDCl3) δC 178.7, 137.5, 134.2, 128.9, 126.8, 78.4, 40.0, 36.3,

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WILLIAMS, BLANN, AND HOLZAPFEL
15.0; EIMS m/z: 212 (M+, 15), 210 (49), 175 (21), 131 (61), 42 (100); HRMS:
calcd for C11H1135ClO2: 210.0448, found: 210.0452.
Cis-5-(4-Chlorophenyl)-4-methyl-2(3H)-dihydrofuranone (4d)
20%; oil; TLC: Rf 0.47 (3:1 hexanes-EtOAc); IR: νmax (CHCl3)/cm−1 3030,
1
3021, 1787, 1498; H NMR: (300 MHz, CDCl3) δH 7.36–7.32 (dm, 2H, J =
8.4 Hz), 7.18–7.14 (dm, 2H, J = 8.4 Hz), 5.55 (d, 1H, J = 5.7 Hz), 2.92–2.78
(m, 2H), 2.37–2.28 (m, 1H), 0.68 (d, 3H, J = 7.2 Hz); 13C NMR: (75 MHz,
CDCl3)δC 176.2, 134.6, 133.8, 128.7, 126.7, 83.3, 37.1, 34.9, 15.2;EIMS m/z:212
(M+, 13), 210 (40), 175 (5), 139 (61), 42 (100); HRMS: calcd for C11H1135ClO2:
210.0448, found: 210.0453.
5-(4-Methoxyphenyl)-2(3H)-dihydrofuranone (4e)
44%; oil; TLC: Rf 0.22 (3:1 hexanes-EtOAc); IR: νmax(CHCl3)/cm−1 3041,
1
3037, 3031, 1782, 1527; H NMR: (300 MHz, CDCl3) δH 7.26–7.22 (dm, 2H,
J = 8.7 Hz), 6.91–6.87 (dm, 2H, J = 8.7 Hz), 5.44 (dd, 1H, J = 8.3 and 6.2 Hz),
3.80 (s, 3H), 2.67–2.55 (m, 3H), 2.27–2.12 (m, 1H); 13C NMR: (75 MHz, CDCl3)
δC 176.8, 159.6, 131.1, 126.9, 114.1, 81.3, 55.3, 30.9, 29.2; EIMS m/z: 192
(M+, 70), 161 (7), 148 (59), 137 (100); HRMS: calcd for C11H12O3: 192.0786,
found: 192.0793.
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