New strategies in carbonylation chemistry: The synthesis of δ-lactones from saturated alcohols and CO

Article abstract of DOI:10.1021/ja9807892

This paper describes the δ-carbonylation of saturated alcohols which uses a 1,5-hydrogen-transfer reaction of alkoxyl radicals and subsequent carbonylation at the δ-carbon atoms as the key. The carbonylation reactions of five classes of saturated alcohols, namely, primary alcohols having primary δ-carbons, primary alcohols having secondary δ-carbons, primary alcohols having tertiary δ-carbons, secondary alcohols having primary δ- carbons, secondary alcohols having secondary δ-carbons, were carded out, in which lead tetraacetate (LTA) was used as a one-electron oxidant to generate the alkoxyl radicals. Carbonylation of these saturated alcohols, except for primary alcohols having tertiary δ-carbons, took place to afford δ-lactones in moderate to good yields. The mechanism of the remote carbonylation likely involves (1) alkoxyl radical generation via LTA oxidation of a saturated alcohol, (2) conversion of this alkoxyl radical to a δ-hydroxyalkyl radical by a 1,5-hydrogen-transfer reaction, (3) CO trapping of the δ-hydroxyalkyl radical yielding an acyl radical, and (4) oxidation and cyclization of the acyl radical to give a δ-lactone. A metal salt-free system was also tested for a substrate derived from a tertiary alcohol having a secondary δ- carbon; the photolysis of an alkyl 4-nitrobenzenesulfenate under CO pressures gave a δ-lactone in moderate yield.

Full text of DOI:10.1021/ja9807892

8692
J. Am. Chem. Soc. 1998, 120, 8692-8701
New Strategies in Carbonylation Chemistry: The Synthesis of
δ-Lactones from Saturated Alcohols and CO
Shinji Tsunoi,† Ilhyong Ryu,*,‡ Tohru Okuda,‡ Minoru Tanaka,† Mitsuo Komatsu,‡ and
Noboru Sonoda‡,§
Contribution from the Department of Applied Chemistry, Faculty of Engineering, and Research Center for
EnVironmental PreserVation, Osaka UniVersity, Suita, Osaka 565-0871, Japan
ReceiVed March 9, 1998
Abstract: This paper describes the δ-carbonylation of saturated alcohols which uses a 1,5-hydrogen-transfer
reaction of alkoxyl radicals and subsequent carbonylation at the δ-carbon atoms as the key. The carbonylation
reactions of five classes of saturated alcohols, namely, primary alcohols having primary δ-carbons, primary
alcohols having secondary δ-carbons, primary alcohols having tertiary δ-carbons, secondary alcohols having
primary δ-carbons, secondary alcohols having secondary δ-carbons, were carried out, in which lead tetraacetate
(LTA) was used as a one-electron oxidant to generate the alkoxyl radicals. Carbonylation of these saturated
alcohols, except for primary alcohols having tertiary δ-carbons, took place to afford δ-lactones in moderate to
good yields. The mechanism of the remote carbonylation likely involves (1) alkoxyl radical generation via
LTA oxidation of a saturated alcohol, (2) conversion of this alkoxyl radical to a δ-hydroxyalkyl radical by a
1,5-hydrogen-transfer reaction, (3) CO trapping of the δ-hydroxyalkyl radical yielding an acyl radical, and (4)
oxidation and cyclization of the acyl radical to give a δ-lactone. A metal salt-free system was also tested for
a substrate derived from a tertiary alcohol having a secondary δ-carbon; the photolysis of an alkyl
4-nitrobenzenesulfenate under CO pressures gave a δ-lactone in moderate yield.
Introduction
Scheme 1. Possible Reaction Sites for Carbonylation of
Alkane and Alcohol
Despite the efforts of many research groups, the selective
and efficient introduction of carbon monoxide into unactivated
hydrocarbons has remained elusive.1 Current methods, irrespec-
tive of whether they employ transition metals or free radicals,
for the carbonylations of alkanes are generally not selective for
different types of C-H bonds (left-hand side of Scheme 1).
Only reactions of symmetrical alkanes, such as methane and
ethane, and cyclic alkanes are certain to give uniform products.
A notable exception reported by Tanaka and co-workers is the
photochemical conversion of alkanes into aldehydes catalyzed
by [RhCl(CO)(PMe3)2],1a,c,o which prefers methyl groups to
methylene groups. Our approach relies upon well-precedented
radical methodology for the activation and functionalization of
a particular C-H bond. By employing a 1,5-hydrogen-transfer
reaction, it is possible to prepare δ-hydroxyalkyl radicals
selectively from the corresponding carbinols (remote function-
alization).2 Treatment of the resulting radicals with CO would
result in the δ-selective carbonylation of saturated alcohols
(right-hand side of Scheme 1). Alkoxyl radical generation/1,5-H
shift sequences have been used extensively in C-heteroatom
bond-forming reactions, such as the Barton reaction.2-10 How-
ever, as for the related C-C bond-forming reactions, examples
are generally restricted to intramolecular cases.11,12
† Research Center for Environmental Preservation.
‡ Department of Applied Chemistry, Faculty of Engineering.
§ Present address: Department of Applied Chemistry, Faculty of
Engineering, Kansai University, Suita, Osaka 564-0073, Japan.
(1) For leading references for carbonylation of alkanes, see: (a) Sakakura,
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(2) For reviews on remote functionalization by 1,5-H shift from C to
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M. J. Am. Chem. Soc. 1961, 83, 4076. (b) Barton, D. H. R.; Beaton, J. M.
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Pure Appl. Chem. 1968, 16, 1.
S0002-7863(98)00789-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/11/1998

Synthesis of δ-Lactones
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8693
We became interested in the early work in this area which
described the preparation of substituted tetrahydrofurans (THFs)
from saturated alcohols by lead tetraacetate (LTA) induced
oxidative cyclization13 in refluxing benzene, since Alper and
one of us previously observed that one-electron metal oxidation
systems are compatible with radical carbonylation systems.14
This THF synthesis, originally discovered in the late 1950s and
mainly pursued by Mihailovic´ and co-workers,13 is thought to
involve a 1,5-hydrogen transfer from the δ-carbon to an alkoxyl
radical A, which is formed by the one-electron oxidation of
saturated alcohol, and the subsequent oxidative cyclization. We
Scheme 2
(4) For examples of 1,5-H shift from C to O‚ by the photolysis of
hypochlorites, see: (a) Greene, F. D.; Savitz, M. L.; Lau, H. H.; Osterholtz,
F. D.; Smith, W. N. J. Am. Chem. Soc. 1961, 83, 2196. (b) Walling, C.;
Padwa, A. J. Am. Chem. Soc. 1961, 83, 2207. (c) Akhtar, M.; Barton, D.
H. R. J. Am. Chem. Soc. 1961, 83, 2214. (d) Mill, J. S.; Petrov, V. Chem.
Ind. 1961, 946. (e) Greene, F. D.; Savitz, M. L.; Osterholtz, F. D.; Lau, H.
H.; Smith, W. N.; Zanet, P. M. J. Org. Chem. 1963, 28, 55. (f) Walling,
C.; Padwa, A. J. Am. Chem. Soc. 1963, 85, 1597. Also see a review: (g)
Walling, C. Pure Appl. Chem. 1967, 15, 69.
(5) For examples of 1,5-H shift from C to O‚ by the photolysis of
hypobromites, see: (a) Akhtar, M.; Hunt, P.; Dewhurst, P. B. J. Am. Chem.
Soc. 1965, 87, 1807. (b) Smolinsky, G.; Feuer, B. I. J. Org. Chem. 1965,
30, 3216. (c) Gibson, T. W.; Erman, W. F. J. Am. Chem. Soc. 1969, 91,
4771. Also see a review: (d) Brun, P.; Waegell, B. Tetrahedron 1976, 32,
517.
(6) For examples of 1,5-H shift from C to O‚ by the photolysis of
hypoiodites generated in situ from alcohols and LTA/I2, see: (a) Meystre,
C.; Heusler, K.; Kalvoda, J.; Wieland, P.; Anner, G.; Wettstein, A. HelV.
Chim. Acta 1962, 45, 1317. (b) Heusler, K.; Kalvoda, J.; Meystre, C.; Anner,
G.; Wettstein, A. HelV. Chim. Acta 1962, 45, 2161. Also see a review: (c)
Kalvoda, J.; Heusler, K. Synthesis 1971, 501. In situ from alcohols and
HgO/I2, see: (d) Akhtar, M.; Barton, D. H. R. J. Am. Chem. Soc. 1964, 86,
1528. In situ from alcohols and iodobenzene diacetate, see: (e) Concepcio´n,
J.-I.; Francisco, C. G.; Herna´ndez, R.; Salazar, J. A.; Sua´rez, E. Tetrahedron
Lett. 1984, 25, 1953. (f) Mart´ın, A.; Salazar, J. A.; Sua´rez, E. J. Org. Chem.
1996, 61, 3999.
envisioned that the putative intermediate B would undergo
carbonylation with CO to give an acyl radical C15 and that the
subsequent oxidation of C leading to an acyloxonium ion D
would be followed by facile deprotonation, providing a carbo-
nylative route to δ-lactones from saturated alcohols (Scheme
2). This has proven to be the case.16
In this paper, we provide the scope and limitations of this
unique LTA-induced δ-carbonylation, which achieved the
C-carbonylation of saturated alcohols for the first time, as well
as a proposed mechanism for this oxidative carbonylation, and
the potential for related δ-carbonylations using metal free
systems.
(7) For examples of 1,5-H shift from C to O‚ by the reaction of ROH
with selenium reagent, see: (a) Dorta, R. L.; Francisco, C. G.; Freire, R.;
Sua´rez, E. Tetrahedron Lett. 1988, 29, 5429. (b) Herna´ndez, R.; Vela´zquez,
S. M.; Sua´rez, E.; Rodr´ıguez, M. S. J. Org. Chem. 1994, 59, 6395.
(8) For examples of 1,5-H shift from C to O‚ by the homolysis of alkyl
arylsulfenate, see: Pasto, D. J.; Cottard, F. Tetrahedron Lett. 1994, 35,
4303.
(9) For examples of 1,5-H shift from C to O‚ by the reaction of ROH
with Ce(IV), see: Trahanovsky, W. S.; Young, M. G.; Nave, P. M.
Tetrahedron Lett. 1969, 2501.
(10) For examples of 1,5-H shift from C to O‚ by the decomposition of
peroxides, see: (a) Kochi, J. K. J. Am. Chem. Soc. 1963, 85, 1958. (b)
Green, M. M.; Cˇ ekovic´, Zˇ. J. Am. Chem. Soc. 1974, 96, 3000. (c) Freerksen,
R. W.; Pabst, W. E.; Raggio, M. L.; Sherman, S. A.; Wroble, R. R.; Watt,
D. S. J. Am. Chem. Soc. 1977, 99, 1536. (d) Kropf, H.; von Wallis, H.
Synthesis 1981, 237. (e) Cˇekovic´, Zˇ.; Cvetkovic´, M. Tetrahedron Lett. 1982,
23, 3791.
(13) For pioneering work on THF-formation by oxidative cyclization of
alcohols with LTA, see: (a) Cainelli, G.; Mihailovic´, M. L.; Arigoni, D.;
Jeger, O. HelV. Chim. Acta 1959, 42, 1124. (b) Mic´ovic´, V. M.; Mamuzic´,
R. I.; Jeremic´, D.; Mihailovic´, M. L. Tetrahedron 1964, 20, 2279. (c)
Mihailovic´, M. L.; Cˇ ekovic´, Zˇ.; Maksimovic´, Z.; Jeremic´, D.; Lorenc, L.;
Mamuzic´, R. I. Tetrahedron 1965, 21, 2799. For leading reviews, see: (d)
Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. Engl. 1964, 3, 525. (e)
Mihailovic´, M. L.; Cˇ ekovic´, Zˇ. Synthesis 1970, 209. (f) Rotermund, G. W.
In Methoden der Organischen Chemie (Houben-Weyl); Mu¨ller, E., Ed.;
Georg Thieme: Stuttgart, 1975, Band 4, Teil 1b, Oxidation II, p 204. (g)
Rubottom, G. M. In Oxidation in Organic Chemistry; Academic Press: New
York, 1982; part D, Chapter I. (h) Mihailovic´, M. L.; Cˇ ekovic´, Zˇ.; Lorenc,
L. In Organic Syntheses by Oxidation with Metal Compounds; Mijs, W. J.;
de Jonge, C. R. H. I., Eds.; Plenum Press: New York 1986; Chapter 14.
(14) Ryu, I.; Alper, H. J. Am. Chem. Soc. 1993, 115, 7543. Also see ref
15e.
(15) For recent reports on free-radical carbonylation, see: (a) Tsunoi,
S.; Ryu, I.; Yamasaki, S.; Fukushima, H.; Tanaka, M.; Komatsu, M.; Sonoda,
N. J. Am. Chem. Soc. 1996, 118, 10670. (b) Ryu, I.; Muraoka, H.; Kambe,
N.; Komatsu, M.; Sonoda, N. J. Org. Chem. 1996, 61, 6396. (c) Tsunoi,
S.; Ryu, I.; Muraoka, H.; Tanaka, M.; Komatsu, M.; Sonoda, N. Tetrahedron
Lett. 1996, 37, 6729. (d) Brinza, I. M.; Fallis, A. G. J. Org. Chem. 1996,
61, 3580. (e) Okuro, K.; Alper, H. J. Org. Chem. 1996, 61, 5312. (f)
Chatgilialoglu, C.; Ferreri, C.; Sommazzi, A. J. Am. Chem. Soc. 1996, 118,
7223. (g) Ryu, I.; Nagahara, K.; Kurihara, A.; Komatsu, M.; Sonoda, N. J.
Organomet. Chem. 1997, 548, 105. (h) Nagahara, K.; Ryu, I.; Komatsu,
M.; Sonoda, N. J. Am. Chem. Soc. 1997, 119, 5465. (i) Tsunoi, S.; Ryu, I.;
Yamasaki, S.; Tanaka, M.; Sonoda, N.; Komatsu, M. Chem. Commun. 1997,
1889. (j) Ryu, I.; Okuda, T.; Nagahara, K.; Kambe, N.; Komatsu, M.;
Sonoda, N. J. Org. Chem. 1997, 62, 7550. (k) Nagahara, K.; Ryu, I.;
Yamazaki, H.; Kambe, N.; Komatsu, M.; Sonoda, N.; Baba, A. Tetrahedron
1997, 53, 14615. (l) Ryu, I.; Fukushima, H.; Okuda, T.; Matsu, K.; Kambe,
N.; Sonoda, N.; Komatsu, M. Synlett 1997, 1265. (m) Ryu, I.; Niguma, T.;
Minakata, S.; Komatsu, M.; Hadida, S.; Curran, D. P. Tetrahedron Lett.
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Chem. 1998, 63, 222. (o) Curran, D. P.; Sisko, J.; Balog, A.; Sonoda, N.;
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1996, 96, 177. (r) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996,
35, 1050.
(11) For examples of 1,5-H shift from C to O‚ via a ring opening of
R-oxiranylcarbinyl radicals and the subsequent 5-exo cyclization, see: (a)
Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J. Org. Chem. 1990, 55,
5181. (b) Kim, S.; Lee, S.; Koh, J. S. J. Am. Chem. Soc. 1991, 113, 5106.
(c) Begley, M. J.; Housden, N.; Johns, A.; Murphy, J. A. Tetrahedron 1991,
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Kim, S.; Koh, J. S. J. Chem. Soc., Chem. Commun. 1992, 1377. (g) Kim,
S.; Koh, J. S. Tetrahedron Lett. 1992, 33, 7391. (h) Breen, A. P.; Murphy,
J. A. J. Chem. Soc., Chem. Commun. 1993, 191. (i) Galatsis, P.; Millan, S.
D.; Faber, T. J. Org. Chem. 1993, 58, 1215. (j) Rawal, V. H.; Krishna-
murthy, V.; Fabre, A. Tetrahedron Lett. 1993, 34, 2899. (k) Kim, S.; Do,
J. Y.; Lim, K. M. Chem. Lett. 1996, 669. Also see: (l) Cˇ ekovic´, Zˇ.; Ilijev,
D. Tetrahedron Lett. 1988, 29, 1441. For examples of 1,5-H shift of the
R-cyanoalkoxyl radical and the subsequent CN migration to form δ-cyano
ketone, see: (m) Kalvoda, J.; Botta, L. HelV. Chim. Acta 1972, 55, 356.
Also see refs 10c and 13h. For reviews of γ-hydrogen abstraction (1,5-H
shift from C to O‚) by the photolysis of aromatic ketones and the subsequent
radical-radical coupling to form cyclobutanols (Norrish type-II reaction),
see: (n) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168. (o) Kanaoka, Y. Acc.
Chem. Res. 1978, 11, 407. (p) Wagner, P. J. Acc. Chem. Res. 1983, 16,
461.
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Cˇ ekovic´, Zˇ. Tetrahedron Lett. 1997, 38, 627. (c) Petrovic´, G. Saicˇic´, R.
N.; Cˇ ekovic´, Zˇ. Tetrahedron Lett. 1997, 38, 7107.
(16) A part of this work has appeared in preliminary form, see: Tsunoi,
S.; Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1994, 116, 5473.

8694 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Tsunoi et al.
Table 1. Control Experiments for Carbonylation of 1-Octanol
Table 2. Carbonylation of Primary Alcohols at the Secondary
δ-Carbonsc
runa [1a] M LTA equiv CO atm temp °C 2ab 3ab 2a/3a
1
2
3
4
5
6
7
8
9
0.5
1.5
1.5
1.5
1.5
1.1
2
1.5
1.5
1.5
1.5
1.1
80
105
80
80
80
80
20
50
80
80
80
80
40
40
40
40
40
40
40
80
40
80
21
63
53
46
39
47
31
44
36
7
42
9
15
22
8
23
27
19
26
0.5
7.0
3.5
2.1
4.9
2.0
1.1
2.3
1.4
0.02
0.02
0.04
0.02
0.02
0.02
0.02
0.02
0.02
0.02
10c
11c,d
<1 >7.0
15 1.5
23
a Recovery of 1a: run 5, 29%; run 10, 85%; run 11, 10%. b GC
yield (%). c Reaction was conducted in CH2Cl2. d Octyl acetate was
formed in 10%.
Results and Discussion
Carbonylation of Primary Alcohols at the Secondary
δ-Carbons. Detailed control experiments were carried out for
the conversion of 1-octanol (1a) to a δ-lactone 2a (Table 1). In
the LTA/CO system, the major competing reaction is direct
oxidation of the δ-hydroxyalkyl radical to give a THF derivative
3a.13 Thus, some parameters, such as concentration, amount
of LTA, CO pressure, and temperature, were varied as deemed
appropriate in order to suppress the undesirable direct oxidation.
Higher concentrations of 1a caused an increase in the amount
of uncarbonylated product 3a (run 4). However, at concentra-
tions less than 0.02 M, the reaction slowed considerably. With
equimolar amounts of LTA, the ratio of carbonylated/uncarbo-
nylated product (2a/3a) was improved, but larger amounts of
the starting alcohol remained unreacted (run 5), whereas with
2 mol equiv of LTA, the formation of 3a became largely
competitive (run 6). Consequently, 1.5 mol equiv of LTA was
chosen. High CO pressures are desirable for this reaction (run
2). Indeed, when CO pressure was reduced to 20 atm (run 7),
the ratio of 2a/3a decreased to 1.1. Interestingly, lower reaction
temperatures gave better 2a/3a ratios (runs 3 vs 9), but at
temperatures below 30 °C, the reaction became very sluggish.
Besides benzene, CH2Cl2 was also tested as a solvent; however,
the reaction was sluggish at 40 °C, and 85% of the starting
alcohol was recovered (run 10). Even at 80 °C, the reaction
was not complete, and octyl acetate was detected as a principal
byproduct in this case (run 11). It is known that 1,5-H shifts
compete with 1,6-H shifts to some extent.4f,g,13c In these
experiments a byproduct containing CO, 2-propyl-6-hexanolide
(4a), which is formed via 1,6-hydrogen transfer17 followed by
carbonylation, was detected in <1/10 ratio relative to 2a, but
as will be referred to later, the formation of this byproduct
depends on the structure of the starting alcohols.18 Under
optimal conditions (run 2, 0.02 M, 105 atm, 40 °C), alcohol 1a
is carbonylated to give δ-lactone 2a in 63% yield, with a 7/1
ratio of 2a/3a. In conclusion, as can be seen in Table 1, lower
a Determined by GC. b Determined by 1H NMR. c Conditions: ROH
(0.4-0.8 mmol), LTA (1.5-2.0 equiv), C6H6 (20-40 mL), CO (80 atm),
40 °C, 3 days (except for run 1: 1 day, runs 6 and 8: 5 days).
concentrations of 1-octanol, smaller amounts of LTA, higher
pressures of CO, and lower reaction temperatures all favored
the carbonylation of the δ-hydroxyalkyl radical over the
undesirable direct oxidation.
Table 2 summarizes the carbonylations of substrates contain-
ing secondary δ-carbon atoms, under the now standard condi-
tions ([ROH] ) 0.02 M, 1.5-2.0 equiv of LTA, 40 °C, 80 atm
(18) A product formed via 1,4-hydrogen transfer was not detected with
3-pentanol and 2,4-dimethyl-3-pentanol. For examples of 1,4-hydrogen-
transfer reactions, see: (a) Wallace, T. J.; Gritter, R. J. J. Org. Chem. 1961,
26, 5256. (b) Brunton, G.; Griller, D.; Barclay, L. R. C.; Ingold, K. U. J.
Am. Chem. Soc. 1976, 98, 6803. (c) Journet, M.; Malacria, M. J. Org. Chem.
1992, 57, 3085. (d) Journet, M.; Malacria, M. Tetrahedron Lett. 1992, 33,
1893.
(17) For examples of 1,6-H shift, see: (a) Kay, I. T.; Williams, E. G.
Tetrahedron Lett. 1983, 24, 5915. (b) Danishefsky, S. J.; Armistead, D.
M.; Wincott, F. E.; Selnick, H. G. Hungate, R. J. Am. Chem. Soc. 1987,
109, 8117. Also see a review: (c) Wagner, P. J. Acc. Chem. Res. 1989, 22,
83.

Synthesis of δ-Lactones
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8695
Table 3. Carbonylation of Secondary Alcohols at the Secondary
δ-Carbone
Scheme 3
Secondary alcohols 1k and 1l also produced ꢀ-lactones via a
1,6-hydrogen-transfer reaction, but the amounts were very small
(<3%, runs 1 and 2). For the other cases examined, the
formation of ꢀ-lactones was negligible.19 Bicyclic δ-lactone 2o
was obtained from 1o in good yield (run 5).
This δ-carbonylation was successfully applied to a concise
synthesis of carpenter bee pheromone20 from optically pure (R)-
(-)-2-hexanol (1n), a commercially available alcohol. Thus,
treatment of 1n with CO in the presence of LTA yielded a cis
and trans mixture of 2-methyl-5-hexanolide (2n) (Table 3, run
4). Preparative HPLC separation of the mixture afforded pure
cis-(2S,5R)-2-methyl-5-hexanolide (ee ≈ 100%),21 a sex phero-
mone of the carpenter bee Xylocopa hirutissima. The observed
quantitative optical yield confirmed that the absolute configu-
ration of the hydroxyl-bearing carbon was completely retained.
Although the reaction of trans-2-cyclohexyl-1-cyclohexanol
(1p) under standard conditions (0.02 M) was sluggish, the
reaction at a higher concentration (0.2 M) yielded tricyclic
δ-lactone 2p in moderate yield (Table 3, run 6). To our surprise,
analysis of the NMR spectra (600 MHz) indicated that tricyclic
δ-lactone 2p was a mixture of eight diastereomers even though
only four diastereomers were possible from 1p. The mixture
was composed of four major diastereomers assigned as trans
isomers with retention of the original stereochemistry, in the
ratio of 55/15/12/6, and four minor diastereomers assigned as
cis isomers with inversion of original stereochemistry, in the
ratio of 4/3/3/2. A possible rationale for this observation is
detailed in Scheme 3. The initially generated alkoxyl radical
trans-E may undergo â scission22 to give a fragment radical F.
The cyclization of radical F back onto the internal aldehyde
would afford an isomerized radical cis-E or the original radical
trans-E.23 The isomerized radical cis-E would undergo 1,5-
hydrogen transfer, CO trapping, and oxidation to give the four
minor products, while radical trans-E would afford the four
a Determined by GC. b Determined by 1H NMR (600 MHz). c Mix-
ture of eight diastereomers. d ROH (1 mmol) and C6H6 (5 mL) were
used. e Conditions: ROH (0.4-0.8 mmol), LTA (1.5-2.0 equiv), C6H6
(20-40 mL), CO (80 atm), 40 °C, 3-7 days.
of CO). Both R,â- and R,γ-disubstituted δ-lactones were
obtained in reasonable yields from the corresponding branched
primary alcohols (runs 2 and 3). Carbonylation of 2-cycloalkyl-
ethanols also took place to give bicyclic δ-lactones (runs 4-7).
δ-Lactones having phenyl and ethoxycarbonyl groups on the
R-side chains were obtained from alcohols 1i and 1j, respectively
(runs 8 and 9). In all cases, the major competing reaction is
oxidation to give THF derivatives. Small quantities of ꢀ-lac-
tones (via 1,6-H shifts) were observed in runs 1 (4%), 2 (5%),
and 8 (4%) and could be eliminated by careful flash chroma-
tography on silica gel to afford pure δ-lactones (ꢀ-lactones come
out faster). In the other cases examined, competitive 1,6-
hydrogen-transfer reactions were negligible.
Carbonylation of Secondary Alcohols at the Secondary
δ-Carbons. The δ-carbonylations of secondary alcohols at the
secondary δ-carbons were examined. As expected, all of
secondary alcohols listed in Table 3 underwent carbonylation
to give R,δ-disubstituted δ-lactones. In general, the yields of
δ-lactones are higher than those from primary alcohols. This
may be due to a decrease in the rate of the reaction leading to
THF derivatives from these secondary alcohols (vide infra).
(19) For example, with 1m, ꢀ-lactone was not detected. We speculate
that, in this case, 1,6-H transfer yields a tertiary radical, which would easily
undergo the subsequent oxidation to give the carbocation rather than CO
trapping (Table 3, run 3).
(20) Wheeler, J. W.; Evans, S. L.; Blum, M. S.; Velthius, H. H. V.; de
Camargo, J. M. F. Tetrahedron Lett. 1976, 4029.
(21) (a) Pirkle, W. H.; Adams, P. E. J. Org. Chem. 1978, 43, 378. (b)
Bacardit, R.; Moreno-Man˜as, M. J. Chem. Ecol. 1983, 9, 703. (c) Mori,
K.; Senda, S. Tetrahedron 1985, 41, 541. (d) Ba¨ckvall, J.-E.; Bystro¨m, S.
E.; Nystro¨m, J. E. Tetrahedron 1985, 41, 5761. (e) Narasaka, K.; Ukaji, Y.
Chem. Lett. 1986, 81. (f) Gerth, D. B.; Giese, B. J. Org. Chem. 1986, 51,
3726. (g) White, J. D.; Somers, T. C.; Reddy, G. N. J. Am. Chem. Soc.
1986, 108, 5352. (h) Ikuba, T.; Nakao, T.; Nishii, S.; Yamamoto, Y. J.
Am. Chem. Soc. 1986, 108, 7420. (i) Katsuki, T.; Yamaguchi, M.
Tetrahedron Lett. 1987, 28, 651. (j) Bernardi, R.; Ghiringhelli, D. Synthesis
1989, 938. (k) Harada, T.; Matsuda, Y.; Imanaka, S.; Oku, A. J. Chem.
Soc., Chem. Commun. 1990, 1641. (l) Schink, H. E.; Ba¨ckvall, J.-E. J. Org.
Chem. 1992, 57, 1588. (m) White, J. D.; Somers, T. C.; Reddy, G. N. J.
Org. Chem. 1992, 57, 4991. (n) Jacobs, H. K.; Mueller, B. H.; Gopalan, A.
S. Tetrahedron 1992, 48, 8891.
(22) For LTA-induced carbonylation via â scission of cyclic alkoxyl
radicals, see: Tsunoi, S.; Ryu, I.; Tamura, Y.; Yamasaki, S.; Sonoda, N.
Synlett 1994, 1009.

8696 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Tsunoi et al.
Table 4. Control Experiments for Carbonylation of
2,6-Dimethyl-4-heptanol
Table 5. Carbonylation of Secondary Alcohols at the Primary
δ-Carbonsb
LTA
run equiv atm
CO temp
2q
%
1q (recovered)
a
a
°C
%
1
1.5
80
40
81 (71)
7
(cis/trans ) 59/41)c
2
1.5
1.5
2.0
20
5
80
40
40
80
62
13
61
12
71
6
3
4b
a GC yield (isolated yield). THF derivatives are always produced in
trace amount (<2%). b Reaction was run for 1 day. c Determined by
1H NMR.
major products. This result is supported by kinetic data reported
by Beckwith and Hay which show that the cyclization/
fragmentation process is in equilibrium (eq 1).24a On the other
hand, complete retention of stereochemistry in the case of 1n
can be easily understood since in this case â scission yields
two fragments, whose recombination is entropically unlikely.
Carbonylation of Primary and Secondary Alcohols at the
Primary δ-Carbons. All of the examples shown above involve
alcohols having secondary δ-carbons. The carbonylation of
a Determined by 1H NMR. b Conditions: ROH (0.4-0.8 mmol),
LTA (1.5-2 equiv), C6H6 (20 mL), CO (80 atm), 60 °C, 2-5 days.
alcohols having primary δ-carbons was also examined.
A
free of contamination by THF derivatives, the carbonylation
can be conducted at a somewhat higher temperature (60 °C).
This low reactivity of the primary carbon permits the selective
carbonylation of alcohol 1w which has both secondary and
primary δ-carbons, a and b. In this case, carbon monoxide could
be incorporated at the secondary δ-carbon a, with high regio-
chemical selectivity (eq 2). Thus, 2-propyl-5-octanolide (2w)
symmetrical secondary alcohol, 2,6-dimethyl-4-heptanol (1q),
which contains four methyl groups on both side chains, was
chosen to conduct control experiments (Table 4). Treatment
of 1q with 1.5 equiv of LTA at 80 atm of CO gave δ-lactone
2q in good yield (run 1). The remarkable efficiency of the
carbonylation of 1q in comparison with that of 1-octanol (Table
1) indicates that primary alkyl radicals prefer to react with CO
rather than to be oxidized with Pb(III or IV). In fact, very little
competitive oxidation of 1q leading to the THF derivative was
observed. This is ascribed to the slower oxidation of primary
radicals compared to that of secondary radicals. The slow side
reaction may enable us to carbonylate alcohols, which have
primary δ-carbons, at relatively low CO pressures and at high
temperatures (80 °C) (runs 2 and 4). On the other hand, when
we carried out the same reaction at 5 atm of CO, the yield of
the δ-lactone was dramatically reduced, and the starting alcohol
was largely recovered (run 3).25
Table 5 lists the results of carbonylations of primary and
secondary alcohols possessing primary δ-carbons. Since the
carbonylation of alcohols having primary δ-carbons is essentially
(23) Heusler, K.; Kalvoda, J.; Anner, G.; Wettstein, A. HelV. Chim. Acta
1963, 46, 352.
(24) (a) Beckwith, A. L. J.: Hay, B. P. J. Am. Chem. Soc. 1989, 111,
2674. The rate constant for 1,5-H shift from C to O‚ has been estimated to
be >108 s-1 (for n-hexyloxy radical), see: (b) Gilbert, B. C.; Holmes, R.
G. G.; Laue, H. A. H.; Norman, R. O. C. J. Chem. Soc., Perkin Trans. 2
1976, 1047.
(25) The reason for the observed low conversion under low CO pressure
conditions remains uncertain.
was formed predominantly over 5-undecanolide (2w′) in a 24/1
ratio. Purification of 2w to eliminate the minor product 2w′
was easily accomplished by flash chromatography on silica gel.
The preferential formation of 2w is reasonable in light of the
weaker C-H bond strength of methylene relative to that of

Synthesis of δ-Lactones
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8697
Table 6. Comparison of the Ratio of δ-Lactone/THFb
a Determined by GC. b Conditions: [ROH] ) 0.02 M (in C6H6), LTA
(1.5-2.0 equiv), CO (80 atm), 40 °C, 1-3 days.
methyl (∆E ) ca. 3 kcal/mol).26 Similar results were obtained
in the case of 4-octanol and 4-nonanol (eq 3).
hydroxyl group to Pb(III or IV) center (in G) or the intervention
of cyclic intermediate H28,29 is essential for the second oxidation
and cyclization step. More work is needed to clarify the precise
mechanism with respect to the intermediacy of H.
Mechanistic Insights
It is notable that unlike primary alcohols, secondary alcohols
having secondary δ-carbons produced only a small amount of
THF byproducts. For example, 2-octanol (1k) gave δ-lactone
2k in 57% yield along with less than 5% yield of 2-methyl-5-
propyltetrahydrofuran.27 Table 6 summarizes the ratio of
δ-lactone/THF for primary alcohol 1b and secondary alcohols
1k and 1l, which have δ-methylene carbons. The relatively
low δ-lactone/THF ratio in primary alcohols compared to that
in secondary alcohols may be a reflection of the relative ease
of THF formation for a primary alcohol. As outlined in Scheme
4, the reactivity difference for the direct oxidation of δ-radicals
may be explained by assuming that the hydroxyl group
coordinates to the Pb(III or IV) center, making the second
oxidation easier. In cyclic intermediate H, a substituent at the
hydroxyl-bearing carbon as found in secondary alcohols would
cause steric congestion.
Limitations and Prospects for the LTA-Free System
In contrast to the successful carbonylation of alcohols having
secondary and primary δ-carbons, alcohols having a tertiary
δ-carbon, such as 1z, did not undergo δ-carbonylation. Ac-
etoxytetrahydrofuran 3z was isolated as the major product
(20%), and the starting alcohol was detected (33%) (eq 5). Both
rapid oxidation of the generated tertiary radical to lead to an
olefin30 and rapid decarbonylation of the tertiary acyl radical31
conspire to prevent carbonylation of this substrate. Further
oxidation of the resultant alkenyl alcohol consumed LTA to
give the THF derivative 3z and the recovered 1z (Scheme 5).32,33
In contrast to primary and secondary alcohols, tertiary alcohol
5a was virtually inert under the reaction conditions employed
(97% recovery of 5a after 3 days) (eq 6). This is presumably
because of the difficulty of the formation of the lead alkoxide
species at the initial step under the standard conditions.13c
It was previously observed by Heusler and Kalvoda that
6â,11â-dihydroxysteroid,13d in which the C-19 methyl group
is equidistant from 6â- and 11â-oxygen atoms (eq 4), undergoes
(28) Rubottom and co-workers proposed the formation of RCOCH2CH2-
Pb(OAc)3 in the ring opening of bicyclic siloxycyclopropanes with LTA,
see: Rubottom, R. G.; Beedle, E. C.; Kim, C.-W.; Mott, R. C. J. Am. Chem.
Soc. 1985, 107, 4230.
(29) Cˇ ekovic´ and co-workers proposed that in the case of the LTA-
oxidation system, the δ-hydroxyalkyl radical is in a tight radical pair with
Pb(III) since the major product from 8-nonen-1-ol was the THF derivative
formed via oxidative cyclization rather than the cyclopentane derivative
formed via 5-exo cyclization. See ref 11l. Also see: Mihailovic´, M. L.;
Konstantinovic´, S.; Vukic´evic´, R. J. Serb. Chem. Soc. 1987, 52, 175.
(30) Hauser, D.; Schaffner, K.; Jeger, O. HelV. Chim. Acta 1964, 47,
1883.
(31) For the decarbonylation order of the acyl radical being tertiary >
secondary > primary acyl radical, see: (a) Chatgilialoglu, C.; Lucarini, M.
Tetrahedron Lett. 1995, 36, 1299. (b) Chatgilialoglu, C.; Ferreri, C.;
Lucarini, M.; Pedrielli, P.; Pedulli, G. F. Organometallics 1995, 14, 2672.
(32) (a) Mihailovic´, M. L.; Cˇ ekovic´, Zˇ.; Stankovic´, J.; Pavlovic´, N.;
Konstantinovic´, S.; Dokic´-Mazinjanin, S. HelV. Chim. Acta 1973, 56, 3056.
(b) Bortrand, M. P.; Surzur, J. M.; Boyer, M.; Mihailovic´, M. L. Tetrahedron
1979, 35, 1365.
(33) The formation of 3z may be accounted for by the cyclization of the
alkoxyl radical onto internal CdC and the subsequent oxidation of the
cyclized primary radical. The carbonylation of the primary radical does
not appear to compete well with the oxidation to yield the acetoxylated
product. It seems probable that stabilization of the three-membered oxonium
cation contributes to this facile oxidation of the primary radical â to oxygen.
For an alternative pathway involving coordination of CdC to Pb, see: (a)
Moriarty, R. M.; Kapadia, K. Tetrahedron Lett. 1964, 1165. (b) Moon, S.;
Lodge, J. M. J. Org. Chem. 1964, 29, 3453.
selective oxidative cyclization. This may lend support to the
intermediacy of Pb-coordinated species. The reaction afforded
only the 6â,19-ether resulting from the attack on the 6â-oxygen
which is less crowded compared with the 11â-oxygen. If we
hypothesize a free cation at C-19, there is no reason for the
cation to choose 6-OH to 11-OH. This, along with the result
shown in Table 6, probably suggests that coordination of the
(26) Wayner, D. D. M.; Griller, D. In AdVances Free Radical Chemistry;
Tanner, D. D., Ed.; JAI Press: Greenwich, 1990; Vol. 1, p 159. The
preference of methylene over methyl in the competitive 1,5-H abstraction
of alkoxyl radical has been documented. See refs 4e-g.
(27) The material balance is fairly poor (70-80%), which may be
attributed in part to the formation of fragmentation products.

8698 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Tsunoi et al.
Scheme 4
the alcohols with 4-nitrobenzenesulfenyl chloride, provides a
convenient method for the generation of alkoxyl radicals. Thus,
the reaction of an alkyl 4-nitrobenzenesulfenate 5b derived from
a tertiary alcohol with CO was conducted under xenon lamp
irradiation in the hope of effecting δ-carbonylation giving a
thioester.37 Analysis of the reaction mixture by NMR indicated
that lactone 6b was formed in 52% yield (eq 7). The formation
of lactone 6b can be rationalized as 6b being derived from an
initially produced thioester which is formed via an SH2 type
reaction of an acyl radical at sulfur.38
Since LTA-induced δ-carbonylation could not be applied to
δ-lactone synthesis from tertiary alcohols, the future work would
make the photolytic δ-carbonylation of alkyl 4-nitrobenzene-
sulfenates be complementary to the LTA-oxidation system.39
Scheme 5
Conclusion
The remote carbonylation of saturated alcohols with CO has
been achieved using LTA as a one-electron oxidant. Remote
carbonylation which takes place at the δ-position of alcohols
provides a convenient one-step synthesis of δ-lactones from
cheap and readily available feedstocks, namely saturated alco-
hols and CO. The LTA-induced system works well in the
carbonylation of primary and secondary alcohols having primary
or secondary δ-carbon atoms. The mechanism of this remote
carbonylation may involve the sequential generation of an
alkoxyl radical, a 1,5-hydrogen-transfer reaction, CO trapping,
and the oxidation/cyclization to give a δ-lactone. In the second
one-electron oxidation step of saturated alcohols with LTA, our
results suggest that coordination of the hydroxyl group to Pb-
(III or IV) center (in G) or intervention of cyclic intermediate
H would be essential.
To demonstrate the generality of our new δ-carbonylation
protocol and to circumvent the limitations, we considered
generating the alkoxyl radical without LTA.2,11,34,35 It is already
known that O-S bonds undergo homolytic cleavage to give
alkoxyl radicals, as does O-O homolysis. It has been reported
that photolytic cleavage of the O-S bond in alkyl 4-nitroben-
zenesulfenates,36 which are readily prepared by the reaction of
Carbonylation of tertiary alcohols, although unsuccessful with
the LTA-induced system, can be achieved via photolysis of alkyl
4-nitrobenzenesulfenates. There is a great possibility that the
photolytic approach would be an efficient alternative to the LTA-
induced δ-carbonylation. The synthesis of δ-lactones is im-
portant in view of the numerous important natural products and
(34) For examples of the generation of alkoxyl radicals from nitrate esters,
see: (a) Vite, G. D.; Fraser-Reid, B. Synth. Commun. 1988, 18, 1339. (b)
Fraser-Reid, B.; Vite, G. D.; Yeung, B. A.; Tsang, R. Tetrahedron Lett.
1988, 29, 1645. Also see ref 12a.
(35) For examples of the generation of alkoxyl radicals from N-
alkoxypyridinethiones and their derivatives, see: (a) Beckwith, A. L. J.:
Hay, B. P. J. Am. Chem. Soc. 1988, 110, 4415. (b) Hartung, J.; Gallou, F.
J. Org. Chem. 1995, 60, 6706. (c) Hartung, J.; Hiller, M.; Schmidt, P. Chem.
Eur. J. 1996, 2, 1014. (d) Hartung, J.; Hiller, M.; Schmidt, P. Liebigs Ann.
1996, 1425. (e) Hartung, J.; Schwarz, M. Synlett 1997, 848.
(36) (a) Beckwith, A. L. J.; Hay, B. P.; Wolliams, G. M. J. Chem. Soc.,
Chem. Commun. 1989, 1202. (b) Pasto, D. J.; L’Hermine, G. J. Org. Chem.
1990, 55, 5815. (c) Pasto, D. J.; L’Hermine, G. Tetrahedron 1993, 49, 3259.
Also see refs 8 and 12c.
(37) Photolysis was carried out using a stainless autoclave with quartz
glass. Schematic photoirradiation apparatus is given in the Supporting
Information in ref 15b.
(38) For atom and group transfer reactions to acyl radicals, see: (a)
Walling, C.; Basedow, O. H.; Savas, E. S. J. Am. Chem. Soc. 1960, 82,
2181. (b) Coveney, D. J.; Patel, V. F.; Pattenden, G.; Thompson, D. M. J.
Chem. Soc., Perkin Trans. 1 1990, 2721. (c) Crich, D.; Chen, C.; Hwang,
J.-T.; Yuan, H.; Papadatos, A.; Walter, R. I. J. Am. Chem. Soc. 1994, 116,
8937. Also see refs 15a, b, h, and j.
(39) The detailed results of δ-carbonylation using photolysis of alkyl
benzenesulfenates will be reported in a separate paper.

Synthesis of δ-Lactones
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8699
Tetrahydro-3-(3-methylbutyl)-4-methyl-2H-pyran-2-one (2c). Ob-
tained as a cis/trans-isomer mixture in a 54/46 ratio. These isomers
were separated by preparative HPLC. cis-2c, a yellow liquid: 1H NMR
(CDCl3, 270 MHz) δ 0.90 (d, 3H, J ) 6.4 Hz), 0.91 (d, 3H, J ) 6.8
Hz), 0.94 (d, 3H, J ) 7.3 Hz), 1.12-1.47 (m, 3H), 1.50-1.75 (m,
2H), 1.80-1.96 (m, 1H), 2.08-2.20 (m, 1H), 2.28-2.42 (m, 1H), 2.44-
2.52 (q-like, 1H, J ≈ 6.4 Hz), 4.20-4.39 (m, 2H); 13C NMR (CDCl3,
68 MHz) δ 16.91 (q), 22.34 (q), 22.65 (q), 24.60 (t), 27.68 (d), 28.10
(d), 30.30 (t), 36.40 (t), 44.23 (d), 65.78 (t), 174.77 (s); IR neat 1744
cm-1; HREIMS calcd for C11H20O2 m/z 184.1458, found 184.1485.
trans-2c, a yellow liquid: 1H NMR (CDCl3, 270 MHz) δ 0.90 (d, 3H,
J ) 6.8 Hz), 0.90 (d, 3H, J ) 6.8 Hz), 1.09 (d, 3H, J ) 6.4 Hz),
1.14-1.37 (m, 2H), 1.43-1.98 (complex m, 6H), 2.10-2.17 (m, 1H),
4.19-4.39 (m, 2H); 13C NMR (CDCl3, 68 MHz) δ 20.63 (q), 22.33
(q), 22.57 (q), 27.64 (t), 28.23 (d), 30.29 (d), 30.89 (t), 35.68 (t), 48.09
(d), 67.22 (t), 173.97 (s); IR neat 1736 cm-1; HREIMS calcd for
C11H20O2 m/z 184.1458, found 184.1478. In comparison with the
spectral data for 2f,43 the major isomer is assigned as a cis isomer.
cis- and trans-Tetrahydro-3-methyl-5-propyl-2H-pyran-2-one
(2d). Obtained as a cis/trans-isomer mixture in a 50/50 ratio, a colorless
liquid: 1H NMR (CDCl3, 270 MHz) δ 0.93 (t, 6H, J ) 6.8 Hz), 1.15-
1.42 (complex m, 15H including 1.23 (d, 3H, J ) 6.8 Hz) and 1.27 (d,
3H, J ) 6.8 Hz)), 1.61-1.82 (complex m, 2H), 1.95-2.17 (complex
m, 3H), 2.45-2.68 (complex m, 2H), 3.93 (dd, 1H, J ) 10.7, 3.9 Hz),
3.97 (dd, 1H, J ) 9.8, 2.5 Hz), 4.26 (dd, 1H, J ) 10.7, 4.9 Hz), 4.34
(dd, 1H, J ) 10.7, 4.9, 2.0 Hz); 13C NMR (CDCl3, 68 MHz) δ 13.99
(q, two superimposed lines), 16.54 (q), 16.87 (q), 19.76 (t), 19.96 (t),
31.67 (d), 32.20 (d), 32.96 (t), 33.21 (d), 34.11 (t), 34.60 (t), 34.74 (t),
35.15 (d), 71.82 (t), 73.43 (t), 174.85 (s), 175.97 (s); IR neat 1740
cm-1; HREIMS for first eluted isomer with GC calcd for C9H16O2 m/z
156.1150, found 156.1132; HREIMS for second eluted isomer with
GC calcd for C9H16O2 m/z 156.1150, found 156.1172.
biologically active compounds containing the δ-valerolactone
unit.40 Carbonylation approaches can contribute to this, and
indeed, a considerable amount of work has been reported on
the transition-metal mediated carbonylation of unsaturated
alcohols to yield lactones thus far.41 However, the synthesis
of δ-lactones from saturated alcohols and CO with the use of
transition metal catalysts has yet to be realized. The present
work clearly demonstrates the validity of free-radical methodol-
ogy for the carbonylation of unactivated C-H bonds.
Experimental Section
All carbonylation reactions were carried out using a stainless steel
autoclave lined with a glass liner. Photoinduced carbonylation of an
alkyl 4-nitrobenzenesulfenate was carried out using a 500-W xenon
lamp and a stainless steel autoclave with quartz glass windows lined
with a standard Pyrex glass liner. Alcohols, 1g, 1o, and 1p, were
prepared by the hydrogenation of the corresponding aromatic alcohols,
2-phenyl-1-propanol, 1-phenyl-2-propanol, and trans-2-phenyl-1-cy-
clohexanol with 5% Rh/C.42 Other alcohols and LTA (90% purity,
wet with acetic acid) were obtained from commercial sources and were
used as they were. Alkyl 4-nitrobenzenesulfenate 5b was prepared from
the reaction of the corresponding lithium alkoxide with 4-nitrobenze-
nesulfenyl chloride. C6H6 was distilled from CaH2. 1H and 13C NMR
spectra were recorded at 270 or 400 MHz or 600 MHz (1H) using CDCl3
with TMS as the internal standard. Flash chromatography was
performed with use of silica gel (Fuji Silysia Chemical, Ltd. BW-
820MH, 70-200 mesh). Preparative HPLC was performed on GPC
columns (JAIGEL 1H and 2H) using CHCl3 as an eluent. Gas
chromatography was carried out on capillary column Supelco SPB5
(0.2 mm × 30 m).
cis- and trans-Hexahydro-cyclopenta[c]pyran-1(3H)-one (2e).
Obtained as a cis/trans-isomer mixture in a 77/23 ratio, a colorless
liquid: 1H NMR (CDCl3, 270 MHz) δ 1.20-2.30 (m, cis 8H and trans
10H), 2.49 (m, cis 1H), 2.89 (td-like, cis 1H, J ≈ 8.4, 9.9 Hz, R-CH),
4.20 (td-like, cis 1H, J ≈ 10.5, 2.5 Hz), 4.28-4.42 (m, cis 1H and
trans 2H); 13C NMR (CDCl3, 68 MHz) δ 22.07 (t, cis), 23.39 (t, cis),
25.13 (t, trans), 28.07 (t, cis), 29.17 (t, trans), 29.83 (t, trans), 31.62 (t,
cis), 33.61 (t, trans), 36.31 (d, trans), 40.19 (d, cis), 42.88 (d, trans),
47.46 (d, cis), 67.37 (t, cis), 68.57 (t, trans), 174.75 (s, trans), 175.14
(s, cis); IR neat 1736 cm-1; HREIMS calcd for C8H12O2 m/z 140.0837,
found 140.0838. In comparison with the spectral data for 2f,43 the major
isomer is assigned as a cis isomer.
Octahydro-4-methyl-1H-2-benzopyran-1-one (2g). Obtained as
a mixture of four diastereomers in a 27/45/14/14 ratio. The major
isomer was isolated in pure form by preparative HPLC, a slightly yellow
liquid: 1H NMR (CDCl3, 270 MHz) δ 0.97 (d, 3H, J ) 6.4 Hz), 1.03
(m, 1H), 1.13-1.33 (m, 4H), 1.70-1.87 (m, 3H), 1.96-2.06 (m, 2H),
2.24-2.31 (m, 1H), 3.89 (dd, 1H, J ) 11.4, 8.4 Hz), 4.32 (dd, 1H, J
) 11.4, 5.4 Hz); 13C NMR (CDCl3, 68 MHz) δ 15.45 (q), 25.33 (t),
25.59 (t), 27.05 (t), 30.89 (t), 34.13 (d), 43.17 (d), 44.62 (d), 73.46 (t),
173.81 (s); IR neat 1728 cm-1; HREIMS calcd for C10H16O2 m/z
168.1150, found 168.1155. [Partial data was obtained for the other
three isomers.] The first eluted isomer with GC: 1H NMR (CDCl3,
270 MHz) δ 1.01 (d, 3H, J ) 6.8 Hz), 3.87 (t-like, 1H, J ≈ 11.0 Hz),
4.22 (dd, 1H, J ) 11.7, 5.9 Hz); 13C NMR (CDCl3, 68 MHz) δ 16.17
(q), 22.39 (t), 24.70 (t), 25.46 (t), 31.47 (t), 33.83 (d), 38.01 (d), 39.93
(d), 71.99 (t), 174.79 (s); HREIMS calcd for C10H16O2 m/z 168.1150,
found 168.1160. The third eluted isomer with GC: 1H NMR (CDCl3,
270 MHz) δ 0.94 (d, 3H, J ) 6.8 Hz), 4.07 (t-like, 1H, J ≈ 11.8 Hz),
4.26 (dd, 1H, J ) 11.3, 6.4 Hz); 13C NMR (CDCl3, 68 MHz) δ 13.45
(q), 22.62 (t), 22.94 (t), 25.32 (t), 27.20 (t), 32.72 (d), 38.59 (d), 43.35
(d), 71.90 (t), 172.94 (s); HREIMS calcd for C10H16O2 m/z 168.1150,
found 168.1157. The fourth eluted isomer with GC: 1H NMR (CDCl3,
270 MHz) δ 1.03 (d, 3H, J ) 7.4 Hz), 4.08 (dd, 1H, J ) 10.9, 4.0
Hz), 4.36 (dd, 1H, J ) 10.9, 4.5 Hz); 13C NMR (CDCl3, 68 MHz) δ
11.28 (q), 25.59 (t), 25.92 (t), 27.43 (t), 29.72 (t), 30.98 (d), 40.02 (d),
40.79 (d), 74.71 (t), 173.54 (s); HREIMS calcd for C10H16O2 m/z
168.1150, found 168.1153.
General Procedure for Synthesis of δ-Lactones. Carbonylation
of 1-adamantaneethanol. To a solution of 1-adamantaneethanol (1h)
(72 mg, 0.4 mmol) in benzene (40 mL) placed in a 100-mL stainless
steel autoclave lined with a glass liner was added LTA (295 mg, 0.6
mmol). The autoclave was sealed, purged twice with 10 atm of carbon
monoxide, and then pressurized with 80 atm of CO, with stirring, at
40 °C. After 3 days, the residual CO was ventilated, and the mixture
was poured into 0.4 N aqueous hydrogen chloride, extracted with ether
(3 × 20 mL), and dried (MgSO4). Rotary evaporation of the solvents
followed by flash chromatography on silica gel (hexane, then 10%
EtOAc-hexane eluent) afforded adamantano[2,1-c]tetrahydro-2H-
pyran-2-one (2h) (55 mg, 67% yield) as a colorless liquid: 1H NMR
(CDCl3, 600 MHz) δ 1.50 (ddd, 1H, J ) 2.2, 5.0, 12.8 Hz), 1.55 (dt,
1H, J ) 5.2, 14.0 Hz), 1.58-1.80 (m, 8H), 1.83 (d of quintet-like, 1H,
J ) 13.1(d), 2.6 Hz), 1.90 (dddd, 1H, J ) 12.7, 0.7, 5.2, 3.1 Hz), 1.99
(quintet-like, 1H, J ≈ 3.0 Hz), 2.01 (quintet-like, 1H, J ≈ 3.0 Hz),
2.40 (br s, 1H), 2.49 (q-like, 1H, J ≈ 2.8 Hz), 4.33 (ddd, 1H, J ) 5.3,
6.2, 11.7 Hz), 4.42 (ddd, 1H, J ) 5.3, 9.3, 11.7 Hz); 13C NMR (CDCl3,
68 MHz) δ 27.73 (d), 27.92 (d), 28.06 (d), 31.55 (s), 32.15 (t), 36.33
(t), 36.37 (t), 37.62 (t), 39.30 (t), 44.84 (t), 50.76 (d), 65.52 (t), 173.03
(s); IR neat 1736 cm-1; HREIMS calcd for C13H18O2 m/z 206.1307,
found 206.1291.
(40) For leading references, see: (a) Endo, A.; Kurodo, M.; Tsujita, Y.
J. Antibiot. 1976, 29, 1346. (b) Ranieri, R. L.; Calton, G. J. Tetrahedron
Lett. 1978, 499. (c) Wovkulich, P. M.; Tang, P. C.; Chadha, N. K.; Batcho,
A. D.; Barrish, J. C.; Uskokovic, M. R. J. Am. Chem. Soc. 1989, 111, 2596.
(d) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599.
(e) Liu, Z.-Y.; He, L.; Zheng, H. Synlett 1993, 191. (f) Shin, I.; Zhou, H.-
Q.; Que, N. L. S.; Liu, H.-W.; Swedenborg, P. D.; Jones, R. L. J. Org.
Chem. 1993, 58, 2923. Also see a review: (g) Nangia, A.; Prasuna, G.;
Rao, P. B. Tetrahedron 1997, 53, 14507.
(41) For selected examples of metal-mediated carbonylation of unsatur-
ated alcohols to lead to δ-lactones, see: (a) Murray, T. F.; Varma, V.;
Norton, J. R. J. Org. Chem. 1978, 43, 353. (b) Alper, H.; Leonard, D. J.
Chem. Soc., Chem. Commun. 1985, 511. (c) Chenal, T.; Naigre, R.; Cipre´s,
I.; Kalck, P.; Daran, J.-C.; Vaissermann, J. J. Chem. Soc., Chem. Commun.
1993, 747. (d) Naigre, R.; Chenal, T.; Cipre´s, I.; Kalck, P.; Daran, J.-C.;
Vaissermann, J. J. Organomet. Chem. 1994, 480, 91. (e) Chow, Y. L.;
Huang, Y.-J.; Dragojlovic, V. Can. J. Chem. 1995, 73, 740.
(42) The general procedure for hydrogenation is given in the Supporting
Information.
(43) Fujiwara, Y.; Okamoto, M. Chem. Pharm. Bull. 1989, 37, 1458.

8700 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Tsunoi et al.
Tetrahydro-3-(2-phenylethyl)-2H-pyran-2-one (2i). Obtained as
a colorless liquid: 1H NMR (CDCl3, 600 MHz) δ 1.59 (m, 1H), 1.77
(d of quintet-like, 1H, J ) 9.0 (d), 6.9 Hz), 1.88 (m, 1H), 1.92 (sextet-
like, 1H, J ≈ 6.8 Hz), 2.13 (sextet-like, 1H, J ≈ 6.8 Hz), 2.26 (d of
quintet-like, 1H, J ) 9.3 (d), 6.8 Hz), 2.44 (ddt, 1H, J ) 5.9, 11.0, 7.4
Hz), 2.73 (t, 2H, J ) 7.3 Hz), 4.28 (t, 2H, J ) 5.9 Hz), 7.15-7.31 (m,
5H); 13C NMR (CDCl3, 68 MHz) δ 21.90 (t), 24.67 (t), 32.77 (t), 32.86
(t), 38.57 (d), 68.08 (t), 125.93 (d), 128.34 (d, two superimposed lines),
141.31 (s), 174.36 (s); IR neat 1736 cm-1; HREIMS calcd for C13H16O2
m/z 204.1150, found 204.1156.
Tetrahydro-2-oxo-2H-pyran-3-acetic acid ethyl ester (2j). Ob-
tained as a colorless liquid: 1H NMR (CDCl3, 600 MHz) δ 1.27 (t,
3H, J ) 7.1 Hz), 1.68 (m, 1H), 1.94 (quintet-like, 2H, J ≈ 6.5 Hz),
2.14 (m, 1H), 2.61 (dd, 1H, J ) 6.7, 17.0 Hz), 2.81 (dd, 1H, J ) 5.3,
17.0 Hz), 2.88-2.99 (m, 1H), 4.16 (q, 2H, J ) 7.1 Hz), 4.33-4.42 (9
line m, 2H); 13C NMR (CDCl3, 68 MHz) δ 14.05 (q), 22.19 (t), 24.76
(t), 35.73 (t), 36.33 (d), 60.68 (t), 68.51 (t), 171.54 (s), 173.34 (s); IR
neat 1732 cm-1; HREIMS calcd for C9H14O4 m/z 186.0888, found
186.0873.
3.96 (td, 1H, J ) 10.7, 4.2 Hz); 13C NMR (CDCl3, 150 MHz) δ 78.90
(d). Isomer of 12% content: 1H NMR (CDCl3) δ 3.93 (td, 1H, J )
10.6, 4.2 Hz); 13C NMR (CDCl3, 150 MHz) δ 80.00 (d). Isomer of
6% content: 1H NMR (CDCl3) δ 4.16 (td, 1H, J ) 11.3, 4.3 Hz); 13
C
NMR (CDCl3, 150 MHz) δ 79.94 (d). Isomer of 4% content: 1H NMR
(CDCl3) δ 4.70 (q-like, 1H, J ≈ 3.3 Hz); 13C NMR (CDCl3, 150 MHz)
δ 76.06 (d). Isomer of 3% content: 1H NMR (CDCl3) δ 4.51 (q-like,
1H, J ≈ 3.3 Hz); 13C NMR (CDCl3, 150 MHz) δ 75.55 (d). Isomer of
3% content: 1H NMR (CDCl3) δ 4.46 (q-like, 1H, J ≈ 3.3 Hz); 13C
NMR (CDCl3, 150 MHz) δ 74.51 (d). Isomer of 2% content: 1H NMR
(CDCl3) δ 4.47 (q-like, 1H, J ≈ 3.3 Hz); 13C NMR (CDCl3, 150 MHz)
δ 80.09 (d).
cis- and trans-Tetrahydro-6-ethyl-4-methyl-2H-pyran-2-one (2t).
Obtained as a cis/trans-isomer mixture in a 55/45 ratio, a slightly yellow
liquid: 1H NMR (CDCl3, 600 MHz) δ 1.00 (t, cis 3H, J ) 7.5 Hz),
1.00 (t, trans 3H, J ) 7.4 Hz), 1.04 (d, cis 3H, J ) 6.3 Hz), 1.10 (d,
trans 3H, J ) 6.6 Hz), 1.12-1.27 (m, cis 1H), 1.55-1.81 (complex
m, cis 2H and trans 4H), 1.89-1.93 (m, cis 1H), 2.00-2.08 (complex
m, cis 2H), 2.14-2.22 (complex m, trans 2H), 2.57 (dd, trans 1H, J )
20.3, 9.4 Hz), 2.67 (ddd, cis 1H, J ) 21.3, 10.4, 2.0 Hz), 4.22 (m, cis
1H), 4.32 (m, trans 1H); 13C NMR (CDCl3, 68 MHz) δ 9.11 (q, cis),
9.52 (q, trans), 21.27 (q, trans), 21.57 (q, cis), 23.70 (d, trans), 26.59
(d, cis), 28.38 (t), 28.81 (t), 34.42 (t), 36.34 (t), 37.36 (t), 37.99 (t),
78.50 (d, trans), 81.77 (d, cis), 171.58 (s, cis), 172.53 (s, trans); IR
neat 1732 cm-1; HREIMS for the cis isomer calcd for C8H14O2 m/z
142.0994, found 142.1002; HREIMS for the trans isomer calcd for
C8H14O2 m/z 142.0994, found 142.0982. In comparison with the
spectral data for 2s,45 the major isomer is assigned as a cis isomer.
5,7-Dimethyl-2-oxabicyclo[3.3.1]nonan-3-one (2v). Obtained as
a slightly yellow liquid: 1H NMR (CDCl3, 270 MHz) δ 0.93 (d, 3H,
J ) 6.4 Hz), 1.00 (s, 3H), 1.02 (td-like, 1H, J ≈ 13.4, 1.5 Hz), 1.13
(td-like, 1H, J ≈ 13.9, 2.0 Hz), 1.47 (td-like, 1H, J ≈ 13.6, 2.0 Hz),
1.57 (dm, 1H, Jdoublet ) 13.4 Hz), 1.72 (m, 1H), 1.81 (dm, 1H, Jdoublet
) 13.6 Hz), 2.09 (dm, 1H, Jdoublet ) 13.9 Hz), 2.29 (dd, 1H, J ) 1.5,
18.6 Hz), 2.43 (dd, 1H, J ) 2.5, 18.6 Hz), 4.79 (septet, 1H, J ) 2.0
Hz); 13C NMR (CDCl3, 68 MHz) δ 21.55 (q), 23.90 (d), 30.13 (q),
30.56 (s), 37.14 (t), 38.97 (t), 43.06 (t), 47.39 (t), 76.10 (d), 171.85
(s); IR neat 1732 cm-1; HREIMS calcd for C10H16O2 m/z 168.1151,
found 168.1140.
Tetrahydro-3,6-dipropyl-2H-pyran-2-one (2w). GC analysis of
the crude extract showed the ratio of 2w/2w′ was 24/1. Rotary
evaporation of the solvent followed by flash chromatography on silica
gel (hexane, then 10% EtOAc-hexane eluent) afforded pure 2w in
61% yield as a cis/trans-isomer mixture in a 41/59 ratio. The cis/trans
isomers of 2w were separated by preparative HPLC. cis-2w, a slightly
yellow liquid: 1H NMR (CDCl3, 270 MHz) δ 0.93 (t, 6H, J ) 6.8
Hz), 1.33-1.73 (m, 9H), 1.86-2.05 (m, 3H), 2.30-2.45 (m, 1H), 4.20-
4.32 (m, 1H); 13C NMR (CDCl3, 68 MHz) δ 13.85 (q), 13.91 (q), 18.08
(t), 19.85 (t), 25.51 (t), 28.87 (t), 34.05 (t), 38.36 (t), 40.60 (d), 81.02
(d), 174.03 (s); IR neat 1728 cm-1; HREIMS calcd for C11H20O2 m/z
184.1463, found 184.1474. trans-2w, a slightly yellow liquid: 1H NMR
(CDCl3, 270 MHz) δ 0.93 (t, 6H, J ) 6.8 Hz), 1.31-1.75 (m, 9H),
1.80-1.96 (m, 2H), 1.99-2.11 (m, 1H), 2.40-2.51 (m, 1H), 4.23-
4.31 (m, 1H); 13C NMR (CDCl3, 68 MHz) δ 13.83 (q), 13.98 (q), 18.36
(t), 20.18 (t), 23.35 (t), 26.69 (t), 32.96 (t), 37.41 (t), 37.95 (d), 77.75
(d), 175.81 (s); IR neat 1736 cm-1; HREIMS calcd for C11H20O2 m/z
184.1463, found 184.1437. In comparison with the spectral data for
2n,44 the major isomer is assigned as a cis isomer.
Tetrahydro-6-methyl-3-propyl-2H-pyran-2-one (2k). Obtained as
a cis/trans-isomer mixture in a 55/45 ratio. These isomers were
separated by preparative HPLC. cis-2k, a colorless liquid: 1H NMR
(CDCl3, 270 MHz) δ 0.93 (t, 3H, J ) 7.1 Hz), 1.35 (d, 3H, J ) 5.9
Hz), 1.39-1.68 (m, 5H), 1.75-2.09 (m, 3H), 2.37-2.52 (m, 1H), 4.38-
4.53 (m, 1H); 13C NMR (CDCl3, 68 MHz) δ 13.91 (q), 20.08 (t), 21.00
(q), 23.26 (t), 28.33 (t), 32.89 (t), 37.67 (d), 74.22 (d), 175.62 (s); IR
neat 1736 cm-1; HREIMS calcd for C9H16O2 m/z 156.1150, found
156.1136. trans-2k, a colorless liquid: 1H NMR (CDCl3, 270 MHz)
δ 0.93 (t, 3H, J ) 7.1 Hz), 1.36 (d, 3H, J ) 6.4 Hz), 1.42-1.62 (m,
5H), 1.86-2.06 (m, 3H), 2.30-2.45 (m, 1H), 4.39-4.48 (m, 1H); 13
NMR (CDCl3, 68 MHz) δ 13.88 (q), 19.79 (t), 22.10 (q), 25.49 (t),
30.69 (t), 33.94 (t), 40.22 (d), 77.60 (d), 173.95 (s); IR neat 1719 cm-1
C
;
HREIMS calcd for C9H16O2 m/z 156.1150, found 156.1165. In
comparison with the spectral data for 2n,44 the major isomer is assigned
as a cis isomer.
Tetrahydro-6-ethyl-3-propyl-2H-pyran-2-one (2l). Obtained as
a cis/trans-isomer mixture in a 55/45 ratio. These isomers were
separated by preparative HPLC. cis-2l, a yellow liquid: 1H NMR
(CDCl3, 600 MHz) δ 0.94 (t, 3H, J ) 7.2 Hz), 1.00 (t, 3H, J ) 7.5
Hz), 1.35-1.46 (m, 3H), 1.49-1.65 (m, 3H), 1.73 (m, 1H), 1.82-
1.88 (m, 1H), 1.88-1.96 (m, 1H), 2.03 (ddd, 1H, J ) 7.8, 13.4, 16.6
Hz), 2.45 (m, 1H), 4.20 (m, 1H); 13C NMR (CDCl3, 68 MHz) δ 9.51
(q), 13.86 (q), 20.14 (t), 23.25 (t), 26.15 (t), 28.23 (t), 32.90 (t), 37.88
(d), 79.23 (d), 175.83 (s); IR neat 1736 cm-1; HREIMS calcd for
C10H18O2 m/z 170.1307, found 170.1292. trans-2l, a yellow liquid:
1H NMR (CDCl3, 600 MHz) δ 0.94 (t, 3H, J ) 7.3 Hz), 0.99 (t, 3H,
J ) 7.5 Hz), 1.32-1.47 (m, 2H), 1.55 (m, 3H), 1.60-1.67 (m, 1H),
1.72 (m, 1H), 1.89-1.96 (m, 2H), 2.03 (ddd, 1H, J ) 3.2, 6.7, 13.4
Hz), 2.39 (m, 1H), 4.20 (m, 1H); 13C NMR (CDCl3, 68 MHz) δ 9.21
(q), 13.91 (q), 19.83 (t), 25.42 (t), 28.30 (t), 29.11 (t), 34.02 (t), 40.60
(d), 82.46 (d), 174.07 (s); IR neat 1728 cm-1; HREIMS calcd for
C10H18O2 m/z 170.1307, found 170.1310. In comparison with the
spectral data for 2n,44 the major isomer is assigned as a cis isomer.
Dodecahydro-6H-dibenzo[b,d]pyran-6-one (2p). Obtained as a
mixture of eight diastereomers in a 55/15/12/6/4/3/3/2 ratio (600 MHz
1H NMR). Four major isomers were assigned to the retention products
(trans) because of the relative larger J value of its CHO signal, and
four minor isomers to the inversion products (cis). The ratio of retention
and inversion was 88/12. After purification by HPLC, the major isomer
Carbonylation of an Alkyl 4-Nitrobenzenesulfenate under Ir-
radiation Conditions. Benzene (25 mL) and sulfenate 5b (169 mg,
0.5 mmol) were placed in a 50-mL stainless steel autoclave used for
irradiation and lined with a Pyrex glass tube. The autoclave was closed,
purged twice with 10 atm of CO, and then charged with 60 atm of CO
and irradiated with stirring for 1 h using a 500-W xenon lamp (>300
nm) placed 30 cm from the solution. After excess CO was discharged,
1
was obtained in a pure form, a white solid: mp. 106-107 °C; H
NMR (CDCl3) δ 0.80-0.92 (m, 2H), 1.15-1.35 (m, 7H), 1.44 (dq-
like, 1H, J ) 3.9, 12.0 Hz), 1.70-1.88 (m, 4H), 1.90-2.00 (m, 3H),
2.06-2.09 (m, 1H), 2.33-2.40 (m, 1H), 3.87 (ddd, 1H, J ) 4.1, 9.9,
11.3 Hz); 13C NMR (CDCl3, 150 MHz) δ 24.37 (t), 25.15 (t), 25.24
(t), 25.96 (t), 26.97 (t), 27.34 (t), 28.85 (t), 32.61 (t), 42.30 (d), 44.85
(d), 47.08 (d), 84.34 (d), 172.97 (s); IR neat 1724 cm-1; HREIMS calcd
for C13H20O2 m/z 208.1463, found 208.1461. [Partial data was obtained
for the other isomers.] Isomer of 15% content: 1H NMR (CDCl3) δ
1
the benzene was evaporated. The residue was found by H NMR to
contain a 52% yield of tetrahydro-6,6-dimethyl-3-hexyl-2H-pyran-2-
one (6b) (vs trioxane internal standard). The spectroscopic data of 6b
(45) (a) Carroll, F. I.; Mitchell, G. N.; Blackwell, J. T.; Sobti, A.; Meck,
R. J. Org. Chem. 1974, 39, 3890. (b) Pirkle, W. H.; Adams, P. E. J. Org.
Chem. 1980, 45, 4117.
(44) Pirkle, W. H.; Adams, P. E. J. Org. Chem. 1979, 44, 2169. Also
see refs 20 and 21c and d.

Synthesis of δ-Lactones
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8701
purified by flash chromatography and preparative HPLC (GPC column)
is listed below: 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, 3H, J ) 6.6
Hz), 1.22-1.45 (m, 14H including 1.41 (s, 3H) and 1.37 (s, 3H)), 1.52-
1.60 (m, 1H), 1.63-1.98 (complex m, 5H), 2.30-2.38 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.02, 22.47, 22.55, 26.64, 28.00, 29.12,
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for assistance in obtaining MS, HREIMS, and 600
MHz NMR spectra.
Supporting Information Available: General procedure for
hydrogenation of aromatic alcohols, procedure for control
experiments (Tables 1 and 4), characterization data for 2a-b,
2f, 2m-o, 2q-s, 2u, 2x-y, 3a, and 3z, procedure for synthesis
of 3z, and cis/trans assignments of 2,5-disubstituted δ-lactones
(9 pages, print/PDF). See any current masthead page for
ordering information and Web access instructions.
29.74, 31.61, 31.68, 33.69, 39.56, 81.57, 173.65; IR neat 1727 cm-1
;
HREIMS calcd for C13H24O2 m/z 212.1776, found 212.1785.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science and Culture, Japan. We thank Dr. Cathleen
M. Crudden for helpful discussions. I.R. thanks the Sumitomo
Foundation for financial support. Thanks are due to the
JA9807892