A Publicationof Reliable Methods
for the Preparationof Organic Compounds

Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper
training in experimental organic chemistry. All hazardous materials should be handledusing the standard procedures for work with chemicals described in references such as"Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C.,
2011;
the
full
text
can
be
accessedfreeofchargeat
http://www.nap.edu/catalog.php?record_id=12654).
All chemical waste should be
disposed of in accordance with local regulations. For general guidelines for the
management of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red“Caution Notes” within a procedure. It is important to recognize that the absence of a
caution note does not imply that no significant hazards are associated with the chemicals
involved in that procedure. Prior to performing a reaction, a thorough risk assessment
should be carried out that includes a review of the potential hazards associated with eachchemical and experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards associatedwith chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and are
conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of
Directors do not warrant or guarantee the safety of individuals using these procedures andhereby disclaim any liability for any injuries or damages claimed to have resulted from orrelated in any way to the procedures herein.

These paragraphs were added in September 2014. The statements above do not supersede any specifichazard caution notes and safety instructions included in the procedure.

DOI:10.15227/orgsyn.069.0188

Organic Syntheses, Coll. Vol. 8, p.562 (1993); Vol. 69, p.188 (1990).

A GENERAL METHOD FOR THE PREPARATION OF 9-, 10-, AND
11-MEMBERED UNSATURATED MACROLIDES: SYNTHESIS OF
8-PROPIONYL-(E)-5-NONENOLIDE[2H-Oxecin-2-one, 3,4,5,8,9,10-hexahydro-9-(1-oxopropyl)-, (E)-]

Submitted by Kevin S. Webb, Edward Asirvatham, and Gary H. Posner1.
Checked by Thais Sielecki and Albert I. Meyers.

1. Procedure
Caution! Benzene has been identified as a carcinogen: OSHA has issued emergency standards on its
use. All procedures involving benzene should be carried out in a well-ventilated hood, and gloves
should be worn.
A flame-dried (Note 1), 500-mL, three necked, round-bottomed flask equipped with a Teflon-coatedmagnetic stirring bar, rubber septa, and an argon inlet is charged with 75 mL of anhydrous
tetrahydrofuran (Note 2) and 8.0 mL (57.1 mmol) of diisopropylamine (Note 3), then cooled to −10°C
via an ice–salt bath. Next 34.8 mL (55.0 mmol) of butyllithium (1.58 M, (Note 4), in hexane) is added
dropwise (over 4 min) to the vigorously stirred diisopropylamine solution, and stirred at −10°C for 20
min. Tributyltin hydride (15.2 mL, 55.0 mmol, (Note 5)) is added dropwise over 5 min to the solution,and the reaction mixture is stirred under argon at −10° to 0°C for an additional 30 min. The flask iscooled to −78°C and stirred for 20 min.
A flame-dried (Note 1), 100-mL, round-bottomed flask equipped with a Teflon-coated magnetic
stirring bar, a rubber septum, and an argon inlet is charged with 50 mL of anhydrous tetrahydrofuran(Note 2) and 4.85 mL (50.1 mmol) of 2-cyclohexen-1-one (Note 6), and cooled to −78°C. This solution(54.85 mL) is cannulated into the tributyltinlithium solution dropwise over 8 min (Note 7), and thesolution is stirred at −78°C under argon for 25 min (Note 8). The same 100-mL, round-bottomed flask ischarged with 50 mL of anhydrous tetrahydrofuran (Note 2) and 6.1 mL (59.4 mmol) of ethyl vinyl
ketone (Note 9), and cooled to −78°C. This solution (56.1 mL) is cannulated into the 500-mL, roundbottomed flask dropwise over 8 min (Note 10), and the solution is stirred for 1.5 hr (Note 11). The
resulting solution is then transferred from a −78°C cold bath to a −23°C cold bath (Note 12) and stirred
at this temperature for 30 min.
A flame-dried (Note 1), 100-mL, three-necked, round-bottomed flask equipped with a Tefloncoated magnetic stirring bar, a Teflon stopcock, rubber septa, and an argon inlet is charged with 6 g ofparaformaldehyde (Note 13). The flask is heated to 165–170°C and the gaseous formaldehyde isbubbled into the −23°C solution (Note 14). After 15 min all of the paraformaldehyde is pyrolyzed (Note15), and the solution becomes slightly cloudy and yellow. The 500-mL, three-necked, round-bottomed
flask is transferred to a −40°C bath (maintained by a Flexicool cryostat) and allowed to stir under argon
for 20 hr. The reaction mixture is quenched at −40°C with 7 mL of saturated ammonium chloride
followed by 8 mL of distilled water. It is warmed to room temperature, poured into a 500-mL separatory

funnel, and diluted with 75 mL of water; the organic layer is separated, and the aqueous layer is
extracted with diethyl ether (2 × 100 mL). The combined organic layers are dried over anhydrous
magnesium sulfate, filtered, and concentrated (Note 16) to afford 29.3 g of crude product.
A flame-dried (Note 1), 1000-mL, three-necked, round-bottomed flask equipped with a Tefloncoated magnetic stirring bar, rubber septa, a 24/40 condenser, and an argon inlet is charged with 300 mLof anhydrous benzene (Note 17) and 29.00 g (65.4 mmol) of lead tetraacetate (Note 18). The suspension
is heated to 80°C and stirred vigorously under argon. A flame-dried (Note 1), 250-mL, round-bottomed
flask equipped with a Teflon-coated magnetic stirring bar, rubber septa, and an argon inlet is charged
with 150 mL of anhydrous benzene (Note 17) and 29.3 g of the crude reaction mixture. This solution iscannulated into the lead tetraacetate suspension over 2 min (Note 19), and the suspension is allowed toreflux for 2.5 hr. The reaction flask is cooled to room temperature, quenched with 200 mL of distilledwater, poured into a 2-L separatory funnel, and diluted with 1000 mL of diethyl ether (Note 29). The
organic layer is washed with saturated sodium bicarbonate solution (3 × 200 mL), aqueous 5%hydrochloric acid (2 × 200 mL), distilled water (200 mL), and brine (200 mL). The organic layer isdried over anhydrous magnesium sulfate and filtered; solvent removal afforded 28.95 g of a crude oil.
This crude residue (light-yellow-brown oil) is purified by short-path column chromatography (Note 21)
to yield 4.37 g (41.5%) of 8-propionyl-(E)-5-nonenolide (Note 22) and (Note 23).

2. Notes
1. All glassware and Teflon-coated magnetic stirring bars were flame-dried under vacuum (0.5 mm) for
5 min, then back-filled with argon. The procedure was repeated a total of 3 times.
2. Baker reagent-grade tetrahydrofuran (99%, obtained from Aldrich Chemical Company, Inc.) was
distilled over sodium metal spheres/benzophenone under an inert atmosphere and used immediately.
3. Diisopropylamine, 99%, was obtained form Aldrich Chemical Company, Inc., and allowed to reflux
over calcium hydride (≥95%, obtained from Aldrich Chemical Company, Inc.) for 24 hr prior to use.
4. Butyllithium in hexane (1.6 M), obtained from Aldrich Chemical Company, Inc., was titrated (using
2,5-dimethoxybenzyl alcohol as the indicator2) just prior to use.
5. Tributyltin hydride, 97%, was obtained form Aldrich Chemical Company, Inc., and must be used
quickly to ensure generation of the tributyltinlithium species. Two minutes after the initial addition oftributyltin hydride the colorless solution turned light yellow.
6. 2-Cyclohexen-1-one, 97%, was obtained from Aldrich Chemical Company, Inc., and was freshly
distilled via short-path distillation.
7. After the 2-cyclohexenone addition was complete, the 100-mL, round-bottomed flask was washedwith 10 mL of anhydrous tetrahydrofuran, and this wash was cannulated into the 500-mL flask (Note 2).
8. A small aliquot of the reaction mixture was removed after 15 min and analyzed by analytical TLC.
The TLC was developed in 20% ethyl acetate:hexane and showed that the 1,4-conjugate addition had
proceeded to completion (Rf = 0.58); the solution was colorless at this point of the reaction.
9. Ethyl vinyl ketone, 97%, was obtained from Aldrich Chemical Company, Inc., and used directly.
10. The reaction mixture turned slightly yellow during addition of ethyl vinyl ketone.
11. A small aliquot was removed from the reaction mixture and analyzed by analytical TLC (20% ethyl
acetate:hexane) to ensure that the Michael addition had proceeded, Rf = 0.44, and Rf = 0.32
corresponding to the diastereomeric intermediates.
12. A −23°C bath was obtained from a mixture of dry ice/carbon tetrachloride. A temperature between−40° and −20°C is necessary.
13. Paraformaldehyde, 95%, was obtained from Aldrich Chemical Company, Inc., and used directly.
14. The argon inlet was equipped with a 16-gauge, 3-in. syringe needle; the transfer cannula was a flexneedle (Z10,091-9) obtained from Aldrich Chemical Company, Inc., and the outlet bubbler was
equipped with a 16-gauge, 3-in., syringe needle.
15. A high-pressure stream of argon was needed to prevent the gaseous formaldehyde frompolymerizing to paraformaldehyde in the transfer flex-needle.
16. The weight of 29.30 g was achieved by attaching the round-bottomed flask to a vacuum (1.5 mm)
and heating via a water bath (55°C) for 4 hr.
17. Benzene (thiophene-free, ≥99%, 900 mL) was obtained from Aldrich Chemical Company, Inc., andwashed with concentrated sulfuric acid (5 × 100 mL), distilled water (100 mL), aqueous 2% sodiumhydroxide solution (100 mL), and distilled water (100 mL), and dried over anhydrous magnesiumsulfate. It was then allowed to reflux over calcium hydride for 24 hr. The checkers found that thebenzene needed to be distilled only from calcium hydride.
18. lead tetraacetate was purchased from Aldrich Chemical Company, Inc., and used directly.
19. The transfer cannula was a 12-in., 16-gauge, double-tipped syringe needle, and the 250-mL flask
was washed with an additional 30 mL of anhydrous benzene (Note 17), which was cannulated into the
1000-mL flask.
20. The 1000-mL, round-bottomed flask was washed with diethyl ether (3 × 100 mL of the 1000 mL).
21. Working on one-half of the present scale, the checkers found that by using Amicon Grace Matrex
Silica Gel, (60 Å, 20–45 m) and an eluting solvent of 10% diethyl ether:hexane, 3.50 g (66.0%) of 8propionyl-(E)-5-nonenolide was obtained. The white solid was further purified by recrystallization from
15 mL of hexane to yield 3.15 g (60.0%) as a white solid.
22. The physical properties are as follows: IR (CHCI3) cm−1; 2933, 1731, 1349, 1210, 1154, 979, 770,
746; 1H NMR (CDCl3, 400 MHz) δ: 1.05 (t, 2 H, J = 7.2), 1.12 (t, 1 H, J = 7.2), 1.70–3.00 (m, 11 H),
3.76–3.82 (m, 0.67 H), 4.15–4.21 (m, 0.33 H), 5.05–5.70 (m, 3 H). When the proton signals at 1.90–
2.90 ppm were irradiated, the two olefinic multiplets collapsed into two doublets (J = 15.2). An
analytical sample (4.37 g) was recrystallized from 20 mL of hexane (Fisher, certified) to yield 4.05 g(38.5%) was a white solid: mp 70–71°C. Anal. calcd. for C12H18O3; C, 68.57; H. 8.57. Found: C, 68.47;
H, 8.68.
23. In order to determine whether the product was a mixture of geometrical isomers (e.g., differing by
cis or trans geometry at the double bond) or conformers, it was necessary to obtain 1H NMR spectra atvarious temperatures. The 400 MHz 1H NMR (d6-DMSO) at 100°C shows that the two triplets (δ 1.05,
1.12) start to collapse to one triplet, the multiplicity of the peaks in the region of δ 5.05–5.70 simplify
greatly, and the initial peak ratios in the region of δ 3.70–4.20 change from 1:2 to 1:3. Therefore, thenonenolide is one pure isomer of only trans double-bond geometry and is able to exist as two stableconformers in solution. The glass capillary gas chromatograph (Hewlett Packard 5890) of 8-propionyl(E)-5-nonenolide shows only one peak with a retention time of 4.21 min (injector temperature 175°C,
detector temperature 225°C).

3. Discussion
The procedure described is a simple, rapid, and convenient method for conversion of n-sized
cycloalkenones into n + 4 alkenolides. Significant but limited progress has been reported in the recent
literature toward the preparation of medium and large-ring lactones via ring-expansion reactions. One of
the most notable and useful developments in this area involves conversion of a cycloalkanone into abicyclic vinylic ether that is oxidatively cleaved to form a ring-enlarged keto lactone.3,4; 5 Recently,
several variations of this ring-enlargement reaction have been reported, including the scission of alkoxy
radicals.6,7,8,9,10,11,12,13,14 In most of these cases, a superfluous functional group (e.g., ketone, iodide), is
produced during cleavage of the bicyclic system. Regiospecific conversion of such functional groups
into a specific alkene structural unit is usually not possible because of the similar chemical environment
α' to the functional group.15 Because many regiospecifically unsaturated lactones are physiologically
active natural products,16,17,18,19 we have developed methodology to prepare unsaturated macrolides
having a carbon–carbon double bond with specific geometry and at a specific position in the macrolide
skeleton.
Because of our interest in one-pot, multicomponent annulations,20,21,22,23,24,25,26 we envisioned aflexible and efficient protocol that would link the four different components via the formation of four
new bonds (a–d, Eq. 1) in one reaction vessel. The intermediate γ-hydroxystannanes thus formed in
Equation 1 could be oxidatively fragmented27,28,29 to produce both ring enlargement and regiospecificformation of an alkenyl unit. This four-atom ring-expansion methodology of common side α,βunsaturated ketones has led to the syntheses of many mono- and disubstituted 9-, 10-, and 11-memberedunsaturated macrolides (Table I).

TABLE I

n R

R'

0 Et

CH3

Yield (%)

trans:cis

0.57

30.5

1 Et

CH3

0.7

47

1 Et

CH2=CH

2.6

39.5

1 Et

o-BrC6H4

5.3

47

1 Et

o-IC6H4

2.6

37

1 Ph

o-IC6H4

1.0

34

1 Et

PhCH2

1.5

43.5

1 Ph

o-BrC6H4CH2

1.0

30

1 Et

o-N(phtl)C6H4

5.0

42

1 Et

H

—

41.5

1 Et 2,3-(MeO)2C6H3CH2

1.0

52

1 Ph2,3-(MeO)2C6H3CH2

1.5

51

1 Et

3-ThienylCH2

0.7

52

1 Ph

3-ThienylCH2

1.8

52

1 Et

3-FurylCH2

0.7

54

1 Ph

3-FurylCH2

7.0

40

2 Et

1.1

Cyclopropyl

53

2 Et

CH3

1.0

40

2 Et

3-(MeO)C6H4

1.5

41.5

2 Ph

o-IC6H4CH2

1.9

38

Based on the data in Table I and on our published results,20,21,22,23,24,25,26 it is clear that five-, six-, andseven-membered cycloalkenones undergo this four-atom ring enlargement reaction to produce medium
ring, unsaturated lactones in overall yields of 30–54%. Permutations on this methodology include using
either ethyl vinyl ketone or phenyl vinyl ketone as the third component, and either substituted
acetaldehydes or substituted benzaldehydes as the last component. The geometrical assignment of the
new carbon–carbon double bond was made from interpreting the 400 MHz 1H NMR decoupled spectrain which each olefinic proton collapsed into a baseline-resolved doublet with coupling constants of J =15–16. The proton decoupling experiments conducted to determine the relative stereochemistry of thevicinal substituents in the disubstituted macrolides were inconclusive; often the magnitude of thecoupling constants were similar or not discernible from the spectra. Therefore, the relative
stereochemistry of the vicinal substituents was established by examining the 1H NMR spectra of theintermediate γ-hydroxystannanes (usually only two were isolated). The trans-hemiketals showed typicalcoupling constants of J = 8–13, while the cis-hemiketals showed coupling constants of J = 2–4. Separate
lead tetraacetate oxidative fragmentation of these γ-hydroxystannanes produced two different ringenlarged lactones, both with specific trans double-bond geometry and differing only in the relative
stereochemistry of vicinal substituents.
This homologous Baeyer–Villiger-type oxidative ring expansion represents a conceptually new
protocol illustrating the substantial value of one-pot, four-component annulations as a flexible andsimple new synthetic method.

References and Notes
1. The Johns Hopkins University, Department of Chemistry, Baltimore, MD 21218. We thank thedonors of the Petroleum Research Fund, administered by the American Chemical Society, andthe NSF (CHE 86-07974) for financial support, and Professor S.-S. Jew for experimental help.
2. Winkle, M. R.; Lansinger, J. M.; Ronald, R. C. J. Chem. Soc., Chem. Commun. 1980, 87.
3. Borowitz, I. J.; Bandurco, V.; Heyman, M.; Rigby, R. D. G.; Ueng, S.-N. J. Org. Chem. 1973,
38, 1234, and references cited therein;
4. Mahajan, J. R.; Araujo, H. C. Synthesis 1976, 111, and references cited therein
5. Immer, H.; Bagli, J. F. J. Org. Chem. 1968, 33, 2457.
6. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 6548;
7. Beckwith, A. L. J.; O'Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun.
1987, 666;
8. Suginome, H.; Yamada, S. Tetrahedron Lett. 1987, 28, 3963; Suginome, H.; Yamada, S.
Tetrahedron 1987, 43, 3371; Suginome, H.; Yamada, S. Chem. Lett. 1988, 245;
9. Beckwith, A. L. J.; Kazlauskas, R.; Syner-Lyons, M. R. J. Org. Chem. 1983, 48, 4718, andreferences cited therein;
10. Schreiber, S. L. J. Am. Chem. Soc. 1980, 102, 6163.
11. See also (f) Stanchev, S.; Hesse, M. Helv. Chim. Acta 1987, 70, 1389, and references citedtherein;
12. Milenkov, B.; Guggisberg, A.; Hesse, M. Tetrahedron Lett. 1987, 28, 315;
13. Schreiber, S. L.; Sammakia, T.; Hulin, B.; Schulte, G. J. Am. Chem. Soc. 1986, 108, 2106;
14. Freire, R.; Marrero, J. J.; Rodriguez, M. S.; Suárez, E. Tetrahedron Lett. 1986, 27, 383.
15. For a useful exception, see Schreiber, S. L.; Hulin, B.; Liew, W.-F. Tetrahedron 1986, 42, 2945.
16. For reviews, see (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569;
17. "Macrolide Antibiotics: Chemistry, Biology and Practice," Omura, S., Ed.; Academic Press:
Orlando, FL, 1984;
18. Masamune, S. Aldrichimica Acta 1978, 11, 23;
19. Nicolaou, K. C. Tetrahedron 1977, 33, 683.
20. Posner, G. H.; Webb, K. S.; Asirvatham, E.; Jew, S.-S; Degl' Innocenti, A. J. Am. Chem. Soc.
1988, 110, 4754;
21. Posner, G. H.; Asirvatham, E.; Webb, K. S.; Jew, S.-S. Tetrahedron Lett. 1987, 28, 5071
22. Posner, G. H.; Asirvatham, E.; Tetrahedron Lett. 1986, 27, 663
23. Posner, G. H.; Lu, S.-B; Asirvatham, E.; Silversmith, E. F.; Shulman, E. M. J. Am. Chem. Soc.
1986, 108, 511
24. Posner, G. H. Chem. Rev. 1986, 86, 831
25. Posner, G. H.; Shulman-Roskes, E. M. J. Org. Chem. 1989, 54, 3514
26. Posner, G. H.; Crouch, R. D. Tetrahedron 1990, 46, 7509.
27. Nakatani, K.; Isoe, S. Tetrahedron Lett. 1984, 25, 5335; 1985, 26, 2209;
28. Ochiai, M.; Ukita, R. T.; Nagao, Y.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985, 637
29. Ochiai, M.; Iwaki, S.; Ukita, T.; Nagao, Y. Chem. Lett. 1987, 133.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)brinesulfuric acid (7664-93-9)hydrochloric acid (7647-01-0)

Benzene (71-43-2)
ethyl acetate (141-78-6)
diethyl ether (60-29-7)
ammonium chloride (12125-02-9)
sodium hydroxide (1310-73-2)
formaldehyde (50-00-0)
sodium bicarbonate (144-55-8)
carbon tetrachloride (56-23-5)
Benzophenone (119-61-9)
sodium (13966-32-0)
magnesium sulfate (7487-88-9)butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
hexane (110-54-3)
argon (7440-37-1)
tributyltin hydride (688-73-3)
calcium hydride (7789-78-8)
2-Cyclohexenone,
2-cyclohexen-1-one (930-68-7)
cyclopropyl (2417-82-5)
diisopropylamine (108-18-9)
2,5-dimethoxybenzyl alcohol (33524-31-1)
Tributyltinlithium ethyl vinyl ketone (1629-58-9)
phenyl vinyl ketone (768-03-6)
8-Propionyl-(E)-5-nonenolide

2H-Oxecin-2-one, 3,4,5,8,9,10-hexahydro-9-(1-oxopropyl)-, (E)- (114633-68-0)
lead tetraacetate (546-67-8)
paraformaldehyde (30525-89-4)
Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved