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Novel route to carboxylic acids via the DCME reaction
Tetrahedron Letters Tetrahedron Letters 45 (2004) 5541–5543
Novel route to carboxylic acids via the DCME reaction John A. Soderquist,* Judith Martinez, Yatsandra Oyola and Iveliz Kock Department of Chemistry, University of Puerto Rico, San Juan, PR 00931-3346, Puerto Rico Received 23 April 2004; revised 27 April 2004; accepted 30 April 2004
Abstract—Brown’s DCME reaction was successfully performed employing B-alkyl-9-oxa-10-borabicyclo[3.3.2]decanes (1) to provide carboxylic acids (2) in good to excellent yields with complete retention of configuration. 2004 Elsevier Ltd. All rights reserved.
Carboxylic acids are key synthetic intermediates in the preparation of many natural products and synthetic drugs. This functionality is classically prepared from primary alcohols, aldehydes, alkenes, and arenes by oxidative methods, by the hydrolysis of nitriles and by the carboxylation of organometallic intermediates. Other modern reported methods such as the Arndt– the Katritzky 1-[(trimethylEistert reaction,1 the silyl)methyl]-1H-1,2,3-benzotriazole protocol,2 3 Kowalsky CH2 Br2 method, and Barton’s radical homologation,4 allow the conversion of a carboxylic acid or its derivatives into their higher homologues. The DCME (a,a-dichloromethyl methyl ether) reaction is commonly used for the preparation of tertiary-carbinols from trialkylboranes,5;6 and ketones from dialkylborinate esters.7 Examples of these processes with 9-BBN systems are illustrated in Scheme 1. This reaction is presumed to occur through the reversible deprotonation of the DCME followed by addition of the carbenoid to the boron with a subsequent series of B fi C migrations producing a boronic ester, which is oxidized to the product. As can be inferred from the above results for 9-BBN systems, the migrations involve first the formation of a borabicyclo[3.3.2]decane intermediate followed by a ring contraction to the bicyclo[3.3.1]nonane product. In addition to steric factors, which play an important role in both the borane as well
Keywords: DCME reaction; Carboxylic acid synthesis; Organoboranes; OBBD; Homologation. * Corresponding author. Tel.: +1-787-751-7779; fax: +1-787-766-1354; e-mail: [email protected] 0040-4039/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.04.180
t-Bu
t-Bu 1. CHCl2OMe LiOCEt 3
B
2.
OH C
[O] 83%
Bu-t
t-Bu
O B
O 1. CHCl2OMe LiOCEt 3 2.
C
[O] 88%
Scheme 1.
as in the base employed, the Lewis acidity of the borane is also critical to the success of the process. Thus, boronic esters are wholly ineffective substrates for the preparation of carboxylic acids through a single alkyl group migration in the DCME reaction.8 The failure of this process led to the development of an organoboranebased method, which uses the more reactive B-alkyl 1,3,2-dithiaborolanes and the carbenoid, LiCCl3 to give the corresponding one-carbon extended carboxylic acids.8 Compared to the DCME process, both the borane and the carbenoid employed in this procedure have numerous disadvantages (e.g., RBBr2 intermediates, )100 C reaction temperature, R groups derived only through hydroboration). Some years ago, we discovered the chemoselective monooxidation of B-alkyl-9-BBNs with anhydrous
5542
J. A. Soderquist et al. / Tetrahedron Letters 45 (2004) 5541–5543
trimethylamine N-oxide (TMANO), which produces air and thermally stable B-alkyl-9-oxa-10-borabicyclo[3.3.2]decanes (1) in excellent yields.9 The remarkable stabilities of these borinate esters makes them ideal partners in the Suzuki–Miyaura coupling10 and other processes,11 where robust stationary boron ligation is essential. Because their Lewis acidities were similar to other borinate esters, their remarkable inertness to further oxidation and 1,2-alkyl migrations compared to the isomeric B-alkoxy-9-BBNs was attributed to a strong resistance toward further ring expansion.9;12 This suggested that the DCME reaction of B-alkyl-9-oxa-10borabicyclo[3.3.2]decanes (OBBDs) could provide a convenient new method for the stereo- and regioselective conversion of alkenes into the corresponding one-carbon extended carboxylic acids (2).
O B
R
1. CHCl2OMe LiOBu-t 2.
[O]
O R
OH 2
1
Through standard hydroboration or organometallic processes, B-substituted-9-BBNs are easily prepared and readily converted to 1 with TMANO in CHCl3 .13 Since crystalline 9-BBN dimer is commercially available, airstable and highly chemo-, stereo-, and regioselective in the hydroboration process, all of the organoboranes prepared through this method were isomerically pure with the exception of those produced from limonene, which was isolated as a 50:50 mixture of diastereomers (1g). The DCME process was successfully performed providing moderate to high yields of the homologated carboxylic acids.14 Table 1 summarizes our results. The Table 1. Preparation of representative carboxylic acids via the DCME reaction Entry
R
Yield (%)a
a b c
n-C8 H17 c-C6 H11 PhCH2 CH2
83 78 85
process is quite general and works for primary-, secondary-, and some tertiary-alkyl groups although it does not work well with hindered OBBDs. The B-R group undergoes exclusive 1,2-migration in the DCME process with the insertion occurring with retention of configuration as evidenced by the trans stereochemistry in pinane-3-carboxylic acid, a feature, which was confirmed by single crystal X-ray analysis.15 While lesser substituted alkyl groups give better yields of 2, even tertiaryalkyl and aryl groups do undergo this process. Although the DCME reaction is usually performed with lithium triethylcarboxide, we found the use of lithium tert-butoxide to be preferable in an earlier application of the DCME process.16 The triethylcarbinol proved difficult to separate from the carboxylic acids, and the greater water solubility and volatility of tert-butanol circumvented these problems. Additionally, the oxidation of the DCME intermediates requires an excess of hydrogen peroxide and the more hindered derivatives required longer oxidation times (e.g., 1d: 12 h). This new DCME methodology provides a particularly convenient protocol for the regio-, stereo-, and chemoselective hydrocarboxylation of alkenes. It is superior to existing alternative methods for the carboxylation of organoboranes because the R groups in 1 can be easily installed by both hydroboration and organometallic methods. Moreover, the protocol involves convenient reaction conditions and reagents and gives higher yields for comparable substrates. It owes its success to the higher Lewis acidity of borinate versus boronate esters together with the special property of the OBBD ring system, which resists ring expansion during the DCME process.
Acknowledgements Financial support from the NASA Space Grant (NGT540012), NSF (CHE0217550), Pfizer, Inc. (University Alliance), NIH-SCORE (SO6-GM08102), and NIHRISE (5R25GM061151) is gratefully acknowledged.
References and notes 50
d e f g
h a b
t-C4 H9 Ph H
PrEtCH
40 63 75b
11
Yields are of isolated, analytically pure material. Isolated as a 50:50 mixture of diastereomers as judged by two sets of equal intensity 13 C NMR for 2g for all except the downfield vinylic and carboxyl carbons (19 total signals). The compound(s) 2g provided a satisfactory elemental analysis for C11 H18 O2 .
1. (a) Mulzer, J. In Comprehensive Organic Functional Group Transformation; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 5, p 144, and 276; (b) Wilnum, J.-Y.; Kamal, M.; Leydet, A.; Roque, J.-P.; Montero, J.-L. Tetrahedron Lett. 1996, 37, 1781– 1782. 2. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789–3791. 3. (a) Kowalski, C. J.; Haque, M. S.; Fields, K. W. J. Am. Chem. Soc. 1985, 107, 1429–1430; (b) Reddy, R. E.; Kowalski, C. J. Org. Synth. 1992, 146. 4. (a) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. C. Tetrahedron Lett. 1991, 32, 3309–3312; (b) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. C. Tetrahedron Lett. 1992, 33, 5013–5016.
J. A. Soderquist et al. / Tetrahedron Letters 45 (2004) 5541–5543
5. (a) Brown, H. C.; Carlson, B. A.; Prager, R. H. J. Am. Chem. Soc. 1971, 93, 2070–2071; (b) Brown, H. C.; Carlson, B. A. J. Org. Chem. 1973, 38, 2422–2424. 6. Brown, H. C.; Katz, J. J.; Carlson, B. A. J. Org. Chem. 1973, 38, 3968–3970. 7. Carlson, B. A.; Brown, H. C. J. Am. Chem. Soc. 1973, 95, 6876–6877. 8. Brown, H. C.; Imai, T. J. Org. Chem. 1984, 49, 892–898. 9. (a) Soderquist, J. A.; Najafi, M. R. J. Org. Chem. 1986, 51, 1330–1336; (b) Soderquist, J. A.; Anderson, C. L. Tetrahedron Lett. 1986, 27, 3961–3962. 10. (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1990, 31, 5541–5542; (b) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470. 11. Wenger, W.; Vasella, A. Helv. Chim. Acta 2000, 83, 1542– 1560. 12. Soderquist, J. A.; Ramos, J.; Matos, K. Tetrahedron Lett. 1997, 38, 6639–6642. 13. Representative procedure for the preparation of 1. To a solution of 9-BBN-H (9.76 g, 80.0 mmol) in THF (80 mL), 1-octene (8.96 g, 80.0 mmol) was added. The reaction mixture was allowed to stir for 4 h with complete reaction being corroborated by 11 B NMR. Subsequently, the solution was cooled to 0 C and a solution of TMANO (6.04 g, 80.0 mmol) in CHCl3 (40 mL) was added dropwise via cannula. The solvents were removed under reduced pressure and the oily residue was diluted in hexanes. The hexanes solution was filtered under nitrogen through silica gel. The filtrate was concentrated to produce 19.15 g (96%) of borinate 1a. 1 H NMR (300 MHz, C6 D6 ) d 0.87 (q, J ¼ 7:6 Hz, 3H), 1.03 (t, J ¼ 7:6 Hz, 2H), 1.27–1.34 (m, 16H), 1.55–1.66 (m, 9H), 4.54 (m, 1H) ppm. 13 C NMR (75 MHz, C6 D6 ) d 14.4, 22.7, 23.1, 24.3 (br s), 24.5, 25.8 (br s), 26.4, 29.9, 30.2, 32.1, 32.4, 33.3, 73.1 ppm. 11 B NMR (96 MHz, C6 D6 ) d 53.9 (s) ppm.
5543
14. To a stirred solution of 1a (2.71 g, 10.8 mmol) and a,adichloromethyl methyl ether (1.37 g, 1.08 mL, 11.9 mmol) in THF (11 mL) at 0 C, a lithium tert-butoxide solution prepared from tert-butanol (4.00 g, 54.0 mmol) and n-BuLi (22.3 mL of 2.42 M, 54.0 mmol) was added dropwise via cannula. After the addition, the reaction mixture was allowed to reach room temperature, which produced a white precipitate (Li salt). After 1 h at room temperature, the solvents were removed in vacuo. Ethanol (43 mL) and solid NaOH (5.20 g, 130 mmol) were added, followed by the dropwise addition of hydrogen peroxide (21.6 mL of 10 M, 216 mmol) at 0 C. The mixture was heated at ca. 50 C for 3 h to destroy the excess of H2 O2 , cooled to room temperature, acidified with 50% aqueous HCl, saturated with sodium chloride, and extracted with ether (2 · 30 mL). The combined organic layers were extracted with a aqueous saturated sodium bicarbonate solution (3· equal volume). These extracts were acidified with 50% aqueous HCl, saturated with NaClðsÞ , and extracted with ether (2· equal volume). The combined extracts were dried over anhydrous MgSO4 and the solvents were removed in vacuo to give nonanoic acid (2a) containing trace quantities of cis-1,5-cyclooctanediol. Vacuum distillation afforded 1.42 g (83%) of 2a (bp 82–83 C, 1 mmHg; lit.17 bp 252–253 C, 760 mmHg). 1 H NMR (CDCl3 ) d 0.97 (t, J ¼ 7:0 Hz, 3H), 1.20–1.58 (m, 12H), 2.18 (t, J ¼ 7:5 Hz, 2H), 10.33 (br s, 1H) ppm. 13 C NMR (CDCl3 ) d 14.0, 22.8, 24.7, 29.0, 29.2, 29.3, 31.9, 34.0, 180.5 ppm. 15. Unpublished studies with Dr. Peter Baran (UPR-RP). 16. (a) Soderquist, J. A.; Shiau, F.-Y.; Lemesh, R. A. J. Org. Chem. 1984, 49, 2565–2569; (b) Soderquist, J. A.; Negron, A. J. Org. Chem. 1989, 54, 2462–2464. 17. The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals, 13th ed.; O’Neil, M. J., Ed.; Merck Research Laboratories: Whitehouse, NJ, 2001; p 7141.
Novel route to carboxylic acids via the DCME reaction John A. Soderquist,* Judith Martinez, Yatsandra Oyola and Iveliz Kock Department of Chemistry, University of Puerto Rico, San Juan, PR 00931-3346, Puerto Rico Received 23 April 2004; revised 27 April 2004; accepted 30 April 2004
Abstract—Brown’s DCME reaction was successfully performed employing B-alkyl-9-oxa-10-borabicyclo[3.3.2]decanes (1) to provide carboxylic acids (2) in good to excellent yields with complete retention of configuration. 2004 Elsevier Ltd. All rights reserved.
Carboxylic acids are key synthetic intermediates in the preparation of many natural products and synthetic drugs. This functionality is classically prepared from primary alcohols, aldehydes, alkenes, and arenes by oxidative methods, by the hydrolysis of nitriles and by the carboxylation of organometallic intermediates. Other modern reported methods such as the Arndt– the Katritzky 1-[(trimethylEistert reaction,1 the silyl)methyl]-1H-1,2,3-benzotriazole protocol,2 3 Kowalsky CH2 Br2 method, and Barton’s radical homologation,4 allow the conversion of a carboxylic acid or its derivatives into their higher homologues. The DCME (a,a-dichloromethyl methyl ether) reaction is commonly used for the preparation of tertiary-carbinols from trialkylboranes,5;6 and ketones from dialkylborinate esters.7 Examples of these processes with 9-BBN systems are illustrated in Scheme 1. This reaction is presumed to occur through the reversible deprotonation of the DCME followed by addition of the carbenoid to the boron with a subsequent series of B fi C migrations producing a boronic ester, which is oxidized to the product. As can be inferred from the above results for 9-BBN systems, the migrations involve first the formation of a borabicyclo[3.3.2]decane intermediate followed by a ring contraction to the bicyclo[3.3.1]nonane product. In addition to steric factors, which play an important role in both the borane as well
Keywords: DCME reaction; Carboxylic acid synthesis; Organoboranes; OBBD; Homologation. * Corresponding author. Tel.: +1-787-751-7779; fax: +1-787-766-1354; e-mail: [email protected] 0040-4039/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.04.180
t-Bu
t-Bu 1. CHCl2OMe LiOCEt 3
B
2.
OH C
[O] 83%
Bu-t
t-Bu
O B
O 1. CHCl2OMe LiOCEt 3 2.
C
[O] 88%
Scheme 1.
as in the base employed, the Lewis acidity of the borane is also critical to the success of the process. Thus, boronic esters are wholly ineffective substrates for the preparation of carboxylic acids through a single alkyl group migration in the DCME reaction.8 The failure of this process led to the development of an organoboranebased method, which uses the more reactive B-alkyl 1,3,2-dithiaborolanes and the carbenoid, LiCCl3 to give the corresponding one-carbon extended carboxylic acids.8 Compared to the DCME process, both the borane and the carbenoid employed in this procedure have numerous disadvantages (e.g., RBBr2 intermediates, )100 C reaction temperature, R groups derived only through hydroboration). Some years ago, we discovered the chemoselective monooxidation of B-alkyl-9-BBNs with anhydrous
5542
J. A. Soderquist et al. / Tetrahedron Letters 45 (2004) 5541–5543
trimethylamine N-oxide (TMANO), which produces air and thermally stable B-alkyl-9-oxa-10-borabicyclo[3.3.2]decanes (1) in excellent yields.9 The remarkable stabilities of these borinate esters makes them ideal partners in the Suzuki–Miyaura coupling10 and other processes,11 where robust stationary boron ligation is essential. Because their Lewis acidities were similar to other borinate esters, their remarkable inertness to further oxidation and 1,2-alkyl migrations compared to the isomeric B-alkoxy-9-BBNs was attributed to a strong resistance toward further ring expansion.9;12 This suggested that the DCME reaction of B-alkyl-9-oxa-10borabicyclo[3.3.2]decanes (OBBDs) could provide a convenient new method for the stereo- and regioselective conversion of alkenes into the corresponding one-carbon extended carboxylic acids (2).
O B
R
1. CHCl2OMe LiOBu-t 2.
[O]
O R
OH 2
1
Through standard hydroboration or organometallic processes, B-substituted-9-BBNs are easily prepared and readily converted to 1 with TMANO in CHCl3 .13 Since crystalline 9-BBN dimer is commercially available, airstable and highly chemo-, stereo-, and regioselective in the hydroboration process, all of the organoboranes prepared through this method were isomerically pure with the exception of those produced from limonene, which was isolated as a 50:50 mixture of diastereomers (1g). The DCME process was successfully performed providing moderate to high yields of the homologated carboxylic acids.14 Table 1 summarizes our results. The Table 1. Preparation of representative carboxylic acids via the DCME reaction Entry
R
Yield (%)a
a b c
n-C8 H17 c-C6 H11 PhCH2 CH2
83 78 85
process is quite general and works for primary-, secondary-, and some tertiary-alkyl groups although it does not work well with hindered OBBDs. The B-R group undergoes exclusive 1,2-migration in the DCME process with the insertion occurring with retention of configuration as evidenced by the trans stereochemistry in pinane-3-carboxylic acid, a feature, which was confirmed by single crystal X-ray analysis.15 While lesser substituted alkyl groups give better yields of 2, even tertiaryalkyl and aryl groups do undergo this process. Although the DCME reaction is usually performed with lithium triethylcarboxide, we found the use of lithium tert-butoxide to be preferable in an earlier application of the DCME process.16 The triethylcarbinol proved difficult to separate from the carboxylic acids, and the greater water solubility and volatility of tert-butanol circumvented these problems. Additionally, the oxidation of the DCME intermediates requires an excess of hydrogen peroxide and the more hindered derivatives required longer oxidation times (e.g., 1d: 12 h). This new DCME methodology provides a particularly convenient protocol for the regio-, stereo-, and chemoselective hydrocarboxylation of alkenes. It is superior to existing alternative methods for the carboxylation of organoboranes because the R groups in 1 can be easily installed by both hydroboration and organometallic methods. Moreover, the protocol involves convenient reaction conditions and reagents and gives higher yields for comparable substrates. It owes its success to the higher Lewis acidity of borinate versus boronate esters together with the special property of the OBBD ring system, which resists ring expansion during the DCME process.
Acknowledgements Financial support from the NASA Space Grant (NGT540012), NSF (CHE0217550), Pfizer, Inc. (University Alliance), NIH-SCORE (SO6-GM08102), and NIHRISE (5R25GM061151) is gratefully acknowledged.
References and notes 50
d e f g
h a b
t-C4 H9 Ph H
PrEtCH
40 63 75b
11
Yields are of isolated, analytically pure material. Isolated as a 50:50 mixture of diastereomers as judged by two sets of equal intensity 13 C NMR for 2g for all except the downfield vinylic and carboxyl carbons (19 total signals). The compound(s) 2g provided a satisfactory elemental analysis for C11 H18 O2 .
1. (a) Mulzer, J. In Comprehensive Organic Functional Group Transformation; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 5, p 144, and 276; (b) Wilnum, J.-Y.; Kamal, M.; Leydet, A.; Roque, J.-P.; Montero, J.-L. Tetrahedron Lett. 1996, 37, 1781– 1782. 2. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789–3791. 3. (a) Kowalski, C. J.; Haque, M. S.; Fields, K. W. J. Am. Chem. Soc. 1985, 107, 1429–1430; (b) Reddy, R. E.; Kowalski, C. J. Org. Synth. 1992, 146. 4. (a) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. C. Tetrahedron Lett. 1991, 32, 3309–3312; (b) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. C. Tetrahedron Lett. 1992, 33, 5013–5016.
J. A. Soderquist et al. / Tetrahedron Letters 45 (2004) 5541–5543
5. (a) Brown, H. C.; Carlson, B. A.; Prager, R. H. J. Am. Chem. Soc. 1971, 93, 2070–2071; (b) Brown, H. C.; Carlson, B. A. J. Org. Chem. 1973, 38, 2422–2424. 6. Brown, H. C.; Katz, J. J.; Carlson, B. A. J. Org. Chem. 1973, 38, 3968–3970. 7. Carlson, B. A.; Brown, H. C. J. Am. Chem. Soc. 1973, 95, 6876–6877. 8. Brown, H. C.; Imai, T. J. Org. Chem. 1984, 49, 892–898. 9. (a) Soderquist, J. A.; Najafi, M. R. J. Org. Chem. 1986, 51, 1330–1336; (b) Soderquist, J. A.; Anderson, C. L. Tetrahedron Lett. 1986, 27, 3961–3962. 10. (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1990, 31, 5541–5542; (b) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470. 11. Wenger, W.; Vasella, A. Helv. Chim. Acta 2000, 83, 1542– 1560. 12. Soderquist, J. A.; Ramos, J.; Matos, K. Tetrahedron Lett. 1997, 38, 6639–6642. 13. Representative procedure for the preparation of 1. To a solution of 9-BBN-H (9.76 g, 80.0 mmol) in THF (80 mL), 1-octene (8.96 g, 80.0 mmol) was added. The reaction mixture was allowed to stir for 4 h with complete reaction being corroborated by 11 B NMR. Subsequently, the solution was cooled to 0 C and a solution of TMANO (6.04 g, 80.0 mmol) in CHCl3 (40 mL) was added dropwise via cannula. The solvents were removed under reduced pressure and the oily residue was diluted in hexanes. The hexanes solution was filtered under nitrogen through silica gel. The filtrate was concentrated to produce 19.15 g (96%) of borinate 1a. 1 H NMR (300 MHz, C6 D6 ) d 0.87 (q, J ¼ 7:6 Hz, 3H), 1.03 (t, J ¼ 7:6 Hz, 2H), 1.27–1.34 (m, 16H), 1.55–1.66 (m, 9H), 4.54 (m, 1H) ppm. 13 C NMR (75 MHz, C6 D6 ) d 14.4, 22.7, 23.1, 24.3 (br s), 24.5, 25.8 (br s), 26.4, 29.9, 30.2, 32.1, 32.4, 33.3, 73.1 ppm. 11 B NMR (96 MHz, C6 D6 ) d 53.9 (s) ppm.
5543
14. To a stirred solution of 1a (2.71 g, 10.8 mmol) and a,adichloromethyl methyl ether (1.37 g, 1.08 mL, 11.9 mmol) in THF (11 mL) at 0 C, a lithium tert-butoxide solution prepared from tert-butanol (4.00 g, 54.0 mmol) and n-BuLi (22.3 mL of 2.42 M, 54.0 mmol) was added dropwise via cannula. After the addition, the reaction mixture was allowed to reach room temperature, which produced a white precipitate (Li salt). After 1 h at room temperature, the solvents were removed in vacuo. Ethanol (43 mL) and solid NaOH (5.20 g, 130 mmol) were added, followed by the dropwise addition of hydrogen peroxide (21.6 mL of 10 M, 216 mmol) at 0 C. The mixture was heated at ca. 50 C for 3 h to destroy the excess of H2 O2 , cooled to room temperature, acidified with 50% aqueous HCl, saturated with sodium chloride, and extracted with ether (2 · 30 mL). The combined organic layers were extracted with a aqueous saturated sodium bicarbonate solution (3· equal volume). These extracts were acidified with 50% aqueous HCl, saturated with NaClðsÞ , and extracted with ether (2· equal volume). The combined extracts were dried over anhydrous MgSO4 and the solvents were removed in vacuo to give nonanoic acid (2a) containing trace quantities of cis-1,5-cyclooctanediol. Vacuum distillation afforded 1.42 g (83%) of 2a (bp 82–83 C, 1 mmHg; lit.17 bp 252–253 C, 760 mmHg). 1 H NMR (CDCl3 ) d 0.97 (t, J ¼ 7:0 Hz, 3H), 1.20–1.58 (m, 12H), 2.18 (t, J ¼ 7:5 Hz, 2H), 10.33 (br s, 1H) ppm. 13 C NMR (CDCl3 ) d 14.0, 22.8, 24.7, 29.0, 29.2, 29.3, 31.9, 34.0, 180.5 ppm. 15. Unpublished studies with Dr. Peter Baran (UPR-RP). 16. (a) Soderquist, J. A.; Shiau, F.-Y.; Lemesh, R. A. J. Org. Chem. 1984, 49, 2565–2569; (b) Soderquist, J. A.; Negron, A. J. Org. Chem. 1989, 54, 2462–2464. 17. The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals, 13th ed.; O’Neil, M. J., Ed.; Merck Research Laboratories: Whitehouse, NJ, 2001; p 7141.