J. H. Babler et al. / Tetrahedron Letters 54 (2013) 1754–1757
1757
5. General procedure for alkene reduction: To a 15-mL 1-neck reaction flask fitted
with a glass stopper [Note: A larger-scale reaction may require the use of a
pressure vessel and/or addition of NaBH4 in small portions.] were added a
small spin bar, 0.18–0.20 mmol of substrate, 0.60 mL of 5:1 (v/v) [10:1 (v/v) in
Table 1, entry 3] liquid amide(s)/H2O, and 7.0 mg (0.034 mmol) of
ruthenium(III) chloride hydrate (Sigma–Aldrich Catalog No. 206229). After
cooling the latter mixture to 0 °C (external ice-H2O bath), 9.0 mg (0.24 mmol)
of NaBH4 powder was added in one portion; and the mixture was subsequently
stirred at 0 °C for 60 min. The reaction was then quenched by addition of
2.0 mL of 2 M aqueous HCl to the reaction flask, followed by 1.0 mL of pentane
and subsequent stirring of the mixture at 0 °C for 15 min. The product was then
isolated by dilution of the reaction mixture with 10 mL of 4:1 (v/v) pentane/
dichloromethane; and solid material was removed by filtration through a small
pad of Hyflo Super-CelÒ filtering aid. After dilution of the filtrate with 10 mL of
pentane, removal of the liquid amide(s) was accomplished by washing the
filtrate with 10% (w/v) aqueous NaCl (4 Â 15 mL portions). The organic layer
was subsequently dried over anhydrous MgSO4, filtered, and the volatile
organic solvents were removed by evaporation at reduced pressure.
6. Structural assignments of products were based on the analysis of proton NMR
spectral data (300 MHz) and on comparison with those exhibited by authentic
samples of these known compounds.12 The proton NMR spectra of most
products in Table 1 are freely accessible via the Spectral Data Base System
(SDBS) maintained by the Japanese National Institute of Advanced Industrial
proton NMR signals (300 MHz) arising from each product and signals assigned
to any unreacted substrate (ascertained from the spectrum exhibited by an
authentic sample of the substrate). Except for entries 10 and 11 in Table 1, no
impurities were detected in the product/unreacted substrate mixtures.
7. The presence of undec-9-en-1-ol,8 characterized by proton NMR absorption at
hydrocarbon 5a (1-isopropyl-4-methylcyclohexane). The 1H NMR spectrum
of 5a is freely accessible via the Spectral Data Base System (SDBS) maintained
by the Japanese National Institute of Advanced Industrial Science and
Technology. The proton NMR spectrum (300 MHz, CDCl3) of alkene 4a was
characterized by signals at d 5.37 (m, 1H); 1.64 (s, 3H, vinyl CH3); and 0.87 (d,
J = 6.6 Hz, 6H).
18. For
a previous synthesis of alkenol 7, see: Baskaran, S.; Islam, I.;
Chandrasekaran, S. J. Org. Chem. 1990, 55, 891–895.
19. Determined by comparison of the proton NMR spectrum of our isolated
product with that exhibited (400 MHz) by an authentic sample of alkenol 7.
The latter spectrum is freely accessible via the Spectral Data Base System
(SDBS; see Ref. 6).
20. No reduction occurred in the absence of RuCl3.
21. This ratio was determined by the analysis of 1H NMR spectral data (300 MHz)
of the isolated product mixture. The proton NMR spectrum (300 MHz, CDCl3) of
unsaturated nitrile 9 was characterized by signals at d 5.07 (m, vinyl H at C-6);
1.69 (s, vinyl CH3); 1.61 (s, vinyl CH3); and 1.08 (d, J = 6.6 Hz, CH3 bonded to C-
3). Saturated nitrile 10 was characterized by signals at d 1.07 (d, J = 6.6 Hz, CH3
bonded to C-3) and 0.87 [d, J = 6.6 Hz, CH(CH3)2].
22. The full 1H NMR spectral data of nitrile 9 can be found in: Sim, T. B.; Yoon, N. M.
Synlett 1995, 726–728.
23. For a previous synthesis of nitrile 10, see: Cohen, N.; Eichel, W. F.; Lopresti, R. J.;
Neukom, C.; Saucy, G. J. Org. Chem. 1976, 41, 3505–3511.
24. Commercially available from Pfaltz & Bauer, (Waterbury, CT, USA).
25. This ratio was determined by integration of the proton NMR signals assigned to
b-caryophyllene (11) [d 4.94 and 4.83 (two singlets; 2-exocyclic methylene
Hs)] versus the corresponding exocyclic methylene Hs in reduction product 13
(singlets at d 4.89 and 4.85). The proton NMR spectrum also exhibited a
corresponding decrease in the area assigned to signals arising from b-
caryophyllene’s vinyl H at C-5 (a multiplet at d 5.30) and vinyl CH3 at C-4 (a
singlet at d 1.61).
26. The full proton NMR spectral data of b-caryophyllene (11) can be found in:
Ichihara, M.; Morikawa, S.; Morikawa, T.; Shinyaku, K. R. Jpn. J. Environ.
Entomol. Zool. 2011, 22, 121–127. The (4Z)-diastereomer of b-caryophyllene
(known as ‘isocaryophyllene’) has also been characterized by 500 MHz 1H NMR
analysis and shown to have signals at d 5.24 (vinyl H at C-5); 4.82 (1 exocyclic
methylene H); 4.74 (1 exocyclic methylene H); and 1.65 (vinyl CH3 at C-4). See:
Fitjer, L.; Malich, A.; Paschke, C.; Kluge, S.; Gerke, R.; Rissom, B.; Weiser, J.;
Noltemeyer, M. J. Am. Chem. Soc. 1995, 117, 9180–9189.
d
5.38–5.42 (m,
2
vinyl H’s), in the isolated product mixture was not
unexpected for reactions involving the formation of a
p
-allyl intermediate.9
For example, hydrogenation of 1-pentene has been reported to be accompanied
by a small amount of isomerization to both E- and Z-2-pentene (which are
reduced more slowly). See: Brown, H. C.; Brown, C. A. J. Am. Chem. Soc. 1963, 85,
1005.
8. For access to the proton NMR spectrum of undec-9-en-1-ol, see: Runge, M.
Brett; Mwangi, M. T.; Bowden, N. B. B. J. Organomet. Chem. 2006, 691, 5278–
5288.
9. The involvement of
a
p
-allylruthenium complex in the Ru+3-catalyzed
27. Unexpected chemoselective reduction of b-caryophyllene to afford 13, ascribed
to the strain of the (E)-trisubstituted double bond in the 9-member ring, has
been reported to occur by the reaction of b-caryophyllene with diimide. See:
Rao, V. V. Ramana; Devaprabhakara, D. Tetrahedron 1978, 34, 2223–2227. The
proton NMR spectrum of 13 (recorded at 90 MHz) reported the signal for the 2
exocyclic methylene Hs as a br s at d 4.85.
reduction of alkenes using NaBH4 in aqueous liquid amides was ascertained
in our previous experimental work. See: Babler, J. H.; White, N. A.; Kowalski, E.;
Jast, J. R. Tetrahedron Lett. 2011, 52, 745–748. Table 1, footnotes g and h, in the
latter publication reported that liquid carboxamides are the favored organic
cosolvent(s) in these Ru+3-catalyzed/NaBH4 reductive transformations.
Aqueous solutions of solid carboxamides failed to dissolve the nonpolar
organic substrates used in this study. Use of tetrahydrofuran or acetonitrile as
the organic cosolvent resulted in vigorous evolution of hydrogen gas and/or a
very sluggish reduction of the alkene functionality.
28. Hutchenson, K. W.; Jackson, S. C.; Manzer, L. E.; Scialdone, M. A.; Seapan, M.
PCT Int. Appl., WO 2008079250 (A2), 2008.
29. Commercially available as a 55/45 mixture of E/Z diastereomers.12 Unsaturated
alcohols 15 and 16 were likewise 55/45 mixtures of E/Z diastereomers (C6–C7
double bond). The E stereoisomer of nerolidol was characterized (1H NMR,
300 MHz, CDCl3) by signals at d 1.61 (br s, CH3 bonded to C-7) and 1.279 (s, CH3
bonded to C-3). The corresponding signals for the Z stereoisomer appeared at d
1.68 and 1.276, respectively.
10. The presence of too much H2O in the reaction mixture significantly decreased
the % conversion of 1 to
2 [e.g., only a 25% conversion when the same
experiment was conducted in 2:1 (v/v) DMA/H2O]. Since an extended reaction
time did not result in a decrease in the % recovery of unreacted dienol 1, the
catalyst may have been deactivated during the course of the reaction.
30. For previous syntheses of 15, 16, and 17, see: Ofner, A.; Kimel, W.; Holmgren,
A.; Forrester, F. Helv. Chim. Acta 1959, 42, 2577–2584.
11. The proton NMR spectrum (300 MHz, CDCl3) of dihydro-
characterized by signals at d 5.30 (m, 1 vinyl H) and 3.74 (sextet, J = 6.0 Hz,
CHOH). -Ionol (1) was characterized by signals at d 5.40 (m, 1H); 5.49
(overlapping multiplets, 2 vinyl H’s); and 4.30 (pentet, J = 6.3 Hz, CHOH). For
access to the proton NMR spectrum of -ionol (1), see Ref. 2.
a-ionol (2) was
31. The proton NMR spectrum (300 MHz, CDCl3) of 16 (55/45 mixture of E/Z
diastereomers) was characterized by signals at d 5.13 (m, 1 vinyl H); 1.68 (s,
vinyl CH3, Z stereoisomer); 1.61 (s, vinyl CH3, E stereoisomer); 1.16 (s, CH3
bonded to C-3, Z stereoisomer); 1.15 (s, CH3 bonded to C-3, E stereoisomer);
0.90 (t, J = 7.2 Hz, 3H); and 0.87 (d, J = 6.6 Hz, 6H). Since no other signals were
observed in the region of d 1.60–1.80 ppm, the C10–C11 double bond had been
completely saturated.
a
a
12. Commercially available from Sigma–Aldrich (Milwaukee, WI, USA)
13. 2:1 Mixture of stereoisomers. The major diastereomer (trans relationship
between the ‘OH’ and isopropenyl substituents) was characterized by 1H NMR
signals at d 5.59 (m, 1 vinyl H) and 4.02 (m, allylic CHOH). The corresponding
signals for the cis diastereomer occurred at d 5.50 (m, 1 vinyl H) and 4.19 (m,
allylic CHOH). The full proton NMR spectral data of ‘cis-carveol’ can be found in
the experimental section of the article cited below in Ref. 14.
14. Rafinski, Z.; Scianowski, J. Tetrahedron: Asymmetry 2008, 19, 1237–1244. This
article reports complete spectral data (1H and 13C NMR) for characterization of
stereoisomers of saturated alcohol 5b.
32. This experiment was conducted using 0.20 mmol of nerolidol, 0.039 mmol of
RuCl3ÁH2O, and 0.22 mmol of NaBH4 in 0.60 mL of 2.5:2.5:1 (v/v/v) DMPU/
DMA/H2O at 0 °C, 60 min.
33. The 1H NMR spectrum (300 MHz, CDCl3) of 15 (55/45 mixture of E/Z
diastereomers) was characterized by signals at d 5.05–5.18 (m, 2 vinyl Hs);
1.90–2.10 (m, 6 allylic Hs); 1.58–1.70 (three vinyl CH3s; singlets at 1.68, 1.62,
1.60); and 0.90 (t, J = 7.2 Hz, CH3).
15. The selective reduction of the isopropenyl moiety in carveol (3b) can be
monitored by 1H NMR analysis: the gradual diminishing of the isopropenyl’s
signal at d 4.74 (br s, 2 vinyl H’s).
34. Since proton NMR analysis of 15 indicated the presence of a small amount
(<5%) of over-reduction [a signal at d 0.87 (d, J = 6.6 Hz, CH(CH3)2 in 16)], the
amount of NaBH4 was decreased to 0.22 mmol to minimize reduction of the
16. Spectroscopic data for alkene 4a can be found in: Villa, G.; Povie, G.; Renaud, P.
J. Am. Chem. Soc. 2011, 133, 5913–5920.
17. This ratio was based on the analysis of proton NMR spectral data (300 MHz) of
the isolated product mixture and comparison with that exhibited by an
authentic sample of limonene (3a) and known data for over-reduced
C10–C11 double bond.
35. To ensure total saturation using the general procedure,5 the amount of
nerolidol was decreased to 0.12 mmol.
36. Corey, E. J.; Yamamoto, H.; Herron, D. K.; Achiwa, K. J. Am. Chem. Soc. 1970, 92,
6635.
Babler, James H.
