Samarium (II) iodide-induced intermolecular coupling of a,b-unsaturated esters with ketones: Reactions of methyl propiolate and ethyl buta-2,3-dienoate with cyclohexanone and its application to synthesis of a terpene carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2013.01.120

The reactions of methyl propiolate and ethyl buta-2,3-dienoate with cyclohexanone induced by SmI2 occurred either at a- or b-position to yield different products depending on with or without a proton source. The synthesis of terpenic acid was demonstrated using this reaction.

Full text of DOI:10.1016/j.tetlet.2013.01.120

Tetrahedron Letters 54 (2013) 1947–1950
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Samarium (II) iodide-induced intermolecular coupling of a,b-unsaturated esters
with ketones: reactions of methyl propiolate and ethyl buta-2,3-dienoate with
cyclohexanone and its application to synthesis of a terpene carboxylic acid
⇑
Masakazu Sono, Natsuki Doi, Eri Yoshino, Sachiko Onishi, Daiki Fujii, Motoo Tori
Faculty of Pharmaceeutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of methyl propiolate and ethyl buta-2,3-dienoate with cyclohexanone induced by SmI2
Received 8 November 2012
Revised 24 January 2013
Accepted 28 January 2013
Available online 4 February 2013
occurred either at
a- or b-position to yield different products depending on with or without a proton
source. The synthesis of terpenic acid was demonstrated using this reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Samarium diiodide
Intermolecular coupling
Methyl propiolate
Ethyl buta-2,3-dienoate
One-electron reductions induced by samarium (II) iodide are
well known and documented.1 These reactions are routinely used
for many synthetic works and mechanistic studies are reported.2
We have reported some results on the reductive cyclization.3
Methyl acrylate (1) reacts with ketone 2 to form lactone 3, which
is an expected product in the well known reaction (Scheme 1).4
Product 3 is thought to be derived from the coupling between a ke-
tyl radical and an electron deficient olefin.
spectra.7 The precise mechanism for a given reductive carbonyl-al-
kene coupling will depend on the specific combination of reactants
and the respective redox potential and rates of reduction of each
component by the lanthanide reagent.
We are interested in the reaction of propiolate (6) with cyclo-
hexanone (7). Meanwhile, the results by Kim et al. reported that
the coupling of cyclohexanone (7) with methyl propiolate (6) gave
a sole product 9 in 74% yield (Scheme 3),8 expected by the mech-
anism via ketyl radical as illustrated in Scheme 1. We have re-
Recent reports have shown the selective conjugate reduction of
the electron-deficient double bond followed by anionic (or possibly
radical) addition to the carbonyl group.5 Comparison of the half-
wave potentials of a,b-unsaturated carbonyls with those of corre-
sponding saturated carbonyl compounds has been extensively
studied in electrochemistry.6 The first waves of carbonyl groups,
referred to as SCE., are À2.45 V (cyclohexanone), À2.25 V (methyl
ethyl ketone), À1.8 V (propionaldehyde), À1.55 V (cyclohex-2-en-
1-one), À1.50 V (acrolein), and À1.42 V (methyl vinyl ketone),
respectively.6 Therefore, the reduction of an
a,b-unsaturated car-
bonyl moiety seems easier than that of an isolated ketone carbonyl
group in electrochemical conception. About the ease of reduction
Scheme 1. Reaction of methyl acrylate (1) with ketone 2.
of a,b-unsaturated carbonyl compounds, we have observed the for-
mation of radical 5 from methyl 3-methylbut-2-enoate (4) induced
by SmI2 through radical trapping with DMPO using the ESR spec-
trum (Scheme 2). We reported these results as the first direct evi-
dence of radical intermediates in SmI2-induced reaction by ESR
⇑
Corresponding author. Tel.: +81 88 602 8462; fax: +81 88 655 3051.
E-mail address: tori@ph.bunri-u.ac.jp (M. Tori).
Scheme 2. Reaction of methyl 3-methylbut-2-enoate (4) with SmI2 in the presence
of DMPO.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.120

1948
M. Sono et al. / Tetrahedron Letters 54 (2013) 1947–1950
Table 2
Reaction of ethyl buta-2,3-dienoate (13) with cyclohexanone (7) induced by SmI2
Scheme 3. Reaction of methyl propiolate (6) with cyclohexanone (7) induced by
SmI2 reported by Kim et al.8
Entrya
Additives
None
Temp (°C)
Ratio(GC–MS)
Table 1
14
15
16
17
SmI2-induced reaction of methyl propiolate (6) with cyclohexanone (7) studied by us
1b
2
0
rt
0
96
62
49
30
0
2
32
0
4
22
16
67
—
14
3
3c
4
tBuOH
(2 equiv)
rt
3
a
b
c
A solution of 1 mmol of 7 and 13 in THF (10 mL) was added into SmI2 (3 mmol).
Isolation yield: 14 (68%) and 16 (3%).
Isolation yield: 14 (49%), 15 (32%), 16 (16%), and 17 (1.5%).
Entrya
Additives
None
Temp (°C)
Ratio(GC–MS)
8
9
10
11
12
1b
2
0
rt
0
0
0
7
27
14
0
0
0
0
100
78
27
15
32
40
3
tBuOH
(3 equiv)
13
10
16
26
4c
rt
10
a
b
c
A solution of 1 mmol of 6 and 7 in THF (10 mL) was added into SmI2 (3 mmol).
Isolation yield: 12 (48%).
Isolation yield: 8 (23%), 9 (8%), 11 (19%), and 12 (5%).
peated this reaction and found that compound 8 was also produced
as well as 9 and other products (Table 1) (vide infra).9 Thus, we
have studied the reactions using propiolate and allenic ester with
cyclohexanone induced by SmI2 under different conditions in de-
tail and demonstrated the utility of this reaction to a synthesis of
the natural product.
Cyclohexanone (7) was subjected to reaction with methyl pro-
piolate (6), the results of which were shown in Table 1. The prod-
ucts were isolated and their structures were characterized. The
ratio was determined by GC-MS to see the product distribution.
Five products were formed depending on the conditions as shown
in Table 1. The spectroscopic data of compound 8 indicated the
presence of hydroxy (3500 cmÀ1) and ester (1710 cmÀ1) groups
as well as an exomethylene (d 5.77, 6.16) establishing its struc-
Scheme 4. Reaction of ketone 18 with methyl propiolate (6).
ture.10 This compound 8 may be formed by the attack at the
a-po-
sition of propiolate to cyclohexanone.
While compound 9 had an
a,b-unsaturated ester [d 6.07 (d,
J = 15.6 Hz), 7.04 (d, J = 15.6 Hz)] moiety as well as a hydroxy
(3450 cmÀ1) group.11 It must be derived by the attack at the b-po-
sition of propiolate to cyclohexanone (Fig 2). This product 9 is the
same as that reported by Kim and co-workers.8 However, 9 was not
a sole product. Compound 1012 (1775, 1750 cmÀ1) is unsaturated
lactone derived from further cyclization of compound 9, with
Z-stereochemistry. Compound 1112 is saturated lactone
(1770 cmÀ1), formed by reduction of compound 10. Compound
1212 is noteworthy, because this compound came from the attack
Figure 1. The cis diastereoisomers.
Ethyl butane-2,3-dienoate (13) and cyclohexanone (7) were re-
acted with 3 equivalents of SmI2 in THF at 0 °C or at rt as shown in
Table 2. The product ratio indicates that compound 14,12 derived
by the
a-attack of allenic ester was the major product (Table 2,
entry 1). But, with a proton source at rt (entry 4), the ratio of
1612 predominated. Again compound 1712 was formed as a result
of the
a
-attack of the anion produced at the
a
-position of allenic
-attack predom-
of the anion produced at the
a-position of the propiolate moiety
ester, although the ratio was not high. Thus, the
a
regardless of before or after cyclization to 10 (vide infra). This com-
inated without additive, and the b-attack was the main reaction
with a proton source. It is because an anion is quenched by a pro-
ton source and a radical reaction should be a main course.
We demonstrate now the application of this reaction to the syn-
pound clearly shows that the b-position of methyl propiolate
worked as a radical and that the a
-position worked as an anion.13
Because the radical formed from methyl propiolate (6) is similar
to allenic ester (Fig. 2), and ethyl buta-2,3-dienoate (13) is consid-
ered to be ‘exomethylene acrylate’, we are interested in the reac-
tion of 13 with 7 induced by SmI2.
thesis of a natural product. The partial structure having
a-methy-
lene-b-hydroxyester derivative is complicated target to
a

M. Sono et al. / Tetrahedron Letters 54 (2013) 1947–1950
1949
Figure 2. Mechanisms for the reaction in Table 1.
by the attack at both
a- and b-positions of
a
,b-unsaturated car-
bonyl compound 6.
In conclusion, the carbon–carbon bond forming reaction by
one-electron reduction using SmI2 starts from not only the reduc-
tion of the ketone giving ketyl radical (A) (to 9, 10, and 11 (via B
and C) or to 12 (via B and D) (carbonyl first route in Fig. 2)), but also
Scheme 5. Bifunctional synthon S derived from methyl propiolate (6).
reduction of the a,b-unsaturated carbonyl moiety giving an anion
radical (E) (to 8 (via F and G, route c) or to 12 (via F and G, route
d) (alkyne first route in Fig. 2)). These depend on the reaction con-
ditions and compete with each other.7 This reaction was success-
fully applied to the synthesis of natural product 19 in one step.
construct. It takes several steps to reach such a partial structure.
Now, we attempt the reaction between known bicyclic ketone
1814 and methyl propiolate (6) with SmI2 in the presence of tBuOH
as a proton source. The product composition was shown in
Scheme 4 and the desired product 1915 was isolated in 18% yield.
Its stereoisomer 2012 was also isolated in 18%, as well as 21–
24.12 The cis-fused isomer of 18 was similarly treated to give both
25 and 26 (Fig. 1).12 The spectroscopic data of four isomeric prod-
ucts, 19, 20, 25, and 26, were compared to each other. By compar-
ison of the spectral data with those of the natural product,16
compound 19 was concluded to be the natural product.
Acknowledgments
We thank Drs. M. Tanaka and Y. Okamoto, Tokushima Bunri
University, for measuring 600 MHz NMR and MS spectra, respec-
tively. This study was financially supported in part by
MEXT.SENRYAKU, 2008.
a
The mechanism is shown in Figure 2 for these cross coupling
reactions. In the case of propiolate, the attack at the b-position
should occur by radical coupling between ketyl radical A and 6
(radical route). The intermediate B can take a proton giving C
(route a) or attack cyclohexanone forming D (route b). Each pro-
duces 9, 10, 11, and 12, respectively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.120.
Compound 8 is produced by an aldol-type carbon–carbon bond
formation. The radical anion E attacks the carbonyl group of 7 at
References and notes
the
a-position to form F. The radical is further reduced by SmI2
1. (a) Molander, G. A. Chem. Rev. 1992, 92, 29–68; (b) Molander, G. A.; Harris, C. R.
Chem. Rev. 1996, 96, 307–338; (c) Molander, G. A. Acc. Chem. Res. 1998, 31, 603–
609; (d) Molander, G. A.; Haris, C. R. Tetrahedron 1998, 54, 3321–3354; (e)
Little, R. D. Chem. Rev. 1996, 96, 93–114.
2. (a) Kagan, H. B.; Namy, L. J.; Girard, P. Tetrahedron 1981, 37, 175–180; (b)
Curran, D. P.; Fevig, T. L.; Totleben, M. J. Synlett 1990, 773–774; (c) Curran, D. P.;
Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992, 943–961; (d) Namy, L. J.;
Collon, J.; Bied, C.; Kagan, H. B. Synlett 1992, 733–734; (e) Curran, D. P.; Gu, X.;
Zhang, W.; Dowd, P. Tetrahedron 1997, 53, 9023–9042; (f) Miller, R. S.; Sealy, J.
M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II J. Am. Chem. Soc.
to afford an anion G, which is protonated by tBuOH (anionic route).
These results suggest that methyl propiolate (6) can be consid-
ered as a bifunctional synthon in which the a- and b-positions both
act as anion equivalents (Scheme 5). Especially the formation of
compound 8 strongly indicates the formation of the species F. Pref-
erential reduction of electron deficient olefin was observed using
ESR by radical trapping experiments.7 Compound 12 was formed

1950
M. Sono et al. / Tetrahedron Letters 54 (2013) 1947–1950
2000, 122, 7718–7722; (g) Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2002,
m/z 184 [M+], 156, 152, 141, 124, 109 (base), 96, 81, 68, 55; HRMS (EI) Found
m/z 184.1086 [M+]. C10H16O3 requires 184.1099.
124, 6895–6899; (h) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372; (i)
Girard, P.; Namy, L. J.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698.
3. (a) Sono, M.; Shoji, T.; Tamaki, T.; Kishi, S.; Tori, M. Heterocycles 2007, 72, 517–
528; (b) Sono, M.; Onishi, S.; Tori, M. Tetrahedron 2003, 59, 3385–3395; (c)
Sono, M.; Hashimoto, A.; Nakashima, T.; Tori, M. Tetrahderon Lett. 2000, 41,
5115–5118; (d) Sono, M.; Nakashiba, Y.; Nakashima, K.; Tori, M. J. Org. Chem.
2000, 65, 3099–3106.
11. Compound 9: Oil; FTIR: 3450, 1720, 1650 cmÀ1 1H NMR (300 MHz, CDCl3) d
;
7.04 (1H, d, J = 15.6 Hz), 6.07 (1H, d, J = 15.6 Hz), 3.74 (3H, s), 1.20–1.90 (10H,
m); 13C NMR (75 MHz, CDCl3) d 167.4 (C), 155.1 (CH2), 117.8 (CH2), 71.6 (C),
51.6 (OCH3), 37.0 (CH2 Â 2), 25.2 (CH2), 21.5 (CH2 Â 2); MS (CI) m/z 185
[M+H]+, 167, 153 (base); HRMS (CI) Found m/z 185.1193 [M+H]+. C10H17O3
requires 185.1177.
4. Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 5763–
5764.
12. See Supplementary data.
13. Similar results were reported by Kagan et al.: Machrouhi, F.; Hamann, B.;
Namy, J.-L.; Kagan, H. B. Synlett 1996, 633–634.
5. (a) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811–4814; (b)
Johnston, D.; Couché, E.; Edmonds, D. J.; Muir, K. W.; Procter, D. J. Org. Biomol.
Chem. 2003, 328–337; (c) Taaning, R. H.; Lindsay, K. B.; Schiøtt, B.; Daasbjerg,
K.; Skrydstrup, T. J. Am. Chem. Soc. 2009, 131, 10253–10262; (d) Hansen, A. M.;
Lindsay, K. B.; Antharjanam, P. K. S.; Karaffa, J.; Daasbjerg, K.; Flowers, R. A., II;
Skrydstrup, T. J. Am. Chem. Soc. 2006, 128, 9616–9617.
6. Wagenknecht, J. H.; Eberson, L.; Utley, J. H. P. In Organic Electrochemistry; Lund,
H., Baizer, M. M., Eds., 3rd ed; Marcel Dekker, Inc.: New York, 1991; pp 453–
470.
14. Nishitani, K.; Suzuki, J.; Ishibashi, H.; Saitoh, Y. Heterocycles 1994, 39, 43–46.
15. Compound 19: IR (FT) 3520, 1715 cmÀ1 1H NMR (600 MHz, CDCl3) d 6.20 (1H,
;
d, J = 0.5 Hz, H-13), 5.84 (1H, d, J = 0.5 Hz, H-13), 4.70 (1H, d, J = 1.6 Hz, H-15),
4.37 (1H, d, J = 1.6 Hz, H-15), 3.80 (3H, s, OCH3), 3.46 (1H, s, OH), 2.39 (1H, br d,
J = 12.3 Hz, H-5), 2.31 (1H, br d, J = 12.6 Hz, H-3), 2.06 (1H, td, J = 12.6, 6.0 Hz,
H-3), 1.84 (1H, td, J = 12.6, 4.0 Hz, H-8), 1.76 (1H, td, J = 12.6, 3.4 Hz, H-9), 1.73
(1H, m, H-6), 1.70 (1H, m, H-8), 1.66 (1H, t, J = 12.3 Hz, H-6), 1.59-1.64 (2H, m,
H-2), 1.45 (1H, br d, J = 12.9 Hz, H-1), 1.39 (1H, td, J = 12.9, 5.5 Hz, H-1), 1.31
(1H, ddd, J = 12.6, 4.1, 2.3 Hz, H-9), 0.73 (3H, s, H-14); 13C NMR (150 MHz,
CDCl3) d 168.2 (CO), 150.7 (C-4), 146.4 (C-11), 123.4 (C-13), 105.1 (C-15), 72.9
(C-7), 52.0 (OCH3), 43.8 (C-5), 41.3 (C-1), 36.9 (C-3), 35.9 (C-9), 35.6 (C-10),
34.4 (C-6), 31.4 (C-8), 23.5 (C-2), 15.5 (C-14); MS (EI) m/z 264 [M+], 246 (base),
231, 187, 171, 123, 93, 43; HRMS (EI) Found m/z 264.1718, Calcd for C16H24O3,
264.1726.
7. Sono, M.; Hanamura, S.; Furumaki, M.; Murai, H.; Tori, M. Org. Lett. 2011, 13,
5720–5723.
8. Kwon, D. W.; Cho, M. S.; Kim, Y. H. Synlett 2001, 627–628.
9. Harb, H. Y.; Procter, D. J. Synlett 2012, 6–20.
10. Compound 8: Oil; FTIR: 3500, 1710, 1620 cmÀ1 1H NMR (300 MHz, CDCl3) d
;
6.16 (1H, d, J = 0.6 Hz), 5.77 (1H, d, J = 0.6 Hz), 3.78 (3H, s), 3.64 (1H, s), 1.5-1.9
(8H, m), 1.22 (2H, m); 13C NMR (75 MHz, CDCl3) d 21.6 (CH2 Â 2), 25.6 (CH2),
36.1 (CH2 Â 2), 51.8 (OCH3), 71.9 (C), 123.4 (CH2), 146.3 (C), 168.2 (C); MS (EI)
16. Zdero, C.; Bohlmann, F.; King, R. M.; Robinson, H. Phytochemistry 1987, 26, 187–
190.