Intramolecular and intermolecular ketone-ester reductive coupling reactions promoted by samarium(II) iodide

Article abstract of DOI:10.1016/S0040-4039(01)01107-8

Intramolecular and intermolecular ketone-ester reductive coupling reactions promoted by SmI₂ have been studied. Substituted 2-hydroxy-5-ethoxycarbonylcyclopentanones, 5-ethoxycarbonylcyclopentenones and α-ketols were prepared in moderate to good yields at room temperature or under reflux under neutral conditions.

Full text of DOI:10.1016/S0040-4039(01)01107-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5745–5748
Intramolecular and intermolecular ketone–ester reductive
coupling reactions promoted by samarium(II) iodide
Yunkui Liua and Yongmin Zhanga,b,
*
aDepartment of Chemistry, Zhejiang University (Campus Xixi ), Hangzhou 310028, PR China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, PR China
Received 23 March 2001; revised 16 May 2001; accepted 21 June 2001
Abstract—Intramolecular and intermolecular ketone–ester reductive coupling reactions promoted by SmI2 have been studied.
Substituted 2-hydroxy-5-ethoxycarbonylcyclopentanones, 5-ethoxycarbonylcyclopentenones and a-ketols were prepared in moder-
ate to good yields at room temperature or under reflux under neutral conditions. © 2001 Elsevier Science Ltd. All rights reserved.
Carbonꢀcarbon bond formation is the essence of
organic synthesis and reductive couplings are amongst
the most valuable methods for making carbonꢀcarbon
bonds. Since pioneering studies by Kagan and follow-
ing investigations by other scientists, SmI2 has been
shown to be an exceedingly reliable, mild, neutral,
selective and a versatile single electron transfer reagent
for promoting reductive coupling reactions.1 For
instance, Barbier reactions,2 Reformatsky reactions,3
pinacol coupling reactions4 and ketyl–olefin coupling
reactions5 have been reported using SmI2 as the
reagent. It is well known that the Barbier-type reactions
of organic halides with esters promoted by SmI2 and
the reductive coupling of ketones with esters induced by
low valent titanium have been widely documented.6,7
However, to the best of our knowledge, there is no
literature report on the reductive coupling reaction of
ketones with esters promoted by SmI2. Recently, we
reported intermolecular and intramolecular ketone–
nitrile cross-coupling reactions promoted by SmI2.8
Now, we wish to describe our preliminary results on a
novel keto-ester reductive cross-coupling reaction pro-
moted by SmI2 (Scheme 1).
Substrates 1, which possess a carbonyl group and two
ethoxycarbonyl groups, undergo intramolecular cross-
coupling reactions even at room temperature under a
nitrogen atmosphere. The reductive cyclization prod-
ucts, substituted 2-hydroxy-5-ethoxycarbonylcyclopen-
tanones 2, were obtained in moderate to good yields at
room temperature. Interestingly, when the reaction was
carried out at reflux, substituted 5-ethoxycarbonylcyc-
lopentenones 3 were obtained as the major products
along with smaller amounts of products 2. These results
are different from those obtained using low valent
titanium, which produce deoxygenated products.7 Table
1 summarizes the results of the intramolecular cycliza-
tion of keto-diester 1. The reaction is highly chemose-
lective, only cyclization products were obtained, while
Scheme 1.
Keywords: ketone; ester; reductive coupling; samarium(II) iodide; 2-hydroxy-5-ethoxycarbonylcyclopentanones; 5-ethoxycarbonyl cyclopen-
tenones; a-ketols.
* Corresponding author. E-mail: yminzhang@mail.hz.zj.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01107-8

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Y. Liu, Y. Zhang / Tetrahedron Letters 42 (2001) 5745–5748
pinacol coupling products of the ketones were not
detected. In this reaction, substituents such as chloro
and alkoxyl groups are not reduced.9
ethyl esters are suited for the reaction. However, they
need longer when the latter are used and afford the
products in lower yields than those of the former (entry
5). As for ketones 1, when benzophenone was used, the
reaction gave a-ketols 6 in moderate yields. For com-
parison, treatment of aromatic aldehydes and esters
with SmI2 at room temperature, even under reflux, did
not give a-ketols 6, only pinacol coupling products 7 in
good yields (entry 8). Treatment of acetophenone and
ethyl benzoate with SmI2, gave a-ketol 6 along with
pinacol 7 (entry 9).
In order to check the reactivity of SmI2 for keto-ester
reductive coupling, we further studied the intermolecu-
lar reaction of ketones or aldehydes 4 with esters 5
induced by SmI2, affording a-ketols 6 and/or pinacols 7
(Scheme 2).
Table 2 summarizes our results on the ketone-ester
reductive couplings. Refluxing conditions are necessary
for better yields. If the reaction was carried out at room
temperature, it was slow and gave lower yields (entry
1). Table 1 shows that both aromatic and aliphatic
A possible mechanism for the formation of substituted
2-hydroxy-5-ethoxycarbonylcyclopentanones and a-
ketols is described in Scheme 3.
Table 1. Intramolecular reductive coupling of keto-diester 1
Entry
R1
R2
T (°C)
Reaction time (h)
Yield (%)a,b
2
3
1
2
3
4
5
6
C6H5
C6H5
Rt
65
Rt
65
Rt
65
Rt
65
Rt
65
Rt
65
4
5
4
5
4
5
5
6.5
3.5
4.5
4
68 (2a)
10
69 (2b)
12
70 (2c)
11
63 (2d)
15
69 (2e)
13
70 (2f)
8
–
55 (3a)
–
54 (3b)
–
57 (3c)
–
45 (3d)
–
51 (3e)
–
60 (3f)
4-ClC6H4
4-CH3C6H4
3,4-OCH2OC6H3
4-ClC6H4
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
5
a Isolated yields.
b 2.2 mmol SmI2 and 1 mmol of 1 were used.
Scheme 2.
Table 2. The intermolecular reductive coupling of ketones with esters
Entry
R1
R2
Reaction time (h)
Yield (%)a
6
7
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
5 (24c)
5
6
5.5
9
3
4
7
9
68b, 37c
62b
61b
63b
45b
65b
60b
–
–
–
–
–
–
–
–
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
n-C3H7
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3OC6H4
H
82c, 84c
45b
Me
28b
a Isolated yields.
b Reaction was carried out under reflux.
c Reaction was carried out at room temperature.

Y. Liu, Y. Zhang / Tetrahedron Letters 42 (2001) 5745–5748
5747
Scheme 3.
In the intramolecular (or intermolecular) keto-ester
coupling reaction, after the formation of ketyl anion A
(or A%), ring closure occurs (or intermediate B% forms)
via radical addition onto the ethoxycarbonyl group.
Sequential transformations led to the target products.
In the intermolecular cross-coupling process, when
aldehydes were used, the pinacol coupling reaction
could proceed prior to the aldehyde–ester reaction
because the ketyl radical from aromatic aldehydes is
more reactive.
Academic Press: London, 1994; Chapter 4; (e) Shibasaki,
M.; Sasai, H. Synth. Org. Chem. Jpn. 1993, 51, 972; (f)
Molander, G. A. Chem. Rev. 1992, 92, 29; (g) Curran, D.
P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett
1992, 943.
2. (a) Sasaki, M.; Collin, J.; Kagan, H. B. New J. Chem.
1992, 16, 89; (b) Souppe, J.; Namy, J. L.; Kagan, H. B.
Tetrahedron Lett. 1982, 23, 3497.
3. Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J.
J. Am. Chem. Soc. 1991, 113, 8036.
4. Namy, J. L.; Kagan, H. B. Tetrahedron Lett. 1983, 24,
765.
In summary, novel reductive cross-coupling reactions of
ketones with esters were successfully achieved with the
aid of samarium(II) iodide. Substituted 2-hydroxy-5-
ethoxycarbonylcyclopentanones, 5-ethoxycarbonylcy-
clopentenones, and a-ketols have been prepared in
moderate to good yields.
5. (a) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J.
Chem. Soc., Chem. Commun. 1986, 624; (b) Otsubo, K.;
Inanaga, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
5663.
6. Krief, A.; Laral, A. M. Chem. Rev. 1999, 99, 745.
7. (a) Shi, D. Q.; Chen, J. X.; Chai, W. Y.; Chen, W. X.;
Kao, T. Y. Tetrahedron Lett. 1993, 34, 2963; (b)
McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983,
105, 1660.
Acknowledgements
8. Zhou, L. H.; Zhang, Y. M.; Shi, D. Q. Tetrahedron Lett.
1998, 39, 8491.
We are grateful to the National Natural Science Foun-
dation of China (Project No. 29872010) and the NSF of
Zhejiang province for financial support.
9. General procedure: A solution of substrate 1 (1 mmol) in
THF (2 mL) was added to SmI2 (2.2 mmol) at room
temperature under a nitrogen atmosphere. The mixture
was then stirred under these conditions until the reaction
was completed (Table 1). The reaction was quenched with
dilute HCl (1 M, 1 mL) and extracted with ether. After the
usual work-up, the crude product was purified by prepara-
tive TLC (ethyl acetate:cyclohexane, 1:6) to give 2 and 3.
The physical data of new compounds are listed. Com-
pound 2c, mixture of stereoisomers. wmax: 3450 (OH), 1750
References
1. For reviews, see: (a) Molander, G. A.; Harris, C. R. Chem.
Rev. 1996, 96, 307; (b) Matsuda, F. Synth. Org. Chem.
Jpn. 1995, 53, 987; (c) Molander, G. A. Org. React. 1994,
46, 21; (d) Imamoto, T. Lanthanides in Organic Synthesis;

5748
Y. Liu, Y. Zhang / Tetrahedron Letters 42 (2001) 5745–5748
(CꢁO), 1714 (CꢁO) cm−1. lH: 7.70–6.95 (9H, m, ArH),
1750 (CꢁO), 1690 (CꢁO), 1647 (CꢁC) cm−1. lH of major
isomer: 7.83–7.06 (10H, m, ArH, ꢁCH), 4.53–4.18 (3H,
m, ring CH, OCH2), 3.52 (1H, d, J=12.0 Hz, ring CH),
2.33 (3H, s, ArCH3), 1.26 (3H, t, J=7.2 Hz, CH3). m/z
(%): 320 (M+, 34.3), 275 (18.74), 246 (100). Anal.
C21H20O3. Calcd C, 78.73; H, 6.29. Found C, 78.85; H,
6.23.
4.26–3.88 (3H, m, OCH2, OH), 3.64–3.20 (2H, m, ring
CH, CH), 2.50–1.78 (5H, m, ArCH3, ring CH2), 1.26–
0.98 (3H, m, CH3). m/z (%): 338 (M+, 1.26), 320 (12),
291 (20.02), 217 (21.49), 105 (100). Anal. C21H22O4.
Calcd C, 74.54; H, 6.55. Found C, 74.46; H, 6.49. Com-
pound 3c, mixture of stereoisomers. wmax: 3080, 3020,
.