Samarium diiodide-promoted intramolecular ketone-ester coupling reaction: Novel cyclization and ring expansion pathway

Article abstract of DOI:10.1016/S0040-4039(02)01007-9

When ethyl 2-substituted-1-indanone-2-carboxylates were treated with samarium diiodide (SmI₂), ring expansion products such as 3-substituted-1,2-naphthoquinones were isolated. Alcohols were also obtained as the mixture of cis- and trans-isomers of hydroxy and ester substituents. A reaction mechanism involving intramolecular addition of samarium ketyl radicals to ester substituents followed by ring expansion was proposed for the formation of the one-carbon homologated products. Similarly, reaction of ethyl 1-substituted-2-oxo-1-cyclopentanecarboxylates with SmI₂ produced 3-substituted-2-hydroxy-2-cyclohexenones along with the corresponding alcohols.

Full text of DOI:10.1016/S0040-4039(02)01007-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5067–5070
Samarium diiodide-promoted intramolecular ketone–ester
coupling reaction: novel cyclization and ring expansion pathway
Kazuki Iwaya, Momoe Nakamura and Eietsu Hasegawa*
Department of Chemistry, Faculty of Science, Niigata University, Ikarashi-2 8050, Niigata 950-2181, Japan
Received 23 April 2002; revised 20 May 2002; accepted 24 May 2002
Abstract—When ethyl 2-substituted-1-indanone-2-carboxylates were treated with samarium diiodide (SmI2), ring expansion
products such as 3-substituted-1,2-naphthoquinones were isolated. Alcohols were also obtained as the mixture of cis- and
trans-isomers of hydroxy and ester substituents. A reaction mechanism involving intramolecular addition of samarium ketyl
radicals to ester substituents followed by ring expansion was proposed for the formation of the one-carbon homologated products.
Similarly, reaction of ethyl 1-substituted-2-oxo-1-cyclopentanecarboxylates with SmI2 produced 3-substituted-2-hydroxy-2-cyclo-
hexenones along with the corresponding alcohols. © 2002 Elsevier Science Ltd. All rights reserved.
Samarium diiodide (SmI2) has been recognized as a
most useful single-electron reductant in synthetic
organic chemistry since its application was first
reported by Kagan and co-workers.1,2 SmI2-promoted
intramolecular reductive coupling reactions of ketone
carbonyls with other functional groups, for example,
formyl, chloro acyl, cyano, olefinic, haloalkyl sub-
stituents have been extensively investigated to achieve
the construction of various carbocycles by Molander
and other chemists.2,3 The involvement of ketyl radicals
has been often proposed as the key intermediates in
these reactions.3,4 Similarly, ketone–ester coupling reac-
tions would be expected to occur since such reactions
are already known under the other electron transfer
conditions.5 In fact, a SmI2-promoted intramolecular
ketone–ester coupling reaction was recently reported.6
However, one may not expect that ester substituents
readily react with samarium ketyl radicals when other
reactive functional groups co-exist in the same
molecules. In this communication, we will report that
SmI2 could promote novel ketone–ester coupling fol-
lowed by ring expansion reactions of ethyl 2-substi-
Table 1. Reaction of various ethyl 2-substituted-1-indanone-2-carboxylates with SmI2
O
OH
O
O
O
O
R
SmI2
THF
+
OEt
OEt
R
R
3
1
2
Exp.
1
R
Conv. (%)
Yield (%)
3 (cis:trans)
2
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
(CH2)3Br
Me
(CH2)2CH3
CH2Ph
CH2CHꢀCH2
(CH2)3CN
95
100
100
100
99
60
44
54
60
60
55
14 (9:5)
41 (1:1)
19 (2:1)
10 (8:5)
24 (8:5)
28 (6:5)
100
Keywords: samarium diiodide; b-ketoester; samarium ketyl radical; ketone–ester coupling; ring expansion; 1,2-naphthoquinone.
* Corresponding author. Tel.: +81-25-262-6159; fax: +81-25-262-6116; e-mail: ehase@chem.sc.niigata-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01007-9

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K. Iwaya et al. / Tetrahedron Letters 43 (2002) 5067–5070
naphthalene 4b12 was isolated in 42% yield along with
3b (6%) and the acetate of 3b (27%) without the forma-
tion of 2b.
tuted-1-indanone-2-carboxylates as well as ethyl 1-sub-
stituted-2-oxo-1-cyclopentanecarboxylates. Surpris-
ingly, carbonꢁbromine bond, carbonꢁcarbon double
bond, and cyano substituent in these substrates did not
react and remained in the products.
On the basis of the observations made, a plausible
mechanism for this novel cyclization and ring expan-
sion reaction is proposed in Scheme 1. Single electron
transfer from SmI2 to the ketone carbonyl of 1 gives the
ketyl radical 5. Subsequent ketyl radical cyclization,
which might be reversible, gives the cyclopropoxy radi-
cal 6. Opening of the cyclopropane ring of 6 liberating
the ethoxy anion, followed by reaction with another
equivalent of SmI2, yields the a-keto enolate 7. This
ring-opening is accelerated by the bulky substituent R
since some steric repulsion between R and OSmI2 sub-
stituents in 6 is expected (see Table 1). The enolate 7
tautomerizes to naphthoxide 8. Protonation of 8 gives 9
while 8 may be readily oxidized by air to produce 2
under the basic conditions. On the other hand, 8 is
sequentially acetylated by acetic anhydride to give 4 as
an isolable product.
When ethyl 2-(3-bromopropyl)-1-indanone-2-carboxy-
late 1a7 was treated with 2.2 equiv. of SmI2 under N2
atmosphere for 30 min in THF, an unexpected orange-
colored solid was isolated.8 On the basis of its spectral
data indicating that bromopropyl side chain still
existed, it was identified as 3-(3-bromopropyl)-1,2-
naphthoquinone 2a.9 Alcohols 3a10 were also obtained
as a mixture of cis- and trans-isomers of hydroxy and
ester substituents. The observation suggests that the
ketone carbonyl part of 1a is first reduced by SmI2, and
that the formed samarium ketyl radical reacts not with
the carbonꢁbromine bond but with the ester sub-
stituent. We soon realized that this novel rearrangement
similarly occurred for the reactions of other indanone
derivatives 18 with SmI2 (Table 1). Further interesting
aspects are pointed out in Table 1. The ratio of 2 to 310
changed depending on the change of substituent
R:bulky R increased the relative yield of 2 (see entries
2, 3, and 4). Unactivated olefin seems to be a tolerable
substituent for the reaction (entry 5).3i Again surpris-
ingly, a nitrile group was inert under the reaction
conditions (entry 6).3f,g,h
We next paid our attention to the mechanism for the
formation of 3. Reaction of 1b with SmI2 in the pres-
ence of t-BuOH (20 equiv.) produced only 3b (61%,
cis:trans=1:4) without the formation of 2b and 9b. In
this case, the ketyl radical 5b is probably protonated
and the formed carbon radical is reduced by SmI2
followed by protonation to give 3b. Indeed, when t-
BuOH was replaced by t-BuOD, high deuterium incor-
poration at C1 position of 3b (98%-d) was observed.
However, this mechanism can not rationalize the for-
mation of 3 in the reactions described above since no
proton donors such as alcohols were added.8 Another
possibility that 3 are produced through an aqueous
work-up13 is also unlikely since the treatment of the
resulting reaction mixture of 1b and SmI2 with D2O
gave 3b containing almost no deuterium. Therefore, we
hypothesized that some sources of either hydrogen
atom or proton may exist in the reaction system. It was
then discovered that reaction of 3,3-dideuterio 1b-d2
with SmI2 resulted in marked deuterium incorporation
In order to gain more information on the reaction
mechanism, several experiments using 1b with SmI2
were conducted. In the above experiments,8 when the
reaction flasks were opened and saturated NaHCO3
was added to the reaction mixtures, the color of the
solutions gradually changed from colorless to orange
which indicated the formation of 2. On the other hand,
addition of 1N HCl to the resulting reaction mixture of
1b with SmI2 did not cause the color change to orange
and gave a crude mixture whose 1H NMR indicated the
existence of 1,2-dihydroxy-3-methylnaphthalene 9b.11
When the reaction mixture was treated with acetic
anhydride (4 equiv.) for 12 h, 1,2-diacetoxy-3-methyl-
EtO
O
SmI2
O
O
O
O
O
SmI2
OSmI2
R
OSmI2
R
SmI2
-EtOSmI2
OEt
OEt
R
R
1
6
5
7
O
O
air
NaHCO3
OH
R
OSmI2
R
2
H+
OAc
2Ac2O
OH
OAc
OH
R
8
R
4
9
Scheme 1.

K. Iwaya et al. / Tetrahedron Letters 43 (2002) 5067–5070
5069
OSmI2
OSmI2
SmI2
O
O
O
O
OSmI2
Me
O
SmI2
OEt
OEt
Me
Me
Me
D
D
D
12b-d
D
D
5b-d2
D
D
7b-d2
1b-d2
SmI2
work-up
O
SmI2
O
O
OH
D
O
D
O
OSmI2
Me
O
work-up
OEt
Me
D
OEt
Me
Me
D
D
11b-d
D
D
D
2b-d
3b-d3
10b-d3
Scheme 2.
at C1 position of 3b (70%-d). This observation suggests
that a reaction mechanism such as Scheme 2 in which
samarium ketyl radical 5b-d2 abstracts hydrogen atom
from the enone 7b-d2 would be in part operating. If this
explanation is correct, samarium ketyl radicals more
efficiently generated than 5b would predominantly react
with 7b to increase the formation of 2b, and then would
decrease the formation of 3b. This indeed happened
when benzophenone (0.6 mmol) was added to the reac-
tion of 1b (0.5 mmol) and SmI2 (2.4 mmol), yielding
87% of 2b without the formation of 3b along with
benzhydrol (54%) and benzpinacol (31%).14
Takeuchi (Niigata College of Pharmacy) and Professor
Masaki Kamata (Faculty of Education and Human
Science, Niigata University) for their useful suggestions
and comments. We thank Professor Takaaki Horaguchi
(Faculty of Science, Niigata University) for his gener-
ous support.
References
1. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
1980, 102, 2693–2698.
2. For representative reviews, see: (a) Molander, G. A.
Chem. Rev. 1992, 92, 29–68; (b) Curran, D. P.; Fevig, T.
L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992, 943–961;
(c) Molander, G. A.; Harris, C. R. Chem Rev. 1996, 96,
307–338; (d) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99,
745–777.
Since it is supposed that the facile conversion from 8 to
2 is driven by the formation of a stable 1,2-naphtho-
quinone structure, the corresponding conversion is not
expected to occur in the reaction of aliphatic substrates
such as ethyl 1-substituted-2-oxo-1-cyclopentanecar-
boxylates 13 with SmI2. In fact, 3-substituted-2-
hydroxy-2-cyclohexenones 14,15 the enol forms of the
a-diketones, were isolated in good yields (62% for 95%
conv. of 13a, 79% for 93% conv. of 13b; 65% for 100%
conv. of 13d) (Scheme 3). The corresponding alcohols
1516 were also obtained (15a: 14%, 15b: 13%, 15d: 23%).
3. Representative intramolecular reactions. Ketone–alde-
hyde: (a) Molander, G. A.; Kenny, C. J. Org. Chem.
1988, 53, 2132–2134; (b) Davey, A. E.; Schaeffer, M. J.;
Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1992,
2657–2666; (c) de Gracia, I. S.; Dietrich, H.; Bodo, S.;
Chiara, J. L. J. Org. Chem. 1998, 63, 5883–5889; (d) Kan,
T.; Hosokawa, S.; Nara, S.; Oikawa, M.; Ito, S.; Mat-
suda, F.; Shirahama, H. J. Org. Chem. 1994, 59, 5532–
5534. Ketone–chloro acyl: (e) see p. 50 in Ref. 2a.
Ketone–nitrile: (f) Molander, G. A.; Wolfe, C. N. J. Org.
Chem. 1998, 63, 9031–9036, also see Ref. 3i; (g) Zhou, L.;
Zhang, Y.; Shi, D. Tetrahedron Lett. 1998, 39, 8491–
8494; Zhou, L.; Zhang, Y.; Shi, D. Synthesis 2000, 91–98;
(h) Kakiuchi, K.; Fujioka, Y.; Yamamura, H.; Tsutsumi,
K.; Morimoro, T.; Kurosawa, H. Tetrahedron Lett. 2001,
42, 7595–7598. Ketone–unactivated olefin: (i) Molander,
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ (No. 13029037) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We are grateful to Professor Seiji
O
O
R
OH
O
O
OH
R
SmI2
THF
OEt
OEt
+
R
15
14
13a: R = (CH2)3Br, 13b: R = Me
13d: R = CH2Ph
Scheme 3.

5070
K. Iwaya et al. / Tetrahedron Letters 43 (2002) 5067–5070
G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236–
8246. Ketone–haloalkyl: (j) Molander, G. A.; Etter, J. B.
J. Org. Chem. 1986, 51, 1778–1786.
cm−1 1H NMR (200 MHz, CDCl3) l 8.06 (dd, J=8, 8
;
Hz, 1H), 7.63 (dd, J=8, 8 Hz, 1H), 7.45 (dd, J=8, 8 Hz,
1H), 7.33–7.27 (m, 2H), 3.46 (t, J=6 Hz, 2H), 2.63 (t,
J=7 Hz, 2H), 2.19–2.05 (m, 2H); 13C NMR (50 MHz,
CDCl3) l 180.9, 179.0, 142.0, 138.5, 136.0, 135.0, 130.6,
130.0 (2C), 129.4, 33.0, 30.8, 28.2. Other 1,2-naphtho-
4. (a) In the reaction of haloalkylated ketones with SmI2,
there has been mechanistic controversy regarding whether
it is carbonyls or carbonꢁhalogen bonds that are first
reduced by SmI2.2b,4b; (b) Curran, D. P.; Gu, X.; Zhang,
W.; Dowd, P. Tetrahedron 1997, 53, 9023–9042.
5. Precedented ketone–ester coupling reactions: (a) Sodium–
liquid ammonia: Gutsche, C. D.; Tao, I. Y. C.; Kozma, J.
J. Org. Chem. 1967, 32, 1782–1790; (b) Low-valent tita-
nium: McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc.
1983, 105, 1660–1661; Furstner, A.; Csuk, R.; Rohrer, C.;
Weidmann, H. J. Chem. Soc., Perkin Trans. 1 1988,
1729–1734; (c) Cathode (Tafel rearrangement):
Grimshaw, J. In Organic Electrochemistry, Lund, H.;
Hammerich, O., Eds.; Marcel Dekker: New York, 2001;
Chapter 10, pp. 411–434.
quinones
2
including known 2b, mp 121–122°C
(observed); mp 121–122°C (lit. Takuwa, A.; Naruta, Y.;
Soga, O.; Maruyama, K. J. Org. Chem. 1984, 49, 1857–
1864) were similarly identified.
10. Identification of 3 were achieved by the comparison of
the spectral data with those of the products obtained by
the NaBH4 reduction of 1.
1
11. Diagnostic peaks of 9b were observed in H NMR of the
reaction mixture of 1b, 3b and 9b: l 7.92 (d, 1H), 7.65 (d,
1H), 2.40 (s, 3H). Several attempts to isolate pure 9b were
not successful since concomitant conversion of 9b to 2b
always occurred.
6. Liu, Y.; Zhang, Y. Tetrahedron Lett. 2001, 42, 5745–
5748.
7. Indanone 1a was prepared by NaH-promoted bromo-
propylation at the C2 position of ethyl 1-indanone-2-car-
boxylate which was obtained by the ethoxy carbonylation
12. Physical and spectral data of 4b: Colorless needles, mp
149–150°C (C2H5OH); IR (KBr) 1762 cm−1 1H NMR
;
(200 MHz, CDCl3) l 7.76–7.73 (m, 2H), 7.60 (s, 1H),
7.46–7.41 (m, 2H), 2.42 (s, 3H), 2.35 (s, 6H); 13C NMR
(50 MHz, CDCl3) l 170.4, 170.2, 141.2, 139.5, 134.2,
132.2, 129.4, 128.9, 128.3 (2C), 128.2, 123.1, 22.5 (2C),
18.9.
of 1-indanone. Other indanones
synthesized.
1 were similarly
8. Typical experimental procedure: A THF solution (1 mL)
of indanone 1a (0.5 mmol) was added dropwise under N2
during 3 min to the THF solution (11 mL) of SmI2 (1.1
mmol) at room temperature. The reaction mixture was
stirred for 30 min, and then it was quenched with satu-
rated aqueous NaHCO3 solution (5 mL), and the solution
was stirred under air for 10 min. The solution was
extracted with Et2O (3×20 mL), and then the organic
layer was washed with saturated aqueous NaHCO3,
Na2S2O3 and NaCl (30 mL), and dried over MgSO4. The
crude reaction mixture obtained by the concentration of
the extract was separated by column chromatography on
silica gel (EtOAc:benzene=1:6) to give naphthoquinone
2a and alcohol 3a. Reactions of other indanones 1 with
SmI2 were performed in the same manner.
13. Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58,
5008–5010.
14. Benzophenone should be more readily reduced than 1b
on the basis of the comparison of their reduction poten-
red
tials (Ep
V versus SCE): −1.68 V for benzophenone
(Roth, H. D.; Lamola, A. A. J. Am. Chem. Soc. 1974, 96,
6270–6275); −2.03 V for 1b.
15. Physical and spectral data of 14b: Colorless solid, mp
38°C; IR (KBr) 3416, 1670, 1644 cm−1 1H NMR (200
;
MHz, CDCl3) l 6.10 (s, 1H), 2.49 (t, J=6 Hz, 2H), 2.36
(t, J=6 Hz, 2H), 2.03–1.91 (m, 2H), 1.91 (s, 3H); 13C
NMR (50 MHz, CDCl3) l 196.2, 145.8, 132.8, 37.8, 32.5,
24.3, 19.0. 14a and 14d were similarly identified.
16. Identification of 15 were achieved by the comparison of
the spectral data with those of the products obtained by
the NaBH4 reduction of 13.
9. Physical and spectral data of 2a: Orange needles, mp
97–98°C (C6H6/n-C6H14); IR (KBr) 1690, 1664, 1584