Synthesis of 2-substituted 1,3-cycloheptanedione via a lewis acid mediated ring expansion reaction

Article abstract of DOI:10.3987/COM-13-S(S)55

We have established a new route to provide 2-substituted 1,3-cycloheptanediones via a Lewis acid mediated ring expansion reaction of cyclobutanones as the key step. The ring expansion reactions were mediated by a series of Lewis acids. Among the used Lewis acids, ZnI2 was the most practical mediator. This route has succeeded in providing the title compounds even on a multi-gram scale. During the research, the Baeyer-Villiger oxidation of the cyclobutanones to obtain the new bicyclic lactones was also examined. The regioselective oxidation was observed in the case of chlorinated cyclobutanones.

Full text of DOI:10.3987/COM-13-S(S)55

HETEROCYCLES, Vol. 88, No. 2, 2014
997
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 997 - 1012. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 27th June, 2013, Accepted, 15th August, 2013, Published online, 22nd August, 2013
DOI: 10.3987/COM-13-S(S)55
SYNTHESIS OF 2-SUBSTITUTED 1,3-CYCLOHEPTANEDIONE VIA A
LEWIS ACID MEDIATED RING EXPANSION REACTION
Kohei Inomata* and Yasuyuki Endo*
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai
981-8558, Japan, E-mail: inomata@tohoku-pharm.ac.jp
This paper is dedicated to Professor Victor Snieckus on the occasion of his 77th
birthday.
Abstract – We have established a new route to provide 2-substituted
1,3-cycloheptanediones via a Lewis acid mediated ring expansion reaction of
cyclobutanones as the key step. The ring expansion reactions were mediated by a
series of Lewis acids. Among the used Lewis acids, ZnI2 was the most practical
mediator. This route has succeeded in providing the title compounds even on a
multi-gram scale. During the research, the Baeyer-Villiger oxidation of the
cyclobutanones to obtain the new bicyclic lactones was also examined. The
regioselective oxidation was observed in the case of chlorinated cyclobutanones.
INTRODUCTION
We have recently established the chiral preparation of a Wieland-Miescher ketone analogue (1b) from
2-methyl-1,3-cycloheptanedione (2b).1 The several chiral amines bearing a heterocyclic moiety, such as
pyrrolidine, tetrazole, or piperazine, mediated the asymmetric intramolecular aldol reaction of the trione (3)
in the presence of trifluoroacetic acid (TFA) to afford 1b in an enantioselective fashion.1c Among the chiral
amines, (S)-2-amino-1-phenyl-3-(pyrrolidin-1-yl)propane (4) was one of the most effective mediator to
afford (R)-1b in high yield accompanied with over 80% ee. In connection with an ongoing synthetic project,
we needed to prepare 2 bearing a variety of substituents (R1). However, there have been few reports
regarding the preparation of 2-substituted 1,3-cycloheptanediones (2) except for only limited substituents
(R1) such as methyl and ethyl groups (Figure 1). 2-4
For example, Hirsch et al. reported that the direct C-ethylation of 2a afforded 2c in low yield along with
3-ethoxy-2-cycloheptenone as a major product.4a The limited direct alkylation of 2a under basic conditions
has also been reported by Swaminathan et al. They succeeded in preparation of 2b and 2c along with the
recovery of the starting 2a.4b

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HETEROCYCLES, Vol. 88, No. 2, 2014
R1
O
R1
a: R1 = H
b: R1 = Me
c: R1 = Et
O
O
O
2
1
O
Me
O
4
TFA
NH2
ref. 1a
(R)-1b
(Yield: 93%, ee: 84%)
2a
N
4
3
O
Figure 1. Preparation of Wieland-Miescher ketone analogue (1) bearing a 7-membered ring
Okamura and co-workers have reported the preparation of 2b from diethyl adipate (5) via an acyloin
condensation, Simmos-Smith cyclopropanation, and subsequent oxidative ring expansion mediated by
FeCl3 (Scheme 1).3c There have been some problems concerning the difficulties of the acyloin condensation
on a large scale and of the effective preparation of 1,1-diiodoethane (7).5 Therefore, practical methods to
prepare 2-substituted 1,3-cycloheptanedione (2) are still required.
Scheme 1
Scheme 2
We have been inspired by Ragan’s synthesis of 2a from 9 via the [2+2] cycloaddition and following zinc
reduction of the chloride and the ring expansion of cyclobutanone.2g Although this process has been

HETEROCYCLES, Vol. 88, No. 2, 2014
999
effective, the undesired 2-acetylcyclopentanone (11a) sometimes has been predominantly obtained under
slightly different reaction conditions, especially on a large scale.2j Also, it has been difficult to handle the
compound (10) due to its instability during the purification process such as column chromatography or
distillation. In Ragan’s synthesis, we considered that the electron withdrawing dichloro substituents have
promoted an undesired ring opening of the cyclobutanone in 10 and its instability against the purified
process, and that the introduction of an electron donating group (EDG) on the cyclobutanone would be able
to control the desired ring expansion to produce 2. We now report the preparation of bicyclic
cyclobutanones (12) bearing a series of substituents (R1) and the regioselective ring expansion reaction of
12 mediated by Lewis acids to afford 2 (Scheme 2).
RESULTS AND DISCUSSION
First of all, we have started the [2+2] cycloaddition between 92j,6 and ketenes, which were prepared from a
variety of acid halides (13), 7-9 in the presence of triethylamine (TEA).10,11 These results are summarized in
Scheme 3 and Table 1. The chloroacetyl chloride (13a) and acetyl chloride (13d) hardly afforded 14a or
14d.11 On the other hand, 2-chloropropionyl chloride (13b) afforded the desired 14b as an inseparable
mixture of two diastereomers regarding the methyl (R1) and chloro (X1) substituents. Based on these results,
we considered that both the -halo (X1) and -alkyl (R1) substituents on 13 were needed to accelerate the
effective [2+2] cycloaddition. The zinc reduction of 14b without a further purification of diastereomers and
following solvolysis of the trimethysilyl group in aqueous 2-propanol (i-PrOH) smoothly proceeded to
afford 12b as a single stereoisomer in 70% yield.
Scheme 3

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HETEROCYCLES, Vol. 88, No. 2, 2014
We next examined versatile acid halides (13) bearing alkyl, branched alkyl and benzyl substituents (R1) for
these processes. Thus, the [2+2] cycloaddition using 13 and following zinc reduction afforded 12 as a single
isomer (entries 3, 5-7). The -bromo acid chloride (13f) and -bromo acid bromide (13i) were also able to
be used for the reaction. However, entry 9 showed that the zinc reduction of 14i bearing an -bromo
substituent revealed a lower yield than that of the corresponding chloride compound (14b). When 13h was
used for the reaction, we could obtain 14h, but the zinc reduction of 14h afforded 11h as a mixture of its
tautomers (15h and/or 16h) without the production of the desired 12h (entry 8).12 This result meant that an
electron withdrawing substituent, such as a phenyl, at the -position of the ketone (14) could not be used in
this process. All of the compounds, (12) and (14), could be easily purified by silica gel column
chromatography without any decomposition of the products. The reaction using 50 g of starting 9 also
obtained almost the same results as entry 2 (entry 10).
Table 1. Preparation of the bicyclic butanones bearing the versatile substituents
Entrya
13
R1
H
X1
Cl
Cl
Cl
H
X2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Yieldb (14, %)
drc,d (14)
NDe
Yieldb (12, %)
1
2
13a
13b
13c
13d
13e
13f
13g
13h
13i
trace
62
NTf
Me
Et
63:37
85:15
NDe
70
3
56
54
NTf
4
H
trace
56
5
Bn
i-Pr
i-Bu
Ph
Cl
Br
Cl
Cl
Br
Cl
73:27
85:15
83:17
91:9
41
6
63
47
7
95
61
56g
8
77
9
10h
Me
39
27:73
67:33
26
13b
Me
83
76
a 5 g of 9 was used in all reactions.
b Isolated yield.
c Diastereomeric ratio.
d Determined by 1H-NMR of the crude products.
e Not determined.
f Not treated.
g Yield of a mixture of 11h and its tautomers (15h and/or 16h). Compound (12h) was not observed.
h 50 g of 9 was used. The [2+2] cycloaddition with 13b was carried out at room temperature.
The relative configuration of 12b was determined by NOE experiments as indicated in Scheme 4. From the
NOE correlations, the stereochemistry between the methyl and hydroxyl substituents must be trans. The
zinc reduction of the chloride in 14b produced the enol (17), and the following kinetic protonation
proceeded from a convex face of the bicyclo[3.2.0]heptane skeleton in 17 to afford 12b as a single

HETEROCYCLES, Vol. 88, No. 2, 2014
1001
stereoisomer (Scheme 4).
Scheme 4
As already described, 14b was obtained as a mixture of diastereomers. As a mixture of the both
diastereomers afforded 12b as a single isomer, we next tried to separate them. Solvolysis of the TMS group
in 14b rapidly proceeded to afford 18 and 19, which were readily separable by column chromatography.
The NOE correlation between the methyl protons at C-7 and a methine proton at C-5 in 19 suggested the
stereochemistry of 19 shown in Scheme 5. The zinc reduction of 18 and 19 respectively afforded 12b and
we could not observe any diastereomers of 12b in both cases. These results support the kinetic protonation
mechanism described above. However, the yields of 12b in the both cases were very low, because of the
decomposition of the starting 18 or 19 during the reactions (Scheme 5).
Cl Me
HO
Me Cl
NOE
7
HO
Zn
O
O
+
14b
12b
i-PrOH
H2O, rt
MeOH
rt
5
H
H
(22%, from 18)
(5%: from 19)
19 (34%)
18 (51%)
mCPBA
NaHCO3
CH2Cl2
CH2Cl2
rt
(74%)
mCPBA
NaHCO3
rt
For 19 (65%)
For 18 (77%)
Cl
Me
O
Me
HO
O
Me
HO
O
O
Me
HO
Cl
HO
O
O
O
+
O
H
H
H
H
20 (single regioisomer)
21 (single regioisomer)
23
22
22:23 = 2:3
inseparable
Scheme 5
At this stage, we examined the Baeyer-Villiger oxidation of the cyclobutanones to compare the electron

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HETEROCYCLES, Vol. 88, No. 2, 2014
donating character at C-5 and C-7 between 12b and 18 or 19. Thus, the treatment of 18 or 19 with
m-chloroperbenzoic acid (mCPBA) in the presence of sodium hydrogen carbonate respectively afforded the
lactone 20 or 21 as a single regioisomer. On the other hand, 12b afforded an inseparable mixture of 22 and
23 (22:23 = 2:3) in 74% yield under the same reaction conditions (Scheme 5). These results showed us that
C-7 in 18 or 19 was the electron withdrawing character due to the chloro substituent, and that both C-5 and
C-7 in 12b were almost the same electron donating character. Since the electron withdrawing chloro
substituent in 18 or 19 would promote the undesired ring opening of the cyclobutanone moiety, 12b was
selected as a substrate for continued ring expansion reactions.
Table 2. Screening of the mediators for the ring expansion reaction of 12b
Yieldb
(2b, %) (11b, %)
Yieldb,c
Entry a
Mediator
AcOH
Solvent
Temperature Time (h)
1
2
i-PrOH-H2O
THF
rt
-
NRd
13
46
52
37
09
56
55
61
46
50
41
-
tert-BuOK
p-TsOH
BF3•OEt2
EtAlCl2
Et2AlCl
AlCl3
0 oC
0 oC
0 oC
0 oC
0 oC
rt
002.5
047.0
000.5
001.5
021.5
109.0
041.5
060.0
000.1
000.2
001.0
50
19
08
10
11
02
19
14
23
14
25
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
5
6
7
8
ZnCl2
rt
9
ZnI2
rt
10
11
12
ZrCl4
0 oC
0 oC
rt
GaCl3
BiBr3
a 100 mg of 12b was used for the all reactions.
b Isolated yield.
c Yield of a mixture of 11b and its tautomers (15b and/or 16b).
d No reaction.
Next, we examined the ring expansion reaction of 12b mediated by Lewis acidic or basic conditions.13,14
The results are summarized in Table 2. All the reactions were performed in the presence of 1.2 equivalents
of the Lewis acidic or Lewis basic mediators to afford 2b accompanied by 11b, which were easily separable
by silica gel column chromatography. The 1H-NMR of 11b in CDCl3 suggested that 11b was obtained as an
inseparable 1:1 mixture of 11b and its tautomers (15b and/or 16b).15 First of all, according to Ragan’s
method,2g 12b was exposed to acetic acid in aqueous 2-propanol. However, no reaction was observed. Basic

HETEROCYCLES, Vol. 88, No. 2, 2014
1003
conditions using potassium tert-butoxide (t-BuOK) in THF predominantly afforded the undesired 11b.
Although most of the Lewis acidic conditions predominantly afforded 2b, the yields of 2b varied. When
AlCl3 was used, the most selective reaction was observed. However, the yield of 2b slightly decreased and
a longer reaction time was required. The stronger Lewis acid, such as ZrCl4 and GaCl3, also rapidly
promoted the reaction, however, both the regioselectivity and yield of the desired 2b decreased. Since ZnI2
exhibited the highest yield of 2b among a variety of tested Lewis acids, we selected it as a mediator to
develop further experiments.
We next examined the solvent effects of the ring expansion reaction of 12b mediated by a stoichiometric
amount of ZnI2. The results are summarized in Table 3. Using nonprotic polar solvents, such as acetonitrile
and THF, and a prolonged reaction time afforded the desired 2b in a lower yield than those in
dichloromethane or 1,2-dichloroethane. Less polar solvents, such as toluene and hexane, decreased the
yield of 2b. Acatalytic reaction was also examined (entry 7). Thus, the reaction using 0.1 equivalent of ZnI2
prolonged the reaction time to completion and afforded 2b in a lower yield than the stoichiometric
conditions. Therefore, we selected the stoichiometric ZnI2 in dichloromethane for further experiments.
Table 3. Solvent effects for the ring expansion reaction of 12b
Time
(h)
Yieldb
(2b, %)
Yieldb,c
(11b, %)
Entrya
Solvent
1
2
CH2Cl2
THF
060.0
261.0
261.0
061.5
061.5
063.0
166.0
61
04
13
57
44
45
50
14
13
26
19
05
25
08
3
MeCN
DCEd
4
5
toluene
hexane
CH2Cl2
6
7e
a 100 mg of 12b was used for the all reactions.
b Isolated yield.
c Yield of a mixture of 11b and its tautomer (15b or 16b).
d 1,2-Dichloroethane
e 0.1 equiv. of ZnI2 was used.
Finally, the optimized conditions for the ring expansion reaction were used with 12 bearing versatile
substituents (Table 4). Most of the substrates (12) predominantly afforded known or unknown
cycloheptanediones (2) accompanied by a tautomeric mixture of 11, 15 and/or 16. The reaction using 27 g

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HETEROCYCLES, Vol. 88, No. 2, 2014
of 12b was also examined to observe the shorter reaction time and the slightly lower yield of 2 than the case
on a small scale (entry 6). We have succeeded in preparing a 2-substituted 1,3-cycloheptanedione bearing
an alkyl, branched alkyl and benzyl groups.
Table 4. Ring expansion reactions of 12 mediated by ZnI2
Substratea
Time
(h)
Yieldb
(2, %)
Yieldb, c
(11, %)
Entry
R1
(12)
1
2
3
4
5
6
12b
12c
12e
12f
Me
Et
60
44
66
38
43
20
61
62
48
69
52
53
14
21
36
19
34
29
Bn
i-Pr
i-Bu
Me
12g
12bd
a 0.1-1.5 g of 12 was used for all reactions.
b Isolated yield.
c Yield of a mixture of 11 and its tautomers (15 and/or 16).
d 27 g of 12b was used.
In conclusion, we have established a new route to provide 2-substituted 1,3-cycloheptanediones (2) via a
Lewis acid mediated ring expansion reaction of cyclobutanones (12) as the key step. The ring expansion
reactions were mediated by a series of Lewis acids. Among the used Lewis acids, ZnI2 was the most
practical mediator. This route succeeded in providing the title compounds even on a multi-gram scale.
During the research, the Baeyer-Villiger oxidation of the cyclobutanones to obtain the new bicyclic lactones
was also examined. The regioselective oxidation was observed in the case of chlorinated cyclobutanones.
The use of 2 to achieve the preparation of a new Wieland-Miescher ketone analogue (1) is currently in
progress.
EXPERIMENTAL
1
Melting points are uncorrected. The H NMR spectra and 13C NMR spectra were recorded on a
JEOL-AX-400 (1H 400 MHz, 13C 100 MHz) spectrometer and calibrated using trimethysilane as the
internal standard. The mass spectra were recorded on a JEOL-DX-303 or JEOL JMS-MS700 spectrometer.
Typical procedure for [2+2] cycloaddition of 9 with 13 and subsequent zinc reduction of 14.
To a stirred solution of 9 (5 g, 32.1 mmol) and triethylamine (TEA, 8.0 mL, 57.7 mmol) in hexane (80 mL)
o
was added 2-chlorobutyryl chloride (13c) (7.23 g, 51.3 mmol) in hexane (10 mL) in one portion at 0 C.

HETEROCYCLES, Vol. 88, No. 2, 2014
1005
After stirring the mixture at rt for 10 min, the mixture was heated to reflux for 17 h. After cooling, the
mixture was filtered to remove the TEA hydrochloride and the filtrate was washed with saturated aqueous
NaHCO3 and brine. After drying (Na2SO4), the solvent was removed under reduced pressure. The residue
was chromatographed (1% Et2O-hexane to 2% Et2O-hexane) to afford 14c (4.76 g, 56%) as a 85:15
diastereomeric mixture and a pale yellow oil. The compound (14c) was used for the next reaction without
further purification. To a stirred solution of 14c (2.0 g, 7.68 mmol) in 2-propanol (20 mL) and H2O (10 mL)
was added zinc powder (2.51 g, 38.4 mmol) in one portion at rt. The mixture was stirred at the same
temperature for 51 h. The mixture was filtered through a Celite pad and the filtrate was evaporated under
reduced pressure. The residue was dissolved in AcOEt and the mixture was washed with saturated aqueous
NaHCO3 and brine. After drying (Na2SO4), the solvent was removed under reduced pressure. The residue
was chromatographed (15% AcOEt-hexane) to afford 12c (643 mg, 54%) as a single stereoisomer and a
colorless oil.
(1S*, 5R*, 7S*)-7-Ethyl-1-hydroxybicyclo[3.2.0]heptan-6-one (12c)
1H-NMR (CDCl3)  1.03 (t, J = 7.2 Hz, 3H), 1.33-1.49 (m, 2H), 1.58-1.83 (m, 3H), 1.85-1.98 (m, 2H),
2.08-2.14 (brs, 1H, D2O exchangeable), 2.22 (dd, J = 6.8 Hz, 13.2 Hz, 1H), 3.26-3.34 (m, 2H); 13C-NMR
(CDCl3)  12.1, 16.7, 26.6, 27.8, 35.1, 68.5, 70.2, 79.8, 215.6; EIMS (m/z) 154 (M+), 126, 97 (100%), 84,
55; HRMS calcd for C9H14O2 154.0994. Found. 154.0995.
(1S*, 5R*, 7S*)-1-Hydroxy-7-methylbicyclo[3.2.0]heptan-6-one (12b)
Yiled: 70% (colorless oil); 1H-NMR (CDCl3)  1.06 (d, J = 7.2 Hz, 3H), 1.30-1.45 (m, 1H), 1.65-1.83 (m,
2H), 1.88 (dd, J = 5.8 Hz, 12.6 Hz, 1H), 1.95 (dd, J = 6.3 Hz, 12.6 Hz, 1H), 2.10-2.16 (brs, 1H, D2O
exchangeable), 2.21 (dd, J = 6.3 Hz, 13.0 Hz, 1H), 3.35 (dd, J = 4.8 Hz, 8.2 Hz, 1H), 3.46-3.54 (m, 1H);
13C-NMR (CDCl3)  6.87, 26.3, 28.0, 34.8, 63.3, 68.6, 79.7, 216.4; EIMS (m/z) 140 (M+), 122, 112, 84
(100%), 83; HRMS calcd for C8H12O2 140.0837. Found. 140.0831.
(1R*, 5R*, 7S*)-7-Benzyl-1-hydroxybicyclo[3.2.0]heptan-6-one (12e)
Yiled: 41% (colorless oil); 1H-NMR (CDCl3)  1.43-1.60 (m, 1H), 1.68-1.86 (m, 2H), 1.88-2.03 (m, 2H),
2.03-2.14 (brs, 1H, D2O exchangeable), 2.28 (dd, J = 5.3 Hz, 13.5 Hz, 1H), 2.73 (dd, J = 9.2 Hz, 15.5 Hz,
1H), 3.02 (dd, J = 5.8 Hz, 15.5 Hz, 1H), 3.39 (dd, J = 4.3 Hz, 8.2 Hz, 1H), 3.81 (quint, J = 4.8 Hz, 1H),
7.19-7.24 (m, 1H), 7.25-7.34 (m, 4H); 13C-NMR (CDCl3)  26.8, 28.0, 29.3, 35.7, 68.80, 68.84, 80.2, 126.3,
128.4, 128.6, 128.9, 138.8, 213.5; EIMS (m/z) 216 (M+), 188, 97 (100%), 91, 84; HRMS calcd for C14H16O2
216.1150. Found. 216.1152.
(1R*, 5R*, 7S*)-1-Hydroxy-7-isopropylbicyclo[3.2.0]heptan-6-one (12f)
1
Yield: 47% (pale yellow oil); H-NMR (CDCl3) 0.97 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H),
1.37-1.51 (m, 1H), 1.70-1.96 (m, 5H), 2.00 (brs, 1H, D2O exchangeable), 2.27 (dd, J = 7.2 Hz, 12.6 Hz, 1H),

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HETEROCYCLES, Vol. 88, No. 2, 2014
3.03 (dd, J = 4.3 Hz, 11.1 Hz, 1H), 3.25 (dd, J = 4.3 Hz, 7.7 Hz, 1H); 13C-NMR (CDCl3)  20.8, 20.9, 24.9,
26.8, 27.6, 35.7, 68.3, 75.1, 80.0, 214.0; EIMS (m/z) 168 (M+), 140, 97 (100%), 84; HRMS calcd for
C10H16O2 168.1150. Found. 168.1149.
(1R*, 5R*, 7S*)-1-Hydroxy-7-isobutylbicyclo[3.2.0]heptan-6-one (12g)
Yield: 61% (pale yellow oil); 1H-NMR (CDCl3)  0.93 (d, J = 7.2 Hz, 6H), 1.25-1.53 (m, 3H), 1.66-1.82 (m,
3H), 1.84-1.97 (m, 2H), 2.05 (brs, 1H, D2O exchangeable), 2.21 (dd, J = 6.8 Hz, 13.5 Hz, 1H), 3.31 (dd, J =
4.3 Hz, 8.2 Hz, 1H), 3.45 (dd, J = 5.8 Hz, 14.0 Hz, 1H); 13C-NMR (CDCl3)  22.3, 22.5, 26.4, 26.5, 27.9,
32.2, 35.5, 67.1, 68.6, 80.1, 215.5; EIMS (m/z) 182 (M+), 154, 111, 84 (100%), 55; HRMS calcd for
C11H18O2 182.1307. Found. 182.1301.
2-(2-Phenylacetyl)cyclopentanone (11h)
Yield: 56% (pale yellow oil) as an equilibrium mixture of 11h and its tautomers (15h and/or 16h); 1H-NMR
(CDCl3) 1.75-2.09 (m, 2H), 2.18-2.32 (m, 1H), 2.41 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.2 Hz, 1H), 3.48 (t, J
= 8.2 Hz, 0.5H), 3.56 (s, 1H), 3.95 (d, J = 15.9 Hz, 0.5H), 4.01 (d, J = 15.5 Hz, 0.5H), 7.20-7.36 (m, 5H),
13.4-13.7 (brs, 0.5H, D2O exchangeable); 13C-NMR (CDCl3)  20.2, 20.5, 25.2, 25.6, 36.7, 38.8, 41.0, 49.7,
60.5, 190.7, 126.8, 127.0, 128.5, 128.6, 128.9, 129.6, 133.6, 135.2, 176.3, 202.0, 205.4, 212.8; EIMS (m/z)
202 (M+), 111 (100%), 91, 83; HRMS calcd for C13H14O2 202.0994. Found. 202.0991.
Solvolysis of 14b
A solution of 14b (1.16 g, 4.71 mmol) in MeOH (10 mL) was a stirred at rt for 1 h. The solvent was
removed under reduced pressure and the residue was chromatographed (silica gel: spherical, 10% to 15%
AcOEt-hexane) to afford 18 (414 mg, 51%) and 19 (276 mg, 34%).
(1R*, 5R*, 7R*)-7-Chloro-1-hydroxy-7-methylbicyclo[3.2.0]heptan-6-one (18)
Colorless oil; 1H-NMR (CDCl3)  1.34-1.48 (m, 1H), 1.57 (s, 3H), 1.82-2.00 (m, 2H), 2.01- 2.11 (m, 2H),
2.17 (dd, J = 6.8 Hz, 13.5 Hz, 1H), 3.08 (s, 1H, D2O exchangeable), 3.63 (d, J = 7.7 Hz, 1H); 13C-NMR
(CDCl3)  16.9, 25.9, 28.3, 34.8, 69.2, 81.3, 83.0, 208.8; EIMS (m/z) 176 (M++2), 174 (M+), 138, 111
(100%), 84; HRMS calcd for C8H1135ClO2 174.0448. Found. 174.0453; HRMS calcd for C8H1137ClO2
176.0418. Found. 176.0417.
(1R*, 5R*, 7S*)-7-Chloro-1-hydroxy-7-methylbicyclo[3.2.0]heptan-6-one (19)
Colorless oil; 1H-NMR (CDCl3)  1.56-1.68 (m, 1H), 1.75 (s, 3H), 1.79-1.97 (m, 3H), 2.07 (dd, J = 6.3 Hz,
11.1 Hz, 1H), 2.16 (s, 1H, D2O exchangeable), 2.59 (dd, J = 6.8 Hz, 12.6 Hz, 1H), 3.47 (d, J = 8.7 Hz, 1H);
13C-NMR (CDCl3) 21.0, 26.2, 29.5, 38.6, 66.0, 78.4, 83.9, 209.2; EIMS (m/z) 176 (M++2), 174 (M+), 138,
111 (100%), 84; HRMS calcd for C8H1135ClO2 174.0448. Found. 174.0413; HRMS calcd for C8H1137ClO2
176.0418. Found. 176.0413.
Typical procedure for zinc reduction of 18 and 19

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1007
To a stirred solution of 18 (100 mg, 0.575 mmol) in a mixture of 2-propanol (3 mL) and H2O (3 mL) was
added zinc powder (188 mg, 2.87 mmol) in one portion at rt. The mixture was stirred at rt for 49 h. The
mixture was then filtered through a Celite pad and the filtrate was evaporated under reduced pressure. The
residue was dissolved in AcOEt and was washed with saturated aqueous NaHCO3 and brine. After drying
(Na2SO4), the solvent was removed under reduced pressure. The residue was chromatographed (15%
AcOEt-hexane) to afford 12b (18 mg, 22%) as a single stereoisomer and colorless oil. All of the
spectroscopic data were identical to 12b as already described.
Typical procedure for the Baeyer-Villiger oxidation of the cyclobutanones.
To a stirred suspension of 18 (100 mg, 0.575 mmol) and NaHCO3 (241 mg, 2.87 mmol) in CH2Cl2 (2 mL)
was added mCPBA (149 mg, 0.862 mmol) in an ice bath. After stirring at the same temperature for 10 min,
the mixture was further stirred at rt for 1.5 h. The mixture was filtered through a Celite pad and the filtrate
was washed with 10 (w/v) % aqueous Na2SO3, saturated aqueous NaHCO3 and brine. After drying
(Na2SO4), the solvent was removed under reduced pressure. The residue was chromatographed (20%
AcOEt-hexane) to afford 20 (84 mg, 77%) as a single regioisomer and a colorless oil.
(3R*,3aR*,6aR*)-3-Chloro-3a-hydroxy-3-methylhexahydro-2H-cyclopenta[b]furan-2-one (20)
1H-NMR (CDCl3)  1.66-1.74 (m, 1H), 1.73 (s, 3H), 1.87-1.96 (m, 2H), 1.97-2.14 (m, 2H), 2.17-2.28 (m,
1H), 2.57 (s, 1H, D2O exchangeable), 4.59 (d, J = 5.3 Hz, 1H); 13C-NMR (CDCl3)  19.5, 23.8, 28.8, 33.0,
69.8, 87.5, 88.2, 172.0; EIMS (m/z) 192 (M++2), 190 (M+), 155, 111 (100%), 90, 83; HRMS calcd for
C8H1135ClO3 190.0396. Found. 190.0388; HRMS calcd for C8H1137ClO3 192.0367. Found. 192.0358.
(3S*,3aR*,6aR*)-3-Chloro-3a-hydroxy-3-methylhexahydro-2H-cyclopenta[b]furan-2-one (21)
Yield: 65% (colorless needles); mp 83-84 oC (from Et2O-hexane); 1H-NMR (CDCl3)  1.56-1.72 (brs, 1H,
D2O exchangeable), 1.80 (s, 3H), 1.82-2.11 (m, 4H), 2.16-2.36 (m, 2H), 4.56 (d, J = 5.3 Hz, 1H); 13C-NMR
(CDCl3)  23.1, 23.8, 30.9, 37.8, 71.0, 86.8, 88.9, 174.1; EIMS (m/z) 192 (M++2), 190 (M+), 155, 111
(100%), 90, 83; HRMS calcd for C8H1135ClO3 190.0396. Found. 190.0403; HRMS calcd for C8H1137ClO3
192.0367. Found. 192.0370.
(3S*,3aS*,6aR*)-3a-hydroxy-3-methylhexahydro-2H-cyclopenta[b]furan-2-one (22) and (3S*,3aR*,
6aR*)-3a-hydroxy-3-methylhexahydro-1H-cyclopenta[c]furan-1-one (23)
Yield: 74% (colorless oil) as an inseparable mixture of 22 and 23; 1H-NMR (CDCl3)  1.26 (d, J = 7.2 Hz,
1.2H), 1.40 (d, J = 6.3 Hz, 1.8H), 1.50-2.80 (m, 6H, 1H: D2O exchangeable), 2.87 (q, J = 7.2 Hz, 0.4H),
2.93 (ddd, J = 1.6 Hz, 3.9 Hz, 7.7 Hz, 0.6H), 4.52 (q, J = 6.3 Hz, 0.6H), 4.54 (d, J = 6.3 Hz, 0.4H); 13C-NMR
(CDCl3)  9.2, 14.2, 23.5, 25.0, 27.6, 30.8, 33.9, 34.3, 45.6, 53.1, 81.8, 86.8, 86.9, 88.9, 178.0, 179.0; EIMS
(m/z) 156 (M+), 128, 100, 84 (100%), 72; HRMS calcd for C8H12O3 156.0786. Found 156.0780.
Typical procedure for a ring expansion reaction of 12.

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To a stirred solution of 12b (100 mg, 0.714 mmol) in CH2Cl2 (3 mL) was added ZnI2 (274 mg, 0.857 mmol)
o
at 0 C. After stirring the mixture for 30 min, the mixture was further stirred at rt for 60 h. After adding
saturated aqueous NaHCO3 at 0 oC, the mixture was filtered through a Celite pad. The filtrate was extracted
with CH2Cl2. The combined organic layer was washed with brine and dried (Na2SO4). The solvent was
removed under reduced pressure. The residue was chromatographed (10% Et2O-hexane to 15%
Et2O-hexane) to afford 11b (14 mg, 14%) as a colorless oil and 2b (61 mg, 61%) as a colorless oil. The
1H-NMR spectrum of 11b in CDCl3 was observed as a 1:1 mixture of 11b and its tautomers (15b and/or
16b).
2-Methyl-1,3-cycloheptanedione (2b)3
1H-NMR (CDCl3)  1.23 (d, J = 6.8 Hz, 3H), 1.78-1.97 (m, 2H), 1.98-2.13 (m, 2H), 2.46-2.65 (m, 4H), 3.75
13
(q, J = 6.8 Hz, 1H); C-NMR (CDCl3)  11.1, 25.7, 43.3, 60.8, 208.0; EIMS (m/z) 140 (M+), 112, 97
(100%); HRMS calcd for C8H12O2 140.0837. Found. 140.0832.
2-Propanoylcyclopentanone (11b)15,16
1H-NMR (CDCl3)  1.06 (t, J = 7.2 Hz, 1.5H), 1.15 (t, J = 7.7 Hz, 1.5H), 1.79-1.96 (m, 1.5H), 2.01-2.13 (m,
1H), 2.27 (q, J = 7.7 Hz, 2H), 2.38-2.58 (m, 3H), 2.82-2.94 (m, 0.5H), 3.38 (t, J = 7.7 Hz, 0.5H), 13.4-13.8
(brs, 0.5H, D2O exchangeable); 13C-NMR (CDCl3)  7.2, 9.3, 20.2, 20.7, 25.3, 25.5, 27.9, 36.3, 36.5, 38.7,
61.6, 108.8, 181.4, 203.4, 205.1, 213.2; EIMS (m/z) 140 (M+), 111 (100%), 84; HRMS calcd for C8H12O2
140.0837. Found. 140.0839.
2-Ethyl-1,3-cycloheptanedione (2c)4
Yield: 62% (pale yellow oil); 1H-NMR (CDCl3)  0.87 (t, J = 7.2 Hz, 3H), 1.80-1.94 (m, 4H), 1.99-2.11 (m,
2H), 2.45-2.60 (m, 4H), 3.57 (t, J = 7.2 Hz, 1H); 13C-NMR (CDCl3)  11.5, 19.6, 25.7, 43.7, 68.3, 207.4;
EIMS (m/z) 154 (M+), 126, 97 (100%), 55; HRMS calcd for C9H14O2 154.0994. Found. 154.0999.
2-n-Butyrylcyclopentanone (11c)17
Yield: 21% (pale pink oil) as an equilibrium mixture of 11c and its tautomers (15c and/or 16c); 1H-NMR
(CDCl3)  0.92 (t, J = 7.2 Hz, 1.5H), 0.97 (t, J = 7.7 Hz, 1.5H), 1.54-1.71 (m, 2H), 1.80-1.96 (m, 1.5H),
2.01-2.12 (m, 1H), 2.18-2.30 (m, 1.5H), 2.38 (m, 3.5H), 2.38-2.58 (m, 3.5H), 2.80 (td, J = 7.7 Hz, 17.4 Hz,
0.5H), 3.37 (t, J = 7.7 Hz, 0.5H), 13.5-13.8 (brs, 0.5H, D2O exchangeable); 13C-NMR (CDCl3)  13.5, 13.7,
16.6, 18.9, 20.2, 20.7, 25.2, 25.5, 36.2, 36.8, 38.6, 44.9, 61.7, 109.4, 178.9, 204.6, 205.1, 213.0; EIMS (m/z)
154 (M+), 126, 111 (100%), 84; HRMS calcd for C9H14O2 154.0994. Found. 154.0994.
2-Benzyl-1,3-cycloheptanedione (2e)18
Yield: 48% (colorless oil); 1H-NMR (CDCl3)  1.78-1.90 (m, 2H), 2.03-2.15 (m, 2H), 2.47 (ddd, J = 3.9 Hz,
8.7 Hz, 14.5 Hz, 2H), 2.55 (ddd, J = 4.3 Hz, 8.7 Hz, 14.5 Hz, 2H), 3.15 (d, J = 6.8 Hz, 2H), 4.22 (t, J = 6.8
Hz, 1H), 7.12-7.20 (m, 3H), 7.21-7.28 (m, 2H); 13C-NMR (CDCl3) 25.0, 31.8, 44.3, 68.3, 126.3, 128.4,

HETEROCYCLES, Vol. 88, No. 2, 2014
1009
128.9, 139.1, 205.4; EIMS (m/z) 216 (M+, 100%), 188, 159, 131, 91; HRMS calcd for C14H16O2 216.1150.
Found. 216.1149.
2-(3-Phenylpropanoyl)cyclopentanone (11e)19
Yield: 36% (pale yellow oil) as an equilibrium mixture of 11e and its tautomers (15e and/or 16e); 1H-NMR
(CDCl3) 1.79-1.91 (m, 2H), 1.99-2.10 (m, 1H), 2.15-2.30 (m, 1H), 2.34-2.46 (m, 2.5H), 2.24 (t, J = 3.0 Hz,
1H), 2.75-2.95 (m, 2H), 3.20 (ddd, J = 4.8 Hz, 7.7 Hz, 16.4 Hz, 0.5H), 3.34 (t, J = 7.7 Hz, 0.5H), 7.14-7.32
(m, 5H), 13.30-13.80 (brs, 0.5H, D2O exchangeable); 13C-NMR (CDCl3)  20.2, 20.7, 25.2, 25.5, 29.3, 31.5,
36.4, 36.8, 38.7, 44.4, 62.0, 109.9, 126.0, 126.2, 128.3, 128.4, 140.7, 140.8, 177.8, 203.6, 204.8, 212.9;
EIMS (m/z) 216 (M+), 198, 111, 91 (100%); HRMS calcd for C14H16O2 216.1150. Found. 216.1145.
2-Isopropyl-1,3-cycloheptanedione (2f)
Yield: 69% (colorless needles); mp 47.5-48 oC (from hexane); 1H-NMR (CDCl3)  0.92 (d, J = 6.8 Hz, 6H),
1.82-1.93 (m, 2H), 1.99-2.10 (m, 2H), 2.42-2.57 (m, 5H), 3.53 (d, J = 7.7 Hz, 1H); 13C-NMR (CDCl3) 
20.1, 25.6, 26.3, 44.4, 73.4, 207.2; EIMS (m/z) 168 (M+), 150, 125, 97 (100%), 84, 69; HRMS calcd for
C10H16O2 168.1150. Found. 168.1156.
2-(3-Methyl-n-butanoyl)cyclopentanone (11f)
1
Yield: 19% (colorless oil) as an equilibrium mixture of 11f and its tautomers (15f and/or 16f); H-NMR
(CDCl3) 0.88-0.99 (m, 6H), 1.86-1.96 (m, 1.75H), 2.00-2.30 (m, 2.25H), 2.55 (t, J = 7.2 Hz, 1H),
2.61-2.69 (m, 0.25H), 3.36 (t, J = 7.7 Hz, 0.25H), 13.56-13.76 (brs, 0.75H, D2O exchangeable); 13C-NMR
(CDCl3)  20.2, 20.6, 22.1, 22.2, 22.4, 23.1, 23.6, 23.8, 25.2, 26.2, 30.5, 34.3, 35.7, 36.8, 37.0, 38.6, 42.8,
42.9, 46.2, 46.5, 51.8, 61.9, 85.7. 110.0, 117.2, 204.3, 206.4, 213.0, 215.0; EIMS (m/z) 168 (M+), 153, 126,
111 (100%), 85, 57; HRMS calcd for C10H16O2 168.1150. Found. 168.1144.
2-Isobutyl-1,3-cycloheptanedione (2g)
Yield: 52% (colorless oil); 1H-NMR (CDCl3) 0.87 (d, J = 6.8 Hz, 6H), 1.49 (sept, J = 6.8 Hz, 1H), 1.72 (t,
J = 7.2 Hz, 2H), 1.82-1.93 (m, 2H), 2.01-2.11 (m, 2H), 2.46-2.61 (m, 4H), 3.74 (t, J = 7.2 Hz, 1H);
13C-NMR (CDCl3)  22.4, 25.7, 25.9, 35.0, 43.6, 65.0, 207.7; EIMS (m/z) 182 (M+), 127 (100%), 111, 55;
HRMS calcd for C11H18O2182.1307. Found. 182.1300.
2-(4-Methyl-n-pentanoyl)cyclopentanone (11g)
Yield: 34% (colorless oil) as an equilibrium mixture of 11g and its tautomers (15g and/or 16g); 1H-NMR
(CDCl3) 0.89, 0.91 (pair of d, J = 6.3 Hz, 6.3 Hz, 6H), 1.43-1.65 (m, 3H), 1.81-1.96 (m, 1.5H), 2.00-2.12
(m, 1H), 2.19-2.30 (m, 2H), 2.38-2.58 (m, 3H), 2.77-2.87 (m, 0.5H), 3.39 (t, J = 8.2 Hz, 0.5H), 13.50-13.80
13
(brs, 0.5H, D2O exchangeable); C-NMR (CDCl3)  20.3, 20.7, 22.2, 22.3, 22.4, 25.4, 25.6, 27.5, 27.8,
31.9, 32.4, 34.3, 36.8, 38.7, 41.1, 61.8, 109.2, 179.8, 204.83, 204.86, 213.2; EIMS (m/z) 182 (M+), 139, 126,
111 (100%); HRMS calcd for C11H18O2182.1307. Found. 182.1304.

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ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of the Japanese Government.
REFERENCES AND NOTES
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8. The acid halides (13) were commercially available or were easily prepared from the corresponding
carboxylic acids by Harpp’s methods described in ref. 7 or by an acid-chlorination of the
corresponding -halocarboxylic acids with thionyl chloride. See also ref. 9. All of acid halides (13)
were purified by distillation before use.
9. Some selected preparation of 13: (a) M. Furukawa, T. Okawara, and Y. Terawaki, Chem. Pharm. Bull.,
1977, 25, 181; (b) T. Tsuchiya and T. Takamoto, Jpn Kokai Tokkyo Koho, JP1996-183761 A; (c) R.
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HETEROCYCLES, Vol. 88, No. 2, 2014
1011
R. Amoroso, G. Bettoni, and B. De Filippis, Chirality, 2001, 13, 102; (e) F. Boschi, P. Camps, M.
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12. Compound 11h was isolated as a single spot by thin layer chromatography (TLC). However, the
13C-NMR spectra of 11h in CDCl3 indicated that there were three carbonyl carbon signals at  202.0,
205.4, and 212.8 and two olefinic carbon signals at  109.7 and 176.3 due to the ,-unsaturated
carbon. Also, we observed a broad singlet proton at  13.4-13.7, which was suggested as a
1
hydrogen-bonded enol proton in the H-NMR spectrum of 11h. These results showed that 11h was
obtained along with its tautomers 15h and/or 16h. Since the two enolic forms 15h and 16h are in a
rapid dynamic equilibrium, the peaks in the NMR spectrum for 15h and 16h cannot be distinguished.
The same tendency was observed for all of the compounds 11 which were obtained by a ring expansion
reaction. See also refs. 15 and 20.
13. M. Hesse, ‘Ring Enlargement in Organic Chemistry’, VCH, Weinheim, 1991.
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1
15. Change in the ratio (11b:15b and/or 16b) in the H-NMR spectrum in different deuterated solvents
was observed as follows: 11b:15b and/or 16b = 1:1 (in C6D5CD3) and 2:1 (in DMSO-d6 or CD3CN).
These results showed that 11b was obtained as an equilibrium mixture with its tautomer 15b and/or
16b.
16. (a) S. Hünig and W. Lendle, Chem. Ber., 1960, 93, 909; (b) J. B. Paine, III, J. R. Brough, K. K. Buller,
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Appl., WO 2012/125797 A1.

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19. T. M. Harris and C. R. Hauser, J. Am. Chem. Soc., 1959, 75, 1160.
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