New ring expansion of cyclobutanones: Synthesis of pyrrolinones, pyrrolidines and pyrroles

Article abstract of DOI:10.1055/s-2004-822900

2,2-Dichlorocyclobutanones reacted with various amines to give ring opening leading to 4,4-dichlorobutanamides. These compounds proved to be suitable substrates for the synthesis of 3-pyrrolin-2-ones, 2-pyrrolidinones, pyrrolidines and pyrroles.

Full text of DOI:10.1055/s-2004-822900

LETTER
1059
New Ring Expansion of Cyclobutanones: Synthesis of Pyrrolinones,
Pyrrolidines and Pyrroles
New
Ring
E
xpansi
u
on of
C
yclob
i
utanon
d
es o Verniest, Stefaan Boterberg, Filip Bombeke, Christian V. Stevens, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
9000 Gent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 19 January 2004
substituted pyrrolinones 2 are blood pressure reducing
agents,6 while 4-[4-(1H-imidazol-1-yl)phenyl]pyrrolino-
nes 3 possess selective positive inotropic properties
(Figure 1).7
Abstract: 2,2-Dichlorocyclobutanones reacted with various
amines to give ring opening leading to 4,4-dichlorobutanamides.
These compounds proved to be suitable substrates for the synthesis
of 3-pyrrolin-2-ones, 2-pyrrolidinones, pyrrolidines and pyrroles.
Key words: cyclobutanones, ring opening, ring expansion, pyr- The present paper describes the synthesis of 4-aryl-3-pyr-
roles, heterocycles
rolin-2-ones from 3-aryl-2,2-dihalocyclobutanones via an
amine-induced ring opening of the cyclobutanone ring
and subsequent ring closure. Furthermore, these interest-
ing compounds proved to be good substrates for further
ring transformation into various five-membered azahet-
erocycles (Scheme 1). Ring opening of dihalocyclobu-
tanones with amines has previously been described only
with fused cyclobutanones like bicycloheptanes, -hep-
tenes and benzocyclobutanones.8 No monocyclic a,a-
dichlorocyclobutanone was ever ring opened by amines.
Cyclobutanones reveal interesting characteristics such as
a high electrophilicity and ring tension which make them
good substrates for ring transformation reactions.1,2 Func-
tionalized cyclobutanones have indeed been the subject of
studies which describe their reactivity with nucleophiles
to induce ring opening, ring contraction and ring expan-
sion.1–4 Various g-butyrolactones and, to a smaller extent,
some g-lactams were synthesized via ring expansion of di-
halocyclobutanones via Baeyer–Villiger3 and Beckmann
rearrangements or Schmidt reactions,4 respectively. Reac-
tion of dichlorocyclobutanones with azides,4a–4c Tamura’s
reagent [O-(methanesulfonyl)-hydroxylamine]4d,e or its
N-alkylated analogue4f resulted in various pyrrolidinones.
Via these ring expansion methodologies, it would be pos-
sible to synthesize pyrrolidinones bearing leaving groups.
These compounds could in turn give rise to pyrrolinones
after elimination. However, no ring expansion of cyclo-
butanones was reported leading to the unsaturated 3-pyr-
rolin-2-ones, a class of compounds of particular
importance as physiologically active compounds and as
synthons for further transformation into various aza-
heterocycles. 3,4-Diarylpyrrolinones 1 were recently
patented and show anti-inflammatory (R = alkyl) and
cyclooxygenase-2 inhibitor (R = aryl) activities.5 N-Un-
pyrrolidinones
O
O
pyrrolidines
NR2
X
X
pyrroles
R1
R1
Scheme 1
Pyrrolidinones, pyrrolidines and pyrroles display a wide
diversity of pharmacological and agrochemical activities
and, accordingly, have received considerable attention in
organic synthesis (Figure 2). Rolipram 4 is a well-known
inhibitor of phosphodiesterase type IV, an anti-inflamma-
tory agent and antidepressant.9 Both enantiomers of
this 3-aryl-2-pyrrolidinone are active. Several 3-aryl-1-
propylpyrrolidines, e.g. 5, show antagonistic effects to-
wards dopaminergic autoreceptors and have a potential
for treatment of central nervous system disorders.10 The
most important 3-arylpyrroles in agrochemistry are pyr-
rolnitrin 6a and derivatives, which are used as antifungals
(e.g. Beret® 6b, Saphire® 6c) and antimycobacterials
(Figure 2).11
OH
O
O
O
RHN
O
H3C
NH
NR
NH
O
Both 2,2-dibromocyclobutanones and 2,2-dichloro-
cyclobutanones were synthesized in order to compare
their ability for ring expansion towards 3-pyrrolinones.
The synthesis of these small ring compounds involves a
[2+2]-cycloaddition of in situ generated dihalogenated
ketenes to substituted styrenes.12,13 In contrast to the
synthesis of 2,2-dibromocyclobutanone, which is a more
laborious and low yielding procedure, 2,2-dichloro-
cyclobutanones are readily obtained from commercially
S
O
N
H3C
N
1a (R = alkyl)
1b (R = aryl)
2 (R = alkyl)
3
Figure 1
SYNLETT 2004, No. 6, pp 1059–1063
Advanced online publication: 01.04.2004
DOI: 10.1055/s-2004-822900; Art ID: G02304ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
5.
2
0
0
4

1060
G. Verniest et al.
LETTER
9b–d as starting materials. In that way, various new 3-
aryl-4,4-dichlorobutanamides 10b–g were synthesized
from the corresponding cyclobutanones 9 in good yield
(Scheme 1).
O
NH
O
N
H3CO
Attempts to cyclize dichlorobutanamides 10 directly to
pyrrolinones by heating in toluene or DMSO yielded only
traces of pyrrolinone 12 after reflux for 15 hours
(Scheme 2). Also heating in aqueous 2 M HCl did not im-
prove the yield. When t-BuOK was used as a base no cy-
clization occurred, probably because the CH of the
CHCl2-moiety is more acidic than the NH of the amide,
resulting in side reactions. However, reaction of dichlo-
robutanamide 10b with 2 equivalents of 2 M NaOMe in
methanol at reflux temperature for 2 hours yielded a mix-
ture of compounds, among others N-isopropyl-4-meth-
oxy-3-phenyl-3-butenamide (13a; a mixture of the E- and
Z-isomer in a ratio 72:28). This enol ether was thought to
be a good substrate for ring closure towards pyrrolin-2-
ones and therefore, the reaction was optimized to yield a
maximum amount of compound 13a. After careful evalu-
ation of the reaction with various equivalents of NaOMe,
different concentrations, reaction times and temperatures,
a selective reaction towards 13a was accomplished with 4
4 Rolipram
5
R1
NH
R2
R3
6a Pyrrolnitrin (R1 = R3 = Cl, R2 = NO2)
6b Beret® (R1 = CN, R2 = R3 = Cl)
6c Saphire® (R1 = CN, R2,R3 = OCF2O)
Figure 2
available starting products. Both 2,2-dibromo-3-phenyl-
cyclobutanone (9a; X = Br) and 2,2-dichloro-3-phenyl-
cyclobutanone (9b; X = Cl) were treated with two
equivalents of isopropylamine to induce ring opening to-
wards 3-aryl-4,4-dihalo-N-isopropylbutanamides (10a,b;
Scheme 2).
When fewer equivalents of amine were used, longer reac- equivalents of 4 M sodium methoxide in methanol at re-
tion times were required and, as a consequence, more side flux temperature for 2 hours. In this way, several enol
products were formed which hamper the recrystallization ether derivatives 13 were synthesized in 82–97% yield
of the butanamides 10. The reaction of cyclobutanone 9b (Scheme 3). The obtained crystalline N-alkyl-4-methoxy-
with aniline did not result in a ring opening even when ap- 3-phenyl-3-butenamides (13) occurred in both the E- and
plying higher temperatures or more polar solvents like Z-isomers in ratios varying from 74:26 to 88:12. The
MeCN or DMSO. The ring opening of 3-phenyl-2,2- major E-isomer could be separated from the mixture by
dichlorocyclobutanone (9b) with isopropylamine pro- column chromatography, whereas the Z-minor isomer
ceeded in much higher yield as compared with 3-phenyl- could not be obtained as a pure isomer.
2,2-dibromocyclobutanone (9a).
O
O
NR2
Cl
X
NHR2
Cl
O
X
heating
O
X
X
or base
X
Cl
R1
8a X = Br
8b X = Cl
R1
R1
R1
9a X = Br, R1 = H (63%)
9b X = Cl, R1 = H (77%)
9c X = Cl, R1 = Cl (79%)
9d X = Cl, R1 = CH3 (69%)
7
11
10
4 equiv NaOMe
4 M in MeOH
∆, 2 h
- HCl,
isomerization
O
X
O
2 equiv R2NH2,
Et2O, r.t., 4–8 h
NHR2
X
O
NR2
NHR2
R1
R1
OCH3
R1
10a X = Br, R1 = H, R2 = i-Pr (52%)
10b X = Cl, R1 = H, R2 = i-Pr (70%)
10c X = Cl, R1 = Cl, R2 = i-Pr (56%)
10d X = Cl, R1 = CH3, R2 = i-Pr (62%)
10e X = Cl, R1 = H, R2 = Pr (72%)
10f X = Cl, R1 = H, R2 = c-Hex (64%)
10g X = Cl, R1 = H, R2 = Bn (58%)
12
13a R1 = H, R2 = i-Pr (91%) (E/Z 88/12)
13b R1 = Cl, R2 = i-Pr (97%) (E/Z 75/25)
13c R1 = CH3, R2 = i-Pr (93%) (E/Z 86/14)
13d R1 = H, R2 = Pr (96%) (E/Z 78/22)
13e R1 = H, R2 = c-Hex (96%) (E/Z 75/25)
13f R1 = H, R2 = Bn (82%) (E/Z 74/26)
Scheme 2
Scheme 3
Because of the difficult synthesis of dibromocyclo-
butanone 9a and the low yield of the ring opening product
10a, further elaboration towards various 3-pyrrolin-2-one
derivatives was carried out with dichlorocyclobutanones
To accomplish a ring closure of 4-methoxy-3-buten-
amides 13, the mixture of both stereoisomers of the enol
ethers were treated with an excess of aqueous 2 M HCl.
After protonation of the enol ether moiety, a nucleophilic
Synlett 2004, No. 6, 1059–1063 © Thieme Stuttgart · New York

LETTER
New Ring Expansion of Cyclobutanones
1061
H2 (4 bar), Pd-C (10%),
EtOH, 50 °C, 20 h
O
O
attack of the amide and subsequent elimination of
methoxide resulted in 4-pyrrolin-2-ones 14, which
isomerized spontaneously to the thermodynamically more
stable 3-pyrrolin-2-ones 15. The value of this reaction
pathway is reflected in the fact that both previous steps (9
to 10 and 10 to 13) proceed in high yield and that in fact
no purification is needed before the ring closure reaction.
With this new ring expansion procedure, several 3-pyrro-
lin-2-ones 15 were synthesized which offer good perspec-
tives for further ring transformations to physiologically
interesting pyrrolidinones, pyrrolidines and pyrroles
(Scheme 4).
NR2
NR2
R1
R1
16a R1 = H, R2 = i-Pr (68%)
16b R1 = Cl, R2 = i-Pr (73%)
16c R1 = CH3, R2 = i-Pr (68%)
16d R1 = H, R2 = Pr (69%)
16e R1 = H, R2 = Bn (74%)
15
1 equiv LiAlH4
Et2O, ∆, 4 h
NR2
R1
17a R1 = H, R2 = i-Pr (76%)
17b R1 = Cl, R2 = i-Pr (70%)
17c R1 = CH3, R2 = i-Pr (75%)
17d R1 = H, R2 = Pr (63%)
17e R1 = H, R2 = Bn (71%)
O
O
excess
NHR2
aq. 2 M HCl
NR2
∆, 2 h
OCH3
R1
R1
Scheme 5
13
14
O
O
O
4 equiv NaOMe
4 M in MeOH
2 equiv i-PrNH2
NH
Cl
NH
O
Cl
15a R1 = H, R2 = i-Pr (69%)
15b R1 = Cl, R2 = i-Pr (57%)
15c R1 = CH3, R2 = i-Pr (59%)
15d R1 = H, R2 = Pr (62%)
15e R1 = H, R2 = c-Hex (64%)
15f R1 = H, R2 = Bn (60%)
Et2O, r.t.,
∆, 2 h
n-Bu
n-Bu
Cl
15 h
n-Bu
NR2
Cl
OCH3
18
19 (100%)
R1
20 (90%), (E/Z: 7/3)
15
excess aq.
2 M HCl, ∆, 1.5 h
10 mol% Pd-C
EtOH, H2
(4 bar)
Scheme 4
O
N
O
N
As stated in the introduction, this is the first ring expan-
sion of cyclobutanones towards 3-pyrrolin-2-ones, which
are suitable synthons for further synthesis, and which
show important physiological activities.5–7
50 °C,
20 h
n-Bu
n-Bu
22 (82%)
21 (94%)
Scheme 6
1-Alkyl-4-aryl-3-pyrrolin-2-ones (15) were reduced with
hydrogen on palladium towards the saturated pyrrolidino-
nes 16 in good yield. Further reduction of pyrrolidinones
16 with LiAlH4 in diethyl ether under reflux for 4 hours
resulted in 3-arylpyrrolidines 17 in 63–76% yield
(Scheme 5). Both classes of compounds have been shown
to possess promising activities from a pharmaceutical and
agrochemical point of view. The novel synthetic pathway
presented here can be performed on a multigram scale and
provides various types of easily available five membered
azaheterocycles.
lo[3.3.1]nonane (9-BBN) was applied here to reduce 3-
pyrrolinones 15 to the corresponding 3-arylpyrroles 23.15
It should be underlined that reaction of 15 with other
hydride sources, e.g. LiAlH4, NaBH4 or BH3 did not yield
pyrroles at all. The best yields were obtained when pyr-
rolinones 15 were treated with 3 equivalents of 9-BBN in
toluene at reflux for 15 hours. This procedure provided
several new 1-alkyl-3-arylpyrroles 23, a class of com-
pounds which exhibit a wide range of agrochemical and
pharmacological properties (Scheme 7).
To expand the scope of the ring expansion, effords were
done to perform the reaction sequence with alkylcyclobu-
tanones (Scheme 6). Ring opening of 3-butyl-2,2-
dichlorocyclobutanone14 (18) with isopropylamine yield-
ed butanamide 19 in quantitative yield. Reaction of 19
with sodium methoxide resulted in enol ether 20 which
could be cyclized by treatment with aqueous HCl. The ob-
tained 4-butyl-3-pyrrolin-2-one (21) was reduced to pyr-
rolidinone 22. These high yielding reactions underline the
value of the conversion of cyclobutanones into pyrrolino-
nes and related heterocycles (Scheme 6).
In summary, a new ring expansion of 3-aryl-2,2-dihalocy-
clobutanones was developed towards 3-pyrrolin-2-ones in
three high yielding steps. These heterocycles are of partic-
ular importance due to their physiological properties and
their versatile reactivity. Selective reductions led to 3-
arylpyrrolidinones, pyrrolidines and pyrroles. This syn-
thetic protocol provides an easy and good yielding synthe-
sis of various interesting azaheterocyclic compounds.
4,4-Dichloro-N-isopropyl-3-phenylbutanamide (10b). To a solu-
tion of 5.00 g (23.25 mmol) 2,2-dichloro-3-phenylcyclobutanone
(9b) in 50 mL of Et2O was added a solution of 2.74 g (46.51 mmol,
2 equiv) isopropylamine in 50 mL of Et2O at 0 °C during 15 min.
The recently disclosed method to convert 3- and 4-pyrro-
lin-2-ones into pyrroles by the use of 9-borabicyc-
Synlett 2004, No. 6, 1059–1063 © Thieme Stuttgart · New York

1062
G. Verniest et al.
LETTER
After addition, cooling was stopped and the reaction mixture was
stirred at r.t. for 8 h. The resulting mixture was poored into 100 mL
of aq 0.5 M NaOH and extracted with Et2O (3 × 100 mL). The or-
ganic phase was dried (MgSO4), filtered and evaporated in vacuo
yielding 4,4-dichloro-N-isopropyl-3-phenylbutanamide (10b) as a
brown solid. Recrystallization (Et2O–hexane–CH2Cl2, 5:1:5); yield
NMR (CDCl3): d = 1.15 (d, J = 7.3 Hz, 3 H), 1.17 (d, J = 7.3 Hz, 3
H), 2.57 and 2.82 (2 × dd, J = 16.8 Hz, 8.9 Hz and 8.3 Hz, 2 H), 3.31
and 3.73 (2 × dd, J = 9.5 Hz, 8.1 Hz and 7.9 Hz, 2 H), 3.53 (m, 1 H),
4.45 (m, 1 H), 7.21–7.37 (m, 5 H). 13C NMR (CDCl3): d = 19.7,
19.9, 37.3, 39.5, 42.5, 49.2, 2 × 126.7, 127.0, 2 × 128.9, 142.7,
173.0. IR (NaCl): 1675, 1601, 1489 cm–1. MS: m/z (%) = 203 (46)
[M+], 189 (23), 188 (100), 117 (25), 104 (74), 91 (31), 56 (25), 43
(25). (16d,e: known compounds)18,19
1
70%, mp 97–98 °C. H NMR (CDCl3): d = 0.91 and 1.07 (2 × d,
J = 6.6 Hz, 6 H), 2.65 and 2.93 (2 × dd, J = 14.5 Hz, 8.6 Hz and 5.9
Hz, 2 H), 3.85–3.94 (m, 1 H), 3.94 (sept, J = 6.6 Hz, 1 H), 5.25 [(s
(b), 1 H], 6.07 (d, J = 4.6 Hz, 1 H), 7.27–7.38 (m, 5 H). 13C NMR
(CDCl3): d = 2 × 22.5, 38.4, 41.4, 52.2, 76.3, 128.0, 2 × 128.4,
2 × 129.0, 137.6, 169.0. IR (KBr): 3342, 1647, 1535 cm–1. MS: m/z
(%) = no M+, 238/240 (12), 202 (100), 115 (15), 101 (18), 86 (48),
69 (42).
1-Isopropyl-3-phenylpyrrolidine (17a). Pyrrolidin-2-one 16a
(0.10 g, 0.49 mmol) was dissolved in 5 mL of dry diethyl ether. To
this mixture 0.02 g (0.52 mmol; 1.05 equiv) LiAlH4 was added at
0 °C. After the addition, the mixture was refluxed for 4 hours and
subsequently quenched with ice-water. Extraction with 3 × 5 mL of
Et2O and drying of the extract (MgSO4) yielded 0.08 g of pyrroli-
dine 17a after removal of the solvent. Purification was performed
with column chromatography (CH2Cl2–MeOH–Et3N, 90:9:1,
(E)-N-Isopropyl-4-methoxy-3-phenyl-3-butenamide (13a). To
1.10 g (4.01 mmol) of butanamide 10b was added 4.0 mL of 4 M
NaOMe in MeOH. After 2 h of reflux, the mixture was poored into
H2O and extracted three times with CH2Cl2. Drying of the extract
(MgSO4), filtration and evaporation of the solvent resulted in bute-
namide 13a as a dark brown solid (E/Z 88:12, yield 0.85 g, 91%),
which could be easily recrystallized from EtOAc or chromato-
graphed on column to yield the pure E-isomer (hexane–EtOAc, 1:1,
Rf = 0.35); yield 0.56 g (60%), mp 106–108 °C. 1H NMR (CDCl3):
d = 1.04 (d, J = 6.6 Hz, 6 H), 3.38 (s, 2 H), 3.78 (s, 3 H), 4.02 (sept,
J = 6.6 Hz, 1 H), 5.70 [s (b), 1 H], 6.59 (s, 1 H), 7.26–7.32 (m, 5 H).
13C NMR (CDCl3): d = 2 × 22.6, 36.2, 41.2, 60.2, 113.9, 2 × 125.2,
126.5, 2 × 128.7, 138.4, 147.3, 170.1. IR (KBr): 3380, 1675, 1520
cm–1. MS: m/z (%) = 233 (62) [M+], 148 (100), 147 (35), 117 (35),
43 (60).
1
Rf = 0.28); yield 0.07 g (76%). H NMR (CDCl3): d = 1.14 (d,
J = 6.3 Hz, 3 H), 1.15 (d, J = 6.3 Hz, 3 H), 1.84–1.97 (m, 1 H),
2.26–2.40 (m, 1 H), 2.47 (m, 1 H), 2.48 and 3.25 (2 × dd, J = 9.2 Hz,
8.9 Hz and 8.3 Hz, 2 H), 2.67 and 3.02 (2 × dt, J = 9.2 Hz, 7.9 Hz
and 6.2 Hz, 2 H), 3.39 (quint, J = 8.6 Hz, 1 H), 7.17–7.33 (m, 5 H).
13C NMR (CDCl3): d = 21.4, 21.5, 32.9, 43.5, 52.3, 55.2, 59.9,
126.3, 2 × 127.3, 2 × 128.4, 144.4. IR (NaCl): 1605, 1498, 1457
cm–1. MS: m/z (%) = 189 (M+, 9), 175 (13), 174 (100), 131 (20), 91
(15), 56 (15), 43 (35). (17d,e: known compounds)20,21
1-Isopropyl-3-phenylpyrrole (23a). To a solution of 1.00 g (5.00
mmol) 3-pyrrolin-2-one 15a in 5 mL of dry toluene was added 3
equiv (1.80 g, 15.00 mmol) of 9-borabicyclo[3.3.1]nonane as a sol-
id dimer. The mixture was refluxed for 15 h and subsequently
poured in 25 mL of H2O. Extraction with Et2O (3 × 25 mL), drying
(MgSO4) and evaporation of the solvents in vacuo afforded pyrrole
23a, which was purified by column chromatography (EtOAc–hex-
ane, 95:5 Rf = 0.25); yield 0.37 g (40%). 1H NMR (CDCl3): d = 1.47
(d, J = 6.6 Hz, 6 H), 4.23 (sept, J = 6.6 Hz, 1 H), 6.44 (dd, J = 2.8
Hz and 2.0 Hz, 1 H), 6.73 (dd, 2.8 Hz and 2.3 Hz, 1 H), 7.02 (dd,
J = 2.3 Hz and 2.0 Hz, 1 H), 7.10–7.16 (m, 1 H), 7.28–7.33 (m, 2
H), 7.49–7.52 (m, 2 H). 13C NMR (CDCl3): d = 2 × 23.9, 51.0,
105.7, 115.1, 119.2, 2 × 124.9, 125.1, 2 × 128.5, 130.9, 136.1. IR
(NaCl): 1602, 1545, 1483 cm–1. MS: m/z (%) = 185 (100) [M+], 170
(84), 143 (81), 115 (46), 105 (32), 43 (21). (23d,e: known com-
pounds)22,23
1-Isopropyl-4-phenyl-3-pyrrolin-2-one (15a). To 2.00 g (8.6
mmol) of 13a was added an excess (25 mL) of an aq 2 M HCl solu-
tion. The suspension was refluxed for 2 h. After cooling, the acidic
mixture was three times extracted with CH2Cl2. Drying of the ex-
tract (MgSO4) and evaporation of the solvent resulted in 1.60 g of
crystalline pyrrolin-2-one 15a. Purification was performed with
column chromatography (EtOAc–hexane, 1:1, Rf = 0.17); yield
1.20 g (69%), mp 75–77 °C (no literature data). 1H NMR, 13C NMR
and MS spectroscopic data were in accordance with literature data
(IR spectroscopic data were not reported).16 IR (KBr): 1655, 1462
cm–1. (15e,f: known compounds).17
1-Isopropyl-4-phenylpyrrolidin-2-one (16a). A solution of 0.93 g
(4.6 mmol) of 3-pyrrolin-2-one 15a and 0.10 g (ca. 10%) of palla-
dium on carbon in 10 mL of dry MeOH, was stirred under H2 atmo-
sphere (4 bar) at 50 °C for 20 h. After filtration over Celite®, the
solvent was removed by evaporation in vacuo, leaving 0.70 g of
pyrrolidinone 16a. A purification by Kugelrohr destillation (bp
108–112 °C/0.15 mmHg) yielded 0.64 g (68%) of pure product. 1H
Acknowledgment
The authors are indebted to the IWT (Flemish Institute for the Pro-
motion of Scientific-Technological Research in Industry), the
FWO-Flanders and Ghent University (GOA) for financial support.
O
3 equiv 9-BBN
toluene, ∆, 15 h
References
NR2
NR2
(1) (a) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988,
27, 797. (b) Nemoto, H.; Fukumoto, K. Synlett 1996, 863.
(2) (a) Conia, J. M.; Salaun, J. R. Acc. Chem. Res. 1972, 5, 33.
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Braz. Chem. Soc. 1996, 7, 371. (c) Mazzini, C.; Lebreton,
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S. J. Org. Chem. 1999, 64, 3306. (f) Brown, R. C. D.; Keily,
J.; Karim, R. Tetrahedron Lett. 2000, 41, 3247.
R1
R1
15
23a R1 = H, R2 = i-Pr (40%)
23b R1 = Cl, R2 = i-Pr (51%)
23c R1 = CH3, R2 = i-Pr (52%)
23d R1 = H, R2 = c-Hex (56%)
23e R1 = H, R2 = Bn (61%)
Scheme 7
Synlett 2004, No. 6, 1059–1063 © Thieme Stuttgart · New York

LETTER
New Ring Expansion of Cyclobutanones
1063
(3) (a) Honda, T.; Kimura, N.; Sato, S.; Kato, D.; Tominaga, H.
J. Chem. Soc., Perkin Trans. 1 1994, 1043. (b) de Mattos,
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