A convenient synthesis of 2,2-diarylcyclobutanones by cerium(IV) ammonium nitrate (CAN) mediated oxidation of methylenecyclopropanes (MCPs)

Article abstract of DOI:10.1055/s-2006-942445

Oxidative ring expansion of methylenecyclopropanes with CAN under oxygen atmosphere was investigated. A facile conversion affording 2,2- diarylcyclobutanones occurred in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942445

PAPER
2531
A Convenient Synthesis of 2,2-Diarylcyclobutanones by Cerium(IV) Ammoni-
um Nitrate (CAN) Mediated Oxidation of Methylenecyclopropanes (MCPs)
O
xidative Ring Ex
i
pansio
jaPs y Nair,* T. D. Suja, Kishor Mohanan
Organic Chemistry Section, Regional Research Laboratory (CSIR), 695019 Trivandrum, India
Fax +91(471)2491712; E-mail: vijaynair_2001@yahoo.com
Received 15 March 2006
tron oxidation of MCPs. This work has led to a synthesis
of 2,2-diarylcyclobutanones and the results are presented
here.
Abstract: Oxidative ring expansion of methylenecyclopropanes
with CAN under oxygen atmosphere was investigated. A facile con-
version affording 2,2-diarylcyclobutanones occurred in good
yields.
Our studies commenced with exposing 2,2-ditolylmethyl-
Key words: CAN, methylenecyclopropane, cyclobutanone, oxy- enecyclopropane (1a)13 to a solution of CAN in methanol
gen, oxidative ring expansion
under argon. Chromatographic separation of the reaction
mixture afforded 2,2-ditolylcyclobutanone (2a) albeit
only in 15% yield. With the assumption that the carbonyl
oxygen originated from the adventitious oxygen present-
ed in the argon, we reinvestigated the reaction under oxy-
gen atmosphere. In this experiment cyclobutanone 2a was
formed in 80% yield from 1a (Scheme 1). The cyclobu-
tanone 2a was characterized on the basis of spectroscopic
data which was completely identical with those reported
for the authentic cyclobutanone.8,14
A number of cyclobutane derivatives are known to be bio-
logically active,1 an example being the antidepressant ac-
tivity
of
certain
3,3-diphenylcyclobutylamine
derivatives.2 In view of this, synthesis of cyclobutane de-
rivatives, like cyclobutanones assumes importance. Only
a handful of general methods are available for the synthe-
sis of cyclobutanones,3 which include [2+2] cycloaddition
of olefins to ketenes or ketene equivalents,4 ring enlarge-
ment of bicyclooxapentanes,5a cyclopropylsilyl enol
ethers,5b and cyclopropanones,5c and a TiCl4–Et3N medi-
ated reaction of diaryl ketones with iminium ions generat-
ed by the oxidation of diisopropylbenzylamine using
iodine.5d
Me
Me
O
CAN, MeOH
O2, r.t., 80%
Methylenecyclopropanes (MCPs) constitute a unique
class of four-carbon synthons exhibiting a multitude of re-
activity patterns.6 The transition metal mediated reactions
of MCPs have been well studied.7 We surmised that
MCPs are well suited for ring enlargement reactions, pos-
sibly delivering cyclobutanones under oxidative condi-
tions. A recent report by Shao and Shi indeed described
the Lewis acid assisted ring expansion reaction of MCPs
in presence of azodicarboxylates to furnish cyclobutanone
derivatives.8 However, the strategy of subjecting MCPs to
a one-electron oxidation reaction to generate a radical cat-
ion susceptible for ring expansion has received only lim-
ited attention.9 In recent years, work in our laboratory and
elsewhere has shown that cerium(IV) ammonium nitrate
(CAN) is a useful reagent for oxidative single-electron-
transfer processes10 leading to a number of novel carbon–
carbon and carbon–heteroatom bond-forming reactions.11
In addition, a number of CAN-mediated transformations
of strained hydrocarbons possessing cyclopropane and
cyclobutane rings, including a number of monoterpenes,
have been reported.12 In this context, it was of interest to
investigate the use of CAN as a reagent for the one-elec-
Me
Me
1a
2a
Scheme 1
To examine the scope of the reaction, a number of diaryl-
substituted MCPs were subjected to oxidative ring expan-
sion under identical conditions. In all cases cyclobu-
tanones were obtained in good yields; the results are
summarized in Table 1.
A mechanistic postulate for the reaction may be outlined
as follows. The initial event is likely to be the single-elec-
tron oxidation of MCP 1a by CAN to furnish radical cat-
ion 3. It is reasonable to assume that the radical centre of
the latter gets converted to hydroperoxide 4 by trapping
molecular oxygen followed by hydrogen abstraction from
methanol. The cationic site may be quenched by nitrate
from CAN to form the intermediate 5. The decomposition
of hydroperoxide to alkoxy radical and its reduction by
Ce(III) with the latter undergoing oxidation to Ce(IV) can
deliver the alkoxide 6. Rearrangement of the alkoxide 6
with the elimination of nitrate will complete the sequence
of reactions leading to product 2a (Scheme 2). It may be
mentioned that the key steps in the mechanistic pathway
outlined here are precedented in our earlier work.15,16
SYNTHESIS 2006, No. 15, pp 2531–2534
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942445; Art ID: Z05206SS
© Georg Thieme Verlag Stuttgart · New York

2532
V. Nair et al.
PAPER
Table 1 CAN-Mediated Reaction of Diarylmethylenecyclopro-
panes with Oxygen and Methanol
O
OMe
CAN, MeOH, O2
r.t., 4 h, 50%
O
R1
CAN, MeOH, O2
R1
r.t., 4 h
R2
7
8
R2
Scheme 3
Entry
R1
R2
Product
2b
Yield (%)
1
2
3
4
5
6
7
Ph
Ph
75
62
82
73
78
57
48
ing point apparatus and are uncorrected. High-resolution mass spec-
tra were recorded under EI/HRMS (at 5000 resolution) using JEOL
JMS 600H mass spectrometer. Gravity column chromatography
was performed on silica gel (100–200 mesh) in hexanes-EtOAc
mixtures as eluent. Solvents were distilled prior to use. CAN used
for the reactions was purchased from Aldrich Co. and was used
without purification. Diarylmethylenecyclopropanes used were pre-
pared from corresponding benzophenones according to the litera-
ture procedure.13
Ph
2-MeC6H4
4-MeC6H4
1-naphthyl
2-naphthyl
4-ClC6H4
2c
Ph
2d
Ph
2e
Ph
2f
4-ClC6H4
2g
Diarylcyclobutanones; General Procedure
4-MeOC6H4 Ph
2h
A solution of CAN (1.26 g, 2.3 mmol) in anhyd MeOH (20 mL),
saturated with O2 was added dropwise to an oxygenated solution of
MCP 1 (1 mmol) in MeOH (10 ml) at r.t. The mixture was stirred
for 4 h. It was then diluted with H2O and extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were washed with
brine and dried (Na2SO4). The residue obtained was subjected to
column chromatography on silica gel using hexanes–EtOAc mix-
ture (95:5) to afford pure product.
Interestingly, CAN-mediated reaction of the monosubsti-
tuted MCP 7 afforded methoxy-substituted aryl cyclopro-
pyl ketone 8 along with a trace amount of cyclobutanone
(Scheme 3). In this case, molecular oxygen presumably
reacts at the benzylic site of the radical cation formed
from 7.15 This may be attributed to the fact that the ben-
zylic position of the radical cation is less sterically hin-
dered when compared to the radical cations formed from
diarylmethylenecyclopropanes.
2a
Colorless viscous oil.
IR (neat): 1780, 1649, 1606, 1512, 1220, 1080 cm–1.
1H NMR: d = 2.28 (s, 6 H), 2.77 (t, J = 8.4 Hz, 2 H), 3.13 (t, J = 8.4
Hz, 2 H), 7.22 (d, J = 8.1 Hz, 4 H), 7.83 (d, J = 8.1 Hz, 4 H).
13C NMR: d = 21.3, 21.9, 25.9, 43.5, 75.9, 126.6, 129.1, 129.6,
130.5, 135.6, 136.6, 139.6, 142.9, 208.9.
In conclusion, we have uncovered an efficient CAN-me-
diated oxidative transformation of MCPs leading to the
formation of cyclobutanones. The reaction may be of in-
terest both from the mechanistic and synthetic stand- HRMS (EI): m/z calcd for C18H18O: 250.1358; found: 250.1368.
points.
2b
Colorless viscous oil.
NMR spectra were recorded in CDCl3 at 300 (1H) and 75 (13C) MHz
IR (neat): 3021, 1780, 1605, 1491, 1450, 1404, 1188, 1079 cm–1.
on a Bruker 300 MHz FT-NMR spectrometer. Chemical shifts (d)
1H NMR: d = 2.80 (t, J = 8.4 Hz, 2 H), 3.12 (t, J = 8.4 Hz, 2 H),
7.15–7.36 (m, 10 H).
are reported relative to TMS (1H) and CDCl3 (13C) as the internal
standards. IR spectra were recorded on Bomem MB Series FT-IR
spectrophotometer. Melting points were recorded on a Büchi melt-
HO
O
–ONO2
Ce (IV)
O2
.
+
MeOH
1a
3
4
O
O
HO
O
Ce (III)
Ce (IV)
ONO2
ONO2
6
5
2a
Scheme 2
Synthesis 2006, No. 15, 2531–2534 © Thieme Stuttgart · New York

PAPER
Oxidative Ring Expansion of MCPs
2533
13C NMR: d = 25.7, 43.3, 76.2, 126.4, 126.9, 128.7, 142.1, 207.8.
HRMS (EI): m/z calcd for C16H14O: 222.1045; found: 222.1057.
8
Yellow viscous liquid.
IR (neat): 3063, 1689, 1571, 1510 cm–1.
2c
1H NMR: d = 1.26 (dd, J = 4.2, 8.1 Hz, 2 H), 1.48 (dd, J = 4.2, 8.1
Colorless viscous oil.
IR (neat): 2931, 1780, 1605, 1583, 1478 cm–1.
1H NMR: d = 2.03 (s, 3 H), 2.52–2.59 (m, 1 H), 3.01–3.24 (m, 3 H),
7.14–7.64 (m, 9 H).
13C NMR: d = 21.2, 24.6, 42.8, 76.5, 125.7, 126.4, 126.7, 126.8,
127.5, 128.6, 132.2, 136.2, 138.9, 140.3, 207.7.
Hz, 2 H), 3.19 (s, 3 H), 7.25–8.33 (m, 7 H).
13C NMR: d = 16.5, 57.2, 69.2, 125.1, 126.5, 127.8, 128.1, 128.2,
129.8, 130.9, 135.5, 198.8.
HRMS (EI): m/z calcd for C15H14O2: 226.0994; found: 226.0984.
Acknowledgment
HRMS (EI): m/z calcd for C17H16O: 236.1201; found: 236.1222.
T.D.S. and K.M. thank the Council of Scientific and Industrial Re-
search, Government of India for research fellowships, Mrs. Soumini
Mathew for NMR spectra and Mrs. S. Viji for HRMS data.
2d
Colorless viscous oil.
IR (neat): 1780, 1604, 1591, 1423 cm–1.
1H NMR: d = 2.31 (s, 3 H), 2.79 (t, J = 8.7 Hz, 2 H), 3.13 (t, J = 8.7
Hz, 2 H), 7.07–7.35 (m, 9 H).
References
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13C NMR: d = 21.0, 25.6, 43.3, 75.9, 126.2, 126.3, 126.8, 128.6,
129.4, 136.4, 139.2, 142.3, 208.5.
HRMS (EI): m/z calcd for C17H16O: 236.1201; found: 236.1233.
2e
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Colorless viscous oil.
IR (neat): 1778, 1605, 1510, 1421, 1220 cm–1.
1H NMR: d = 2.67–2.75 (m, 1 H), 3.21–3.37 (m, 3 H), 7.15–7.89 (m,
12 H).
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126.9, 127.2, 128.7, 129.1, 131.8, 132.3, 133.3, 134.9, 139.4, 207.8.
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HRMS (EI): m/z calcd for C20H16O: 272.1201; found: 272.1201.
2f
Colorless viscous oil.
IR (neat): 1778, 1605, 1591, 1510, 1421 cm–1.
1H NMR: d = 2.88 (t, J = 8.4 Hz, 2 H), 3.21 (t, J = 8.7 Hz, 2 H),
7.24–7.93 (m, 12 H).
13C NMR: d = 25.6, 43.5, 76.3, 115.7, 124.2, 125.5, 125.7, 126.4,
126.9, 127.7, 128.7, 129.1, 130.3, 130.4, 135.2, 137.2, 139.5, 208.4.
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HRMS (EI): m/z calcd for C20H16O: 272.1201; found: 272.1201.
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2g
Colorless solid.
Mp 98–99 °C.
IR (KBr): 1780, 1651, 1489, 1400, 1088 cm–1.
1H NMR: d = 2.78 (t, J = 8.4 Hz, 2 H), 3.18 (t, J = 8.4 Hz, 2 H),
7.26–7.27 (m, 8 H).
13C NMR: d = 25.7, 43.5, 74.9, 127.6, 129.0, 133.2, 140.1, 207.1.
HRMS (FAB, [M + H]): m/z calcd for C16H12Cl2O: 291.02; found:
291.02.
2h
Colorless viscous oil.
IR (neat): 3063, 2988, 1776, 1645, 1600, 1515 cm–1.
1H NMR: d = 2.82 (t, J = 8.4 Hz, 2 H), 3.14 (t, J = 8.4 Hz, 2 H), 3.75
(s, 3 H), 6.80–7.34 (m, 9 H).
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128.7, 138.4, 142.4, 158.4, 208.6.
HRMS (EI): m/z calcd for C17H16O2: 252.1150; found: 252.1140.
Synthesis 2006, No. 15, 2531–2534 © Thieme Stuttgart · New York

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V. Nair et al.
PAPER
elsewhere,15,16 it is strongly felt that the mechanistic
(14) While this manuscript was under completion, Chen et al.
reported the synthesis of 2,2-diarylcyclobutanones using the
CAN-mediated reaction of MCPs in MeOH–THF–H2O
mixture: Chen, W.; Huang, X.; Zhou, H.; Ren, L. Synthesis
2006, 609A. Comparison of the results reveals that our
reactions afford about 25–30% higher yields of the products.
In addition, on the basis of work in our laboratory and
postulate of Chen et al. is untenable.
(15) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem.
Res. 2004, 37, 21; and references cited therein.
(16) Rossle, M.; Wermer, T.; Frey, W.; Christoffers, J. Eur. J.
Org. Chem. 2005, 5031; and references cited therein.
Synthesis 2006, No. 15, 2531–2534 © Thieme Stuttgart · New York