Synthesis of γ-halogenated ketones via the Ce(IV)-mediated oxidative coupling of cyclobutanols and inorganic halides

Article abstract of DOI:10.1016/j.tetlet.2008.12.114

A straightforward method for the synthesis of γ-halo-substituted ketones formed via the CAN-initiated oxidative addition of halides to 1-substituted cyclobutanols has been developed. This method has short reaction times, and provides access to a range of bromo and iodo γ-substituted ketones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.12.114

Tetrahedron Letters 50 (2009) 1264–1266
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of
c-halogenated ketones via the Ce(IV)-mediated oxidative
coupling of cyclobutanols and inorganic halides
*
Brian M. Casey, Cynthia A. Eakin, Robert A. Flowers II
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward method for the synthesis of c-halo-substituted ketones formed via the CAN-initiated
oxidative addition of halides to 1-substituted cyclobutanols has been developed. This method has short
Received 19 September 2008
Revised 14 December 2008
Accepted 22 December 2008
Available online 9 January 2009
reaction times, and provides access to a range of bromo and iodo
c
-substituted ketones in good to excel-
lent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CAN
Cyclobutanol
c
-Substituted ketone
Oxidative coupling
1. Introduction
Cerium(IV) reagents, namely cerium(IV) ammonium nitrate
(CAN), have been used extensively by organic chemists as single-
electron oxidants.6 CAN has proven to be a cost-effective, versatile
reagent that is capable of mediating novel carbon–carbon and car-
bon–heteroatom bonds.7,8 Previous research from our group has
shown that b-substituted ketones are accessible through the use
of CAN.9 By selectively oxidizing an inorganic anion in the pres-
ence of a 1-substituted cyclopropanol with CAN, the generated
inorganic radical was added to the cyclopropanol resulting in ring
opening. After a subsequent oxidation of the radical intermediate
and deprotonation, b-substituted ketones were produced in very
good to excellent yields. In addition to quick reaction times, these
reactions worked for both 1-aryl- and 1-alkyl-cyclopropanols as
well as a variety of inorganic anions. Based on this precedent,
we sought to examine whether this method could be extended
Ketones with
c
-halo substitutions are useful starting materials
-substi-
tuted ketone moieties in neurological agents such as spiperidol
and haldol (Fig. 1) are incorporated by utilizing -chloro ketones
in particular as starting materials.1,2 Ketones with
-chloro substi-
for the synthesis of biologically active compounds. The
c
c
c
tutions have been used also in the synthesis of antagonists for the
melanin-concentrating hormone (MCH1) receptor.3 The ability to
efficiently generate starting materials containing
subunits has the potential to greatly impact the synthesis of novel,
pharmaceutically active compounds.
c-halo ketone
Although
porated into molecules traditionally through
use of other -halo ketones such as -iodo or bromo ketones may
c
-substituted ketone functionalities have been incor-
c
-chloro ketones, the
c
c
be synthetically beneficial since these halides are better leaving
to 1-substituted cyclobutanols thereby providing access to c-
groups than chloride. However, the synthetic approaches to struc-
substituted ketones. The results of these studies are presented
turally diverse
of synthetic routes for
there is no general method for producing
aryl- and aliphatic -chloro ketones can be synthesized via Fri-
edel–Crafts or Grignard reactions.4 Typically,
-iodo and bromo ke-
tones are produced by refluxing -chloro ketones in the presence
c
-halo ketones have been limited to only a handful
-chloro and a few -bromo ketones. While
-chloro ketones, both
herein.
c
c
c
c
c
c
of either iodide or bromide. While useful, these conversions typi-
cally require long reaction times and superstoichiometric amounts
of the desired halide.5 The development of a general and direct
OH
N
NH
O
Cl
O
N
N
O
route to c-iodo and bromo ketones would be of interest.
F
A
F
B
* Corresponding author. Tel.: +1 610 758 4048.
E-mail address: rof2@lehigh.edu (R.A. Flowers).
Figure 1. Structures of spiperidol (A) and haldol (B).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.114

B. M. Casey et al. / Tetrahedron Letters 50 (2009) 1264–1266
1265
Table 2
Synthesis of
2. Results and discussion
c
-bromo ketones15
To examine the breadth of c-substituted compounds that could
O
R'
2eq CAN
50% H2O:CH2Cl2
be achieved from the oxidation of inorganic anions with CAN, both
1-aryl- and 1-alkyl-cyclobutanols were synthesized. These starting
materials were generated via the reaction of cyclobutanone, or 2-
ethyl-cyclobutanone for 1f, with a variety of Grignard reagents.10,11
The reactions produced acceptable product yields, and were puri-
fied by nonchromatographic methods. The 1-phenyl-cyclobutanol
(1a) was purified by recrystallization from n-pentane at reduced
temperature (ꢀ20 °C). Substrates 1c,f were synthesized quantita-
tively and required no additional purification. For all other starting
materials (1b,d and e), short-path distillations at reduced pressure
were used to purify gram quantities of the desired compounds.
In an initial study, sodium iodide (NaI) was oxidized with CAN
in the presence of substrate 1a using reaction conditions [20%
H2O/acetonitrile (MeCN)] previously employed for the oxidative
addition of inorganic anions to 1-substituted cyclopropanols.9
+
KBr
Br
R
OH
R
1a-f
3a-f
R'
Substrate
Product
R
R0
Yield (%)
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
Ph
H
H
H
H
H
Et
87a
70a
95a
NDb
NDb
37c
p-CH3O-Ph
p-F-Ph
Cyclohexyl
n-hexyl
p-F-Ph
a
Isolated yield.
b
Mixture of 1-alkyl-cyclobutanol,
ketones.
c-bromo ketone and a,c-dibrominated
Determined by 1H NMR.
c
While c-iodo ketone 2a was generated as the major product, multi-
NMR data showed that brominations of 1d–e resulted in a mixture
ple side products were observed by 1H NMR analysis of the crude
reaction mixture. Since changes in solvent often times can impact
the chemoselectivity of reactions initiated by CAN, several solvent
systems were examined to determine if the reaction yield could be
improved.12 Among the solvent systems screened, 1H NMR analysis
showed that 20% H2O/1,2-dimethoxyethane (DME) generated 2a
almost exclusively. As a result, this solvent system was utilized
of starting material, desired
ketones.
c-bromo ketone and a,c-dibrominated
The presence of
a-brominated products suggests formation of
molecular bromine during the course of the reaction. A series of
experiments were performed to determine if this supposition
was correct (Table 3). Ketone 4 was used in these experiments
since it is structurally similar to the starting material 1d and prod-
uct 3d. Initially, 1 equiv of 4 was reacted with 0.5 equiv of molec-
ular bromine (entry 1). In a subsequent experiment, substrate 4
was reacted with an equivalent of both CAN and KBr, which should
generate an equal amount of molecular bromine if bromine atom
homocoupling occurs following oxidation. Experiments contained
in entries 1 and 2 show identical ratios of 5:4, a finding consistent
with in situ formation of molecular bromine. Interestingly, the
yield of 5 was increased by the addition of excess CAN (entry 3),
an observation which is indicative of a larger mechanistic role of
cerium beyond oxidation, presumably through Lewis acid
activation.
for the other unsubstituted substrates. As shown in Table 1, c-iodo
ketones 2a–e were obtained in good to very good isolated yields
for both 1-aryl- and 1-alkyl-cyclobutanols.
To examine the regioselectivity of the ring opening, 1f was sub-
jected to the same reaction conditions. While product 2f was formed
exclusively, the reaction mixture contained unreacted starting
material. After scanning a series of solvent and reaction conditions,
optimal yields of 2f were obtained in 20% H2O/MeCN at 0 °C.
Next, the synthesis of c-bromo ketones was examined. In previ-
ous work on the synthesis of b-substituted ketones, the oxidation
of bromide anion by CAN was shown to be relatively slow com-
pared to the oxidation of iodide. In order to avoid the possibility
of direct oxidation of 1a–f by CAN, these brominations were per-
formed in a two-phase solvent system of 50% H2O/methylene chlo-
ride (CH2Cl2).14 In an initial experiment, the bromination of 1a
using potassium bromide (KBr) as the bromide anion source pro-
vided 3a in an 87% isolated yield (Table 2). Under similar experi-
mental conditions, the bromination of aryl substrates 1b–c
produced 3b–c in good to excellent yields. While complete conver-
sion to 3f was not achieved even at reduced temperatures, bromin-
ation of 1f exhibited the same regioselectivity as the iodination.
Surprisingly, reactions of 1-alkyl-cyclobutanols 1d–e produced
3d–e in yields of less than 20%. Examination of GC–MS and 1H
From the data obtained, the mechanistic pathway shown in
Scheme 1 is proposed. Initially, bromine anion is oxidized by
CAN to bromine radical, which adds to the 1-substituted cyclobu-
tanol 1d. Bromine atom addition to cyclobutanols is supported by
the observation that no
c-substituted products were obtained
when 1d was treated with molecular bromine. The intermediate
1d0 generated from the ring opening of 1d is less stable than the
corresponding benzylic radicals of 1-aryl-cyclobutanols 1a–c. As
a result, 1-alkyl-cyclobutanols are expected to be less reactive
allowing homocoupling of bromine atoms to become a competitive
pathway. Following a second oxidation by CAN of 1d0 and deproto-
nation, molecular bromine adds
a
to the carbonyl of 3d producing
the
a,c
-dibrominated ketone 3d0.
Table 1
Synthesis of
c
-iodo ketones13
Table 3
O
a
-Bromination of aliphatic substrates
R'
2eq CAN
20% H2O:DME
+
NaI
O
O
I
R
OH
B
r
R
1a-f
2a-f
R'
Substrate
Product
R
R0
Yielda (%)
4
5
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2fb
Ph
H
H
H
H
H
Et
79
67
79
64
80
80
p-CH3O-Ph
p-F-Ph
Cyclohexyl
n-hexyl
p-F-Ph
Entry
Conditionsa
Ratio (5:4)b
1
2
3
4 (0.33 mmol), Br2 (0.17 mmol)
4 (0.33 mmol), KBr (0.33 mmol), CAN (0.66 mmol)
4 (0.33 mmol), KBr (0.33 mmol), CAN (0.83 mmol)
3:1
3:1
9:1
a
a
Isolated yield.
Conditions: Reaction run at 0 °C in 20% H2O/MeCN.
50% H2O/CH2Cl2.
Ratios determined by GC.
b
b

1266
B. M. Casey et al. / Tetrahedron Letters 50 (2009) 1264–1266
ketones that can be used as starting materials for the synthesis
of more complex compounds containing c-substituted ketones.
OH
+
+
Br
Br CAN
Br
OH
1d
1d'
Acknowledgement
+
Br
Br
CAN
-(H+)
R.A.F. is grateful to the National Institutes of Health
(1R15GM075960-01) for support of this work.
O
O
Br
Br2
-(HBr)
Br
Br
Supplementary data
3d'
3d
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.114.
Scheme 1. Proposed pathway to dibrominated ketones.
References and notes
Since bromination was only successful in the case of 1-aryl-
substituted cyclobutanols, other oxidants were examined to deter-
mine whether the desired products could be obtained. Iodinations
and brominations with NaI and KBr were performed with Cu-
ClO4ꢁ6H2O in MeCN.16 However, only a complex mixture of reac-
1. van Winjngaarden, I.; Kruse, C. G.; van der Heyden, J. A. M.; Tulip, M. Th. M. J.
Med. Chem. 1988, 31, 1934.
2. Iorio, M. A.; Paszkowska Reymer, T.; Frigeni, V. J. Med. Chem. 1987, 30, 1906.
3. Chen, C-A.; Jiang, Y.; Lu, K.; Daniewska, I.; Mazza, C. G.; Negron, L.; Forray, C.;
Parola, T.; Li, B.; Hegde, L. G.; Wolinksy, T. D.; Craig, D. A.; Kong, R.; Wetzel, J.
M.; Andersen, K.; Marzabadi, M. R. J. Med. Chem. 2007, 50, 3883.
4. Uchida, M.; Komatsu, M.; Morita, S.; Kanbe, T.; Yamasaki, K.; Nakagawa, K.
Chem. Pharm. Bull. 1989, 37, 958.
5. Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726.
tions products was obtained, none being the
c-haloketone. The
use of ferrocenium hexafluorophosphate in CH2Cl2 provided only
unreacted starting material in all cases.17
6. (a) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862; (b) Nair, V.; Balagopal, L.;
Rajan, R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21; (c) Nair, V.; Panicker, S. B.;
Nair, L. G.; George, T. G.; Augustine, A. Synlett 2003, 156; (d) Molander, G. A.
Chem. Rev. 1992, 92, 29.
Due to the rapid evolution and applications of ‘click chemistry’,
direct routes to incorporation of azide into molecules would be
very useful in synthesis. The extension of this approach to the
oxidative addition of azide to 1-substituted cyclobutanols was
examined. Unfortunately, oxidative addition of azide anions to 1-
substituted-cyclobutanols has been disappointing thus far. When
1 equiv of sodium azide (NaN3) was oxidized by CAN in the pres-
ence of 1 equiv of 1a–e, evolution of nitrogen gas was observed
even at reduced temperatures providing only starting material
after reaction work-up. Even though azide anion is oxidized much
faster than 1a–e by CAN, the homocoupling of azide radicals and
subsequent decomposition to evolve N2 gas are favoured over rad-
ical addition to cyclobutanols. When 5 equiv excesses of NaN3 and
CAN were used with 1 equiv of 1a, equal amounts of the desired
7. Paolobelli, A. B.; Ceccherelli, P.; Pizzo, F. J. Org. Chem. 1995, 60, 4954.
8. Nair, V.; Nair, L. G.; George, T. G.; Augustine, A. Tetrahedron 2000, 56, 7607.
9. Jiao, J.; Nguyen, L. X.; Patterson, D. R.; Flowers, R. A. Org. Lett. 2007, 9, 1323.
10. (a) Hahn, R. C.; Corbin, T. F.; Shechter, H. J. Am. Chem. Soc. 1968, 90, 3404; (b)
Çelebi, S.; Leyva, S.; Modarelli, D. A.; Platz, M. S. J. Am. Chem. Soc. 1993, 115, 8613.
11. General procedure for the synthesis of 1-substituted cyclobutanols: All glassware
was flame-dried before use. Cyclobutanone (13.4 mmol) was dissolved in
25 mL of diethyl ether and purged with N2. The temperature was reduced to
0 °C. The appropriate Grignard reagent (14.7 mmol) was added dropwise with
stirring. The reaction was allowed to stir for an additional 3 h. Water was
added slowly to quench the reaction. The organic layer was removed, and the
aqueous layer was extracted three times with ether. The organic layers were
combined, dried with MgSO4, filtered and concentrated. Pure 1-substituted
cyclobutanols were then obtained by recrystallization from n-pentane at
ꢀ20 °C (1a) or short-path, low pressure distillation (1b,d and e). Compounds
1c,f were produced in quantitative yields and required no additional
purification. 1H NMR and 13C NMR were used to assess purity, and are
included in the Supplementary data. Tabulated experimental details and
product yields are also included in the Supplementary data.
c
-azido product and the
isolated yields of less than 20%. Although the synthesis of
ketones using this method was inefficient, subsequent transforma-
c
-nitrato compound were generated with
c
-azido
tions using the accessible c-iodo and bromo products can produce
12. (a) Zhang, Y.; Raines, A. J.; Flowers, R. A. J. Org. Chem. 2004, 69, 6267; (b) Zhang,
Y.; Raines, A. J.; Flowers, R. A. Org. Lett. 2003, 5, 2363.
13. General procedure for the synthesis of c-iodo ketones: Sodium iodide (0.33 mmol)
other substrates including azides and nitriles.18,19
Since CAN is a versatile single-electron oxidant capable of oxi-
dizing a variety of functional groups, this Ce-mediated protocol
may appear to be incompatible with more complex substrates.
However, rate studies performed by our research group have
shown that the oxidation of inorganic anions by CAN is extremely
fast indicating that these reagents are oxidized preferentially to
other functional groups. Additionally, previous studies on the rela-
tive rates of oxidation of substrates and functional groups have
shown that selective oxidations can be achieved using CAN.9,20
As a result, this protocol should be applicable to complex mole-
cules providing that substrates do not contain functional groups
with rates of oxidation similar to inorganic anions.
was dissolved in 1 mL of H2O, and was added to the 1-substituted cyclobutanol
(0.33 mmol) in 2 mL of DME. The reaction was then purged with N2. CAN
(0.67 mmol) was dissolved in 2 mL of DME, and was added dropwise via
syringe with stirring. After stirring for 30 min, the volatiles were removed from
the reaction via rotary evaporation. Water was added, and then extracted three
times with diethyl ether. The organic layers were combined, dried with MgSO4,
filtered and concentrated. The
c
-iodo ketones 2a–f were purified further by
flash chromatography using
a
15% ethyl acetate/hexanes solution as the
eluting solvent. 1H NMR and 13C NMR were used to assess purity, and are
included in the Supplementary data.
14. Nair, V.; Panicker, S. B.; Augustine, A.; George, T. G.; Thomas, S.; Vairamani, M.
Tetrahedron 2001, 57, 7417.
15. General procedure for the synthesis of
c-bromo ketones: Potassium bromide
(0.33 mmol) was dissolved in 1vmL H2O, and was added to the 1-substituted
cyclobutanol (0.33 mmol) in 3 mL of CH2Cl2. The reaction was then purged
with N2. CAN (0.67 mmol) was dissolved in 2 mL H2O, and was added dropwise
via syringe with stirring. After stirring for 30 min, the volatiles were removed
from the reaction via rotary evaporation. Water was added, and then extracted
three times with diethyl ether. The organic layers were combined, dried with
3. Conclusions
MgSO4, filtered and concentrated. The
c-bromo ketones 3a–c were purified
An alternative route to both
been developed. The synthesis of
tuted cyclobutanols is general producing both aryl- and alkyl-
iodo ketones in good to very good yields. While the synthesis of
aliphatic -bromo ketones proved to be more difficult, 1-aryl-c-
bromo ketones were obtained in good to excellent yields. In both
cases, the halide was shown to add selectively to the least hindered
carbon of the cyclobutanol. This method has short reaction times,
c
-iodo and
c-bromo ketones has
further by flash chromatography using a 15% ethyl acetate:hexanes solution as
the eluting solvent. 1H NMR and 13C NMR were used to assess purity, and are
included in the Supplementary data.
c
-iodo ketones from 1-substi-
c
-
16. Kirchgessner, M.; Sreenath, K.; Gopidas, K. R. J. Org. Chem. 2006, 71, 9849.
17. Jahn, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001, 3333.
18. Singh, P. N. D.; Muthukrishnan, S.; Murthy, R. S.; Klima, R. F.; Mandel, S. M.;
Hawk, M.; Yarbough, N.; Gudmundsdóttir, A. D. Tetrahedron Lett. 2003, 44,
9169.
19. Iida, S.; Togo, H. Synlett 2008, 11, 1639.
20. Jiao, J.; Zhang, Y.; Devery, J. J.; Xu, L.; Deng, J.; Flowers, R. A. J. Org. Chem. 2007,
72, 5486.
c
and provides access to a range of structurally diverse
c-halo