An efficient and general approach to β-functionalized ketones

Article abstract of DOI:10.1021/ol070159h

Figure presented The oxidation of selected anlons (N₃ ^-, SCN^-, I^-, and Br^-) by eeric ammonium nitrate (CAN) in the presence of substituted cyclopropyl alcohols provides a novel approach to β-functionalized ketones. The protocol has a number of advantages including short reaction times, ease of reagent handling, and mild, neutral reaction conditions. Overall, this method provides an alternative pathway to important starting materials and intermediates in organic synthesis.

Full text of DOI:10.1021/ol070159h

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1323-1326
An Efficient and General Approach to
-Functionalized Ketones
â
Jingliang Jiao, Larry X. Nguyen, Dennis R. Patterson, and Robert A. Flowers II*
Department of Chemistry, Lehigh UniVersity, Bethlehem, PennsylVania 18015
rof2@lehigh.edu
Received January 22, 2007
ABSTRACT
-
-
-
-
The oxidation of selected anions (N3 , SCN , I , and Br ) by ceric ammonium nitrate (CAN) in the presence of substituted cyclopropyl
alcohols provides a novel approach to -functionalized ketones. The protocol has a number of advantages including short reaction times,
â
ease of reagent handling, and mild, neutral reaction conditions. Overall, this method provides an alternative pathway to important starting
materials and intermediates in organic synthesis.
Ketones substituted in the â position are important starting
materials in organic chemistry. Among this group, â-halo
ketones are extremely useful intermediates in organic
synthesis and act as precursors to enones, annulated com-
pounds, heterocyclic derivatives, and dicarbonyl products.1
In spite of their importance as precursors to a large range of
important intermediates,2 only a few of methods have been
developed to synthesize â-substituted ketones.3 The synthesis
of â-substituted ketones by 1,4-addition of HX (X ) Cl,
Br, I) or trimethylsilyl iodide to the corresponding enone is
sometimes experimentally inconvenient since the use of
reactive or moisture sensitive reagents is required.3b,d More
recent approaches to â-substituted ketones, while useful,
provide access to a limited range of compounds.4,5 As a
consequence, the development of new synthetic methods
offering a general approach for the introduction of diverse
functionality to the â position of a carbonyl group still
constitutes a challenge in organic chemistry.
Cerium(IV) ammonium nitrate (CAN) has found wide
applications in carbon-heteroatom bond forming reactions
in organic synthesis.6 The reported carbon-heteroatom bond
formations mediated with CAN include C-Br, C-I, C-S,
C-N, and C-Se bonds. These reactions usually involve the
generation of heteroatom-centered radicals from the oxidation
of anions and addition of the heteroatom radicals to alkenes
or alkynes.
(1) (a) House, H. O. Modern Synthetic Organic Reactions, 2nd ed.;
Benjamin: Menlo Park, CA, 1972. (b) Jung, M. E. Tetrahedron 1976, 32,
3-31. (c) Gawley, R. E. Synthesis 1976, 777-794.
(2) (a) Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2004, 69, 6907-
6908. (b) Sonda, S.; Katayama, K.; Kawahara, T.; Sato, N.; Asano, K. Bio.
Med. Chem. 2004, 12, 2737-2747. (c) Lagoja, I. M.; Pannecouque, C.;
Van Aerschot, A.; Witvrouw, M.; Debyser, Z.; Balzarini, J.; Herdewijn,
P.; De Clercq, E. J. Med. Chem. 2003, 46, 1546-1553. (d) Dohle, W.;
Lindsay, D. M.; Knochel, P. Org. Lett. 2001, 3, 2871-2873. (e) Sharma,
V. L.; Bhandari, K.; Chatterjee, S. K. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1991, 30B, 876-877. (f) Fujiwara, M.; Hitomi, K.; Baba,
A.; Matsuda, H. Synthesis 1990, 106-109. (g) Narasimhan, N. S.; Patil, P.
A. Tetrahedron Lett. 1986, 27, 5133-5134. (h) Singh, H.; Batra, M. S.;
Singh, P. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1985,
24B, 131-136.
On the basis of this precedent, we reasoned that Ce(IV)
oxidation of an anion in the presence of a cyclopropyl alcohol
would provide a route to â-substituted ketones as shown in
Scheme 1. Since cyclopropyl units are readily accessible via
the Kulinkovich reaction,7 the ring opening of cyclopropanols
and the carbon-heteroatom bond formation mediated with
(3) (a) Marx, J. N. Tetrahedron 1983, 39, 1529-1531. (b) Marx, J. N.
Tetrahedron Lett. 1971, 12, 4957-4960. (c) Miller, R. D.; Mckean, D. R.
Tetrahedron Lett. 1980, 21, 2639-2642. (d) Miller, R. D.; Mckean, D. R.
Tetrahedron Lett. 1979, 20, 2305-2308. (e) Johnson, C. R.; Cheer, C. J.;
Goldsmith, D. J. J. Org. Chem. 1964, 29, 3320-3323. (f) Murai, S.; Seki,
Y.; Sonoda, N. J. Chem. Soc., Chem. Commun. 1974, 1032-1033. (g)
Kosak, A. I.; Leyland, H. M. J. Org. Chem. 1956, 21, 733-735. (h)
Hilgetag, G.; Martini, A. PreparatiVe Organic Chemistry; John Wiley and
Sons, Inc.: New York, 1972; p 128. (i) Armstrong, C.; Blair, J. A.; Homer,
J. J. Chem. Soc., Chem. Commun. 1969, 103-104.
(4) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett. 2001, 3, 803-
805.
(5) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.;
Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700-3704.
(6) (a) Nair, V.; Panicker, S. B.; Nair, L. G.; George, T. G.; Augustine,
A. Synlett 2003, 156-165. (b) Nair, V.; Balagopal, L.; Rajan, R.; Mathew,
J. Acc. Chem. Res. 2004, 37, 21-30.
10.1021/ol070159h CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/03/2007

Table 1. Synthesis of â-Functionalized Ketones through Ring Opening of Cyclopropanols
product,
yieldb
product,
yieldb
entry
R, substrate
M+X-
conditionsa
entry
R, substrate
M+X-
conditionsa
1
2
3
4
5
6
7
8
Ph, 1
Ph, 1
Ph, 1
Ph, 1
p-CH3OPh, 2
p-CH3OPh, 2
p-CH3OPh, 2
p-CH3OPh, 2
NaN3, a
NH4SCN, b
NaI, c
A
B
A
C
A
B
A
C
1a, 77%
1b, 87%
1c, 90%
1d, 71%
2a, 83%
2b, 89%
2c, 92%
2d, 75%
9
10
11
12
13
14
15
16
cyclohexyl, 3
cyclohexyl, 3
cyclohexyl, 3
cyclohexyl, 3
CH3, 4
CH3, 4
CH3, 4
CH3, 4
NaN3, a
NH4SCN, b
NaI, c
A
B
A
C
A
B
A
C
3a, 71%
3b, 90%
3c, 96%
3d, 92%
4a, 70%
4b, 85%
4c, 86%
4d, 83%
KBr, d
KBr, d
NaN3, a
NH4SCN, b
NaI, c
NaN3, a
NH4SCN, b
NaI, c
KBr, d
KBr, d
a Conditions: (A) 2 equiv of CAN, 1 equiv of substrate in CH3CN containing 20% H2O; (B) 2 equiv of CAN, 1 equiv of substrate in CH3CN; (C) 2 equiv
of CAN, 1 equiv of substrate in 50% CH2Cl2 50% H2O. b Isolated yield.
CAN could provide a novel, efficient, and general approach
to a variety of â-substituted ketones.
medium for the reaction as sodium azide is not soluble in
many neat organic solvents. Evaluation of a wide range of
conditions showed that acetonitrile containing 20% water
provided the highest yield of â-azido ketone 1a, and as a
result, this medium was used as the first choice for any anion
not soluble in neat solvent. With this initial study completed,
the synthesis of â-azido ketones was extended to several
cyclopropanols 2-4. Both aryl- and alkyl-substituted cyclo-
propanols (1-4) afforded corresponding â-azido ketones in
good to high isolated yields (70-83%) as shown in Table 1
(entries 1, 5, 9, and 13). Next, the CAN mediated strategy
was employed to construct other carbon-heteroatom bonds
including C-S, C-I, and C-Br. Starting cyclopropanols
(1-4) and appropriate ionic compounds (M+X-) were used
in these transformations. The products and isolated yields
are collected in Table 1. It is important to note that column
chromatography was required after most reactions and
isolated â-substituted ketones were prone to decomposition
in neat form, so they were stored in CDCl3 after isolation.
To test this approach in the formation of carbon-sulfur
bonds, ammonium thiocyanate was adopted to supply the
thiocyanate anion (entries 2, 6, 10, and 14). In these reactions,
acetonitrile was employed since ammonium thiocyanate has
good solubility in this medium. Once again, the reaction
worked well for both aryl cyclopropanols (1 and 2) and alkyl
cyclopropanols (3 and 4). Very good isolated yields (85-
90%) of â-thiocyanato ketones (1b-4b) were obtained with
this strategy.
Scheme 1
The synthesis of substituted cyclopropyl alcohols 1-4
shown in Table 1 was carried out by using the Kulinkovich
reaction and provided good isolated yields in the range of
63-82%. In an initial experiment, sodium azide was chosen
as the first anion to react with a cyclopropyl alcohol since
oxidation of this anion with CAN has been previously
reported.8 Reaction of 1 with NaN3 in the presence of 2 equiv
of CAN in methanol produced a moderate yield (50%) of
the 3-azido-1-phenylpropanone along with dimer and nitrated
products as side products.
Since solvent is known to play an important role in a range
of Ce(IV)-initiated bond-forming reactions,9,10 a series of
mixed solvent systems were examined to determine the best
(7) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.; Pritytskaya,
T. S. Zh. Org. Khim. 1989, 25, 2244-2245. (b) Kulinkovich, O. G. Eur. J.
Org. Chem. 2004, 22, 4517-4529. (c) Choi, J.-R.; Cho, D.-G.; Roh, K.
Y.; Hwang, J.-T.; Ahn, S.; Jang, H. S.; Cho, W.-Y.; Kim, K. W.; Cho,
Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. Chem. 2004, 47, 2864-2869. (d) Shirai,
M.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1999, 40, 5331-5332. (e) De
Meijere, A.; Savchenko, A. J. Organomet. Chem. 2004, 689, 2033-2055.
(8) Trahanovsky, W. S.; Robbins, M. D. J. Am. Chem. Soc. 1971, 93,
5256-5258.
(9) Nair, V.; Panicker, S. B.; Augustine, A.; George, T. G.; Thomas, S.;
Vairamani, M. Tetrahedron 2001, 57, 7417-7422.
(10) (a) Zhang, Y.; Raines, A. J.; Flowers, R. A., II J. Org. Chem. 2004,
69, 6267-6272. (b) Zhang, Y.; Raines, A. J.; Flowers, R. A., II Org. Lett.
2003, 5, 2363-2365.
Since ketones containing a good leaving group in the
â-position would provide access to a wide range of starting
materials for further reaction, iodide and bromide salts were
examined. Sodium iodide was chosen as the source of iodide
ions and potassium bromide as the source of bromide ions.
As shown in Table 1 (entries 3, 7, 11, and 15), four
cyclopropanols (1-4) were reacted with sodium iodide in
the presence of CAN in acetonitrile containing 20% water.
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Org. Lett., Vol. 9, No. 7, 2007

Each reaction provided excellent isolated yields (86-96%)
of the corresponding â-iodo ketones (1c-4c). Attempts to
form C-Br bonds with use of acetonitrile containing 20%
water proved disappointing with isolated yields of the
â-bromo ketones varying from 22% to 46%. In these
reactions, oxidation of cyclopropyl alcohols occurred pre-
dominantly to generate dimers as major products. Bromide
ions are considerably harder to oxidize (based on thermo-
dynamic redox potentials).11 As a result, oxidation of
cyclopropyl alcohols becomes a competitive reaction. To
circumvent this process, a two-phase solvent system of
dichloromethane and water was utilized.9 In this system,
CAN and bromide are soluble in the aqueous phase, whereas
the cyclopropyl alcohol is only soluble in the organic phase
leading to selective oxidation of the bromide ion. This solvent
milieu provided isolated yields of â-bromo products in the
range of 71-92% (entries 4, 8, 12, and 16).
bicyclic alcohol. This approach, if successful, would provide
access to tandem ring expansion-addition reactions provid-
ing a useful protocol for the synthesis of a medium sized
cyclic carbocycle containing a â-substituted ketone moiety.
To examine the practicality of this approach, bicyclic alcohol
8 was synthesized employing a previously published proce-
dure12 and subjected to the CAN mediated ring-opening
-
reaction in the presence of N3 , I-, and Br-. All of the data
are summarized in Table 3.
Table 3. Ring Expansion of Bicyclic Alcohol
To investigate the regioselectivity of more highly substi-
tuted cyclopropyl alcohols, 2-ethyl-1-phenylcyclopropanol
(5) was prepared as a diastereomeric mixture with use of
entry
M+X-
conditionsa
product (yield)
1
2
3
NaN3
NaI
KBr
A
A
C
9a (56%)b
9b (68%)c
9c (60%)c
-
the Kulinkovich method. Three nucleophiles N3 , I-, and
Br- were reacted with compound 5 and the results are shown
in Table 2. Examination of the data in Table 2 shows that
a See footnote a in Table 1 for conditions. b GC yield. c Isolated yield.
The results in Table 3 show that the ring-opening reaction
results in ring-expansion to produce â-functionlized cyclo-
heptanones for all three anions examined. However, the
isolated yields are only moderate due to the presence of side
Table 2. Reactions of Anions with
2-Ethyl-1-phenylcyclopropanol
1
products. Analysis of the reaction mixture with H NMR
allowed the identification of three major side products as
shown in Scheme 2. The side products obtained from this
major product
(yield)
ratio of
6:7
entry
M+X-
conditionsa
Scheme 2. Side Products from Oxidation of 8
1
2
3
4
NaN3
NaI
KBr
NaI
A
A
C
A
6a (48%)b
6b (66%)c
6c (59%)c
6b (60%)c
6:1
6:1
6:1
7:1d
a See footnote a in Table 1 for conditions. b GC yield. c Isolated yield.
d Reaction run at 0 °C.
the observed regioselectivities in the ring-opening reactions
are good and provide modest isolated yields. On the basis
of 1H NMR analysis, all the ratios of product 6 to product 7
-
are 6:1 for N3 , I-, and Br- irrespective of the anion utilized
(entries 1-3). Products 6a-c are likely favored due to attack
of the X• radical on the least hindered side of the cyclopropyl
ring. When the ring opening of 5 was carried out at 0 °C in
the presence of NaI, a marginally improved regioselectivity
(7:1) was obtained albeit with a slightly lower yield (entry
4).
With the success in forming carbon-heteroatom bonds
in the â position of acyclic ketones, we next attempted to
synthesize â-substituted cyclic ketones using the CAN
mediated method through the ring opening of a bridgehead
analysis are consistent with oxidation of 8, indicating that
the rate of reaction of this bicyclic alcohol with CAN is on
the same order as the oxidations of anions used in this study.
Presumably, the mechanism in this reaction could be different
from the one shown in Scheme 1 with the oxidation of 8
followed by halide addition.
(11) Harris, D. C. QuantitatiVe Chemical Analysis, 6th ed.; Freeman:
New York, 2003.
(12) Lee, B. H.; Sung, M. J.; Blackstock, S. C.; Cha, J. K. J. Am. Chem.
Soc. 2001, 123, 11322-11324.
Org. Lett., Vol. 9, No. 7, 2007
1325

Recent work in our group has shown that the rates of
oxidation by CAN are highly dependent on substrate structure
and solvent conditions.10,13 On the basis of these previous
studies, we reasoned that protection of 8 with a more
sterically encumbered trimethylsilyl group would reduce the
rate of oxidation of substrate while simultaneously allowing
us to test the mechanism shown in Scheme 1. Treatment of
10 with CAN in the presence of NaI at 0 °C provided
3-iodocycloheptanone in high yield as shown in Scheme 3.
short reaction time, ease of reagent handling, high yields,
and extensive use of â-functionalized ketones in organic
synthesis, this method provides an alternative pathway to
important starting materials and intermediates in organic
synthesis. Furthermore, the concomitant ring expansion and
â-functionalization shown in Scheme 3 indicate that this
protocol provides a new pathway to obtain â-functionalized
ketones which are difficult to synthesize in other ways.
Detailed mechanistic studies and the use of this method in
the synthesis of more complex systems are currently being
explored. Results of these experiments will be reported in
due course.
Scheme 3
Acknowledgment. R.A.F. is grateful to the National
Institutes of Health (1R15GM075960-01) for support of this
work and to Dr. Rebecca Miller and Mr. James Devery at
Lehigh University for their useful comments on the manu-
script. L.X.N. acknowledges the Center for Emeritus Sci-
entists in Academic Research at Lehigh University for
support of his research on this project.
In conclusion, a novel approach to â-functionalized
ketones with good to excellent yields has been discovered.
Considering the mild and neutral conditions of the protocol,
Supporting Information Available: General methods,
experimental protocols, and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Zhang, Y.; Flowers, R. A., II J. Org. Chem. 2003, 68, 4560-4562.
OL070159H
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