Highly enantioselective direct organocatalytic α-chlorination of ketones

Article abstract of DOI:10.1002/anie.200460462

A C₂-symmetric diamine serves as the organocatalyst in an asymmetric α-chlorination reaction of simple ketones (e.g., cyclohexanone, diethyl ketone). Optically active α-chloroketones are formed with excellent enantioselectivities using N-chlorosuccinimide (NCS) as the chlorine source (see scheme). These products have broad synthetic utility, in particular for pharmaceutical applications.

Full text of DOI:10.1002/anie.200460462

Angewandte
Chemie
tioselective halogenation reactions have been limited to
particular systems such as 1,3-dicarbonyl compounds using
Lewis acid[4] or cinchona alkaloid catalysts.[5] The first
catalytic highly enantioselective a-chlorination and a-bromi-
nation reactions of carbonyl compounds were reported by
Lectka et al. with perhaloquinone-derived halogenation
reagents and a cinchona alkaloid catalyst in a tandem
halogenation/esterification of acid chlorides.[6] Very recently,
these procedures were complemented by the a-chlorination
of aldehydes with low-molecular-weight organocatalysts, a
method reported by MacMillan et al. and us independently.[7]
This novel reaction also complements previous proline-
catalyzed a-amination and a-oxidation reactions of alde-
hydes[8] and ketones,[9] and it was demonstrated that the a-
chloroaldehydes could be transformed into optically active
epoxides, non-proteinogenic amino acids, a-chloro ester
derivatives, a-chloro alcohols and a-amino alcohols.[7b] In
this communication we present the development of the first
organocatalytic asymmetric a-chlorination of ketones using
N-chlorosuccinimide (NCS) as an inexpensive chlorine
source, yielding optically active a-chloroketones in good
yields and excellent enantioselectivities.
We initiated our studies of the a-chlorination reaction by
screening a number of known and novel organocatalysts for
the a-chlorination of cyclohexanone 1a by NCS [Eq. (1)] and
some representative results are shown in Table 1.
(S)-Proline (3a) catalyzed the formation of a-chlorocy-
clohexanone (2a) in good yields, but unfortunately 2a was
formed as a racemate (entry 1). In contrast to this result, (S)-
prolinamide (3b), an excellent catalyst for the a-chlorination
of aldehydes,[7b] afforded 2a with up to 81% ee; however, the
yield of 2a was moderate (40%, entry 2). Several other
organocatalysts 3c–i were employed for the a-chlorination
reaction (entries 3–11), and it is notable that 3e, which is an
excellent catalyst for the a-chlorination of aldehydes, did not
catalyze the a-chlorination of ketones (entry 5). Interestingly,
the spiro derivative 3h provided 2a with 88% ee but in low
yield (17%, entry 10).[10] We envisioned that the sterically less
demanding catalyst 4,5-diphenylimidazolidine[11] 3i (4,5-DPI)
could improve the reaction rate, and to our delight we
obtained 2a in 65% yield and 97% ee (entry 11).
The moderate yields of a-chlorocyclohexanone (2a)
obtained (entries 2 and 11) led us to investigate the reaction
course by 1H NMR studies of the reaction mixture. We
discovered that the conversion into 2a accounted for only
approximately 60% of the NCS consumed, as significant
amounts of polychlorinated cyclohexanones were also
obtained. Furthermore, it was observed that chlorination of
the catalyst also occurred to some degree, another factor
responsible for the moderate yields. The detection of the
polychlorinated species led us to investigate the dichlorina-
tion of cyclohexanone. Therefore, we studied the chlorination
reaction of racemic a-chlorocyclohexanone (rac-2a) with
NCS catalyzed by 10 mol% 4,5-DPI·AcOH salt (vide infra).
Interestingly, catalyst 3i·AcOH, was found to catalyze not
only the chlorination of rac-2a but also a kinetic chiral
resolution of rac-2a [Eq. (2)].
Enantioselective Chlorination
Highly Enantioselective Direct Organocatalytic
a-Chlorination of Ketones**
Mauro Marigo, Stephan Bachmann, Nis Halland,
Alan Braunton, and Karl Anker Jørgensen*
The stereoselective formation of carbon–halogen bonds is an
important challenge in organic synthesis that has recently
received considerable attention[1] due to the usefulness of the
products as versatile synthetic intermediates.[2] Furthermore,
halides are often introduced into pharmaceutical compounds
to decrease the rate of metabolic degradation without
affecting the pharmacological effects.[3] Until recently, enan-
[*] M. Marigo, Dr. S. Bachmann, Dr. N. Halland, Dr. A. Braunton,
Prof. Dr. K. A. Jørgensen
The Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 AarhusC (Denmark)
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
[**] This work was supported by a grant from The Danish National
Research Foundation and by the EU (grant HMPT-CT-2001-00317
for M.M.)
2,6-Dichlorocyclohexanone 2aa was obtained in 27%
yield and 87% ee after 20 h, and for the remaining mono-
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 5507 –5510
DOI: 10.1002/anie.200460462
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5507

Communications
We next turned our attention to the use of other ketones
and discovered that, for example, tetrahydropyran-4-one
(1b), was much less reactive than cyclohexanone (1a) as
only a low yield of a-chlorotetrahydropyran-4-one (2b) was
obtained [Eq. (3)] (Table 2, entry 1).
Table 1: Screening of catalysts 3 (10–20 mol%) for the enantioselective
a-chlorination of cyclohexanone (1a).[a]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
1
(S)-proline (3a)
(S)-prolinamide (3b)
(S)-prolinol (3c)
24
24
24
65[f]
40[e]
5[f]
0
81
45
2[d]
3
Table 2: Screening of acid additivesfor the a-chlorination of tetrahy-
dropyran-4-one (1b).[a]
4
5
24
24
20[f]
20
–
<5[f]
Entry Add.
Equiv Solv.
1b
NCS
Yield ee
(equiv) (equiv) [%][b] [%][c]
1
2
3
4
–
–
CH2Cl2
5
5
1
1
1
1
1
1
1.5
2.0
30
53
15
19
62
50
63
72
90
84
97
87
68
91
97
98
6
7
0.75
72
12[f]
58
23
0
PhCO2H
PhCO2H
AcOH
CF3CO2H
ClCH2CO2H
0.20 CH2Cl2
0.20 MeCN 2.5
0.10 MeCN 2.5
0.10 CH2Cl2
0.10 MeCN 2.5
8
9
0.75
72
10[f]
34
62
39
5[d]
6
5
7
2-NO2-PhCO2H 0.25 MeCN
2-NO2-PhCO2H 0.25 MeCN
1
1
8[e]
10
22
17[f]
65[e]
88
97
[a] Procedure: To a mixture of 1b (0.5–2.5 mmol), additive, and 3i
(0.05 mmol) in the indicated solvent (1 mL) at À108C wasadded NCS
(0.5–0.6 mmol), and the reaction mixture wasstirred for 24 h. [b] Con-
version of tetrahydropyran-4-one determined by GC and based on NCS
asthe limiting reagent. [c] ee determined by CSP-GC. [d] Reaction time
4 h. [e] Reaction performed at À248C.
11[d]
20
[a] Procedure: To a mixture of 1a (1.25–2.5 mmol) and catalyst in CH2Cl2
wasadded NCS (0.5 mmol), and the reaction mixture wasstirred at
ambient temperature for the time indicated. [b] Conversion of cyclo-
hexanone determined by GC and based on NCS as the limiting reagent.
[c] Enantiomeric excess determined by CSP-GC. [d] Reaction performed
at À248C. [e] Moderate yield due to formation of polychlorinated
products(see text). [f] Moderate yield due to low conversion.
This result led us to develop reaction conditions for a-
chlorination of less reactive ketones, and it turned out that
variation of the solvent, the amount of ketone and NCS, and
the addition of acids[12] could influence the outcome of the
reaction. Table 2 shows some results for the screening of
various acid additives with 4,5-DPI 3i as the catalyst for the a-
chlorination of 1b.
The use of benzoic acid in combination with 4,5-DPI 3i
increased the reaction rate, and the optically active product
2b was obtained in 53% yield, a significant improvement over
the reaction without additive (Table 2, entries 1 and 2).[13]
Various solvents were also screened for the reaction, and it
was found that the reaction in MeCN was cleaner and the
formation of polychlorinated pyranones was suppressed since
only minor amounts were formed as determined by GC-MS
and 1H NMR spectroscopy. Furthermore, the optical purity of
the a-chloropyranone (2b) was better (97% ee) than when
the reaction was conducted in CH2Cl2 (entries 2 and 3). The
best results in terms of reactivity and asymmetric induction
were obtained with 2-nitrobenzoic acid.[14] The enhanced
reactivity allowed us to use NCS in a slight excess, and 2b was
obtained in 63% yield and 97% ee (entry 7). This result is
particularly remarkable since the reactions of ketones cata-
lyzed by proline derivatives are usually sluggish, and a large
excess of ketone is often necessary to obtain high yields.
Lowering the reaction temperature to À248C improved the
yield and enantioselectivity to 72% and 98% ee, respectively
(entry 8).
chloro compound 2a, 47% ee of (S)-2a was found indicating
that (2R)-chlorocyclohexanone is converted to (R,R)-2,6-
dichlorocyclohexanone (2aa). The fact that (2R)-chlorocy-
clohexanone, the major enantiomer obtained in the a-
chlorination of cyclohexanone catalyzed by 3i·AcOH, is the
more reactive enantiomer in the second chlorination step
shows that the asymmetric induction for the first chlorination
step is even better than observed. This also explains the slight
decrease in optical purity observed after extended reaction
times, as well as the formation of polychlorinated ketones.
Similar observations were made for the tetrahydropyran-4-
one (1b, vide infra).
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The general scope of the organocatalytic enantioselective
a-chlorination of various cyclic and acyclic ketones is
presented in Table 3. The cyclic ketones 1a–d were converted
alumina, and 2e,f were isolated after conversion to the
corresponding thiophenyl ketone using thiophenol (see the
Supporting Information). It should be noted that a-chlor-
oketones 2c,d racemize during flash chromatography on
neutral alumina, and in order to isolate optically active
products in situ reduction to the a-chloro alcohols is
recommended.
Table 3: Organocatalytic enantioselective a-chlorination of cyclic and
acyclic ketonesby NCS catalyzed by 10–20 mol% 4,5-DPI 3i.[a]
Entry
Ketone
T [8C]
Prod.
Yield [%][b]
ee [%][c]
An important aspect of the a-chlorination reaction of
ketones is that the optically active a-chloroketones obtained
provide highly versatile chiral building blocks for a variety of
synthetic transformations. In Scheme 1 the transformation of
(R)-a-chlorocyclohexanone (2a) into a-chloro-e-lactone (4)
and cis-2(R)-chlorocyclohexan-1(S)-ol (5) are shown. Lac-
tone 4 was formed in 81% yield by a regioselective Baeyer–
Villiger oxidation using urea hydrogen peroxide (UHP) and
trifluoroacetic anhydride (TFAA), without a decrease in
optical purity. Furthermore, cyclohexanol 5 was formed in
good yield and with a diastereoselectivity of > 10:1 by
reduction of (R)-a-chlorocyclohexanone 2a using NaBH4 in
MeOH (see the Supporting Information).[17]
1
À24
2a
82(54)[f]
97
2[d]
À24
À24
2b
2c
72(50)[g]
83(65)
98
93
3
4
À24
2d
76(63)
93
The absolute configuration of the a-chloroketones was
determined to be (R) by transformation of 5 into trans-2(S)-
azidochlorocyclohexan-1(S)-ol (6) by treatment with NaN3 in
DMF, and comparison of the optical rotation with literature
values (Scheme 1).[18] After TMS protection of 6 to obtain 7,
the enantiomeric excess was determined by GC using a chiral
stationary phase and it was found that the optical purity had
not decreased during the transformations. Furthermore, the
elution order of the enantiomers confirmed the assignment of
the absolute configuration.[19] Azide 6 can also be transformed
easily into the highly useful protected amino alcohol 8 in 93%
yield by a simple hydrogenolysis/protection procedure.[20]
In summary, we have developed the first catalytic
asymmetric a-chlorination of ketones affording optically
active a-chloroketones. The reaction proceeds in moderate
to high yields and excellent enantioselectivities using inex-
pensive NCS as the chlorine source. Furthermore, we have
developed a novel organocatalytic system comprising an
easily available imidazolidine catalyst and a carboxylic acid
and demonstrated the synthetic usefulness of the a-chlor-
oketones formed in the catalytic reaction.
5[e]
À10
À10
2e
2 f
62(51)[h]
40(35)[h]
86
89
6[e]
[a] Reaction conditions: To a mixture of ketone (0.5 mmol), 4,5-DPI 3i
(0.1 mmol, 20 mol%) and 2-NO2-PhCO2H (0.25 mmol, 50 mol%) in
MeCN at the indicated temperature wasadded NCS (1.0 mmol,
2.0 equiv), and the reaction mixture wasstirred for 20 h. [b] Determined
1
by H NMR spectroscopy using an internal standard and confirmed by
GC analysis. Yields of isolated products are shown in brackets (see the
Supporting Information). [c] ee determined by CSP-GC. [d] Performed
using 10 mol% 4,5-DPI 3i and 0.25 equiv. 2-NO2-PhCO2H. [e] Performed
using 5 equiv. of ketone. Reaction time 40 h. [f] Isolated after Baeyer–
Villiger oxidation to lactone 4. [g] Isolated after NaBH4 reduction to the
corresponding chloroalcohol 9. [h] Isolated as the corresponding
thiophenyl ketone.
into the corresponding a-chloroketones 2a–d with excellent
enantioselectivities (90–98% ee) and in good yields even
though the ketone is not used in excess (Table 3, entries 1–4).
In these reactions, full conversion of the
ketone was observed together with the a-
chloroketone product and a minor amount of
the polychlorinated ketone as a by-product.
For the acyclic ketones 3-pentanone (1e) and
4-heptanone (1 f), good enantiomeric excesses
of the corresponding a-chloroketones 2e,f
were also obtained; however, yields were
slightly lower due to their lower reactivity,
and an excess of ketone was required.[15]
Isolation of the a-chloroketone products
from the polychlorinated ketones was found
to be difficult on silica and, furthermore, a
slight racemization was found to occur.[16]
Scheme 1. Synthetic transformations of (R)-a-chlorocyclohexanone 2a.
Therefore, a-chloroketone 2a was converted
to lactone 4 by Baeyer–Villiger oxidation, and
2b to the corresponding chloroalcohol 9 by reduction with
NaBH4. a-Chloroketones 2c,d were purified on neutral
Received: April 27, 2004
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Communications
Barbas III, Angew. Chem. 2004, 116, 2474; Angew. Chem. Int.
Ed. 2004, 43, 2420.
[13] We believe that acid additives promote enamine formation and
suppress chlorination of the catalyst.
[14] 2-Nitrobenzoic acid (20 mol%) led to less than 1% conversion
after 18 h in the absence of 4,5-DPI 3i in a 1:1 mixture of
cyclohexanone and NCS at ambient temperature.
[15] Less than 1% conversion of 1e and 1 f was observed in the
absence of 2-nitrobenzoic acid.
[16] No racemization was found to occur during filtration through a
short silica plug.
[17] In order to obtain high diastereoselectivities, dry MeOH, careful
temperature control, and slow addition of NaBH4 were required.
[18] H. Hꢂnig, P. Seufer-Wasserthal, F. Fꢃlꢂp, J. Chem. Soc. Perkin
Trans. 1 1989, 2341.
[19] L. E. Martinez, J. L. Leighton, D. H. Carsten, E. N. Jacobsen, J.
Am. Chem. Soc. 1995, 117, 5897.
[20] T. Govindaraju, R. G. Gonnade, M. M. Bhadbhade, V. A.
Kumar, K. N. Ganesh, Org. Lett. 2003, 5, 3013.
Keywords: asymmetric catalysis · halogenation · homogeneous
catalysis · ketones
.
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[10] The catalytic properties of these compounds were found during
1H NMR investigations of the mechanism of the a-chlorination
of cyclohexanone by NCS catalyzed by (1R,2R)-diphenylethy-
lenediamine. These investigations showed that the active catalyst
was the condensation product between (1R,2R)-diphenylethy-
lenediamine and cyclohexanone (3h) and not (1R,2R)-dipheny-
lethylenediamine.
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