NHC-mediated chlorination of unsymmetrical ketenes: Catalysis and asymmetry

Article abstract of DOI:10.1002/ejoc.201000864

NHCs promote the efficient chlorination of unsymmetrical disubstituted ketenes with a range of chlorinating agents; chiral NHCs display promising levels of asymmetric induction in the chlorination process with up to 61% ee observed using 2,3,4,5,6,6-hexac

Full text of DOI:10.1002/ejoc.201000864

FULL PAPER
DOI: 10.1002/ejoc.201000864
NHC-Mediated Chlorination of Unsymmetrical Ketenes: Catalysis and
Asymmetry
James Douglas,[a] Kenneth B. Ling,[a] Carmen Concellón,[a] Gwydion Churchill,[b]
Alexandra M. Z. Slawin,[a] and Andrew D. Smith*[a]
Keywords: Homogeneous catalysis / Asymmetric synthesis / N-Heterocyclic carbene / Ketenes / Chlorination
NHCs promote the efficient chlorination of unsymmetrical di-
substituted ketenes with a range of chlorinating agents; chi-
ral NHCs display promising levels of asymmetric induction
in the chlorination process with up to 61% ee observed using
2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone.
Introduction
A range of methods has been developed in recent years
that allow the catalytic asymmetric α-chlorination of carb-
onyl compounds.[1] Notable protocols within this area in-
clude the organocatalytic enamine strategies of MacMil-
lan[2] and Jørgenson,[3] as well as SOMO catalysis by Mac-
Millan,[4] which all deliver α-chloro aldehydes with high ee
values. Lectka has developed a series of elegant halogena-
tion strategies using cinchona alkaloid derivatives with in
situ generated ketenes that deliver α-halogenated esters in
excellent ee,[5] while Rovis and co-workers have shown that
chiral N-heterocyclic carbenes (NHCs) deliver α-chloro es-
ters in high ee from α,α-dichloroaldehydes and phenols.[6]
These tactics all give secondary alkyl halides with excellent
levels of enantiocontrol,[7] with strategies for the generation
of tertiary alkyl halides relatively less investigated.[8] Stoi-
chiometric practices toward this goal have employed silyl
enol ethers,[9] while the catalytic asymmetric halogenation
of 1,3-dicarbonyls and related compounds have also been
reported.[10] Notably, Fu has recently utilised planar chiral
PPY derivative 10 to generate tertiary α-chloro esters with
excellent enantiocontrol (up to 95% ee) from unsymmetri-
cal disubstituted ketenes and 2,2,6,6-tetrachlorocyclohexa-
none 9 (Figure 1).[11,12]
As part of a research programme focused upon the devel-
opment of applications of Lewis base catalysis[13] in synthe-
sis,[14] we, together with extensive work from Ye, have
probed the ability of NHCs[15] to promote the reaction of
disubstituted ketenes and a range of electrophiles. This
methodology has proven suitable for a number of formal
Figure 1. Selected strategies for the catalytic asymmetric α-haloge-
nation of carbonyls.
[a] EaStCHEM, School of Chemistry, University of St Andrews,
North Haugh, St Andrews, KY16 9ST, UK
Fax: +44-1334-463808
[2+2][16] and [4+2][17] cycloaddition reactions, as well as
asymmetric esterification reactions with benzhydrol[18] or 2-
phenylphenol.[19] As an extension of this research, and
building upon the literature precedents for catalytic α-halo-
View this journal online at
E-mail: ads10@st-andrews.ac.uk
[b] AstraZeneca, Process Research and Development,
Macclesfield, Cheshire, SK10 2NA, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000864.
wileyonlinelibrary.com
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5863

A. D. Smith et al.
FULL PAPER
genation, we reasoned that NHCs may be able to promote lysts 14–18, however the intermediate succinimide adduct
the halogenation of unsymmetrical, disubstituted ketenes, 20 proved to be extremely unstable to any attempts at puri-
giving access to a range of tertiary α-halo esters. We de- fication. To circumvent this issue, the crude reaction prod-
scribe herein our results within this area.
ucts were directly subjected to methanolysis, affording the
corresponding α-chloro methyl esters in acceptable yields
over the 2 steps. Again, only low levels of enantioselectivity
were observed with all of the precatalysts screened, with -
valine-derived precatalyst 16 proving optimal in this case,
giving 21 in 39% yield and 11% ee (Table 2).[20,21]
Results and Discussion
Evaluating Chlorinating Agents with NHC-Mediated
Catalysis
Table 2. NHC-promoted chlorination of ethyl phenyl ketene using
NCS.
Preliminary studies began with evaluating the reactivity
of 2,2,6,6-tetrachlorocyclohexanone 9 with NHCs as this
reagent had given the highest enantioselectivities in the
chlorination of ketenes by Fu et al.[11] In the presence of a
range of azolium salt precatalysts 14–17 and using
KHMDS as the base to generate the corresponding NHC
in situ, no chlorination of ethyl phenyl ketene 12 was ob-
served. However, in the presence of -pyroglutamic-acid-de-
rived precatalyst 18 and Cs2CO3 as the base, moderate con-
version to the α-chloro ester in essentially racemic form was
observed. Lowering the reaction temperature to –40 °C had
no discernible effect on the enantioselectivity of this pro-
cess, again returning 13 (Ͻ5% ee) in modest yield (Table 1).
Entry
Azolium
salt
Base
Yield of 21 (%)[a] ee (%)[b]
1
2
3
4
5
14
15
16
17
18
KHMDS
KHMDS
KHMDS
KHMDS
Cs2CO3
0
–
Ͻ5
11
39
39
15
28
Table 1. NHC-promoted chlorination of ethyl phenyl ketene using
2,2,6,6-tetrachlorocyclohexanone.
Ͻ5
Ͻ5
[a] Isolated yield. [b] Determined by chiral GC analysis, see Sup-
porting Information for details.
The chlorinating reagent was next changed to hexachlo-
roacetone 22, and again good conversion of ketene 12 to
the corresponding α-chloro ester 23 was observed in the
presence of NHCs prepared from a range of azolium salt
precatalysts. In this series, up to 29% ee was observed by
employing the aminoindanol-derived precatalyst 15
(Table 3).[20,21]
Table 3. NHC-promoted chlorination of ethyl phenyl ketene using
hexachloroacetone.
Entry
Azolium salt
Base
Yield (%)[a] ee (%)[b]
1
2
3
4
14
15
16
17
18
18
KHMDS
KHMDS
KHMDS
KHMDS
Cs2CO3
–
–
–
–
47
35
–
–
–
–
Ͻ5
Ͻ5
Entry
Azolium salt
Base
Yield (%)[a]
ee (%)[b]
1
2
3
4
5
14
15
16
17
18
KHMDS
KHMDS
KHMDS
KHMDS
Cs2CO3
44
47
67
72
37
–
29 (ent)
Ͻ5
8
Ͻ5
5
6[c]
Cs2CO3
[a] Isolated yield. [b] Determined by chiral GC analysis of the cor-
responding methyl ester, see Supporting Information for details. [c]
Reaction performed at –40 °C.
[a] Isolated yield. [b] Determined by chiral GC analysis of the cor-
responding methyl ester, see Supporting Information for details.
Due to the low reactivity of 2,2,6,6-tetrachlorocyclohexa-
none 9 in this protocol, our attention next turned to the
Finally, we changed the chlorinating reagent to
more reactive chlorinating reagent N-chlorosuccinimide 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone 5. Good-to-
(NCS). Good conversion of ketene 12 was observed at excellent reactivity was observed using all precatalysts 14–
–40 °C using NHCs generated from azolium salt precata- 18, with -pyroglutamic-acid-derived precatalyst 18 opti-
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NHC-Mediated Chlorination of Unsymmetrical Ketenes
mal, giving the corresponding α-chloro pentachlorophenyl and Duan,[23] were unsuccessful[24] and so the optimised
esters in excellent yields and up to 54% ee. Attempts to conditions were applied to a range of aryl-alkyl ketene sub-
increase the enantioselectivity of the reaction by lowering strates in order to probe the scope of the chlorinating reac-
the reaction temperature were unsuccessful. No reaction tion. 2- and 4-substitution of the aryl unit of the ketene is
was observed when the reaction was maintained at –60 °C, readily tolerated, as is variation of the alkyl chain from
whilst allowing the reaction to warm gradually from –60 °C methyl to n-butyl, all giving excellent isolated yields (up to
to room temperature gave 24 in slightly reduced enantio- 97% yield) of the corresponding α-chloro ester with modest
selectivity. It was additionally found that employing a slight levels of enantioselectivity (26–61% ee) (Table 5).[25]
excess (1.1 equiv.) of ketene was optimal both in terms of
enantioselectivity (up to 61% ee) and ease of purification,
since it was often difficult to separate any remaining dien-
Table 5. Generality of the NHC-promoted chlorination of alkyl
one 5 from the pentachlorophenyl ester 24 (Table 4).[20,21]
aryl ketenes using 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone.
In the racemic series the structure of α-chloro ester product
24 was unambiguously confirmed by X-ray crystallographic
analysis (Figure 2).[22]
Table 4. NHC-promoted chlorination of ethyl phenyl ketene using
2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone.
Entry Ketene Ar
R
Product Yield (%)[a] ee (%)
1
2
12
25
26
27
28
29
Ph
Ph
4-MeC6H4
4-MeC6H4
2-ClC6H4
4-ClC6H4
Et
nBu
Et
Me
Et
Et
24
30
31
32
33
34
90
67
88
76
97
91
61[b]
34[c]
48[c]
44[c]
26[c]
44[c]
3[d]
4
5
6
Entry
Azolium salt
Base
Yield (%)[a]
ee (%)[b]
[a] Isolated yield. [b] Determined by chiral GC analysis of the cor-
responding methyl ester, see Supporting Information for details.
[c] Determined by 1H NMR analysis of the corresponding (S)-α-
methylbenzylamide, see Supporting Information for details. [d]
1.5 equiv. of ketene 26 and 25 mol-% of 18 were used.
1
2
3
4
14
15
16
17
18
18
18
KHMDS
KHMDS
KHMDS
KHMDS
Cs2CO3
Cs2CO3
Cs2CO3
65
89
43
77
92
90
86
–
6
22
Ͻ5
57
61
53
5
6[c]
7[d]
Further investigations attempted to extend this method-
ology to the use of alternative halogenating reagents. Al-
though no fluorination was observed under a range of con-
ditions when using N-fluorobenzenesulfonimide (NFSI),
excellent reactivity was observed with 2,4,4,6-tetrabromocy-
clohexa-2,5-dienone 35 as the halogenating reagent, giving
α-bromo ester 36 in 92% isolated yield and 45%ee
(Scheme 1). Unfortunately, exhaustive attempts to derivat-
ise α-bromo ester 36 in order to exemplify its synthetic util-
ity proved unsuccessful, with the forcing conditions re-
quired for transesterification or amidation resulting in eli-
mination of HBr.
[a] Isolated yield. [b] Determined by chiral GC analysis of the cor-
responding methyl ester, see Supporting Information for details. [c]
1.1 equiv. of ketene were used. [d] The reaction was warmed grad-
ually from –60 °C to room temp.
A variety of mechanistic possibilities exist in this reaction
manifold, with one plausible mechanism for the chlorina-
tion reaction outlined below (Figure 3). Initial attack of in
situ generated NHC 38 to ketene 12, preferentially anti- to
the aryl unit of the ketene,[26] generates azolium enolate in-
termediate 39, with subsequent stereoselective chlorination
affording enantiomerically enriched α-chloro acylazolium
species 41. Nucleophilic attack of the pentachlorophenolate
anion 40 (which is generated as a by-product from the chlo-
rination step) onto the acylazolium species 41 produces α-
chloro ester 24 and liberates NHC 38 to re-enter the cata-
Figure 2. Molecular representation of the X-ray crystal structure
of (Ϯ)-24 (H atoms removed for clarity).
Further attempts to increase the enantioselectivity of the lytic cycle. At this stage, it has not proven possible to delin-
reaction by tuning the reactivity of the chlorinating reagent, eate conclusively this mechanistic Scheme or to discount
in line with previous studies by Bartoli et al.[10d] and Mayr alternative reaction pathways.[27]
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A. D. Smith et al.
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Scheme 1. NHC-promoted bromination of ethyl phenyl ketene using 2,4,4,6-tetrabromocyclohexa-2,5-dienone.
and –60 °C were obtained using an immersion cooler (HAAKE
EK 90). “In vacuo” refers to the use of a Büchi Rotavapor R-2000
rotary evaporator with a Vacubrand CVC2 vacuum controller or a
Heidolph Laborota 4001 rotary evaporator with a vacuum control-
ler. Dry solvents were obtained from a solvent purification system
(MBraun, SPS-800). PE refers to the fraction of petroleum ether
boiling between 40 and 60 °C. Triethylamine was distilled from
CaH2. Ketenes were prepared as previously reported[19] from the
corresponding acid chloride. 2,2,6,6-Tetrachlorocyclohexanone 9
(Aldrich) was recrystallised from pentane/CH2Cl2. N-Chlorosuc-
cinimide was recrystallised from distilled water and dried in vacuo
for 48 h. 4,4,6-Tetrabromocyclohexa-2,5-dienone 35 was prepared
according to the literature[28] with additional freeze drying and trit-
uration with dry Et2O. 5,7,7-Trichloroquinolin-8(7H)-one was pre-
pared according to the literature.[10d] All other reagents were used
directly as supplied without further purification. Flash column
chromatography was carried out with silica gel 60 (0.043–
0.060 mm) (Merck) or on aluminium oxide (activated, basic,
Brockmann I, ca. 150 mesh) (Aldrich) in the solvent system stated.
Analytical thin-layer chromatography was performed on commer-
cially available pre-coated aluminium-backed plates (Merck silica
Kieselgel 60 F254). TLCs were visualised either by UV fluorescence
(254 nm), or by staining with basic KMnO4 solution. Melting
points were recorded on an Electrothermal apparatus and are un-
corrected. Infrared spectra were recorded on a Perkin–Elmer Spec-
trum GX FT-IR Spectrometer and analysed either as thin films
between NaCl plates (thin film) or via solid KBr disk (KBr) as
stated. Absorption maxima (νmax) are quoted in wavenumbers
Figure 3. Proposed mechanism and catalytic cycle for the NHC-
mediated chlorination of ketene 12 using 2,3,4,5,6,6-hexachloro-
cyclohexa-2,4-dienone.
1
(cm–1) and only structurally significant peaks are analysed. H and
13C nuclear magnetic resonance (NMR) spectra were acquired on
either a Bruker Avance 300 (300 MHz 1H, 75.4 MHz 13C) or a
Bruker Avance 400 (400 MHz 1H, 100 MHz 13C) spectrometer in
the deuterated solvent stated. 13C NMR spectra were recorded with
proton decoupling. Chemical shifts (δ) are quoted in parts per mil-
lion (ppm) and referenced to residual solvent peaks or to SiMe4 as
an internal standard (δ = 0.00 ppm). Coupling constants, J, are
quoted in Hz. The abbreviations s, d, t, dd, q and m denote singlet,
doublet, triplet, doublet of doublets, quartet, and multiplet, respec-
tively. The abbreviation Ar is used to denote aromatic. GC analysis
was performed on a Fison 800 gas chromatograph using a CP-
Chirasil-Dex CB column. Mass spectrometric (m/z) data were ac-
quired by electrospray ionisation (ESI) or chemical ionisation (CI),
at the EPSRC National Mass Spectrometry Service Centre, Swan-
sea ([M]+, [M + H]+, [M + NH4]+ quoted). CI MS was carried out
on a Micromass Quattro II spectrometer. High resolution ESI was
carried out on a Finnigan MAT 900 XLT; a Thermofisher LTQ
Orbitrap XL spectrometer was used to obtain high resolution ESI
MS for accurate mass determination but also provided fragmenta-
tion data for the characterisation of samples. Values are quoted as
a ratio of mass to charge in Daltons.
Conclusions
In conclusion, we have demonstrated that NHCs pro-
mote the efficient chlorination of disubstituted ketenes with
a range of chlorinating agents, generating the correspond-
ing tertiary α-halo esters in good yield. Chiral NHCs pro-
mote catalytic asymmetric halogenation using polyhalogen-
ated quinones, with modest, although promising levels of
asymmetric induction (up to 61% ee). Current studies are
aimed at the further optimisation of the asymmetry in this
reaction manifold and developing novel modes of asymmet-
ric catalysis using enantiomerically pure NHCs.
Experimental Section
General: All reactions involving moisture-sensitive reagents were
performed under an atmosphere of argon or nitrogen using stan-
dard vacuum line techniques and with dry solvents. All glassware
was flame dried and allowed to cool under vacuum. “Room tem-
perature” (room temp.) refers to 20–25 °C. Temperatures of –40
General Procedure A: To a flame dried Schlenk flask under an ar-
gon atmosphere was added azolium salt (0.050 mmol), base
(0.045 mmol) and toluene (3 mL) and the mixture stirred for
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NHC-Mediated Chlorination of Unsymmetrical Ketenes
20 min. A solution of the requisite ketene (0.50 mmol) in toluene
(6 mL) was added, immediately followed by the requisite chlorinat-
ing reagent (0.50 mmol). Toluene (1 mL) was added to wash resid-
ual solid into solution and the reaction was stirred for 3 h at room
temperature before concentration in vacuo. The resulting crude
residue was purified by flash column chromatography (silica, PE)
to provide the title compound.
NMR: δH (400 MHz, CDCl3) = 7.65–7.60 (m, 2 H, ArH), 7.42–
7.32 (m, 3 H, ArH), 2.66–2.51 (m, 2 H, CH2CH3) and 1.03 (t, J =
7.2 Hz, 3 H, CH2CH3) ppm. δC (75 MHz, CDCl3) = 166.2, 142.4,
136.3, 128.7, 128.3, 127.0, 124.6, 90.4, 74.4, 34.0 and 8.7 ppm. m/z
HRMS (CI+), [M + NH4]+, C13H10O235Cl6NH4+ requires 425.9155,
found 425.9150 (+1.1 ppm).
Perchlorophenyl 2-Chloro-2-phenylbutanoate (24): General pro-
cedure B. Azolium salt 18 (28.5 mg, 0.050 mmol, 0.1 equiv.),
Cs2CO3 (14.6 mg, 0.045 mmol, 0.09 equiv.), ketene 12 (80 mg,
0.55 mmol, 1.1 equiv.) and 5 (150 mg, 0.50 mmol, 1.0 equiv.) in tol-
uene (10 mL) for 3 h at –40 °C gave a crude product which was
purified by flash column chromatography (silica, PE) to give 24 as
a white solid (201 mg, 90% yield); m.p. 83–84 °C. [α]2D0 = +14.8 (c
= 0.50, CHCl3). IR (KBr disk): νmax = 2976, 1773 (C=O), 1386,
1362, 1190, 1183, 1082, 990, 912, 863, 827, 767, 745, 722 and 698.
NMR: δH (400 MHz, CDCl3) = 7.70–7.67 (m, 2 H, ArH), 7.46–
7.35 (m, 3 H, ArH), 2.69 (dq, J = 14.5 7.2 Hz, 1 H, CHAHBCH3),
2.56 (dq, J = 14.5 7.3 Hz, 1 H, CHAHBCH3) and 1.09 (t, J =
7.2 Hz, 3 H, CH2CH3) ppm. δC (75 MHz, CDCl3) = 166.7, 143.9,
137.3, 132.2, 132.0, 128.9, 128.6, 127.7, 127.1, 74.9, 34.3 and
General Procedure B: To a flame dried Schlenk flask under an ar-
gon atmosphere was added azolium salt (0.050 mmol), base
(0.045 mmol) and toluene (3 mL) and the mixture stirred for
20 min. The mixture was then cooled to –40 °C in a cryostatic bath
before addition of a –40 °C solution of the requsite ketene
(0.50 mmol) in toluene (6 mL), immediately followed by the requi-
site chlorinating agent (0.50 mmol). Toluene (1 mL) was added to
wash residual solid into solution and the reaction was stirred for
3 h at –40 °C before opening the flask to the air for 30 min and
concentration in vacuo. The resulting crude residue was purified
by flash column chromatography (silica, PE) to provide the title
compound.
Representative experimental procedures for the synthesis of each
compound are detailed below; full experimental details for all reac-
tions performed are included in the Supporting Information.
+
9.1 ppm. m/z HRMS (CI+), [M + NH4]+, C16H10O235Cl6NH4 re-
quires 461.9154, found 461.9150 (+0.8 ppm). GC Analysis (of the
corresponding methyl ester 16): 61% ee [CP-Chirasil-Dex CB col-
umn; 100 °C (60 min) 1.0 °C/min to 120 °C; 11.6 psi H2; retention
times; 46.7 (minor), 47.8 (major)].
2,6,6-Trichlorocyclohex-1-en-1-yl 2-Chloro-2-phenylbutanoate (13):
General procedure A. Azolium salt 18 (28.5 mg, 0.05 mmol,
0.1 equiv.), Cs2CO3 (14.7 mg, 0.045 mmol, 0.09 equiv.), ketene 12
Perchlorophenyl 2-Chloro-2-phenylhexanoate (30): General pro-
cedure B. Azolium salt 18 (28.5 mg, 0.05 mmol, 0.1 equiv.), Cs2CO3
(14.6 mg, 0.045 mmol, 0.09 equiv.), ketene 25 (95.8 mg, 0.55 mmol,
1.1 equiv.) and 5 (150 mg, 0.50 mmol, 1.0 equiv.) in toluene (10 mL)
for 3 h at –40 °C gave a crude product which was purified by flash
(73.1 mg, 0.5 mmol, 1.0 equiv.) in (6 mL) and
9 (118 mg,
0.05 mmol, 1.0 equiv.) in toluene (10 mL) for 16 h gave a crude
product which purified by flash column chromatography (alumina,
25% EtOAc/PE) to give 13 as a colourless oil (90 mg, 47%) with
spectroscopic data in accordance with the literature.[11] [α]2D0 = 0.0
(c = 0.4, CH2Cl2). NMR: δH (400 MHz, CDCl3) = 7.69–7.64 (m, 2
H, ArH), 7.41–7.32 (m, 3 H, ArH), 2.75–2.63 (m, 3ϫ CH2), 2.59–
2.47 (m, 1 H, CH2) overlapping 2.57 (t, J = 6.2 Hz, 2 H, CH2),
2.01–1.94 (m, 2 H, CH2) and 1.10 (t, J =7.2 Hz, 3 H, CH2CH3)
ppm.
column chromatography (silica, PE) to give 30 as a white solid (158,
67% yield); m.p. 66–72 °C. [α]2D0 = +5.9; 34% ee;
ν
max
(KBr disk):
[29]
2959, 2933, 1773 (C=O) 1494, 1445, 1385, 1360, 1178, 1133, 1052,
981, 914, 825, 769, 721 and 702. NMR: δH (400 MHz, CDCl3) =
7.69–7.66 (m, 2 H, ArH), 7.44–7.34 (m, 3 H, ArH), 2.61 (ddd, J =
14.6 10.9 4.1 Hz, 1ϫ CH2), 2.50 (ddd, J = 14.6 11.7 4.1 Hz, 1ϫ
CH2) and 1.62–1.52 (m, 1ϫ CH2), 1.46–1.34 (m, 3ϫ CH2) and
0.93 (t, J 7.2, 3 H, CH3) ppm. δC (75 MHz, CDCl3) = 166.7, 143.9,
137.6, 132.2, 132.0, 129.0, 128.6, 127.8, 127.0, 74.3, 40.8, 26.7, 22.7
Methyl 2-Chloro-2-phenylbutanoate (16): General procedure B.
Azolium salt 16 (17.4 mg, 0.050 mmol, 0.1 equiv.), KHMDS (0.5 
in toluene, 0.09 mL, 0.045 mmol, 0.09 equiv.), ketene 12 (73.1 mg,
0.5 mmol, 1.0 equiv.) and 19 (66.8 mg, 0.050 mmol, 1.0 equiv.) in
toluene (10 mL) for 3 h at –40 °C before warming to room temp.
gave a crude product. Treatment of the crude mixture with DMAP
(183 mg, 1.50 mmol, 3.0 equiv.) in MeOH (5 mL) at room temp.
for 16 h gave a crude product which was purified by flash column
chromatography (silica, 5% EtOAc/PE) to give 21 as a colourless
oil (47 mg, 39% yield, with respect to ketene) with spectroscopic
data in accordance with the literature.[11] [α]2D0 = –2.6 (c = 0.2,
CH2Cl2). GC Analysis 11% ee [CP-Chirasil-Dex CB column;
100 °C (60 min) 1.0 °C/min to 120 °C; 11.6 psi H2; retention times;
41.3 (minor), 43.7 (major)]. NMR: δH (300 MHz, CDCl3) = 7.50–
7.47 (m, 2 H, ArH), 7.39–7.30 (m, 3 H, ArH), 3.76 (s, 3 H, OCH3),
2.51 (dq, J = 14.4 7.2 Hz, 1 H, CHAHBCH3), 2.36 (dq, J = 14.4
7.2 Hz, 1 H, CHAHBCH3) and 0.98 (t, J = 7.2 Hz, 3 H, CH2CH3)
ppm.
+
and 14.0 ppm. m/z HRMS (ES+) [M + NH4]+, C18H14O235Cl6NH4
requires 489.9459, found 489.9463 (–0.9 ppm).
Perchlorophenyl 2-Chloro-2-(p-tolyl)butanoate (31): General pro-
cedure B. Azolium salt 18 (71.3 mg, 0.125 mmol, 0.25 equiv.),
Cs2CO3 (39.1 mg, 0.120 mmol, 0.24 equiv.), 26 (160.2 mg,
0.75 mmol, 1.5 equiv.) and 5 (150 mg, 0.05 mmol, 1.0 equiv.) in tol-
uene (10 mL) for 3 h at –40 °C before warming to room temp. gave
a crude product which was purified by flash column chromatog-
raphy (silica, PE) to give 31 as a white solid (202 mg, 88% yield);
m.p. 66–72 °C. [α]2D0 = +7.4 (c = 0.50, CHCl3); 48% ee. IR (KBr
disk): νmax = 2921, 1784 (C=O), 1511, 1452, 1386, 1362, 1205, 1130,
1067, 1020, 886, 791, 715 and 519. NMR: δH (400 MHz, CDCl3)
= 7.57–7.53 (m, 2 H, ArH), 7.22 (d, J = 8.0 Hz, 2 H, ArH), 2.67
(dq, J = 14.5 7.3 Hz, 1 H, CHAHBCH3), 2.53 (dq, J = 14.5 7.3 Hz,
1 H, CHAHBCH3) 2.38 (s, 2 H, ArCH3) and 1.09 (t, J = 7.3 Hz, 3
H, CH2CH3) ppm. δC (75 MHz, CDCl3) = 166.8, 144.0, 138.2,
134.4, 132.2, 132.0, 129.3, 127.8, 127.0, 74.9, 34.3, 21.2 and
Perchloroprop-1-en-2-yl 2-Chloro-2-phenylbutanoate (23): General
procedure B. Azolium salt 17 (19.7 mg, 0.050 mmol, 0.1 equiv.),
KHMDS (0.5  in toluene, 0.090 mL, 0.045 mmol, 0.09 equiv.), ke-
tene 12 (73.1 mg, 0.500 mmol, 1.0 equiv.) and 22 (0.050 mL,
0.050 mmol, 1.0 equiv.) in toluene (10 mL) for 3 h at –40 °C gave a
crude product which was purified by flash column chromatography
(silica, 2.5% EtOAc/PE) to give 23 as a colourless oil (148 mg, 72%
yield). [α]2D0 = +2.1 (c = 0.49, CH3Cl). IR (thin film): νmax = 2940,
1773 (C=O), 1600 (C=C), 1447, 1162, 1064, 997 and 762 cm–1.
9.1 ppm. m/z HRMS (ES+) [M + NH4]+, C17H12O235Cl6NH4 re-
+
quires 475.9302, found 476.9307 (–1.0 ppm).
Perchlorophenyl 2-Chloro-2-(p-tolyl)propanoate (32): General pro-
cedure B. Azolium salt 18 (28.5 mg, 0.05 mmol, 0.1 equiv.), Cs2CO3
(14.6 mg, 0.045 mmol, 0.09 equiv.), ketene 27 (80.4 mg, 0.55 mmol,
1.1 equiv.) and 5 (150 mg, 0.50 mmol, 1.0 equiv.) in toluene (10 mL)
Eur. J. Org. Chem. 2010, 5863–5869
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5867

A. D. Smith et al.
FULL PAPER
for 3 h at –40 °C gave a crude product which was purified by flash
column chromatography (silica, PE) to give 32 as a white solid
(169 mg, 76% yield); m.p. 66–68 °C. [α]2D0 = +12.8 (c = 0.53,
CHCl3); 44% ee. IR (KBr disk): νmax = 2922, 1762 (C=O), 1512,
1444, 1382, 1360, 1202, 1185, 1084, 1053, 887, 815, 794, 721 and
518. NMR: δH (400 MHz, CDCl3) = 7.65–7.57 (m, 2 H, ArH),
7.25–7.22 (m, 2 H, ArH), 2.39 (s, 3 H, ArCH3) and 2.34 [s, 3 H,
C(2)CH3]; δC (100 MHz, CDCl3) = 167.1, 144.0, 139.2, 136.0,
167.1, 145.8, 137.6, 135.4, 129.0, 128.7, 128.6, 120.5, 118.6,
69.3, 35.3 and 10.7 ppm. m/z HRMS (ES+) [M + NH4]+,
+
C16H16O2N179Br4NH4
requires 569.7906, found 569.7909
(–0.5 ppm). HPLC (Chiralpak OJ-H, flow rate = 1.0 mL/min,
isohexane/ethanol = 70:30): tR = 2.5, 6.5 min. The absolute config-
uration of 36 could not be determined absolutely and was assigned
by analogy to that of 24.
Supporting Information (see also the footnote on the first page of
this article): Full experimental details and spectroscopic data for
all products are available.
132.3, 132.1, 129.4, 127.8, 126.7, 69.2, 29.6 and 21.3 ppm. m/z
HRMS (ES+), [M
+
NH4]+, C16H14O235Cl6NH4 requires
+
461.9148, found 461.9150 (–0.5 ppm).
Perchlorophenyl 2-Chloro-2-(2-chlorophenyl)butanoate (33): General
procedure B. Azolium salt 18 (28.5 mg, 0.05 mmol, 0.1 equiv.),
Cs2CO3 (14.6 mg, 0.045 mmol, 0.09 equiv.), ketene 28 (99.3 mg,
0.55 mmol, 1.1 equiv.) and 5 (150 mg, 0.50 mmol, 1.0 equiv.) in tol-
uene (10 mL) for 3 h at –40 °C gave a crude product which was
purified by flash column chromatography (silica, PE) to give 33 as
a white solid (233 mg, 97% yield); m.p. 83–85 °C. [α]2D0 = +3.6 (c =
0.44, CHCl3); 26% ee. IR (KBr disk): νmax = 2982, 2940, 1781
(C=O), 1465, 1431, 1382, 1359, 1166, 1130, 1066, 988, 910, 822,
764, 754, 718, 726 and 674. δH (400 MHz, CDCl3) = 8.01–7.98 (m,
1 H, ArH), 7.45–7.32 (m, 3 H, ArH), 3.11 (dq, J 14.8 7.4, 1 H,
CHAHBCH3), 2.65 (dq, J 14.8 7.4, 1 H, CHAHBCH3) and 0.89 (t,
J 7.4, 3 H, CH2CH3). δC (75 MHz, CDCl3) = 164.9, 143.7, 134.1,
132.3, 132.0, 132.0, 131.0, 130.8, 130.3, 128.0, 127.1, 75.1, 31.4 and
Acknowledgments
The authors would like to thank the Royal Society of Chemistry
(RSC) for a University Research Fellowship (to A. D. S.), AstraZ-
eneca and the Engineering and Physical Sciences Research Council
(EPSRC) (Case studentship to J. D.), the EPSRC (K. B. L., C. C.)
and the Ministerio de Educación y Ciencia (C. C.). The EPSRC
mass spectrometry facility is also acknowledged.
[1] For a selection of relevant reviews, see M. Marigo, K. A.
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8.6 ppm. m/z HRMS (ES+), [M + NH4]+, C16H9O235Cl7NH4 re-
+
quires 495.8755, found 495.8760 (–1.1 ppm).
Perchlorophenyl 2-Chloro-2-(4-chlorophenyl)butanoate (34): General
procedure B. Azolium salt 18 (28.5 mg, 0.05 mmol, 0.1 equiv.),
Cs2CO3 (14.6 mg, 0.045 mmol, 0.09 equiv.), ketene 29 (99.3 mg,
0.55 mmol, 1.1 equiv.) and 5 (150 mg, 0.50 mmol, 1.0 equiv.) in tol-
uene (10 mL) for 3 h at –40 °C gave a crude product which was
purified by flash column chromatography (silica, PE) to give 34 as
a white solid (218 mg, 91% yield); m.p. 88–92 °C. [α]2D0 = +6.2 (c =
0.53, CHCl3); 44% ee. IR (KBr disk): νmax = 2983, 2942, 1791
(C=O), 1595, 1491, 1390, 1362, 1172, 1099, 1081, 1018, 874, 820,
728, 717 and 517. NMR: δH (400 MHz, CDCl3) = 7.65–7.60 (m, 2
H, ArH), 7.43–7.38 (m, 2 H, ArH), 2.68 (dq, J = 14.5 7.2 Hz, 1 H,
CHAHBCH3), 2.55 (dq, J = 14.5 7.2 Hz, 1 H, CHAHBCH3) and
1.08 (t, J = 7.2 Hz, 3 H, CH2CH3) ppm. δC (75 MHz, CDCl3) =
166.2, 143.8, 136.0, 135.1, 132.3, 132.1, 128.7, 128.6, 127.6, 74.3,
34.4 and 8.9 ppm. m/z HRMS (ES+) [M]+, C16H9O235Cl7+ requires
477.8417, found 477.8417 (+0.1 ppm).
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2,4,6-Tribromophenyl 2-Bromo-2-phenylbutanoate (36): To a flame
dried Schlenk flask under an argon atmosphere was added azolium
salt 18 (28.5 mg, 0.05 mmol, 0.1 equiv.), Cs2CO3 (14.6 mg,
0.045 mmol, 0.09 equiv.) and toluene (3 mL) and the mixture
stirred for 20 min. The mixture was then cooled to –40 °C in a
cryostatic bath before addition of a solution of 12 at –40 °C
(73.1 mg, 0.55 mmol, 1.1 equiv.) in toluene (6 mL), immediately fol-
lowed by 2,4,4,6-tetrabromocyclohexa-2,5-dienone 35 (205 mg,
0.50 mmol, 1.0 equiv.). Toluene (1 mL) was added to wash residual
solid into solution and the solution stirred for 3 h at –40 °C. The
solution was warmeded to room temperature over 16 h then con-
centrated in vacuo to give a crude product which was purified by
flash column chromatography (silica, 2% EtOAc/PE) to give 36 as
a colourless oil (257 mg, 92% yield). [α]2D0 = +11.0 (c = 0.7, CHCl3).
IR (KBr disk): νmax = 3071, 2976, 1762 (C=O), 1560, 1494, 1437,
1373, 1178, 1066, 953, 910, 857, 806, 743 and 694. NMR: δH
(300 MHz, CDCl3) = 7.74–7.71 (m, 2 H, ArH), 7.66 (br. s, 2 H,
C6H2Br3), 7.41–7.31 (m, 3 H, ArH), 2.78–2.61 (m, 2 H, CH2CH3)
and 1.07 (t, J = 7.2 Hz, CH2CH3) ppm. δC (75 MHz, CDCl3) =
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5868
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5863–5869

NHC-Mediated Chlorination of Unsymmetrical Ketenes
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comparison with the literature (see ref. [11]).
[21] It should be noted that KHMDS (1 equiv.) alone did not pro-
mote the chlorination of ketene 12 with either N-chlorosuc-
cinimide 19, hexachloroacetone 22 or 2,3,4,5,6,6-hexachlorocy-
clohexa-2,4-dienone 5. In contrast, in the absence of any azol-
ium salt, Cs2CO3 (1 equiv.) was found to promote efficient
chlorination of ketene 12 with both N-chlorosuccinimide 19
and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone 5 but not
hexachloroacetone 22. Although throughout we have employed
a slight excess of azolium salt over the base in order to try and
minimise any background reaction, we cannot be certain that
this base-promoted reaction has been completely suppressed.
This may be a contributory factor in the modest enantio-
selectivities observed in most cases. We have also tried an N-
Mesityl analogue of precatalyst 15 (10 mol-%) in this protocol
[toluene, –40 °C, KHMDS (9 mol-%) and 2,3,4,5,6,6-hexachlo-
rocyclohexa-2,4-dienone 5], giving 24 in 73% isolated yield but
Ͻ5% ee.
[22] CCDC-779563 (for 24) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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α-chloro ester, even at room temperature.
[13]
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1
[29] Determined by H NMR analysis of the corresponding (S)-α-
methylbenzylamide, see Supporting Information for details.
Received: June 16, 2010
Published Online: September 3, 2010
Eur. J. Org. Chem. 2010, 5863–5869
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5869