Neodymium(III)-mediated reformatsky-type reactions of α-halo ketones with carbonyl compounds

Article abstract of DOI:10.1002/ejoc.200700240

In a neodymium(III) iodide induced process, α-bromo ketones 1 and aldehydes 2 are effectively converted into aldol products 3. This Reformatsky-type reaction proceeds through the formation of a neodymium enolate at room temperature in CH₂Cl₂. The analogous reaction in the presence of NdBr₃/NaI at 50°C in THF favors the formation of corresponding aldol-Tishchenko products 5 in good yields. Studies to define the scope and limitations of these reactions mediated by neodymium(III) salts are also described. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700240

FULL PAPER
DOI: 10.1002/ejoc.200700240
Neodymium(III)-Mediated Reformatsky-Type Reactions of α-Halo Ketones
with Carbonyl Compounds
Stefan F. Kirsch*[a] and Clémence Liébert[a]
Keywords: Neodymium / Aldol reactions / Lanthanides / Enolates
In
a
neodymium(III) iodide induced process, α-bromo
sponding aldol–Tishchenko products 5 in good yields. Stud-
ketones 1 and aldehydes 2 are effectively converted into al- ies to define the scope and limitations of these reactions me-
dol products 3. This Reformatsky-type reaction proceeds
through the formation of a neodymium enolate at room tem-
perature in CH2Cl2. The analogous reaction in the presence
of NdBr3/NaI at 50 °C in THF favors the formation of corre-
diated by neodymium(III) salts are also described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
other metals in low oxidation states have been utilized for
the oxidative addition step to generate various metal enol-
ates.[12] In 1985, Fukuzawa and coworkers developed an al-
ternative and facile route for the formation of cerium(III)
enolates that does not involve oxidation of the metal spe-
cies.[13] Therein, treatment of α-bromo ketones with CeI3 in
THF at 23 °C resulted in the formation of the correspond-
ing enolates, which in the presence of an aldehyde electro-
phile gave α,β-unsaturated ketones through a formal aldol
condensation [Equation (1)].[14] Because there is only a lim-
ited number of reports on the use of other trivalent lantha-
nide salts for this type of carbon–carbon bond forma-
tion,[15] we envisioned that an improvement of this reaction
might be accomplished by employing neodymium(III) salts
instead of cerium triiodide.[16]
Introduction
Although historically the use of lanthanide reagents in
organic synthesis has involved only a handful of rather sim-
ple lanthanide salts, these reagents have provided an exten-
sive series of remarkable reactions.[1] For example, the most
spectacular development has occurred with the one-electron
reductant [SmI2(thf)x], which is now a standard reagent for
a variety of attractive processes.[2] Only recently, the di-
valent lanthanide chemistry was expanded to other metals
in the series such as [TmI2(dme)2][3] and [NdI2(thf)5].[4]
Whereas lanthanide(III) salts are commonly used as Lewis
acidic reagents for carbonyl activation,[5,6] organolanthan-
ide reagents are mainly based on cerium trichloride (e.g.
CeCl3/RLi).[1,7] Since the pioneering work by Imamoto and
coworkers in the early 1980s,[8] organocerium compounds
are widely applied to facilitate a variety of nucleophilic ad-
dition reactions.[9] Owing to the fact that cerium is unlikely
the best of the available lanthanides for every transforma-
tion using organolanthanide compounds,[10] we initiated
studies to improve the efficiency of trivalent lanthanide rea-
gents by variation of the metal. Herein, we report a new
approach to aldol products through neodymium organyls
by utilizing the reaction of α-halo ketones and carbonyl
compounds in the presence of stoichiometric amounts of
neodymium(III) salts.
(1)
Results and Discussion
The classical Reformatsky reaction is a convenient proto-
col for carbon–carbon bond formation by using the zinc-
induced reaction of α-halocarbonyl compounds with alde-
hydes and ketones.[11] During this redox process, insertion
of zinc into the halogen–carbon bond takes place forming
a nucleophilic equivalent to a zinc enolate. Additionally,
To this end, we initiated our preliminary studies of the
neodymium(III)-mediated carbon–carbon bond formation
with substrates 1a and 2a as previously employed by Fuku-
zawa and coworkers.[13] We were pleased to find that forma-
tion of ketol product 3aa was best accomplished by treat-
ment of a preformed mixture of α-bromo ketone 1a and
aldehyde 2a with 1.2 equiv. of NdI3 in CH2Cl2 at 0 °C for
18 h (Scheme 1). Under these rather mild conditions, 3-hy-
droxy-1-phenylpentan-1-one (3aa) was obtained in 80%
yield as the sole product.
[a] Department Chemie, Technische Universität München,
Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49-89-2891-3315
E-mail: stefan.kirsch@ch.tum.de
Eur. J. Org. Chem. 2007, 3711–3717
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3711

S. F. Kirsch, C. Liébert
FULL PAPER
Solvent had a marked influence on product formation.
Whereas the formation of ketol 3aa was not observed in
cyclohexane, DMF, or Et2O at 23 °C,[17] the use of THF at
23 °C resulted in the formation of α,β-unsaturated ketone
4aa in 72% yield. Interestingly, toluene was an excellent sol-
vent for the neodymium(III)-mediated carbon–carbon bond
formation reaction providing ketol product 3aa even at
40 °C in good yield (74%). Increasing the reaction tempera-
ture in toluene to 90 °C led to lower yields of 3aa (42%),
whereas acetophenone was isolated as the major byproduct
in 40% yield.
Mixtures of 2-bromoacetophenone (1a) and propional-
dehyde (2a) in CH2Cl2 were exposed to further commer-
cially available neodymium(III) salts to initiate the Re-
formatsky-type conversion. Although the desired transfor-
mation was found to be clean in the presence of NdI3, treat-
ment with NdBr3 or NdCl3, in contrary, did not afford ke-
tol 3aa in CH2Cl2 at 23 °C.
Table 1 illustrates the scope of the NdI3-mediated reac-
tion. A broad variety of α-bromo carbonyls with R1 being
aryl and heteroaryl substituents readily add to simple alde-
hyde 1a in the presence of NdI3 in CH2Cl2 at 0 °C to give
the corresponding products in moderate to very good yields
(Table 1, Entries 1–9). Although the neodymium enolate de-
rived from electron-deficient substrate 1f reacted to give ke-
tol 3fa, this reaction was conducted at 23 °C to obtain rea-
sonable yields (Table 1, Entry 6). The reactions of α-halo
carbonyls bearing alkyl substituents for R1 proved less use-
ful as they did not afford product formation under the stan-
dard conditions. In these cases, 3.0 equiv. of SnCl2 was uti-
lized as an efficient additive to obtain desired ketol prod-
ucts 3.[13a] For instance, α-bromo carbonyl compound 1j
Scheme 1. Formation of 3aa from 1a and 2a in the presence of
NdI3.
Depending on the reaction temperature, the use of stoi-
chiometric amounts of NdI3 in CH2Cl2 also produced α,β-
unsaturated ketone 4aa (through subsequent elimination of
3aa), anti 1,3-diol monoester 5aa (through the aldol–Tish-
chenko reaction), and diol 6aa (through a second aldol re-
action of 3aa). For example, decreasing the reaction tem-
perature to –20 °C also led to the exclusive formation of
ketol product 3aa (73%), although a longer period of time
was required to reach complete consumption of the starting
material. Nevertheless, when the reaction was performed at
23 °C, expected ketol product 3aa was formed in rather low
yield (19%). These conditions resulted in the formation of
4aa as the major product (36%) accompanied by trace
amounts of 5aa (Ͻ5%) and 6aa (Ͻ5%). Although trace
amounts of 5aa and 6aa were quite frequently detected dur-
ing our optimization studies, we could not identify reaction
conditions leading to the exclusive formation of either
product.
Table 1. Formation of ketols 3 from α-bromo ketones 1 and aldehydes 2.
Entry
R1 (1)
No.
R2 (2)
no.
Conditions[a]
Product
Yield 3 [%][b]
1
2
3
4
5
6
7
8
Ph
3-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
4-O2NC6H4
2,5-(MeO)2C6H3
1-(benzofuran-2-yl)
2-thienyl
tBu
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et
Et
Et
Et
2a
2a
2a
2a
2a
2a
2a
2a
2a
2f
2b
2b
2c
2d
2e
2f
0 °C, 18 h
0 °C, 48 h
0 °C, 18 h
0 °C, 18 h
0 °C, 72 h
23 °C, 18 h
0 °C, 18 h
0 °C, 18 h
0 °C, 18 h
23 °C, 48 h
23 °C, 4 h
23 °C, 18 h
23 °C, 18 h
0 °C, 18 h
0 °C, 18 h
0 °C, 18 h
0 °C, 18 h
0 °C, 18 h
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
80
78
68
74
71
44
62
67
82
36
65
77
27
44
78
61
62
70[f]
1g
1h
1i
9
Et
CH2Ph
Ph
10[c]
11[d,e]
12
13
14
15
16
17
18
1j
3jf
1k
1a
1a
1a
1a
1a
1a
1a
3kb
3ab
3ac
3ad
3ae
3af
3ag
3ah
Ph
4-NO2–C6H4
CϵCPh
CH2Ph
CH(CH3)2
C6H11
CH(CH3)Ph
2g
2h
[a] Conditions: 1.0 equiv. of 1 (0.1 ), 1.0 equiv. of 2, 1.2 equiv. of NdI3, CH2Cl2. [b] Yield of pure product after column chromatography.
[c] Addition of 3 equiv. of SnCl2. [d] Conditions: 1.0 equiv. of 1 (0.1 ), 1.0 equiv. of 2, 1.2 equiv. of NdI3, 3.0 equiv. of SnCl2, THF. [e]
1-Chloropropan-2-one was used. [f] erythro:threo, 70:30.
3712
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3711–3717

NdIII-Mediated Reactions of α-Halo Ketones with Carbonyl Compounds
FULL PAPER
with R1 = tBu reacted with aldehyde 2f to give ketol prod- ketols 3. For example, substrates 1j and 1k did not undergo
uct 3jf in 36% yield by using a combination of NdI3 and the Reformatsky-type reaction in the absence of SnCl2
SnCl2 in CH2Cl2 at 23 °C (Table 1, Entry 10).[15] Both ali- (Table 1, Entries 11 and 12). To our surprise, the use of CuI,
phatic and aromatic aldehydes were successfully employed SbI3, and Sc(OTf)3 in THF favored the aldol–Tishchenko
in these transformations (Table 1, Entries 12–18). Only the reaction to give diol monoesters 5 as predominant prod-
sterically hindered pival aldehyde failed to undergo the Re- ucts.[18,19] Accordingly, reaction of substrate 1j with benzal-
formatsky-type transformation.
dehyde in the presence of 1.2 equiv. of NdI3 and 3 equiv. of
Of primary importance, the neodymium(III)-mediated CuI in THF at 23 °C generated anti diol monoester 5jb in
reaction was also found to proceed smoothly by using α- 82% isolated yield (Scheme 4). The formation of the syn
bromo ester 1l as a classical Reformatsky substrate. In this product was not observed under these conditions. With
case, exposure of 1l and benzaldehyde to 1.2 equiv. of NdI3 3 equiv. of SbI3 as the additive, the starting carbonyl re-
in CH2Cl2 at 23 °C for 18 h afforded corresponding product acted smoothly to give 5jb in 81% yield. In the case of
3lb in 70% yield [Equation (2)]. Under similar conditions, Sc(OTf)3, substoichiometric amounts were sufficient to
cerium(III) salts were reported to be ineffective.[12a]
cause the aldol–Tishchenko reaction.
(2)
As exemplified for secondary bromides 1m and 1n, sub-
strates capable of generating diastereoisomers were effec-
tively converted into the desired products, albeit with poor
diastereoselectivity (Scheme 2). Typical anti:syn ratios in
these NdI3-mediated reactions are in the range of 70:30,
only marginally depending on the reaction temperature and
solvent.
Scheme 4. NdI3-mediated aldol–Tishchenko reactions in the pres-
ence of additives.
Alternatively, diol monoester 5jb was obtained through
the neodymium(III)-mediated aldol–Tishchenko reaction
by utilizing a combination of NdBr3 and NaI in THF at
50 °C [Equation (3)]. Notably, the anti product was found
as a single diastereoisomer. To obtain reproducible results
for this conversion, it was mandatory to stir the mixture of
NdBr3 and NaI in THF at 50 °C for at least 24 h before
adding substrates 1j and 2b to this mixture. In the absence
of NdBr3, the aldol–Tishchenko reaction did not take place.
NdBr3 without the addition of NaI was unreactive. Al-
though a couple of aryl-substituted α-bromo carbonyls 1
also reacted to give aldol–Tishchenko products 5 as major
products by using these reaction conditions [Equation (4)],
the conversion proved to be not as general as the synthesis
of ketols 3 discussed previously. For example, reaction of
2-bromo-1-(thiophen-2-yl)ethanone (1i) with benzaldehyde
(2b) failed to give expected diol monoester 5ib, providing
Scheme 2. Diastereoselectivity in NdI3-mediated Reformatsky-type
reactions.
Although we have not yet conducted detailed mechan-
istic studies, we believe that neodymium enolates might be
initially formed from α-bromo ketones or α-bromo esters
upon treatment with NdI3, as it was postulated by Fukuz-
awa and coworkers for the reactivity of CeI3 (Scheme 3).[13]
This step apparently proceeds through halide oxidation in-
stead of the metal center being formally oxidized. Subse-
quent reaction with the electrophilic aldehydes results in the
formation of the observed products.
(3)
Scheme 3. Plausible mechanism through neodymium(III) enolates.
To further expand the scope of neodymium(III)-medi-
ated carbon–carbon bond formations, we briefly examined
the effect of additives on product distribution. In general,
the addition of SnCl2 proved to facilitate the formation of
(4)
3713
Eur. J. Org. Chem. 2007, 3711–3717
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

S. F. Kirsch, C. Liébert
FULL PAPER
8.1 Hz, 1 H), 7.86 (d, J = 7.8 Hz, 1 H), 8.06 (s, 1 H) ppm. 13C
NMR (90.6 MHz, CDCl3): δ = 10.0, 29.6, 45.0, 69.1, 123.2, 126.7,
130.4, 131.3, 136.4, 138.7, 199.5 ppm. LRMS (EI): m/z (%) = 258
(21) [M]+, 183 (100), 157 (26), 155 (28), 76 (21). HRMS: calcd. for
C11H13O2Br [M]+ 258.0078; found 258.0079.
instead ketol 3ib in 32% yield after 24 h through a Re-
formatsky-type reaction. The subsequent Tishchenko reac-
tion was found to be slow in the case of this substrate.
1-(4-Chlorophenyl)-3-hydroxypentan-1-one (3ca): Following the ge-
neral procedure, 3ca was obtained as a pale yellow oil (68%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 1.00 (t, J = 7.5 Hz, 3 H), 1.46–1.72 (m, 2
H), 3.00 (dd, J = 17.6, 8.6 Hz, 1 H), 3.12 (dd, J = 17.6, 3.1 Hz, 1
H, OH), 4.09–4.18 (m, 1 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.89 (d, J
= 8.6 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 10.1, 29.5,
44.8, 69.2, 129.1, 129.6, 135.3, 140.1, 199.8 ppm. LRMS (EI): m/z
(%) = 212 (2) [M]+, 141 (35), 139 (100), 111 (23). HRMS: calcd.
for C11H13O2Cl [M]+ 212.0604; found 212.0601.
Conclusions
The feasibility of employing neodymium(III) salts to in-
duce a Reformatsky-type reaction of α-halo carbonyls with
aldehydes was demonstrated. We show for the first time that
depending upon the reaction conditions the use of NdI3 can
lead to the exclusive formation of aldol products under mild
conditions. It is anticipated that the lessons learned in this
series of experiments should result in new applications for
trivalent neodymium salts in organic synthesis.
3-Hydroxy-1-(p-tolyl)pentan-1-one (3da):[21] Following the general
procedure, 3da was obtained as a pale yellow oil (74%) after flash
chromatography on silica (20% EtOAc/P). 1H NMR (250 MHz,
CDCl3): δ = 1.01 (t, J = 7.4 Hz, 3 H), 1.47–1.70 (m, 2 H), 2.41 (s,
3 H), 2.99 (dd, J = 17.5, 8.9 Hz, 1 H), 3.16 (dd, J = 17.5, 2.7 Hz,
1 H), 3.33 (br. s, 1 H), 4.12–4.14 (m, 1 H), 7.26 (d, J = 8.1 Hz, 2
H), 7.85 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ
= 10.1, 21.8, 29.5, 44.5, 69.3, 128.3, 129.5, 134.5, 144.5, 200.8 ppm.
LRMS (EI): m/z (%) = 192 (4) [M]+, 134 (20), 119 (100), 105 (18),
91 (36). HRMS: calcd. for C12H16O2 [M]+ 192.1150; found
192.1150.
Experimental Section
General: All reactions were carried out with magnetic stirring under
an Ar atmosphere; NdI3 was handled in a glove box. Common
solvents [pentane (P), ethyl acetate (EtOAc), tetrahydrofuran
(THF), and CH2Cl2] were distilled prior to use. All other reagents
and solvents were used as received. 1H NMR spectra were obtained
with a 500 MHz, 360 MHz, or 250 MHz FT-NMR spectrometers.
13C NMR spectra were recorded at 90.6 MHz and 62.9 MHz.
Chemical shifts are reported in ppm relative to solvent signal. Mul-
tiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q
(quadruplet), m (multiplet), dd (doublet of doublets). Flash
chromatography was performed with E. Merck silica gel (43–
60 µm). The eluent used is reported in parentheses. Thin-layer
chromatography (TLC) was performed on precoated glass-backed
plates (Merck Kieselgel 60 F254), and components were visualized
by observation under UV light or by treating the plates with
KMnO4/H2SO4 followed by heating.
3-Hydroxy-1-(4-phenyl)phenylpentan-1-one (3ea): Following the ge-
neral procedure, 3ea was obtained as a pale yellow oil (71%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 1.04 (t, J = 7.4 Hz, 3 H), 1.53–1.73 (m, 2
H), 3.06 (dd, J = 17.5, 8.9 Hz, 1 H), 3.22 (dd, J = 17.5, 2.8 Hz, 1
H), 3.32 (br. s, 1 H), 4.14–4.19 (m, 1 H), 7.38–7.51 (m, 3 H), 7.62
(dd, J = 8.1, 1.3 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 8.03 (d, J =
8.4 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 10.1, 29.6,
44.7, 69.3, 127.3, 127.4, 128.5, 128.8, 129.1, 135.7, 139.9, 146.3,
200.7 ppm. LRMS (EI): m/z (%) = 254 (10) [M]+, 228 (22), 196
(34), 188 (34), 182 (100), 152 (33). HRMS: calcd. for C17H18O2
[M]+ 254.1307; found 254.1304.
Representative Procedure for the Formation of 3 by Using NdI3: 3-
Hydroxy-1-phenylpentan-1-one (3aa):[20] A solution of 2-bromo-1-
phenylethanone (1a; 39.8 mg, 0.20 mmol) in dry CH2Cl2 (2 mL)was
added to neodymium triiodide (124.0 mg, 0.24 mmol). Propional-
dehyde 2a (0.20 mmol) was then added at once, and the resulting
solution was cooled to 0 °C. After stirring for 18 h, the reaction
was quenched by the addition of a saturated aqueous solution of
sodium thiosulfate (0.5 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2ϫ2 mL). The com-
bined organic layer was dried (Na2SO4) and concentrated under
reduced pressure. The crude material was purified by flash
chromatography on silica gel (20% EtOAc/P) to afford 3aa
(28.3 mg, 0.16 mmol, 80%). 1H NMR (250 MHz, CDCl3): δ = 1.01
(t, J = 7.4 Hz, 3 H), 1.48–1.73 (m, 2 H), 3.03 (dd, J = 17.7, 8.8 Hz,
1 H), 3.18 (dd, J = 17.7, 2.8 Hz, 1 H), 3.28 (br. s, 1 H), 4.10–4.19
(m, 1 H), 7.46 (t, J = 7.4 Hz, 2 H), 7.58 (t, J = 7.3 Hz, 1 H), 7.95
(d, J = 7.2 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 10.1,
29.5, 44.7, 69.2, 128.2, 128.8, 133.6, 137.0, 201.1 ppm. LRMS (EI):
m/z (%) = 178 (4) [M]+, 160 (18), 149 (22), 120 (24), 106 (22), 105
(100), 77 (63). HRMS: calcd. for C11H14O2 [M]+178.0994; found
178.0995.
3-Hydroxy-1-(4-nitrophenyl)pentan-1-one (3fa): Following the gene-
ral procedure, 3ga was obtained as a pale yellow oil (44%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 1.03 (t, J = 7.4 Hz, 3 H), 1.50–1.75 (m, 2
H), 2.89 (br. s, 1 H), 3.10 (dd, J = 17.8, 7.4 Hz, 1 H), 3.18 (dd, J
= 17.8, 4.2 Hz, 1 H), 4.19 (app t, J = 5.8 Hz, 1 H), 8.11 (d, J =
8.9 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR (90.9 MHz,
CDCl3): δ = 10.3, 29.7, 45.6, 69.1, 124.0, 129.3, 141.4, 150.7,
199.2 ppm. LRMS (EI): m/z (%) = 223 (1) [M]+, 205 (18), 194 (31),
150 (100). HRMS: calcd. for C11H13NO4 [M]+ 223.0845; found
223.0845.
1-(2,5-Dimethoxyphenyl)-3-hydroxypentan-1-one (3ga): Following
the general procedure, 3ga was obtained as a pale yellow oil (62%)
after flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 0.98 (t, J = 7.4 Hz, 3 H), 1.43–1.66 (m, 2
H), 2.99 (dd, J = 18.0, 9.2 Hz, 1 H), 3.24 (br. s, 1 H), 3.26 (dd, J
= 18.0, 2.5 Hz, 1 H), 3.78 (s, 3 H), 3.86 (s, 3 H), 4.02–4.12 (m, 1
1-(3-Bromophenyl)-3-hydroxypentan-1-one (3ba): Following the ge- H), 6.90 (d, J = 9.0 Hz, 1 H), 7.03 (dd, J = 9.0, 3.2 Hz, 1 H), 7.26
neral procedure, 3ba was obtained as a pale yellow oil (78%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 1.01 (t, J = 7.4 Hz, 3 H), 1.50–1.66 (m, 2
H), 3.01 (dd, J = 17.7, 8.6 Hz, 1 H), 3.11 (dd, J = 17.7, 3.1 Hz, 1
H, OH), 4.10–4.17 (m, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.69 (d, J =
(d, J = 3.2 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 10.1,
29.6, 50.1, 55.9, 56.2, 69.6, 113.4, 113.9, 120.8, 128.1, 153.5, 153.6,
202.8 ppm. LRMS (EI): m/z (%) = 238 (33) [M]+, 202 (16), 165
(100), 119 (31). HRMS: calcd. for C13H18O4 [M]+ 238.1205, found
238.1205.
3714
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3711–3717

NdIII-Mediated Reactions of α-Halo Ketones with Carbonyl Compounds
FULL PAPER
1-(Benzofuran-2-yl)-3-hydroxypentan-1-one (3ha): Following the ge-
neral procedure, 3ha was obtained as a pale yellow oil (67%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(360 MHz, CDCl3): δ = 1.02 (t, J = 7.5 Hz, 3 H), 1.55–1.69 (m, 2
H), 3.06 (dd, J = 17.0, 8.9 Hz, 1 H, OH), 3.16 (dd, J = 17.0, 3.0 Hz,
3-Hydroxy-1,5-diphenylpent-4-yn-1-one (3ad): Following the general
procedure, 3ad was obtained as a pale yellow oil (44%) after flash
chromatography on silica (20% EtOAc/P). 1H NMR (250 MHz,
CDCl3): δ = 3.45 (dd, J = 17.6, 3.7 Hz, 1 H), 3.46 (br. s, 1 H), 3.59
(dd, J = 17.6, 7.8 Hz, 1 H), 5.21–5.28 (m, 1 H), 7.29–7.31 (m, 3
1 H), 4.15–4.21 (m, 1 H), 7.31 (t, J = 7.9 Hz, 1 H), 7.48 (t, J = H), 7.41–7.64 (m, 5 H), 8.00 (dd, J = 8.5, 1.2 Hz, 2 H) ppm. 13C
7.1 Hz, 1 H), 7.54–7.59 (m, 2 H), 7.70 (d, J = 7.7 Hz, 1 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 10.0, 29.7, 45.2, 69.3, 112.6,
113.6, 123.6, 124.2, 127.1, 128.7, 152.6, 155.9, 191.7 ppm. LRMS
NMR (90.6 MHz, CDCl3): δ = 45.7, 59.3, 85.2, 88.7, 122.6, 128.3,
128.4, 128.6, 128.9, 131.9, 133.9, 136.6, 199.0 ppm. LRMS (EI):
m/z (%) = 250 (27) [M]+, 249 (52), 131 (58), 105 (100). HRMS:
(EI): m/z (%) = 218 (24) [M]+, 200 (45), 160 (60), 145 (100), 118 calcd. for C17H14O2 [M]+ 250.0994; found 250.0995.
(19). HRMS: calcd. for C13H14O3 [M]+ 218.0943; found 218.0946.
3-Hydroxy-1,4-diphenylbutan-1-one (3ae): Following the general
3-Hydroxy-1-(thiophen-2-yl)pentan-1-one (3ia): Following the gene-
ral procedure, 3ia was obtained as a pale yellow oil (82%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H), 1.47–1.72 (m, 2
H), 2.98 (dd, J = 17.0, 8.8 Hz, 1 H), 3.12 (dd, J = 17.0, 3.0 Hz, 1
H), 3.19 (br. s, 1 H), 4.08–4.17 (m, 1 H), 7.14 (dd, J = 4.8, 3.8 Hz,
1 H), 7.66 (dd, J = 4.8, 1.0 Hz, 1 H), 7.73 (dd, J = 3.8, 1.0 Hz, 1
H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 10.1, 29.6, 45.4, 69.5,
128.4, 132.6, 134.4, 144.2, 193.7 ppm. LRMS (EI): m/z (%) = 184
procedure, 3ae was obtained as a pale yellow oil (78%) after flash
chromatography on silica (20% EtOAc/P). 1H NMR (360 MHz,
CDCl3): δ = 2.85 (dd, J = 13.6, 6.3 Hz, 1 H), 2.98 (dd, J = 13.6,
7.2 Hz, 1 H), 3.10–3.15 (m, 2 H), 3.22 (br. s, 1 H), 4.48–4.55 (m, 1
H), 7.22–7.36 (m, 5 H), 7.45 (t, J = 7.2 Hz, 2 H), 7.59 (t, J =
7.3 Hz, 1 H), 7.913 (d, J = 7.1 Hz, 2 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 43.1, 44.3, 69.1, 126.7, 128.2, 128.7, 128.8, 129.6,
133.6, 136.9, 138.2, 200.6 ppm. LRMS (EI): m/z (%) = 222 (11)
[M – H2O]+, 150 (50), 120 (16), 105 (100). HRMS: calcd. for
(5) [M]+, 167 (24), 155 (14), 126 (34), 111 (100). HRMS: calcd. for C16H14O [M – H2O]+ 222.1045; found 222.1046.
C9H12O2S [M]+ 184.0558; found 184.0559.
3-Hydroxy-4-methyl-1-phenylpentan-1-one (3af): Following the ge-
1-Hydroxy-4,4-dimethyl-1-phenylpentan-3-one (3jf):[22] Following
the general procedure, 3jf was obtained as a pale yellow oil (36%)
after flash chromatography on silica (20% EtOAc/P). 1H NMR
neral procedure, 3af was obtained as a pale yellow oil (61%) after
flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 0.99 (d, J = 5.5 Hz, 3 H), 1.02 (d, J =
(250 MHz, CDCl3): δ = 1.12 (s, 9 H), 2.60 (dd, J = 17.8, 8.2 Hz, 1 5.5 Hz, 3 H), 1.74–1.87 (m, 1 H), 3.03 (dd, J = 17.5, 9.2 Hz, 1 H),
H), 2.71 (dd, J = 17.8, 3.7 Hz, 1 H), 2.74 (dd, J = 13.6, 6.1 Hz, 1
H), 2.87 (dd, J = 13.6, 7.3 Hz, 1 H), 3.16 (br. s, 1 H), 4.27–4.29
(m, 1 H), 7.22–7.35 (m, 5 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ
3.18 (dd, J = 17.5, 2.6 Hz, 1 H), 3.19 (br. s, 1 H), 4.00–4.01 (m, 1
H), 7.47 (t, J = 7.5 Hz, 2 H), 7.58 (td, J = 7.5, 2.3 Hz, 1 H), 7.96
(dd, J = 7.5, 1.3 Hz, 2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ
= 26.4, 42.5, 43.0, 44.5, 69.1, 126.7, 128.6, 129.5, 138.3, 217.3 ppm. = 18.0, 18.7, 33.3, 42.1, 72.6, 128.2, 128.8, 133.6, 137.2, 201.4 ppm.
LRMS (EI): m/z (%) = 202 (22) [M – H2O]+, 121 (34), 92 (29), 85
(53), 57 (100). HRMS: calcd. for C14H18O [M – H2O]+ 202.1358;
found 202.1362.
4-Hydroxy-4-phenylbutan-2-one (3kb):[23] Following the general
procedure, 3kb was obtained as a pale yellow oil (65%) after flash
chromatography on silica (20% EtOAc/P). 1H NMR (250 MHz,
CDCl3): δ = 2.20 (s, 3 H), 2.77–2.96 (m, 2 H), 3.28 (br. s, 1 H),
LRMS (EI): m/z (%) = 192 (1) [M]+, 149 (40), 120 (12), 105 (100).
HRMS: calcd. for C17H14O2 [M]+ 250.0994; found 250.0995.
3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one (3ag):[12o] Following
the general procedure, 3ag was obtained as a pale yellow oil (62%)
after flash chromatography on silica (20% EtOAc/P). 1H NMR
(360 MHz, CDCl3): δ = 1.01–1.36 (m, 5 H), 1.41–1.55 (m, 1 H),
1.61–1.82 (m, 4 H), 1.93–1.94 (m, 1 H), 3.05 (dd, J = 17.4, 9.1 Hz,
5.16 (dd, J = 8.6, 3.9 Hz, 1 H), 7.28–7.37 (m, 5 H) ppm. 13C NMR 1 H), 3.16 (s, 1 H), 3.19 (dd, J = 17.4, 2.6 Hz, 1 H), 3.96–4.03 (m,
(90.6 MHz, CDCl3): δ = 30.9, 52.1, 70.0, 125.8, 127.9, 128.7, 142.9, 1 H), 7.44–7.50 (m, 2 H), 7.55–7.62 (m, 1 H), 7.95–7.99 (m, 2 H)
209.1 ppm. LRMS (EI): m/z (%) = 164 (78) [M]+, 146 (56), 131
(20), 107 (100), 105 (57). HRMS: calcd. for C10H12O2 [M]+
164.0837; found 164.0836.
ppm. 13C NMR (90.6 MHz, CDCl3): δ = 26.3, 26.4, 26.7, 28.5,
29.2, 42.3, 43.3, 72.0, 128.2, 128.8, 133.6, 137.2, 201.5 ppm. LRMS
(EI): m/z (%) = 232 (1) [M]+, 150 (70), 120 (13), 105 (100). HRMS:
calcd. for C15H20O2 [M]+ 232.1463; found 232.1464.
3-Hydroxy-2-methyl-1-phenylpentan-1-one (3ma):[24] Following the
general procedure, 3ma was obtained as a pale yellow oil (70%)
after flash chromatography on silica (20% EtOAc/P). 1H NMR
3-Hydroxy-1,3-diphenylpropan-1-one (3ab): Following the general
procedure, 3ab was obtained as a pale yellow oil (77%) after flash
chromatography on silica (20% EtOAc/P). 1H NMR (250 MHz,
CDCl3): δ = 3.38 (d, J = 6.1 Hz, 2 H), 3.61 (br. s, 1 H), 5.36 (t, J
= 6.1 Hz, 1 H), 7.31–7.60 (m, 8 H), 7.96 (d, J = 7.3 Hz, 2 H) ppm. (500 MHz, CDCl3): δ = 0.99 (t, J = 7.4 Hz, 1 H, syn), 1.00 (t, J =
13C NMR (90.6 MHz, CDCl3): δ = 47.5, 70.2, 125.9, 127.8, 128.3,
128.7, 128.8, 133.8, 136.8, 143.1, 200.3 ppm. LRMS (EI): m/z (%)
= 226 (36) [M]+, 208 (43), 120 (53), 105 (100). HRMS: calcd. for
C15H14O2 [M]+ 226.0994; found 226.0995.
7.4 Hz, 2 H, anti), 1.28 (d, J = 7.3, Hz, 1 H, syn), 1.29 (t, J =
7.3 Hz, 2 H, anti), 1.44–1.55 (m, 2 H, syn and anti), 1.57–1.65 (m,
2 H, syn and anti), 2.89 (br. s, 0.70 H, anti), 3.08 (br. s, 0.30 H,
syn), 3.52 (dq, J = 3.1, 7.2 Hz, 0.30 H, syn), 3.57–3.63 (m, 0.70 H,
anti), 3.79–3.84 (m, 0.70 H, anti), 3.96–3.99 (m, 0.30 H, syn), 7.49–
7.53 (m, 2 H, syn and anti), 7.59–7.63 (m, 1 H, syn and anti), 7.97–
7.99 (m, 2 H, syn and anti) ppm. 13C NMR (90.6 MHz, CDCl3): δ
= 10.3 (anti), 10.6 (syn), 11.2 (syn), 15.6 (anti), 27.4 (syn), 27.9
(anti), 44.3 (syn), 45.5 (anti), 73.1 (syn), 75.5 (anti), 128.5 (anti),
128.6 (syn), 128.8 (anti), 128.9 (syn), 133.4 (anti), 133.5 (syn), 136.2
(anti), 136.9 (syn), 205.9 (syn and anti) ppm. LRMS (EI): m/z (%)
= 192 (2) [M]+, 174 (13), 134 (55), 123 (28), 105 (100), 77 (57).
HRMS: calcd. for C12H16O2 [M]+ 192.1150; found 192.1159.
3-Hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one (3ac): Following
the general procedure, 3ac was obtained as a pale yellow oil (27%)
after flash chromatography on silica (20% EtOAc/P). 1H NMR
(250 MHz, CDCl3): δ = 3.33 (dd, J = 17.9, 8.3 Hz, 1 H), 3.43 (dd,
J = 17.9, 3.8 Hz, 1 H), 3.85 (d, J = 3.0 Hz, 1 H), 5.44–5.48 (m, 1
H), 7.48 (t, J = 7.6 Hz, 2 H), 7.59–7.64 (m, 3 H), 7.95 (dd, J = 8.6,
1.3 Hz, 2 H), 8.24 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 47.1, 69.4, 124.0, 126.7, 128.3, 129.0, 134.2, 136.4,
147.6, 150.4, 200.0 ppm. LRMS (EI): m/z (%) = 271 (33) [M]+,
253 (24), 120 (23), 105 (100). HRMS: calcd. for C15H13NO4 [M]+
271.0845; found 271.0846.
Ethyl 3-Hydroxy-3-phenylpropanoate (3lb): Following the general
procedure, 3lb was obtained as a pale yellow oil (70%) after flash
Eur. J. Org. Chem. 2007, 3711–3717
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3715

S. F. Kirsch, C. Liébert
FULL PAPER
chromatography on silica (20% EtOAc/P). 1H NMR (500 MHz,
CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H), 2.65–2.82 (m, 2 H), 2.91 (br.
s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 5.14 (dd, J = 8.1, 4.7 Hz, 1 H),
7.28–7.40 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 14.3,
43.5, 61.0, 70.5, 125.8, 128.0, 128.7, 142.7, 172.6 ppm. LRMS (EI):
m/z (%) = 194 (42) [M]+, 107 (100), 105 (74), 79 (38). HRMS: calcd.
for C11H14O3 [M]+ 194.0943; found 194.0942.
[3]
[4]
a) J.-J. Shie, P. S. Workman, W. J. Evans, J.-M. Fang, Tetrahe-
dron Lett. 2004, 45, 2703–2707; b) ·W. J. Evans, N. T. Allen, J.
Am. Chem. Soc. 2000, 122, 2118–2119.
a) W. J. Evans, P. S. Workman, Organometallics 2005, 24, 1989–
1991; b) W. J. Evans, N. T. Allen, P. S. Workman, J. C. Meyer,
Inorg. Chem. 2003, 42, 3097–3099; c) W. J. Evans, P. S. Work-
man, N. T. Allen, Org. Lett. 2003, 5, 2041–2042; d) M. N.
Bochkarev, A. A. Fagin, Chem. Eur. J. 1999, 5, 2990–2992.
For leading reviews, see: a) S. Kobayashi, M. Sugiura, H. Kita-
gawa, W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302; S. Ko-
bayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209–217; for
selected examples, see: b) K. N. Jayaprakash, B. Fraser-Reid,
Org. Lett. 2004, 6, 4211–4214; c) H. C. Aspinall, J. S. Bissett,
N. Greeves, D. Levin, Tetrahedron Lett. 2002, 43, 323–325; d)
M. P. Sibi, S. Manyem, Org. Lett. 2002, 4, 2929–2932.
For the use of CeCl3 as a Lewis acid, see inter alia: a) G. Bar-
toli, R. Beleggia, S. Giuli, A. Giuliani, E. Marcantoni, M.
Massaccesi, M. Paoletti, Tetrahedron Lett. 2006, 47, 6501–
6504; b) G. Bartoli, R. Giovannini, A. Giuliani, E. Marcan-
toni, M. Massaccesi, P. Melchiorre, M. Paoletti, L. Sambri,
Eur. J. Org. Chem. 2006, 1476–1482; c) G. Bartoli, M. Bosco,
A. Giuliani, E. Marcantoni, A. Palmieri, M. Petrini, L. Sambri,
J. Org. Chem. 2004, 69, 1290–1297; d) G. Bartoli, M. Bosco, A.
Giuliani, E. Marcantoni, A. Calmieri, M. Petrini, L. Sambri, J.
Org. Chem. 2004, 69, 1290–1297; e) R. Dal pozzo, A. De Nino,
L. Mariuolo, A. Procopio, A. Tagarelli, G. Sindona, G. Bartoli,
J. Org. Chem. 2002, 67, 9093–9095; f) A. L. Gemal, J.-L. Luche,
J. Am. Chem. Soc. 1981, 103, 5454–5459; g) J.-L. Luche, J. Am.
Chem. Soc. 1978, 100, 2226–2227; h) B. M. Trost, M. J. Bog-
danwiczs, J. Am. Chem. Soc. 1973, 95, 2038–2040; for a review,
see: i) G. Bartoli, E. Marcantoni, L. Sambri, Synlett 2003,
2101–2116.
[5]
[6]
Representative Procedure for the Formation of 5 by Using NdBr3: 3-
Hydroxy-1,3-diphenylpropyl Benzoate (5ab):[19h] A mixture of neo-
dymium tribromide (46.1 mg, 0.12 mmol) and NaI (59.6 mg,
0.40 mmol) in THF (1 mL) was stirred at 50 °C for 18h. Then, a
solution of 2-bromo-1-phenylethanone (19.9 mg, 0.10 mmol) and
benzaldehyde (21.2 mg, 0.20 mmol) in THF (0.5 mL) was added.
Stirring was continued for 18 h. The reaction was quenched by the
addition of a saturated aqueous solution of sodium thiosulfate
(0.5 mL), and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (2ϫ2 mL). The combined organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The
crude material was purified by flash chromatography on silica gel
(20% EtOAc/P) to afford 5ab (26.2 mg, 0.08 mmol, 79%). 1H
NMR (360 MHz, CDCl3): δ = 2.15–2.46 (m, 2 H), 2.92 (br. s, 1
H), 4.80 (dd, J = 6.1, 3.2 Hz, 1 H), 6.33 (dd, J = 10.2, 3.0 Hz, 1
H), 7.21–7.64 (m, 13 H), 7.94–8.10 (m, 2 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 46.6, 70.3, 73.7, 125.7, 126.2, 127.4, 127.9,
128.3, 128.4, 128.5, 129.6, 129.9, 133.1, 140.4, 143.7, 166.3 ppm.
LRMS (EI): m/z (%) = 314 (12) [M – H2O]+, 210 (60), 105 (100).
HRMS: calcd. for C22H18O2 [M – H2O]+ 314.1306; found 314.1307.
3-Hydroxy-4,4-dimethyl-1-phenylpentyl Benzoate (5jb):[19h] Follow-
ing the general procedure, 5jb was obtained as a yellow oil (58%).
1H NMR (360 MHz, CDCl3): δ = 0.93 (s, 9 H), 1.88–1.89 (m, 1
H), 2.20–2.21 (m, 1 H), 2.66 (br. s, 1 H), 3.41 (br. d, J = 10.6 Hz,
1 H), 6.34 (dd, J = 10.8, 2.5 Hz, 1 H), 7.24–7.59 (m, 8 H), 8.09–
8.10 (m, 2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 25.7, 34.5,
39.8, 74.2, 75.1, 126.1, 127.8, 128.4, 128.5, 129.7, 130.1, 133.1,
141.2, 166.5 ppm. LRMS (EI): m/z (%) = 312 (5) [M]+, 294 (7), 507
(35), 133 (85), 105 (100). HRMS: calcd. for C20H24O3 [M]+
312.1725; found 312.1723.
[7]
[8]
H. C. Aspinall, Chem. Rev. 2002, 102, 1807–1850.
a) T. Imamoto, Pure Appl. Chem. 1990, 62, 747–776; b) T. Im-
amoto, N. Takiyama, K. Nakamura, T. Hatajima, Y. Kamiya,
J. Am. Chem. Soc. 1989, 111, 4392–4398; c) T. Imamoto, N.
Takiyama, K. Nakamura, Tetrahedron Lett. 1985, 26, 4763–
4766; d) T. Imamoto, T. Kusumoto, Y. Tawarayama, T. Mita,
Y. Hatanaka, M. Yokoyama, J. Org. Chem. 1984, 49, 3904–
3912.
For reviews, see: a) H.-J. Liu, K.-S. Shia, X. Shang, B.-Y. Zhu,
Tetrahedron 1999, 55, 3803–3830; b) R. Dalpozzo, A. De Nino,
G. Bartoli, L. Sambri, E. Marcantoni in Recent Research De-
velopments in Organic Chemistry (Ed.: S. G. Pandalai),
Transworld Research Network, 2001, vol. 5, pp. 181–191; for
selected examples, see: c) U. Groth, C. Kesenheimer, J. Neid-
höfer, Synlett 2006, 1859–1862; d) D. Enders, J. Gries, Z.-S.
Kim, Eur. J. Org. Chem. 2004, 4471–4482; e) D. Enders, C.
Thiebes, Synlett 2000, 1745–1748; f) A. Fürstner, H. Weintritt,
J. Am. Chem. Soc. 1998, 120, 2817–2825; g) C. Alcaraz, U.
Groth, Angew. Chem. 1997, 109, 2590–2592; Angew. Chem. Int.
Ed. Engl. 1997, 36, 2480–2482; h) S. E. Denmark, J. P. Edwards,
O. Nicaise, J. Org. Chem. 1993, 58, 569–578; i) S.-i. Fukuzawa,
K. Hirai, J. Chem. Soc. Perkin Trans. 1 1993, 1963–1965.
For the use of other organolanthanides, see: A. Krasovskiy, F.
Kopp, P. Knochel, Angew. Chem. 2006, 118, 511–515; Angew.
Chem. Int. Ed. 2006, 45, 497–500.
[9]
3-Hydroxy-3-phenyl-1-(thiophen-2-yl)propan-1-one (3ib):[19h] Fol-
lowing the general procedure for the formation of 5, 3ib was ob-
tained as a yellow oil (32%). 1H NMR (360 MHz, CDCl3): δ =
3.31 (s, 1 H), 3.33 (d, J = 3.0 Hz, 1 H), 3.51 (d, J = 3.0 Hz, 1 H),
5.32–5.36 (m, 1 H), 7.13 (dd, J = 5.0, 3.9 Hz, 1 H), 7.28–7.33 (m,
1 H), 7.36–7.40 (m, 2 H), 7.43–7.46 (m, 2 H), 7.68 (dd, J = 5.0,
1.1 Hz, 1 H), 7.71 (dd, J = 3.9, 1.1 Hz, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 48.1, 70.4, 125.9, 127.9, 128.4, 128.7,
132.8, 134.6, 142.9, 144.0, 192.9 ppm. LRMS (EI): m/z (%) = 214
(75) [M – H2O]+, 213 (100), 185 (29), 111 (42).
[10]
[11]
Acknowledgments
For reviews, see: a) P. G. Cozzi, Angew. Chem. 2007, 119, 2620–
2623; Angew. Chem. Int. Ed. 2007, 46, 2568–2571; b) R.
Ocampo, W. R. Dolbier Jr, Tetrahedron 2004, 60, 9325–9374; c)
J. Podlech, T. C. Maier, Synthesis 2003, 633–655; d) A.
Fürstner, Synthesis 1989, 571–590.
We are grateful to Florian Schmidt for technical assistance. We
thank Prof. Dr. Th. Bach and his group for helpful discussions and
support.
[12]
[1] a) T. Imamoto in Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming, S. L. Schreiber), Pergamon Press, Oxford,
1991, vol. 4, pp. 231–250; b) T. Imamoto, Lanthanides in Or-
ganic Synthesis, Academic Press, London, 1994; c) P. G. Steel,
J. Chem. Soc. Perkin Trans. 1 2001, 2727–2751; d) G. A. Mo-
lander, Chem. Rev. 1992, 92, 29–68.
For other metals than zinc in the Reformatsky reaction, see
inter alia: Cr: a) L. Wessjohann, T. Gabriel, J. Org. Chem. 1997,
62, 3772–3774; b) L. A. Wessjohann, G. Scheid, Synthesis 1999,
1–36; c) J.-E. Dubois, G. Axiotis, E. Bertounesque, Tetrahedron
Lett. 1985, 26, 4371–4372; d) F. Orsini, E. M. Lucci, Tetrahe-
dron Lett. 2005, 46, 1909–1911; e) S.-i. Fukuzawa, H. Matsuz-
awa, S.-i. Yoshimitsu, J. Org. Chem. 2000, 65, 1702–1706; f)
J. M. Concellón, C. Concellón, J. Org. Chem. 2006, 71, 4428–
[2] For a review, see: G. A. Molander, C. R. Harris, Chem. Rev.
1996, 96, 307–338.
3716
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3711–3717

NdIII-Mediated Reactions of α-Halo Ketones with Carbonyl Compounds
FULL PAPER
4432; In: g) S. A. Babu, M. Yasuda, I. Shibata, A. Baba, J.
Org. Chem. 2005, 70, 10408–10419; Ge: h) H. Kagoshima, Y.
Hashimoto, D. Oguro, K. Saigo, J. Org. Chem. 1998, 63, 691–
697; Sn: i) I. Shibata, T. Suwa, H. Sakakibara, A. Baba, Org.
Lett. 2002, 4, 301–303; j) T. H. Chan, C. J. Li, Z. Y. Wei, J.
Chem. Soc. Chem. Commun. 1990, 505–507; Co:; k) F. Orsini,
J. Org. Chem. 1997, 62, 1159–1163; Mn: l) M. Hojo, H. Har-
ada, H. Ito, A. Hosomi, J. Am. Chem. Soc. 1997, 119, 5459–
5460; Ce: m) ref.[8d]; Sb: n) Y. Z. Huang, C. Cheng, Y. Shen, J.
Chem. Soc. Perkin Trans. 1 1988, 2855–2859; Ti: o) M. Shim-
izu, F. Kobayashi, R. Hayakawa, Tetrahedron 2001, 57, 9591–
9595.
síkan, T. Ohshima, H. Masu, K. Katagiri, Y. Sei, K. Yamagu-
chi, M. Shibasaki, Chem. Eur. J. 2005, 11, 5195–5204; c) C.
Schneider, M. Hansch, T. Weide, Chem. Eur. J. 2005, 11, 3010–
3021; d) K. Rohr, R. Herre, R. Mahrwald, Org. Lett. 2005, 7,
4499–4501; e) V. Gnanadesíkan, Y. Horiuchi, T. Ohshima, M.
Shibasaki, J. Am. Chem. Soc. 2004, 126, 7782–7783; f) C. M.
Mascarenhas, S. P. Miller, P. S. White, J. P. Morken, Angew.
Chem. 2001, 113, 621–623; Angew. Chem. Int. Ed. 2001, 40,
601–603; g) C. Schneider, M. Hansch, Chem. Commun. 2001,
1218–1219; h) L. Lu, H.-Y. Chang, J.-M. Fang, J. Org. Chem.
1999, 64, 843–853; i) C. M. Mascrenhas, M. O. Duffy, S.-Y.
Liu, J. P. Morken, Org. Lett. 1999, 1, 1427–1429; j) P. M. Bod-
nar, J. T. Shaw, K. A. Woerpel, J. Org. Chem. 1997, 62, 5674–
5675; k) R. Mahrwald, G. Costisella, Synthesis 1996, 1087–
1089; l) D. P. Curran, R. L. Wolin, Synlett 1991, 317–319; m)
E. R. Burkhardt, R. G. Bergman, C. H. Heathcock, Organome-
tallics 1990, 9, 30–44; n) D. A. Evans, A. H. Hoveyda, J. Am.
Chem. Soc. 1990, 112, 6447–6449; for reviews, see:; o) J. Mlyn-
arski, Eur. J. Org. Chem. 2006, 4779–4786; p) R. Mahrwald,
Curr. Org. Chem. 2003, 7, 1713–1723.
[13] a) S.-i. Fukuzawa, T. Tsuruta, T. Fujinami, S. Sakai, J. Chem.
Soc. Perkin Trans. 1 1987, 1473–1477; b) S.-i. Fukuzawa, T.
Fujinami, S. Sakai, J. Chem. Soc. Chem. Commun. 1985, 777–
778.
[14] For a dehydration protocol using CeCl3·7H2O–NaI, see: a) G.
Bartoli, M. Bosco, R. Dalpozzo, A. Giuliani, E. Marcantoni,
T. Mecozzi, L. Sambri, E. Torregiani, J. Org. Chem. 2002, 67,
9111–9114; b) G. Bartoli, D. C. Bellucci, E. Marcantoni, L.
Sambri, M. Petrini, E. Torregiani, Org. Lett. 2000, 2, 1791–
1793.
[20] T. Sato, H. Matsuoka, T. Igarashi, M. Minomura, E. Muray-
ama, J. Org. Chem. 1988, 53, 1207–1212.
[15] A combination of NdCl3 and SnCl2 was previously examined
for the use in Reformatsky-type reactions, see ref.[13a]
[16] For the use of NdIII salts in organic synthesis, see, for example:
D. A. Evans, S. G. Nelson, M. R. Gagné, A. R. Muci, J. Am.
Chem. Soc. 1993, 115, 9800–9801.
[17] In Et2O, 2-iodoacetophenon was exclusively obtained.
[18] a) M. S. Kulpinski, F. F. Nord, J. Org. Chem. 1943, 8, 256–270.
[19] For selected examples of aldol–Tishchenko reactions, see: a) J.
Mlynarski, B. Rakiel, M. Stodulski, A. Suszczynska, J. Frelek,
Chem. Eur. J. 2006, 12, 8158–8167; b) Y. Horiuchi, V. Gnanade-
[21] V. A. Martin, D. H. Murray, N. E. Pratt, Y. Zhao, K. F. Albiz-
ati, J. Am. Chem. Soc. 1990, 112, 6965–6978.
[22] S. Lou, J. A. Westbrook, S. E. Schaus, J. Am. Chem. Soc. 2004,
126, 11440–11441.
[23] L. S. Hegedus, R. K. Stiverson, J. Am. Chem. Soc. 1974, 96,
3250–3254.
[24] R. Mahrwald, B. Ziemer, Tetrahedron 1999, 55, 14005–14012.
Received: March 16, 2007
Published Online: June 12, 2007
Eur. J. Org. Chem. 2007, 3711–3717
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3717