Bismuth-mediated reductive dehalogenation of α-halocarbonyl compounds

Article abstract of DOI:10.1139/v03-172

Bismuth metal, activated by ammonium hydrogen fluoride, was found to reduce various α-halocarbonyl compounds efficiently and chemoselectively in aqueous media to give the dehalogenated reduction products in excellent yields.

Full text of DOI:10.1139/v03-172

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Bismuth-mediated reductive dehalogenation of
1
␣
-halocarbonyl compounds
Yoon Joo Lee and Tak Hang Chan
Abstract: Bismuth metal, activated by ammonium hydrogen fluoride, was found to reduce various α-halocarbonyl
compounds efficiently and chemoselectively in aqueous media to give the dehalogenated reduction products in excellent
yields.
Key words: bismuth, reduction, α-halocarbonyl compounds, fluoride salts, aqueous media, bismuth enolates, aldol
reaction.
Résumé : On a observé que le bismuth métallique activé par du fluorure d’ammonium permet de réduire en milieu
aqueux divers composés α-halocarbonylés de façon efficace et chimiosélective pour conduire avec de bons rendements
à la formation des produits de réduction déshalogénés.
Mots clés : bismuth, réduction, composés α-halocarbonylés, fluorures, milieu aqueux, énolates de bismuth, réaction
aldolique.
[
Traduit par la Rédaction] Lee and Chan 74
Introduction
structurally diverse α-bromo and α-iodoketones and esters
was found to undergo the reductive dehalogenation by this
procedure, to provide the corresponding reduction products
in excellent yields. More recently, a useful employment of
indium metal for the reductive dehalogenation reaction in
aqueous media was reported by Chae et al. (23). One very
important aspect of these reduction systems involving in-
dium metal is the use of water as a reaction medium, which
has attracted considerable interest in recent years in the con-
text of green chemistry (24). We are interested in seeking an
alternative to indium for aqueous reactions because of the
high cost of indium and its potential toxicity. In this connec-
tion, among the heavy metals such as indium, antimony,
mercury, and lead, bismuth metal is relatively inexpensive
and nontoxic (25). In 1995, Ren et al. (26) reported the
selective reduction of carbon–carbon double bonds in α,β-
unsaturated esters by sodium borohydride in combination
with bismuth chloride in ethanol. Subsequently, they also
found the NaBH –BiCl system to be very effective for the
The reductive dehalogenation of α-halocarbonyl com-
pounds (without affecting the carbonyl group) has received
considerable attention in organic chemistry. A number of re-
agents have been developed for this selective reduction, in-
cluding: (i) reducing agents, such as zinc in acetic acid (1),
sodium dithionate (2), organotin hydrides (3), borohydride
(
(
4), and low-valent transition metal salts (e.g., titanium(III)
5), vanadium(II) (6), and chromium(II) (7)); (ii) strong
nucleophiles that may act as reducing agents, such as iodide
ions (8), phosphines (9), iodophosphines (10), iodotrimethyl-
silane (11), thiols (12), selenols (13), tellurolates (14), and
amines (15); (iii) stoichiometric amounts of zero-valent tran-
sition metal carbonyls of iron (16), cobalt (17), and molyb-
denum (18); (iv) heterogeneous hydrogenation catalysts
involving transition metal surfaces (19); and (v) composite
reducing systems of tin or silicon hydrides with transition
metal catalysts, such as palladium (20) and molybdenum
4
3
(
21). The choice of a reducing agent usually depends on
reduction of nitroarenes to primary amines (27). More re-
cently, BiCl –Al and BiCl –Sm have been used to mediate
what other functional groups are present. Typically, these
methods have to be carried out with organic solvents as the
reaction media. Recently, Ranu et al. (22) reported an effi-
cient and general methodology for the chemoselective reduc-
tion of α-halocarbonyl compounds in aqueous media. They
discovered that indium metal could reduce α-halocarbonyl
compounds to the corresponding dehalogenated carbonyl
compounds in water under sonication. A wide range of
3
3
the coupling of α-bromocarbonyl compounds with aldehydes
(
28). In all these cases, it was presumed that activated bis-
muth was generated by the reduction of the bismuth chlo-
ride, even though bismuth metal by itself was not active.
Recently, we found that many metals can be rendered reac-
tive in aqueous media by the activation of fluoride salts (29).
We have therefore examined the possibility of activating
bismuth metal by fluoride salts in aqueous media for various
reactions.
Received 24 May 2003. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 28 November 2003.
2
Y.J. Lee and T.H. Chan. Department of Chemistry, McGill
University, Montreal, QC H3A 2K6, Canada.
Results and discussion
1This article is part of a Special Issue dedicated to professor
Ed Piers.
Corresponding author (e-mail: tak-hang.chan@mcgill.ca).
During our investigation into the allylation of carbonyl
compounds mediated by bismuth metal, ammonium hydro-
gen fluoride was found to be an effective promoter in aque-
2
Can. J. Chem. 82: 71–74 (2004)
doi: 10.1139/V03-172
© 2003 NRC Canada

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Can. J. Chem. Vol. 82, 2004
Table 1. Reduction of α-halocarbonyl compounds mediated by bismuth metal in the presence of NH HF in aqueous media.
4
2
Entry
α-Halocarbonyl compound
Time (h)
Product
Isolated yield (%)
100a
100a
63a
88
1
2
3
4
5
6
7
8
9
MeCOCHMeBr
2
5
MeCOCH Me
2a
2a
2b
2c
2d
2e
2f
2
EtCOCH Br
EtCOCH3
MeCOCH3
PhCOCH3
2
MeCOCH Cl
14 days
2
PhCOCH Br
2
4
5
24
1
4
16
3
20
2
PhCOCHMeBr
PhCOCH Me
92
2
PhCOCMe Br
PhCOCHMe2
HO CCH Me
95
2
a
HO CCHMeBr
100
2
2
2
HO CCHPhBr
HO CCH Ph
2g
2h
2i
65
2
2
2
a
HO CCOCH Br
HO CCOCH
100
2
2
2
3
1
1
1
0
1
2
MeO CCH Br
MeO CCH
3
100a
2
2
2
p-NO PhCOCH Br
p-NO PhCOCH
2j
94
92
2
2
2
3
p-BrPhCOCH Br
p-BrPhCOCH3
2k
2
a
1
Determined by H NMR. The product was not isolated, owing to its low boiling point or solubility.
ous media (30). This prompted us to initiate a systematic
investigation into the reduction of α-halocarbonyl com-
pounds (1) by bismuth metal with ammonium hydrogen flu-
oride in aqueous media (Scheme 1). The results are
summarized in Table 1.
Scheme 1.
As can be seen in Table 1, bismuth metal activated by am-
monium hydrogen fluoride could effectively reduce various
α-halocarbonyl compounds in aqueous media at room tem-
perature, to provide the corresponding dehalogenated
reduction products in fairly high yields. It should be empha-
sized that in the absence of the fluoride salt, the reduction
with bismuth did not proceed to any significant extent. The
reduction of the chloro compound (entry 3) was found to be
much slower in comparison with those of the bromo com-
pounds. It is important to note that this reduction system is
highly chemoselective. Usually, the nitro group is very sen-
sitive to reduction by metals. However, under these reduc-
tion conditions, p-nitroacetophenone could be obtained
successfully without reducing the nitro group (entry 11).
This should be compared with the BiCl –NaBH system,
ion intermediate 3 (31). While the precise mechanism for the
bismuth-mediated reductive dehalogenation of α-
halocarbonyl compounds is not known at this point, the fact
that the radical self-coupling product 4 was not observed as
a side product under the reaction condition suggests that the
reduction did not undergo the SET process (Scheme 2, path
a). It is more likely that the reduction by bismuth metal in
the presence of ammonium hydrogen fluoride in aqueous
media proceeds through the formation of a bismuth enolate
intermediate 5 (Scheme 2, path b), which, on protonation,
gives the reduction product 2. Similar bismuth enolates have
3
4
which reduces nitro function as well (27). Furthermore, in
the case of 2,4′-dibromoacetophenone, the bromo group on
the aromatic ring also remained unaffected (entry 12). These
results indicate that the present reaction conditions for the
reduction of α-halocarbonyl compounds to dehalogenated
carbonyl compounds are compatible with the nitro groups
and the haloaryl, as well as the carbonyl, groups (ketone,
acid, and ester). Finally, no reductive pinacol coupling prod-
ucts, derived from the carbonyl function, were observed
been invoked for the BiCl –Al mediated aldol condensation
3
(
28).
Supporting evidence for the intermediacy of bismuth
enolate was obtained by carrying out an aldol condensation
under the same reaction conditions. 3-Bromoisobutyro-
phenone (1e) and benzaldehyde in the presence of bismuth
and NH HF were stirred in water at room temperature over-
4
2
night. The reaction proceeded cleanly, and the starting 1e
was completely consumed. In addition to the reduction prod-
uct 2e in 63% yield, the aldol product 6 was obtained in
37% yield (Scheme 3). It appeared that, in the competition
between protonation and aldol reaction, the protonation pro-
cess was favoured. One should be able to increase the yield
of the aldol product 6 by increasing the rate of aldol conden-
sation or suppressing the protonation reaction. This can be
achieved by decreasing the amount of water (Table 2, entry
2), since the rate of the aldol reaction is dependant on the
concentration of aldehyde. Alternatively, one can also reduce
(
29a).
The exact role of the fluoride salt in the activation of
metal in aqueous media is not known. Many metals may be
unreactive in water because of the formation of water-
insoluble metal oxide on the metal surface. Previously, it
was suggested that the fluoride anion may render the metal
oxide water soluble through formation of complex fluoride
salts and allow further reaction at the metal surface to take
place (29a). Metal-mediated reactions in aqueous media may
proceed by different mechanisms, depending on the metal
used. In many cases, it is considered that metal-mediated
aqueous reactions go through a single electron transfer
the rate of protonation by replacing water with D O, taking
2
advantage of the kinetic isotope effect (32). This was indeed
found to be the case (Table 2, entries 3 and 4). These results
suggest that bismuth metal, under fluoride activation, may
(
SET) process on the metal surface, generating a radical an-
©
2003 NRC Canada

Lee and Chan
73
Scheme 2.
Scheme 3.
Table 2. Bismuth-mediated crossed aldol type reaction of 2-
bromoisobutyrophenone (1e) with benzaldehyde in the presence
of NH HF in aqueous media.
Experimental
4
2
General information
Chemicals were purchased from Aldrich or Alfa Aesar
Chemical Company. Thin layer chromatography was per-
formed on plastic plates precoated with silica gel (60 F254),
which were developed using a mixture of hexane and ethyl
acetate as the eluent. Analytes were visualized by UV light
or by dipping the plate into a developing agent (a solution of
ammonium molybdate and ceric sulfate in dilute sulfuric
acid) and heating with a heat gun. Column chromatography
was performed on 230–400 mesh silica gel. Melting points
were determined using a Gallenkamp apparatus and were
Entry
Solvent (mL)
Yield (%) of 6a
Yield (%) of 2ea
1
2
3
4
H O (5)
37
56
76
82
63
44
24
18
2
H O (1)
2
D O (5)
2
D O (1)
2
Note: Ratio 1e:benzaldehyde:Bi:NH HF = 1:1.1:1.5:1.5 mmol.
4
2
a
1
Determined by H NMR of the crude product.
be a viable method to mediate crossed aldol type reactions,
and its scope should be further explored (33).
1
13
uncorrected. H NMR spectra and C NMR spectra were re-
corded on a Varian Mercury 300 MHz spectrometer at ambi-
ent temperature. Chemical shifts (δ) were reported in parts
per million (ppm) and referenced to CDCl at δ 7.25 ppm for
3
1
13
H and δ 77.00 ppm for C. The multiplicity of each signal
Conclusion
was indicated by s (singlet), d (doublet), t (triplet), q (quar-
tet), quint (quintet), sept (septet), and m (multiplet). Cou-
pling constants (J) were reported in Hertz (Hz).
The bismuth-mediated reductive dehalogenation of α-
halocarbonyl compounds in aqueous media was investigated.
Bismuth metal, activated by ammonium hydrogen fluoride,
was found to reduce various α-halocarbonyl compounds effi-
ciently under mild conditions, to afford the corresponding
dehalogenated reduction products in excellent yields. The re-
sults showed that the reduction was highly chemoselective
and suggested that the reduction products were presumably
formed from the bismuth enolate intermediate.
General procedure for bismuth-mediated reductive
dehalogenation
To a mixture of an α-halocarbonyl compound (1 mmol),
bismuth powder (1.5 mmol), and NH HF (1.5 mmol) was
4
2
added distilled water (1 mL). The reaction mixture was vig-
orously stirred at room temperature until the reaction was
©
2003 NRC Canada

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4
Can. J. Chem. Vol. 82, 2004
completed (1–24 h). Additional distilled water (10 mL) was
added to the reaction mixture, and the product was extracted
with diethyl ether (3 × 30 mL). The combined organic layer
was dried over anhydrous Na SO and filtered. After the
evaporation of solvent under reduced pressure, the crude
product was purified by flash column chromatography on
silica gel, using 2% ethyl acetate in hexane as the eluent, to
give the corresponding pure reduction product. Their identi-
ties were confirmed by comparison with authentic samples.
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Bismuth-mediated aldol type reaction
To a mixture of 2-bromoisobutyrophenone (1 mmol),
benzaldehyde (1.1 mmol), bismuth powder (1.5 mmol), and
1
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NH HF (1.5 mmol) was added water or D O (1 or 5 mL).
4
2
2
The reaction mixture was vigorously stirred at room temper-
ature for 12 h. Additional distilled water (10 mL) was added
to the reaction mixture, and the product was extracted with
diethyl ether (3 × 30 mL). The combined organic layer was
dried over anhydrous Na SO and filtered. After the evapo-
1
(1975); (c) R. Noyori, Y. Hayakawa, H. Takaya, S. Murai, R,
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2
4
ration of solvent under reduced pressure, the crude product
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1
was analyzed by H NMR for product distribution. The mix-
1
ture was purified by flash column chromatography on silica
gel, using 5% ethyl acetate in hexane as the eluent, to give
the reduction product 2e and the aldol product 6 (34) as a
(
(
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–
1
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white solid. mp 105–107 °C. IR (CHCl ) (cm ): 3475 (O—
3
1
H), 1672 (C~O). H NMR (300 MHz, CDCl ) δ: 7.58–7.54
m, 2H), 7.48–7.25 (m, 8H), 5.15 (d, J = 3.8 Hz, 1H), 2.92
d, J = 3.8 Hz, 1H), 1.27 (s, 3H), 1.22 (s, 3H). C NMR
75 MHz, CDCl ) δ: 211.59, 140.04, 139.51, 130.37, 127.86,
27.81, 127.64, 127.58, 126.98, 78.82, 52.52, 24.34, 19.70.
3
(
(
(
1
3
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3
1
1
2
2
(
5
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