Iridium-catalyzed isomerization/bromination of allylic alcohols: Synthesis of α-bromocarbonyl compounds

Article abstract of DOI:10.1002/chem.201402350

α-Brominated ketones and aldehydes, with two adjacent electrophilic carbon atoms, are highly valuable synthetic intermediates in organic synthesis, however, their synthesis from unsymmetrical ketones is very challenging, and current methods suffer from low selectivity. We present a new, reliable, and efficient method for the synthesis of α-bromocarbonyl compounds in excellent yields and with excellent selectivities. Starting from allylic alcohols as the carbonyl precursors, the combination of a 1,3-hydrogen shift catalyzed by iridium(III) with an electrophilic bromination gives α-bromoketones and aldehydes in good to excellent yields. The selectivity of the process is determined by the structure of the starting allylic alcohol; thus, α-bromoketones formally derived from unsymmetrical ketones can be synthesized in a straightforward and selective manner. Synthon shuffle: An efficient and high-yielding synthetic route to prepare α-bromoketones and aldehydes is presented (see scheme, Cp=pentamethylcyclopentadienyl). The method relies on 1,3-hydrogen shift/bromination of allylic alcohols catalyzed by Ir^III complexes. The products are obtained in excellent yields and as single constitutional isomers.

Full text of DOI:10.1002/chem.201402350

DOI: 10.1002/chem.201402350
Full Paper
&
Synthetic Methods
Iridium-Catalyzed Isomerization/Bromination of Allylic Alcohols:
Synthesis of a-Bromocarbonyl Compounds
Antonio Bermejo Gꢀmez,[a, b] Elis Erbing,[a, b] Marꢁa Batuecas,[a] Ana Vꢂzquez-Romero,[a] and
Belꢃn Martꢁn-Matute*[a, b]
Abstract: a-Brominated ketones and aldehydes, with two
adjacent electrophilic carbon atoms, are highly valuable syn-
thetic intermediates in organic synthesis, however, their syn-
thesis from unsymmetrical ketones is very challenging, and
current methods suffer from low selectivity. We present
a new, reliable, and efficient method for the synthesis of a-
bromocarbonyl compounds in excellent yields and with ex-
cellent selectivities. Starting from allylic alcohols as the car-
bonyl precursors, the combination of a 1,3-hydrogen shift
catalyzed by iridium(III) with an electrophilic bromination
gives a-bromoketones and aldehydes in good to excellent
yields. The selectivity of the process is determined by the
structure of the starting allylic alcohol; thus, a-bromoke-
tones formally derived from unsymmetrical ketones can be
synthesized in a straightforward and selective manner.
Introduction
Brominated compounds are highly versatile intermediates in
organic synthesis that can undergo various transformations in-
cluding nucleophilic substitution[1] and transition-metal-cata-
lyzed cross-coupling reactions.[2] Consequently, the develop-
ment of efficient and selective methods for their preparation is
important.[3] Bromination reactions have traditionally been ac-
complished by using bromine. However, because of the toxici-
ty and high reactivity of bromine, a number of safer alternative
reagents have been prepared in recent years. Among them, N-
bromoamide reagents have been used in a great number of ef-
ficient and even diastereo- and enantioselective transforma-
tions.[4] Difficulties commonly encountered during the synthe-
sis of halogenated compounds include a lack of selectivity and
an incompatibility of the reaction conditions with certain func-
tional groups. For example, in the halogenation of unsymmet-
rical ketones with two enolizable positions (a and a’), a mixture
of products is usually obtained (Scheme 1). This selectivity may
be controlled in some instances by an electronic and/or steric
Scheme 1. a-Bromination of unsymmetrical ketones.
differentiation of the two enolizable positions, which can result
in selective halogenation.[5] Low selectivities may also be seen
with substrates containing benzylic positions, or with electron-
rich aromatics, because both of these are prone to bromina-
tion.
During the last few years, we have reported alternative se-
lective methods for the synthesis of a-fluoro[6a–b] and a-chloro
ketones and aldehydes[6c] in excellent yields and under mild re-
action conditions. The methodology formally relies on the for-
mation of in situ catalytic amounts of enolates from allylic al-
cohols. This is achieved by using transition-metal catalysts that
can promote a 1,3-hydrogen shift.[7] In the presence of electro-
philic halogenating reagents,[6] a-fluoro and a-chlorocarbonyl
compounds are obtained in excellent yields and, more impor-
tantly, as single constitutional isomers (Scheme 2).[8,9]
A major challenge to be overcome in this tandem process is
the compatibility of the transition-metal catalysts with the hal-
ogenating agents.[10,11] We found that [Cp*IrCl2]2 in aqueous
[a] A. B. Gꢀmez, E. Erbing, M. Batuecas, A. Vꢁzquez-Romero, B. Martꢂn-Matute
Department of Organic Chemistry
and Berzelii Center EXSELENT
Arrhenius Laboratory
Stockholm University,
SE-106 91 Stockholm, Sweden.
Fax: (+) 46815 49 08
E-mail: belen@organ.su.se
[b] A. B. Gꢀmez, E. Erbing, B. Martꢂn-Matute
Berzelii Center EXSELENT
on Porous Materials
Stockholm University,
SE-106 91 Stockholm, Sweden.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402350.
Scheme 2. Synthesis of a-halocarbonyl derivatives from allylic alcohols.
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solvent mixtures was an excellent catalyst that was compatible
with halogenating agents such as Selectfluor and N-chlorosuc-
cinimide (NCS).[6] Furthermore, the reactions could be carried
out under an atmosphere of air and at room temperature in
short reaction times.
Table 1. Screening of reaction conditions.[a]
Inspired by their unique reactivities and important roles as
synthetic intermediates in organic synthesis, in this paper, we
present the results of our investigations into the synthesis of
a-bromocarbonyl compounds from allylic alcohols. Reaction
conditions, including the nature of the catalyst and the solvent
system, were evaluated so that the tandem 1,3-hydrogen shift/
bromination process could be achieved. Furthermore, due to
the high reactivity of common brominating agents such as
bromine and N-bromosuccinimide (NBS), a key factor in the de-
velopment of this new transition-metal-catalyzed bromination
method was the use of a mild and underexplored brominating
reagent. The scope and limitations of this bromination reaction
are presented.
Solvent (v/v)
2 (equiv) Conv. [%][b] Yield [%][b]
3a 4a 5a
1
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (5:1)
THF/H2O (1:5)
THF/H2O (2:1)
THF/H2O (2:1)
2a (1.1)
2b (1.1)
2c (1.1)
2d (1.1)
2c (0.55)
2c (0.55)
2c (0.55)
2c (0.7)
2c (0.7)
2c (0.7)
2c (0.7)
>99
>99
>99
44
84
38
68
93
46
>99
2
–
–
–
–
>99
2[c]
3
–
21
1
14
2
79 <1
42 <1
4
5
6
7
8
9[d]
70
36
42
86
44
90
1
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
25
7
Results and Discussion
4
9
1
10[e] THF/H2O (2:1)
We first investigated the tandem 1,3-hydrogen shift/bromina-
tion of allylic alcohols using the conditions previously reported
by our group for the corresponding fluorination or chlorination
process.[6] The chosen system was oct-1-en-3-ol (1a) as starting
allylic alcohol, in a mixture of tetrahydrofuran (THF) and water
(1:1 v/v), with [Cp*IrCl2]2 (0.5 mol%) as the catalyst in the pres-
ence of common electrophilic brominating reagents (2a–c;
1.1 equiv, Table 1). When N-bromosuccinimide (NBS; 2a) was
used, only the undesired nonbrominated ketone 5a was
formed almost quantitatively (>99%; Table 1, entry 1). Al-
though full conversion was achieved by using tetrabutylammo-
nium tribromide (2b), a mixture of unidentified products was
obtained in which neither 3a, 4a, nor 5a were detected
(Table 1, entry 2). The best result was obtained when 5,5-dibro-
mo-2,2-dimethyl-1,3-dioxane-4,6-dione (5,5-dibromo Meldrum’s
acid; 2c) was used, which gave full conversion into a mixture
of brominated (3a) and nonbrominated (5a) ketones in
a 79:21 ratio (Table 1, entry 3). When the less common 2,2-di-
bromo-5,5-dimethylcyclohexane-1,3-dione (2,2-dibromodime-
done; 2d) was used, the conversion into the desired product
3a was lower under the chosen reaction conditions, but the
selectivity was significantly improved (Table 1, entry 4).
11[e]
Et2O/H2O (2:1)
12[e] 2-MethylTHF/H2O (2:1) 2c (0.7)
3
11
3
7
<1
4
13[e] MeCN/H2O (2:1)
14[e,f] EtOH/H2O (2:1)
15[e] THF/EtOH (2:1)
2c (0.7)
2c (0.7)
2c (0.7)
>99
<1
66
>99
70
26
<1
46
91
66
84
54
8
<1
20
9
16[e] 1,4-Dioxane/H2O (2:1) 2c (0.7)
17[e] Acetone/H2O (2:1)
18[e] Acetone/H2O (5:1)
19[e] Acetone/H2O (1:1)
20[e] Acetone/H2O (1:2)
2c (0.7)
2c (0.7)
2c (0.7)
2c (0.7)
4
95
76
10
22
[a] Unless otherwise noted: [1a]=0.2m, [Cp*IrCl2]2 (0.5 mol%) at room
temperature. Reaction time for entries 1–4=16 h and for 5–20=3 h. All
reactions were run under an atmosphere of air. [b] Determined by
1H NMR spectroscopic analysis using 2,3,5,6-tetrachloronitrobenzene as
internal standard. [c] Full conversion into an unidentified mixture of prod-
ucts. [d] 0.4m. [e] 0.1m. [f] A complex mixture of by-products was formed.
Table S1). When the relative amount of H2O was increased
under otherwise identical conditions, moderate yields and infe-
rior 3a/5a ratios were obtained (Table 1, entry 7 and Table S1).
A drastic decrease in the amount of water in THF or acetone
afforded yields of less than 10% (See Tables S1 and S2), which
may be explained by the low solubility of the iridium complex
in organic solvents.
To improve these results, we screened a range of reaction
conditions including the concentration and the THF/water
ratio, the catalyst loading, and the number of equivalents of
brominating agent 2c. The reactions were stopped after 3 h in
the optimization study to detect differences in the reaction
outcomes. When the number of equivalents of 2c was de-
creased to 0.55 in THF/H2O (1:1, 0.2m), the ratio 3a/5a was im-
proved (Table 1, entry 5 vs. 3). Interestingly, even though less
than 1 equiv of 2c was used, 3a was obtained in a yield as
high as 70%, indicating that this brominating agent is able to
deliver both of its Br atoms to form the product. Increasing
the relative amount of THF in the solvent system gave better
3a/5a ratios, although the conversion gradually decreased as
the amount of THF was increased (Table 1, entry 6 and
Further optimization studies were then conducted with
a THF/H2O ratio of 2:1. The concentration of allylic alcohol 1a,
the number of equivalents of 2c, and the catalyst loading
were varied (Table 1, entries 8–10 and Table S1). It can be con-
cluded that the best results [99% conv. into 3a (90%) and 5a
(9%)] were obtained with 0.7 equiv of 2c, 0.5 mol% [Cp*IrCl2]2
(i.e., 1 mol% Ir), and [1a]=0.1m (Table 1, entry 10). Better re-
sults were not achieved when acidic, basic, or neutral buffers,
or different reaction temperatures were used (40 or 08C). It is
worth mentioning that a,b-unsaturated ketone 4a was not de-
tected, except under the conditions described in entries 3 and
4 (Table 1), for which less than 1% 4a was formed.
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We then studied the effect of different solvent mixtures on
the 1,3-hydrogen shift/bromination of 1a (0.1m concentration)
with 2c (0.7 equiv) catalyzed by [Cp*IrCl2]2 (0.5 mol%). The use
of Et2O, 2-methyltetrahydrofuran (2-methylTHF), or MeCN, in
combination with H2O (2:1) (Table 1, entries 11–13), gave very
low conversions of the starting allylic alcohol. In EtOH/H2O
(2:1), most 1a decomposed and bromoketone 3a was ob-
tained in only 26% yield (Table 1, entry 14). In the absence of
water, when a mixture of EtOH/THF (1:2) was used, no reaction
occurred (Table 1, entry 15). In 1,4-dioxane/H2O (2:1), a moder-
ate conversion and low selectivity were achieved (Table 1,
entry 16). On the other hand, acetone/H2O (2:1) gave essential-
ly the same results as obtained with THF/H2O (2:1) (Table 1,
entry 17 vs. 10). Because acetone is a more environmentally
friendly solvent than THF, which is particularly important for
large-scale applications, further optimization was carried out in
aqueous acetone (Table 1, entries 18–20 and Table S2). Howev-
er, the conversion and the selectivity decreased as the solvent
ratio was varied by either increasing or decreasing the ace-
tone/H2O ratio.
The formation of nonbrominated ketone 5a occurs when
transition-metal-catalyzed isomerization of the allylic alco-
hol[12,13,14] competes with the desired 1,3-hydrogen shift/bromi-
nation. The former process occurs in the absence of brominat-
ing agent. We have previously observed that the isomerization
of allylic alcohols into carbonyl compounds is accelerated
when the transition-metal-catalyzed reaction is carried out
under acidic conditions.[6a] The formation of 5a when 2c was
used as the brominating agent could thus be ascribed to the
lower stability of this reagent compared with that of 2d, which
results in the formation of traces of acid in the aqueous reac-
tion medium. Furthermore, 2c can deliver both bromine atoms
forming Meldrum’s acid, which decomposes under the reaction
conditions to give acidic species. In contrast, 2,2,-dibromodi-
medone (2d) does not decompose in solution so the forma-
tion of unwanted 5a is suppressed. Other important advantag-
es of using 2d as brominating agent are: i) it can be prepared
easily on a multi-gram scale from available and inexpensive
starting materials in one step,[15] and ii) although only one bro-
mine atom is used, the monobrominated by-product can be
recovered from the reaction medium to be transformed back
into 2d (Scheme 4).
Despite the high conversions achieved, the formation of
ketone 5a diminishes the applicability of this bromination
methodology because challenging purifications are needed to
separate this by-product from 3a. In the best cases described
so far, high conversion into an approximate 91:9 mixture of
3a/5a was obtained in either a THF/H2O or an acetone/H2O
solvent mixture (Table 1, entries 10 and 17). The effect of the
nature of the brominating agent on the outcome of the reac-
tion had, however, only been evaluated in THF/H2O mixtures
(see Table 1). We therefore tested brominating agent 2a, 2b
and 2d again in acetone/H2O (Scheme 3). The use of NBS (2a,
1.2 equiv) or tetrabutylammonium tribromide (2b, 1.2 equiv)
resulted in decomposition of allylic alcohol 1a to give complex
reaction mixtures in which neither ketone 4a nor 5a was de-
tected. We were delighted to observe that with 2d (1.2 equiv),
1a was fully converted into a mixture containing the desired
a-bromoketone 3a (99%) and enone 4a (1%). The formation
of 5a was completely suppressed under these conditions. The
number of equivalents of 2d could not be decreased further
(Table S3), because 2d was able to transfer only one of its bro-
mine atoms to the product. Interestingly, formation of traces
of 4a may indicate the formation of iridium hydride intermedi-
ates, which may act as catalytically active species.[7b,11]
Scheme 4. a) Synthesis of 2,2-dibromodimedone 2d. b) Reusability of the
monobrominated by-product after catalytic bromination with 2d.
The scope of the reaction was then investigated by explor-
ing the 1,3-hydrogen shift/bromination of a variety of allylic al-
cohols under the conditions shown in Scheme 3 (i.e., with 2d
as brominating agent). We observed that substrates with aro-
matic groups and, in particular those in which these groups
were conjugated with the double bond of the allylic alcohol (e.
g., 1i–l in Table 2), required reaction times as long as 42 h.
With the aim of finding a more active catalyst with a broad
substrate scope, we investigated the use of other related IrIII
[16a]
complexes: [Cp*Ir(H2O)3]SO4
and [(Cp*Ir)2(OH)3]OH·11H2O.[16b]
Reactions were carried out in NMR tubes using deuterated sol-
vents, and were followed by 1H NMR spectroscopy. Figure 1
shows the conversion of 1 f as a function of time. The bromi-
Scheme 3. 1,3-Hydrogen shift/bromination of 1a with 2a–d. Conversions
and ratios were determined by H NMR spectroscopy using 2,3,5,6-tetra-
chloronitrobenzene as internal standard.
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nation was faster with hydroxo
complex [(Cp*Ir)2(OH)3]OH·11H2O,
which gave 90% of 3 f in only
10 min, and reached full conver-
sion within 20 min. None of the
catalysts produced the by-prod-
uct 5 f.
Table 2. Scope of the 1,3-hydrogen shift/bromination of allylic alcohols.[a]
Allylic alcohol (2)
t [h]
Product (3)
Yield [%][b]
90 (99)
1
1a
0.5
3a
2
3
4
5
1b
1c
1d
1e
1.5
3
3b
3c
3d
3e
97 (98)[c]
73 (86)[d]
76 (98)[e]
71 (80)[f]
The scope of the reaction was
therefore investigated by using
[(Cp*Ir)2(OH)3]OH·11H2O and 2d
(1.2 equiv) in acetone/H2O (2:1).
In general, aliphatic allylic alco-
hols reacted much more quickly
than those containing a conju-
gated aromatic ring. Increased
steric hindrance at the aliphatic
chain was well tolerated (Table 2,
entries 2–5 vs. entry 1). For sub-
strates containing two olefinic
substituents on the alcohol
carbon, bromination only oc-
curred at the least substituted
double bond (Table 2, entries 4,
5, 7, and 8). Trisubstituted
double bonds further away from
the allylic alcohol moiety did not
react (Table 2, entries 3 and 4).
The presence of a nonconjugated
aromatic ring did not slow down
the reaction (Table 2, entry 6 vs.
1). However, when the aromatic
ring was conjugated, longer re-
action times were needed
(Table 2, entries 7–8 vs. 6). This
was particularly so for those sub-
strates in which the aromatic
ring was conjugated with the re-
active double bond, which may
be due to a loss of conjugation
during the reaction. For these
2
3.5
6
7
1 f
1g
1h
1i
0.5
24
4
3 f
3g
3h
3i
96 (98)
46 (92)
79 (88)
85 (92)
83 (96)
8
9[g]
24
24
10[g]
1j
3j
11[g]
12[g]
13[g]
1k
1l
24
24
24
3k
3l
82 (94)
88 (96)
87 (90)
1m
3m
substrates,
a
higher catalyst
loading was needed (Table 2, en-
tries 9–15). An excellent example
showing the efficiency of this
methodology is shown in
Table 2, entry 15, whereby 1o,
with two allylic alcohol moieties,
was transformed into bis(a-bro-
moketone) 3o in excellent yield.
The attempted preparation of
3o directly from the correspond-
ing nonbrominated diketone
would result in a complex mix-
ture of brominated products
with the Br group at either of
the a or a’ carbon atoms of
each of the carbonyl groups or
14[g]
1n
1o
24
24
3n
3o
45 (52)
87 (92)
15[g,h]
16
17
1p
1q
5
6
3p
3q
91 (96)
86 (99)
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yield, and 3g, which, although it
was formed in very good yield,
decomposed during purification.
A control experiment performed
with allylic alcohol 1 f in the ab-
sence of the iridium catalyst for
72 h afforded exclusively starting
material.
Table 2. (Continued)
Allylic alcohol (2)
t [h]
Product (3)
Yield [%][b]
70 (85)
18[g]
1r
24
3r
[a] Reaction conditions: allylic alcohol (1, 1.0 mmol), 2,2-dibromodimedone (2d, 1.2 mmol), [(Cp*Ir)2(OH)3]·11H2O
(1.0 mol%, 2 mol% Ir), acetone/H2O (2:1 v/v, 0.1m on allylic alcohol), RT under air atmosphere. [b] Isolated
1
yield; yields determined by H NMR spectroscopy using 2,3,5,6-tetrachloronitrobenzene as internal standard are
a-Bromocarbonyl compounds
are important synthetic inter-
mediates in organic chemistry.
This bromination methodology
can be used as the key step in
given in parentheses. In cases were a quantitative yield was not obtained, the remainder was starting material.
[c] d.r.=1:2 [d] d.r.=1:1. [e] E/Z=1:1. [f] d.r.=1:1. [g] [(Cp*Ir)2(OH)3]·11H2O (2.0 mol%). [h] 2d (2.4 equiv).
the selective preparation of a variety of functionalized mole-
cules. Selected examples are shown in Scheme 5. Upon treat-
ment of 3 f with KI, a-iodoketone 6 is obtained in good yields.
a-Iodoketones are also important synthons in organic synthe-
sis. a-Bromocarbonyl compounds contain two consecutive
electrophilic carbon atoms, which makes them important pre-
cursors in the synthesis of a variety of heterocyclic compounds.
For example, treatment of 3 f with thiourea afforded 2-amino-
thiazole 7 in excellent yield.[6c] Additionally, reduction of the
carbonyl functional group of a-bromocarbonyls affords anoth-
er highly versatile building block in organic synthesis. Thus,
treatment of 3 f with NaBH4 gave bromohydrin 8 in good
yields and with excellent diastereoselectivity.
Conclusions
We have developed a new method for the synthesis of a-bro-
moketones in excellent yields as single constitutional isomers
from allylic alcohols. The method can also be used to synthe-
size a-bromoaldehydes. The reactions are catalyzed by
[(Cp*Ir)2(OH)3]OH·11H2O and carried out in aqueous acetone,
and they do not require the use of an inert atmosphere. As
brominating agent, 2,2-dibromodimedone afforded the best
results, because it suppressed the formation of nonbrominated
carbonyl by-products and was compatible with functionalized
alcohols without yielding undesired polybrominated species.
Mechanistic investigations are in progress, and the results will
be reported in due course. a-Bromocarbonyl compounds are
very versatile synthetic intermediates. Thus, this new proce-
dure is expected to be of great interest to the scientific com-
munity, both in academia and in industry, because it opens up
new and efficient synthetic routes for the preparation of
a large variety of building blocks.
Figure 1. Conversion of 1 f catalyzed by three IrIII complexes (1 mol% Ir).
at either of the benzylic positions. Importantly, primary allylic
alcohols also reacted to give a-bromoaldehydes in good yields
(Table 2, entries 16–18). All the products were isolated in very
good yields, except for 3n, which was produced in a moderate
Experimental Section
General Information
All iridium-catalyzed reactions were carried out in closed glass vials
under an atmosphere of air. Air- and moisture-sensitive reactions
used to prepare the starting allylic alcohols were carried out in
oven-dried glassware under an atmosphere of dry nitrogen. Re-
agents were used as obtained from commercial suppliers without
further purification. Acetone was used as obtained from a commer-
cial supplier (puriss p.a.). Flash chromatography was carried out on
Scheme 5. a-Bromoketones as synthetic intermediates
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60 ꢅ (35–70 mm) silica gel (Acros Kieselgel 60) using pentane or
pentane/EtOAc or pentane/Et2O mixtures as eluent. Analytical TLC
was carried out on aluminum-backed plates (1.5 ꢅ, ca. 5 cm) pre-
coated (0.25 mm) with silica gel (Merck, Silica Gel 60 F254). Com-
pounds were visualized either by exposure to UV light or by dip-
ping the plates in a solution of 0.75% KMnO4 (w/v) in an aqueous
solution of K2CO3 0.36m. Melting points were recorded in a metal
covered as white crystals after drying under reduced pressure
(790 mg, 61%, 0.61 equiv). M.p. 174–1768C; 1H NMR (400 MHz,
CDCl3, TMS): d=6.60 (br. s, 1H), 2.52 (br. s, 2H), 2.43 (br. s, 2H),
1.11 ppm (s, 6H); 13C NMR (100 MHz, CDCl3, TMS): d=190.6, 169.7,
100.8, 50.9, 42.6, 32.2, 28.2 ppm; HRMS (ESI): m/z calcd for
C8H11O279Br+Na+: 240.9835 [M+Na]+; found: 240.9828.
1
block and are uncorrected. H NMR spectra were recorded at 400
Synthesis of 2,2-dibromo-5,5-dimethylcyclohexane-1,3-dione
(2d) from 2-bromo-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one:
N-Bromosuccinimide (446 mg, 2.5 mmol, 1.1 equiv) was added in
one portion to a solution of 2-bromo-3-hydroxy-5,5-dimethylcyclo-
hex-2-en-1-one (0.50 g, 2.28 mmol) in a mixture of EtOH and H2O
(3:1 v/v, 8 mL). The reaction mixture was stirred for 3 h and the re-
sulting white solid formed was collected by filtration and washed
several times with water. The residual solvent was removed under
rotatory evaporation at 408C for 2 h, and then the material was
kept under reduced pressure (<2 mmHg) overnight. Compound
2d was obtained as a white solid (664 mg, 2.23 mmol, 98%).
or 500 MHz; 13C NMR spectra were recorded at 100 or 125 MHz
with a Bruker Advance spectrometer. 1H and 13C NMR chemical
shifts (d) are reported in ppm from tetramethylsilane, using the re-
sidual solvent resonance (CHCl3: dH =7.26 ppm and CDCl3: dC =
77.0 ppm) as an internal reference. Coupling constants (J) are
given in Hz. High-resolution mass spectra (HRMS) were recorded
with a Bruker microTOF ESI-TOF mass spectrometer. NMR yields
were calculated using 2,3,5,6-tetrachloronitrobenzene as internal
standard.
Synthesis
Acknowledgements
Synthesis of 2,2-dibromo-5,5-dimethylcyclohexane-1,3-dione
(2d): Prepared by a modification of a reported procedure.[15] 5,5-Di-
methylcyclohexa-1,3-dione (10 g, 71.3 mmol) was dissolved in
a mixture of EtOH and H2O (3:1 v/v, 140 mL), and N-bromosuccini-
mide (26.8 g, 150 mmol, 2.1 equiv) was added in four portions
(5 min between each portion). The reaction mixture was stirred for
5 h, then the resulting white solid formed was collected by filtra-
tion and washed several times with water. The residual solvent was
removed under rotatory evaporation at 408C for 2 h, and the re-
maining material was kept under reduced pressure (<2 mmHg)
overnight. Compound 2d was obtained as a white solid (19.5 g,
This project was supported by the Knut and Alice Wallenberg
Foundation, the Swedish Research Council (VR), and the Swed-
ish Governmental Agency for Innovation Systems (VINNOVA)
through the Berzelii Center EXSELENT. B. M.-M. was supported
by VINNOVA through a VINNMER grant. A. V.-R. thanks the
Wenner-Gren Foundation for a postdoctoral grant, and M. B.
thanks the Spanish MEC for a predoctoral grant.
1
65.4 mmol, 92%). M.p. 148–1508C; H NMR (400 MHz, CDCl3, TMS):
Keywords: allylic compounds
ketones · synthetic methods
· bromination · iridium ·
d=2.99 (s, 4H), 1.00 ppm (s, 6H); 13C NMR (100 MHz, CDCl3, TMS):
d=192.9, 66.6, 48.3, 30.7, 27.8 ppm; HRMS (ESI): m/z calcd for
C8H12O379Br2 +Na+: 336.9045 [M+H2O+Na]+; found: 336.9045.
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Received: February 25, 2014
Revised: March 31, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 8
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7
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FULL PAPER
Synthon shuffle: An efficient and high-
yielding synthetic route to prepare a-
bromoketones and aldehydes is pre-
sented (see scheme). The method relies
on 1,3-hydrogen shift/bromination of al-
lylic alcohols catalyzed by IrIII complexes.
The products are obtained in excellent
yields and as single constitutional iso-
mers.
&
Synthetic Methods
A. B. Gꢀmez, E. Erbing, M. Batuecas,
A. Vꢁzquez-Romero, B. Martꢂn-Matute*
&& – &&
Iridium-Catalyzed Isomerization/
Bromination of Allylic Alcohols:
Synthesis of a-Bromocarbonyl
Compounds
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
8
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!