A tandem oxidation procedure for the conversion of alcohols into 1,1-dibromoalkenes

Article abstract of DOI:10.1055/s-2004-820027

A practical and concise route to dibromoalkenes directly from activated alcohols in good to excellent yields using a new Tandem Oxidation Procedure (TOP) is reported. We also describe the use of these dibromoalkenes as intermediates in a one-pot route to 4,5-dihydro-1H-imidazoles and in the synthesis of bromoalkynes through MTBD-induced elimination.

Full text of DOI:10.1055/s-2004-820027

LETTER
819
A Tandem Oxidation Procedure for the Conversion of Alcohols into
1,1-Dibromoalkenes
C
onversion of
t
A
lcoh
e
ols into 1,1-
v
D
ibromoalk
e
enes n A. Raw, Mark Reid, Estelle Roman, Richard J. K. Taylor*
University of York, Heslington, York, YO10 5DD, UK
Received 2 February 2004
Ph3P=CBr2 (1)
Abstract: A practical and concise route to dibromoalkenes directly
from activated alcohols in good to excellent yields using a new Tan-
dem Oxidation Procedure (TOP) is reported. We also describe the
use of these dibromoalkenes as intermediates in a one-pot route to
4,5-dihydro-1H-imidazoles and in the synthesis of bromoalkynes
through MTBD-induced elimination.
O
or
Br
R
H
R
Ph3PCHBr2 Br (2),
Br
base
Equation 1
Key words: dibromoalkenes, tandem oxidation procedure, one-
pot, MTBD
cation of our Tandem Oxidation Procedure (TOP) to the
preparation of 1,1-dibromoalkenes directly from alcohols
(Equation 2). Previously we have demonstrated that TOP
methodology can be employed for a range of MnO2-medi-
ated oxidation-Wittig processes,14 including those involv-
ing non-activated phosphonium salts,15 giving a variety of
alkenes directly from alcohols, by-passing the need to iso-
late intermediate aldehydes and simplifying the original
two step procedure. This methodology has since been
employed by other groups.16
1,1-Dibromoalkenes are valuable synthetic intermediates
and are readily converted into amidines,1 disubstituted
bromoalkenes,2 Z-bromoalkenes,3 E-bromoalkenes,4 di-
substituted alkynes,5 trisubstituted alkenes,5 terminal
alkynes (the Corey–Fuchs reaction),6 bromoalkynes7 and
carboxylic acid derivatives1 (Figure 1).
R'
NHR'
NR'
R
H
R
R
Br
MnO2,
Br
R
RCH2OH
RCHO
RCH=CBr2
2, base
Equation 2
R'
Br
Br
N
R
R
R'
H
Initial studies were carried out with the electron deficient
aromatic alcohol, p-nitrobenzyl alcohol (Scheme 1). Thus
p-nitrobenzyl alcohol (1 equiv), MnO2 (10 equiv), 1-me-
thyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD)17 (3,
2.3 equiv), phosphonium salt 29 (3.0 equiv) and 4 Å mo-
lecular sieves in THF under reflux afforded the desired di-
bromoalkene 4 in a poor 24% yield after 15 hours
(Table 1, entry i). Interestingly, however, bromoalkyne 5
was also isolated in 10% yield indicating that MTBD may
be basic enough also to carry out the elimination of HBr
and thus form bromoalkynes in a one-pot 3-step sequence
from activated alcohols.
Br
O
R
R'
Br
H
R'
R
R
R
R'
Figure 1
Dibromoalkenes are usually prepared using the procedure
of Ramirez et al.8 which involves treating aldehydes with
phosphorane 1, generated from the reaction of tri-
phenylphosphine and carbon tetrabromide. Alternatively,
dibromomethylphosphonium salt 29 can be isolated and
used to form ylide 1 (Equation 1).10,11 More recently
dibromoalkenes have also been formed through the inter-
mediacy of hydrazones.12
The reaction was then repeated, reducing the amounts of
MTBD 3 and Wittig salt 2 to 1.5 and 2.2 equivalents, re-
spectively (entry ii). Dichloromethane was then found to
be the solvent of choice to circumvent solubility issues
and increase ease of work-up. Gratifyingly, this resulted
in an improved yield of 30% of dibromoalkene 4 with no
bromoalkyne 5 detected. However, p-nitrobenzaldehyde 6
was also recovered and therefore optimization of the stoi-
chiometries was investigated (Table 1). Increasing the
amount of Wittig salt 2 used to 3.0 equivalents resulted in
a marked increase in the yield of dibromoalkene 4 (80%)
with only a trace of aldehyde 6 remaining (entry iii). Fi-
nally, increasing the amount of Wittig salt further to 3.5
Given the problematic nature of some aldehydes and the
fact that there are many more commercially available al-
cohols than aldehydes,13 we decided to explore the appli-
SYNLETT 2004, No. 5, pp 0819–0822
0
2.
0
4.
2
0
0
4
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-820027; Art ID: D02204ST
© Georg Thieme Verlag Stuttgart · New York

820
S. A. Raw et al.
LETTER
Br
Br
CHO
MnO2, 2,
OH
MTBD 3, Solvent,
4 Å mol sieves
Br
O2N
O2N
O2N
O2N
4
5
6
N
N
N
Me
3
Scheme 1
Table 1 Optimization of Study Towards the Synthesis of Dibromoalkene 4
Entry
Conditions
4 (%)
24
5 (%)
6 (%)
i
THF, 2.3 equiv MTBD, 3.0 equiv 2, reflux, 15 h
CH2Cl2, 1.5 equiv MTBD, 2.2 equiv 2, reflux, 14 h
CH2Cl2, 1.5 equiv MTBD, 3.0 equiv 2, reflux, 14.5 h
CH2Cl2, 1.5 equiv MTBD, 3.5 equiv 2, reflux, 16 h
CHCl3, 1.5 equiv MTBD, 3.5 equiv 2, reflux, 15 h
10
0
0
ii
iii
iv
v
30
Ca. 50
80
0
Trace
86
0
0
0
56
0
equivalents resulted in complete consumption of interme- the literature for the conversion from the aldehyde. The
diate p-nitrobenzaldehyde and an isolated yield of 86% of low yield obtained from p-methoxybenzyl alcohol (entry
the desired dibromoalkene 4 (entry iv). The use of chloro- iii) deserves comment, however. This is presumably due
form as a reaction solvent was also investigated in an to the reduced electrophilicity of the intermediate p-meth-
attempt to reduce the reaction time (entry v). Dibromo- oxybenzaldehyde. Also, it should be pointed out that with
alkene 4 was isolated in a respectable yield but the dichlo- electron-deficient examples (entries ii and viii), much
romethane procedure was preferred for p-nitrobenzyl higher yields can be achieved by carrying out the reaction
alcohol (entry iv). However, in most other examples chlo- in refluxing dichloromethane rather than chloroform; the
roform was the preferred solvent. The scope of the proce- lower temperature presumably minimizes side-reactions
dure was investigated using a range of alcohols (Table 2). of the reactive electron deficient dibromoalkene products.
Table 2 shows that good to excellent yields of the dibro- We also carried out a brief study to investigate further in
moalkenes were obtained directly from a range of activat- situ elaborations of the 1,1-dibromoalkenes. Initially we
ed alcohols including electron-neutral, electron-deficient looked at the in situ dibromoalkene formation–elimina-
and electron-rich aromatic examples (entries i–iii), an tion reaction to afford the corresponding bromoalkynes
aromatic diol (entry iv), heterocyclic examples (entries v following the promising results referred to earlier. At-
and vi) and allylic and propargylic examples (entries vii tempts to increase the yield of the bromoalkyne 5 by a
and viii). An aliphatic example was also studied but the one-pot method, however, proved fruitless (max. yield,
reaction was slow and low yielding (entry ix). The syn- 35%). Nevertheless, a two step process in which dibro-
thetic utility of this one-pot method is further emphasized moalkene 4 was first isolated and purified and then treated
by the fact that comparable, or indeed better yields (en- with MTBD (1.5 equiv at r.t.) was also investigated and
tries iv19 and vi20), can be obtained directly from the sub- furnished the desired bromoalkyne 5 in 85% yield from
strate alcohol compared to those previously reported in dibromoalkene 4 (Scheme 2).
Br
Br
MnO2, 2,
OH
MTBD 3, CH2Cl2
Br
MTBD 3, CH2Cl2,
4 Å mol. sieves,
reflux, 17 h
r.t. 10 min
85%
O2N
O2N
O2N
5
4
86%
Scheme 2
Synlett 2004, No. 5, 819–822 © Thieme Stuttgart · New York

LETTER
Conversion of Alcohols into 1,1-Dibromoalkenes
821
Table 2 Investigation of the Scope and Limitation of the Dibromoalkene Synthesis.18
Entry
i
Alcohol
Product
Reaction time (h)
18
Isolated yield (%)a
73
Br
OH
Br
ii
17
86b
Br
OH
OH
Br
O2N
O2N
iii
iv
v
18
20
18
46 (64)c
86
Br
Br
MeO
HO
MeO
Br
OH
Br
Br
Br
85
Br
Br
OH
S
S
vi
17
84d
Br
OH
Br
N
N
vii
17
84
Br
Br
OH
OH
Br
Br
viii
3.5
65e
ix
36
14
OH
Br
Br
a Reaction carried out in refluxing chloroform unless otherwise stated.
b In CH2Cl2 (56% in CHCl3).
c Yield calculated with respect to recovered p-methoxybenzaldehyde.
d In CH2Cl2 (28% in CHCl3).
e Eliminated dialkynyl bromide isolated in 5% yield.
Huh et al. have demonstrated that dibromoalkenes may be These dibromoalkenes are useful synthetic intermediates
reacted with ethylenediamine to furnish 4,5-dihydro-1H- for a variety of functional group interconversions and we
imidazoles.1 Thus, we next went on to investigate a one- have further demonstrated their utility by carrying out an
pot synthesis of such heterocycles directly from p-ni- MTBD-induced elimination of 4 to afford bromoalkyne 5
trobenzyl alcohol. After some optimization we have de- as well as developing a practical and straightforward syn-
veloped a simple procedure to give 4,5-dihydro-1H- thesis of 4,5-dihydro-1H-imidazole (7) directly from p-ni-
imidazole (7) in 81% yield directly from p-nitrobenzyl trobenzyl alcohol without the need to isolate either the
alcohol (Scheme 3).21
aldehyde or dibromoalkene intermediates in the reaction
pathway. Further in situ applications of the dibromoal-
kenes are under investigation.
In summary, we have reported a concise and high yielding
synthesis of dibromoalkenes from activated alcohols.
H
N
Br
NH2
(ii)H2N
81%
(i) MnO2, 2,
OH
Br
N
MTBD 3, CH2Cl2,
4 Å mol. sieves,
reflux
O2N
O2N
O2N
4
7
Scheme 3
Synlett 2004, No. 5, 819–822 © Thieme Stuttgart · New York

822
S. A. Raw et al.
LETTER
(16) (a) Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999,
40, 1229. (b) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.;
Mitchell, H. J.; Wei, H.-X.; Weyershausen, B. Angew.
Chem. Int. Ed. 2001, 40, 3849. (c) Mladenova, M.;
Tavlinova, M.; Momchev, M.; Alami, M.; Ourévitch, M.;
Brion, J. D. Eur. J. Org. Chem. 2003, 2713. (d) Nicolaou,
K. C.; Li, Y.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.;
Weyershausen, B.; Mitchell, H. J.; Wei, H.-X.; Guntupalli,
P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003, 125,
15433.
Acknowledgment
We are grateful to the EPSRC for postdoctoral support (ROPA fel-
lowship, S.A.R.), to the EPSRC, Oxford Chemicals and The Gen
Foundation for studentship support (M.R.), and to ENSIACET,
Toulouse for exchange support (E.R.).
References
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(18) Representative Procedure. To a suspension of activated
manganese dioxide (Aldrich, 21764-6; 867 mg, 9.97 mmol),
phosphonium salt 2 (1.80 g, 3.50 mmol) and ground 4Å
molecular sieves (100 mg) in solvent (CH2Cl2 or
chloroform; 10 mL) was added MTBD 3 (0.22 mL, 1.50
mmol). The reaction mixture was heated at reflux for 30 min,
cooled to r.t., then a solution of alcohol (1 mmol) in solvent
(5 mL) added. The reaction mixture was then heated at reflux
for the time specified, cooled to r.t. and filtered through
Celite®. The resulting filtrate was then pre-loaded on to
silica and the dibromoalkenes purified by silica
chromatography, eluting with EtOAc/petroleum ether.
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dioxide (Aldrich, 21764-6; 867 mg, 9.97 mmol),
phosphonium salt 2 (1.80 g, 3.50 mmol) and ground 4 Å
molecular sieves (100 mg) in CH2Cl2 (10 mL) was added
MTBD 3 (0.22 mL, 1.50 mmol). The reaction mixture was
heated at reflux for 30 min, cooled to r.t., then a solution of
p-nitrobenzyl alcohol (153 mg, 1 mmol) in CH2Cl2 (5 mL)
was added. The reaction mixture was then heated at reflux
for 17 h, cooled to r.t. and filtered through Celite®.
Ethylenediamine (10 mL) was added and the reaction
mixture concentrated in vacuo to afford a purple oil which
was partitioned between conc. aq NH3 solution (40 mL) and
CH2Cl2 (40 mL). The NH3 solution was further extracted
with CH2Cl2 (2 × 20 mL). The combined organics were then
concentrated in vacuo then redissolved in CH2Cl2 (20 mL)
and extracted with 10% aq HCl (20 mL). The aqueous
extracts were then basified to pH 12 with 10 M NaOH
solution and extracted with CH2Cl2 (4 × 10 mL) and the
combined organics were dried over Na2SO4 and
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concentrated in vacuo to afford the title compound 7 (166
mg, 81%) as a purple solid (mp 124–126 °C, lit.1 135–137
°C). 1H NMR data were consistent with those reported in the
literature.1
Synlett 2004, No. 5, 819–822 © Thieme Stuttgart · New York