Synthesis of dibromoolefins via a tandem ozonolysis-dibromoolefination reaction

Article abstract of DOI:10.1016/j.tetlet.2012.11.121

In this Letter we outline the synthesis of a variety of dibromoolefins (DBOs) from a series of alkenes by coupling an oxidative cleavage and a reaction with a phosphorous ylide. This approach strategically avoids isolation of reactive aldehyde intermediates and presents one of the few examples coupling carbon-carbon bond formation with ozonolysis.

Full text of DOI:10.1016/j.tetlet.2012.11.121

Tetrahedron Letters 54 (2013) 792–795
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of dibromoolefins via a tandem ozonolysis–dibromoolefination
reaction
⇑
Brenna Arlyce Brown , Jonathan G. C. Veinot
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we outline the synthesis of a variety of dibromoolefins (DBOs) from a series of alkenes by
coupling an oxidative cleavage and a reaction with a phosphorous ylide. This approach strategically
avoids isolation of reactive aldehyde intermediates and presents one of the few examples coupling car-
bon–carbon bond formation with ozonolysis.
Received 18 October 2012
Revised 7 November 2012
Accepted 12 November 2012
Available online 3 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ozonolysis
Dibromoolefination
Aldehydes
Corey–Fuchs reaction
Aldehydes are reactive functional groups that are useful handles
for many chemical transformations. One of the most useful exam-
ples of this is their reaction with phosphorus ylides to produce al-
Step 1:
Step 2:
1
kenes: the Wittig reaction. This reactivity has also been expanded
to the synthesis of alkynes,2 and dibromoolefins.3 In addition to
3
being employed in the synthesis of terminal alkynes, dibromoole-
fins (DBOs) can be used in the preparation of bromoalkynes—an
4
important starting material for the Cadiot–Chodkiewicz reaction.
DBOs are also used as starting materials in the Suzuki–Miyaura
5
and Stille couplings, as well as Fritch–Buttenberg–Wiechell
6
rearrangements.
As part of our ongoing studies to investigate the chemical
manipulation of fatty acid methyl esters, we aimed to synthesise
1
,1-dibromodecene, 3a, from methyl oleate, 1. The first of two
steps (Scheme 1) in our proposed reaction was oxidative cleavage
of the carbon–carbon double bond to generate nonanal, 2a. We
chose to employ ozonolysis as the preferred oxidative cleavage
7
method because of its relative simplicity, and low toxicity. How-
ever, ozonolysis produces ozonides and hydroperoxyacetals that
must be reduced to form the desired aldehyde. Unfortunately,
these particular intermediates are unstable and potentially hazard-
ous. To limit the formation of these undesired products, 1 equiv of
N-methylmorpholine-N-oxide (NMO) can be added to the reaction
Scheme 1. Synthesis of 1,1-dibromodecene from methyl oleate.
8
that reducing the amount of NMO from the 3 equiv used by Dus-
1
sault et al. to 1 equiv did not impact the yield. H NMR analysis
mixture to form the target aldehydes by reacting with the carbonyl
9
of the crude reaction products showed the presence of a peak at
.77 ppm, consistent with an aldehyde proton and no evidence of
a signal consistent with the starting alkene protons. Unfortunately,
isolation and subsequent separation of the aldehydes proved
impossible. The major product isolated by flash column chroma-
tography (FCC) was nonanoic acid, 4 (Fig. 1). Another product
oxide. We found that this approach was successful in cleaving
9
methyl oleate and producing the desired aldehydes. We also found
⇑
Corresponding author.
E-mail address: brennab@ualberta.ca (B.A. Brown).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.121

B. A. Brown, J. G. C. Veinot / Tetrahedron Letters 54 (2013) 792–795
793
in the dibromoolefination. It is also worth noting the 1H NMR
shows no evidence of dimerisation or over-oxidation to benzoic
acid.
To reduce the reaction time, the Z/C/P mixture was reacted for
6
h in refluxing dichloromethane (DCM) before addition of the
Figure 1. Competing products in the isolation of nonanal (2a).
ozonolysis mixture (Table 1, entry 2). After over 7 days of reaction,
no dibromoolefin was detected by TLC and the reaction was
stopped.
observed when trying to obtain pure nonanal was the nonyl non-
anoate, 5 (Fig. 1).
To facilitate a more efficient reaction, the relative proportions of
Z/C/P were increased from 2.0 to 2.5 equiv per equivalent of alde-
hyde (Table 1, entry 3). The yield increased to 79%, and though
there was no evidence of an unreacted aldehyde or starting mate-
rial in the product, the reaction time required for this conversion
remained quite long, at 120 h. Increasing the Z/C/P concentrations
to 3.0 equiv per equivalent of aldehyde resulted in conversion to
dibromoolefin in only 3 h, and the reaction yield increased to
85% (Table 1, entry 8). The resulting product, 1,1-dibromo-2-phen-
ylethene, was isolated as a light yellow oil and required no further
purification.
1
0
To avoid this complication, we chose to explore the possibility
of bypassing isolation of the aldehyde and performing ozonolysis
and dibromoolefination in one step. Similar strategies have proven
successful in the synthesis of alkenes and alkynes from primary
1
1
alcohols, but few examples have been published demonstrating
this kind of carbon–carbon bond formation performed in tandem
1
2
with ozonolysis. A recent publication from Willand–Charnley
and Dussault demonstrating tandem ozonolysis and carbon–car-
bon bond formation highlights the importance of the findings we
1
3
report here. To date, all reports of tandem reactions of this type
have been limited to terminal olefins and enolates. Here we dem-
onstrate an effective cleavage of internal olefins.
With the reaction conditions optimised, we applied this method
to a variety of alkenes to evaluate the generality of the approach
(See: Table 2). 3.0 equiv of each Zn, CBr , and PPh for each equiv-
4 3
As a model system for this reaction, we investigated the reac-
tions of trans-stilbene. It was chosen because, as a symmetric al-
kene, only a single product would be produced. Furthermore,
being relatively electron-rich, it was expected to proceed smoothly
through the ozonolysis procedure.
Using 2.0 equiv of each Zn, CBr , and PPh (Z/C/P) for each
4 3
equivalent of aldehyde produced, the reaction was not complete
after six days (Table 1, entry 1), as indicated by the presence of
alent of aldehyde was reacted for 24 h, after which the alkene was
ozonolysed and added to the reaction mixture. The reactions were
monitored by TLC and H NMR. It was immediately evident that
yields had dropped compared to reaction with trans-stilbene; how-
ever, they are comparable to the literature yields when a two-step
process is employed. No further purification was required for en-
tries 1–4.
1
Unexpected results were obtained when the starting material
was trans-4-stilbenemethanol (Table 2, entry 5). Conspicuously ab-
two compounds clearly separable using TLC (R
f
= 0.35 and 0.62 in
1
1
8
:1 hexanes:ethyl acetate) as well as a downfield peak in the
H
sent from the H NMR spectrum were peaks arising from benzylic
1
NMR at 10.06 ppm, consistent with the presence of benzaldehyde.
methylene protons at about d = 4.8 ppm. The crude H NMR
Of important note, there was no evidence of the trans-stilbene
showed the expected peaks associated with 1,1-dibromo-2-phen-
ylethene, as well as an unexpected singlet at d = 7.57 ppm. To sep-
arate this unknown impurity from 1,1-dibromo-2-phenylethene, it
was selectively precipitated as a cream-coloured solid at low tem-
1
14
starting material in either the TLC or the H NMR analyses. These
observations are suggestive of the alkene proceeding efficiently
through the ozonolysis and the delay in reaction is likely occurring
Table 1
a
Reaction conditions used in the synthesis of 1,1-dibromo-2-phenylethene
b
Reaction timec (h)
Total timed (h)
Yielde (%)
Entry
Zn/CBr
4.0f
4
/PPh
3
(equiv)
1
2
3
4
5
6
7
8
120
—
146
—
167
165
118
48
58
0
f,g
4.0
5.0
6.0
6.0
6.0
6.0
h
120
120
72
24
3
79
83
75
74
84
85
i
i
i
i
26
27
i
6.0
3
a
General procedure: Zn, CBr
4
3
, PPh were added to an argon filled, flame-dried round bottom flask and then suspended in DCM
(0.3 M). The mixture was stirred between 23 and 48 h followed by addition of the post-ozonoylsis mixture by canula. The reaction was
stirred until complete, as determined by TLC.
b
4 3
Number of equivalents for each Zn, CBr , and PPh .
c
d
e
f
Reaction time following addition of ozonolysis mixture.
Total reaction time including time for reacting the Zn/CBr
All yields are for isolated product.
4 3
/PPh .
2
.0 equiv of each Zn, CBr
Zn/CBr /PPh was reacted in refluxing DCM.
.5 equiv of each Zn/CBr
.0 equiv of each Zn/CBr
4 3
, PPh for 1.0 equiv of aldehyde produced.
g
h
i
4
3
2
3
4
/PPh
/PPh
3
for 1.0 equiv of aldehyde produced.
for 1.0 equiv of aldehyde produced.
4
3

7
94
B. A. Brown, J. G. C. Veinot / Tetrahedron Letters 54 (2013) 792–795
Table 2
higher than those obtained when we employed the two-step
Tandem ozonolysis–dibromoolefination on alkenes
procedure. Importantly, this new tandem approach provides the
desired products with no evidence of oxidation, degradation, or
dimerisation.
Entry Alkene
DBO
Yielda
%)
(
In summary, we have shown oxidative alkene cleavage by
ozonolysis that can be coupled to a Corey–Fuchs type dibromoolef-
ination and have successfully generated synthetically valuable
dibromoolefins. This was achieved while realising good yields
without isolating the reactive aldehyde intermediate. We have
shown that this method can be applied successfully to a variety
of alkenes and that it avoids the potential for concentrating
ozonolysis mixtures that still contain ozonides.
Br
Br
Br
1
64
56
Br
Br
Br
Br
2
Br
Br
Acknowledgments
The authors thank the Natural Science and Engineering
Research Council of Canada (NSERC) and the University of Alberta
for continued generous financial support. We thank Dr. F.G. West
for his valued insight and discussions involved in developing this
chemistry. We also thank the Analytical and Instrumentation
Laboratory, Mass Spectrometry Facility, and NMR Laboratory in
the Department for Chemistry at the University of Alberta for
assistance in the characterisation of synthetic compounds.
3
4
65
24
Br
Br
Br
Br
Br
—
—
Supplementary data
5
Br
Br
Supplementary data (experimental details and full characterisa-
OH
1
13
tion data on all compounds along with the H and C NMR for all
new compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.121.
HO
References and notes
5
6
4
6
1.
Selected references: (a) Wittig, G.; Geissler, G. Liebigs Ann. 1953, 580, 44; (b)
Bestmann, H. J.; Vostrowsky, O. Top. Curr. Chem. 1983, 109; (c) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863; (d) Nicolaou, K.; Harter, M. W.; Gunzner, J.
L.; Nadin, A. Liebigs Ann. Chem. 1997, 1283; (e) Edmonds, M.; Abell, A. Modern
Carbonyl Olefination 2004, 1.
6
a
2. (a) Syeferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379; (b)
Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521; (c) Roth, G.
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Isolated yields.
3
.
(a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745; (b)
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perature (À20–0 °C) in a minimum amount of hexanes. The 1H
NMR showed only two singlets: d = 7.57 ppm (4H) and
d = 7.49 ppm (2H). The IR spectrum of the sample did not show sig-
nals consistent with O–H or sp3 C–H functional groups and the
4
.
.
5
641; (b) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Tetrahedron
6 4
mass spectrum provides a molecular formula of C10H Br . Based
on this data we assert this product is 7 (Scheme 2). Oxidation of
2006, 62, 1675.
6. Eisler, S.; Tykwinski, R. R. J. Am. Chem. Soc. 2000, 122, 10736.
the benzylic alcohol during ozonolysis could result in the forma-
7. (a) Bailey, P. S. Ozonation in Organic Chemistry In Vol. 1; American Press: New
York, 1978; (b) MollatduJourdin, X.; Noshi, M.; Fuchs, P. L. Org. Lett. 2009, 11,
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5
43.
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9. Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Org. Lett. 2006, 8, 3199.
Having established appropriate conditions for effective tandem
ozonolysis–dibromoolefination, we revisited the synthesis of 3
8.
1
0. Compound 5 was obtained when trying to produce nonanal from recovered
nonanoic acid during the ozonolysis procedure by first reducing 4 to nonanol
and then using a Swern oxidation to get the aldehyde.
(
Table 2, entry 6). The two resulting dibromoolefins, 3a and 3b,
were separated using flash column chromatography. The large dif-
ference between the R values of 3a and 3b, (0.73 and 0.44, respec-
11. (a) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198; (b) Quesada, E.;
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Schaffner, C. P. Synth. Comm. 2009, 39, 299.
f
tively) allowed for effective isolation of the two products. While
yields were remained lower than those observed for the trans-
stilbene reaction (66% for 3a, 54% for 3b) they are substantially
12. (a) Schloss, J. D.; Paquette, L. A. Synth. Comm. 1998, 28, 2887; (b) Hon, Y.; Lu, L.;
Chang, R., et al Tetrahedron 2000, 56, 9269.
Scheme 2. Proposed formation of the unexpected product obtained for reaction with trans-4-stilbenemethanol.

B. A. Brown, J. G. C. Veinot / Tetrahedron Letters 54 (2013) 792–795
795
1
1
3. Willand-Charnley, R.; Dussault, P. H. J. Org. Chem. 2012. http://dx.doi.org/
0.1021/jo3015775.
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Comprehensive Organic Synthesis–Selectivity, Strategy and Efficiency in
Modern Organic Chemistry In Trost, B. M., Fleming, I., Eds.; Elsevier, 1991.
Vol. 7.
1
4. Ozonolysis conditions were determined as part of other ongoing studies in our
1
laboratory. Ozonolysis products were analysed by H NMR