Stereo- and regioselective halogenation of norbornenes directed by neighboring group participation

Article abstract of DOI:10.1016/j.tetlet.2016.10.105

Directing the outcome of electrophilic addition reactions of norbornenes could be a challenging task. We have found that the ionic addition of bromine to dichloro-norbornene 2 is accompanied with the formation of a bromonium cation followed by anchimeric assistance of juxtaposed chlorine to give five-membered chloronium cation, which upon reacting with bromide gives norbornane 4 in >90% yield. At higher temperatures, however, the radical addition of Br₂dominates so that dibromo compound 3 appears as the principal reaction product (72%). Stereo- and regioselective rearrangements of norbornenes, reported herein, could be of interest for the syntheses of complex haloalkanes.

Full text of DOI:10.1016/j.tetlet.2016.10.105

Accepted Manuscript
Stereo- and Regioselective Halogenation of Norbornenes Directed by Neigh-
boring Group Participation
Radoslav Z. Pavlović, Sarah E. Border, Judith Gallucci, Jovica D. Badjić
PII:
S0040-4039(16)31439-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.105
TETL 48275
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
3 October 2016
24 October 2016
27 October 2016
Please cite this article as: Pavlović, R.Z., Border, S.E., Gallucci, J., Badjić, J.D., Stereo- and Regioselective
Halogenation of Norbornenes Directed by Neighboring Group Participation, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.105
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Graphical Abstract
Stereo- and Regioselective Halogenation of
Norbornenes Directed by Neighboring
Group Participation
Leave this area blank for abstract info.
Radoslav Z. Pavlovića, Sarah E. Border a, Judith Galluccia and Jovica D. Badjića*

1
Tetrahedron Letters
Stereo- and Regioselective Halogenation of Norbornenes Directed by
Neighboring Group Participation
Radoslav Z. Pavlovića, Sarah E. Border a, Judith Galluccia and Jovica D. Badjića*
a Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210 (USA)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Directing the outcome of electrophilic addition reactions of norbornenes could be a challenging
task. We have found that the ionic addition of bromine to dichloro-norbornene 2 is accompained
with the formation of a bromonium cation followed by anchimeric assistance of juxtaposed
chlorine to give five-membered chloronium cation, which upon reacting with bromide gives
norbornane 4 in >90 % yield. At higher temperatures, however, the radical addition of Br2
dominates so that dibromo compound 3 appears as the principal reaction product (72%). Stereo-
and regioselective rearrangements of norbornenes, reported herein, could be of interest for the
syntheses of complex haloalkanes.
Available online
Keywords:
Electrophilic Addition
Neighboring Group Participation
Bromination
2009 Elsevier Ltd. All rights reserved.
Norbornenes
Haloalkane Synthesis
Molecular baskets of type 1 (Figure 1A) are dynamic modular
hosts comprising a set of folded aromatic gates at their portal for
controlling the rate by which small molecules enter/exit their
inner cavity.1 These C3 symmetric cavitands can be
functionalized with polar groups to give amphiphiles2 or
bolaamphiphiles3 capable of assembling into hierarchical
materials in aqueous environments.4 Moreover, baskets with
amino acids at their portal have also been shown to (a) hold
transition metal-containing ligands acting as a secondary
coordination sphere in catalysis or sensing5 or (b) trap
organophosphonates akin in size and shape to nerve agents.6 The
preparation of the concave platform of these versatile hosts
(Figure 1A), comprising a flat aromatic base fused to three
bicyclo[2.2.1]heptane rings,7 begins with the bromination of
norbornene compound 2 to give 3 in 72 % yield (Figure 1B).8 At
a high temperature (150º C), this reaction was suggested8 to
occur via a radical mechanism9 with the principle product 3
forming by syn addition of bromine to the sterically more
accessible exo side. At lower temperatures,8 however, we were
unable to identify our desired product and refrained from fully
characterizing the reaction’s outcome by focusing on completing
the synthesis of basket 1 (Figure 1). Accordingly, ionic
halogenations of norbornene derivatives10 are known to be
followed with Wagner-Meerwein rearrangements11 in which a
complex mixture of products is obtained by way of -bridging
nonclassical carbocations.12 In line with it, we re-examined the
bromination of norbornenes of type 2 (Figure 1B) to discover an
interesting rearrangement reaction taking place by anchimeric
assistance of halogens.13 The rearrangement dominates the
reaction’s outcome at lower temperatures and can be directed to
give one haloalkane product in a stereo- and regioselective
manner. We reason that our discovery could be of interest for the
rapid and stereoselective synthesis of complex haloalkanes acting
as insecticides, fire retardants or pharmaceuticals.14
(A)
R
N
O
O
R = functional
aromatic or polar
aliphatic groups
O
O
N
N
R
R
1
O
O
(B)
Cl
Cl
Br
Br
Br
Br
Br2
nonane
150 ºC
72 %
Cl
Cl
Cl
Cl
3
2
Figure 1. (A) Energy-minimized structure of a molecular basket
(MMFFs, Spartan) holding CBr4 with folded aromatic gates at its
portal. Chemical structure of basket 1 is shown on the right. (B)
Bromination of 2 at a high temperature was reported to give 3 as the
major product.
A
gradual addition of bromine to compound 2 in
dichloromethane was found to, within a range of temperatures
(from 78 to 150 ºC, Table 1), lead to the formation of two
products 3 and 4 in different proportions (Scheme 1A). To
quantify the outcome of these reactions, we used GC and NMR
while the constitutional and stereoisomeric assignment of
products was completed with 2D NMR spectroscopy.

2
Tetrahedron Letters
Table 1. The bromination of 2 at various temperatures and in different solvents gives two products 3 and 4, whose ratio was determined
with gas chromatography.
Solvent
Reaction Conditionsa
Compound 3 (%)
Compound 4 (%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C9H20
−78 C
−78 C; 1 mol equiv. of 2,4,6-tri-tert-butylphenol
25 C
4b
93b
2
98
9b
3
86b
97
25 C; 1 mol equiv. of 2,4,6-tri-tert-butylphenol
150 C
72
37
28
C9H20
150 C; 3.1 mol equiv. of 2,4,6-tri-tert-butylphenol
63
a One molar equivalent of Br2 was used in all reactions. bNon-reacted
substrate 2 comprises the remaining material.
that greater thermal energy supplied to the reacting system (i.e.
heating) would promote the formation of this molecule (Table 1).
On the basis of earlier studies,9,11 we reasoned that higher
temperatures ought to facilitate the homolytic cleavage of
bromine thereby promoting a radical bromination occurring via
radical intermediate (Scheme 1A). Indeed, the addition of radical
quencher (2,4,6-tri-tert-butylphenol) to the reaction mixture
suppressed the production of 3 (Table 1) to validate its formation
via radical pathway! The results of this experiment also suggest
that the aforementioned contribution of the ionic pathway b
(Scheme 1A) is playing a minor role (if any) in giving cis
dibromide 3. To summarize, the bromination of 2 occurs by
simultaneous ionic and radical pathways: the first dominates at
lower temperatures and is mediated by halogen anchimeric
assistance, while the later prevails at higher temperatures via syn
addition of bromine.
In accordance with the assignment, E2 eliminations of 3 and 4
promoted with strong base t-BuOK gave olefins 9 and 10
(Scheme 1B) with the expected exo removal of halides
dominating each reaction’s outcome; note that 3 gives 9, while 4
leads to compound 10. At last, the conversion of 2 into 3 and 4
(Scheme 1A) is a kinetically controlled process. After products 3
and 4 were kept in nonane at 150 ºC for 15 minutes, we found
(1H NMR) that their proportion (3:4 = 59:41) remained
unchanged.
To account for the predominant formation of 4, at lower
temperatures (Table 1), we reasoned that an ionic addition of
bromine to 2 should yield bromonium cation15 5 in equilibrium
with nonclassical cation 7.10 Next, a rapid conversion of three-
membered bromonium 5 into the more stable five-membered
chloronium 6 (E>10)16 is expected to take place (Scheme 1A).17
At last, the chloronium 6 could react with juxtaposed bromide
nucleophile at its less hindered carbon along CCl+ bonds
(pathway a) to give the principle product 4. Alternatively, the
substitution at the more hindered C-2 could take place to give
product 3 (pathway b, Scheme 1A). In this vein, one may also
surmise that the formation of 3 could occur by the exo attack of
the bromide on the electrophilic C-2 in 7 although this reaction is
known to be a less preferred mode of the opening (higher Ea)10 of
norbornyl cation. In fact, a complete absence of the 1,3-
substitution product 8, among others (Scheme 1),10 is indicative
of the nonclassical ion 7 not participating in the reaction. To
further account for the formation of cis dibromide 3, we noted
The results of the bromination of bis-mesylate 11 and
thioether 15 (Figure 2) give credence to the notion that the
elusive and five-membered chloronium ion16-17 6 (Scheme 1A)
(A)
Br
Br2
CH2Cl2
OMs
OMs
OMs
11
12 O
94%
Br2
Br
Br
2
OMs
O
S
O
O
OMs
OSO2CH3
13
14
H3C
Br
(A)
(B)
Br
Br2
Cl
Cl
Br
Br
Br
Br
Br2
+
12
see Table 1
Cl
Cl
Cl
Br
Cl
Cl
Cl
2
4
3
Br
Br
(C)
Cl
Cl
Br
Br2
b
Br2
a
not observed
Br
CH2Cl2
74%
SPh
SPh
SPh
Br
PhS
Br
Br
Br
Br
15
16
Br
Br
b
Br
3
Cl
1
Cl
Cl
Cl
Cl
Cl
Figure 2. (A) The bromination of bis-mesylate 11 results in 5-exo-
trig cyclization of 13 giving cyclic ether 12. (B) ORTEP
representation of the structure of 12 in solid state; single crystals of
12 were obtained by slow evaporation of its CH2Cl2/hexane
solution. (C) The bromination of 15 gives sulfonium salt 16.
Cl
Cl
a
8
7
6
5
Br
(B)
Br
t-BuOK
Br
+
9%
91%
THF / 0 ºC
Cl
Br
Cl
Cl
10
9
takes part in the ionic addition described above. That is to say,
when bromine was added to 11 there followed an exclusive
formation of cyclic ether 12 in 94 % yield (Figure 2A). We
deduce that a rapid nucleophilic attack of an oxygen atom from
methylsulfonate group in bromonium 13 on juxtaposed C-2
carbon gives intermediate 14.18 The attack of bromide anion on
the polarized and unhindered methyl group then prompts a rapid
departure of good leaving groups (SO2 and cyclic ether) and
4
Br
Br
t-BuOK
THF / 0 ºC
82%
Cl
Cl
3
Scheme 1. (A) Postulated mechanistic pathways for the
bromination of norbornene derivative 2. (B) Elimination reactions
of 3 and 4 gave the expected alkenes 9 and 10.

3
therefore the formation of 12; the nucleophilic attack of the
bromide at the sulfur atom is another possibility for the
conversion of 14 into 12. Importantly, the solid-state structure of
cyclic ether 12 corroborates the spectroscopically deduced trans
relationship of the bromide and ether oxygen groups; in fact,
norbornenes 17 and 19 (Scheme 2). With more nucleophilic
halogens (I>Br>Cl),21 embedded in the bicyclic reactants, we
expected a more effective anchimeric assistance along the series
21719.16 Indeed, in the case of 17 there was a sole formation
of tetrabromo product 18 without any competing radical
bromination at 78 ºC (Scheme 2); note that compound 18 was
found to be unstable at 150 ºC in nonane (15 min), and possibly
giving elimination products that were difficult to distinguish with
1H NMR spectroscopy. Interestingly, compound 19 would in the
presence of bromine give a complex mixture of products yet
upon the addition of radical quencher BHT there was no reaction
observed. Currently, we have no additional experimental data to
provide an explanation for this observation. With phenylselenyl
bromide, the electrophilic selenylation of 2 in CH2Cl2 gave rise to
two products 21 and 22 with, presumably, both arising from
common seleniranium ion 20 (Scheme 2).22 In particular, we
postulate that 21 forms by the anchimeric assistance of the
adjacent chlorine atom (pathway a, Scheme 2) setting the trans
stereochemistry at carbons C-2 and C-3 of the norbornane and
allowing the positional exchange of two different halogen atoms.
We also hypothesize that in consequence of a greater persistency
of seleniranium ion 20 (Scheme 2), than bromonium 5 (Scheme
1A),23 the classical anti electrophilic addition (AdE2) of PhSeBr
took place with the dominant formation of 22; the ratio of 21:22
was determined with 1H NMR spectroscopy to be 13:87 (Scheme
2). That is to say, the more stable and bridged cationic
intermediate 20 is sufficiently persistent to allow the nucleophilic
attack by not only neighboring CH2Cl group but also the external
bromide anion. At last, the electrophilic sulfenylation24 of 17
with phenylsulfenyl chloride gave the expected products 23 and
24 by mechanism akin to the electrophilic selenylation.25
stereoselective
syntheses
of
tetrahydrofurans18
and
halogenolactons19 by 5-exo-trig cyclizations have already been
reported and discussed by others.20 Finally, thioether 15 was in
the same manner converted into cyclic sulfonium salt 16 (Figure
2C), which was stable enough for isolation and full
characterization at ambient conditions.
To additionally examine the scope of the procedure, we
studied the stereoselective bromination of dibromo- and dioiodo-
Br
Br
Br2
t-BuOK
THF
80%
Br
Br
CH2Cl2
98%
Br
Br
18
9
17
Br
Br2 / BHT
CH2Cl2
no product
PhSe
I
19
I
PhSe
(a)
13
Cl
Br
Cl
Br
Cl
Cl
21
PhSe
PhSeBr
CH3CN
92%
Cl
Cl
(b)
Br
Cl
Cl
2
PhSe
(a)
20
87
(b)
Cl
Cl
Br
22
PhS
Br
(a)
31
Br
Cl
23
PhSCl
CH2Cl2
85%
Br
Br
17
In conclusion, we discovered a synthetic method for obtaining
polyhalogenated derivatives of norbornane via anchimeric
assistance of halogens. The procedure is straightforward, high
yielding, regio- and stereoselective with potential to be extended
to a variety of bicyclic or cyclic systems and thereby facilitating
the synthesis of natural products and other useful materials.14,26
PhS
Cl
69
Br
Br
24
(b)
Scheme 2. The anchimeric assistance of either chlorine or bromine
atoms affects the outcome of the examined electrophilic addition
reactions in a predictable manner. The bromination of 19 at 78 ºC
with 3,5-di-tert-4-butylhydroxytoluene (BHT, 3 mol equiv.) did
not show any product (1H NMR spectroscopy).
4, 1329; (c) Bolzan, A.; Bortoluzzi, M.; Borsato, G.; Fabbro, C.; Dastan, A.;
De Lucchi, O.; Fabris, F. Helv. Chim. Acta 2015, 98, 1067.
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Am. Chem. Soc. 2006, 128, 5887.
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2008, 64, 4377.
(12) Scholz, F.; Himmel, D.; Heinemann, F. W.; Schleyer, P. v. R.; Meyer,
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Acknowledgments
This work was financially supported with funds obtained from
the U.S. National Science Foundation under CHE1305179. We
would like to thank S. Jing and Prof. T. V. RajanBabu of the
Ohio State University for assistance with gas chromatography.
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4
Tetrahedron
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Br
Br
Br2
CH2Cl2
Cl
Br
Cl
Br
Cl
Cl

Highlights
(1) The ionic addition of Br2 to dihalo-norbornenes gives rearranged
norbornanes
(2) The radical addition of Br2 to dihalo-norbornenes gives syn-dibromo product
(3) The anchimeric assistance of halides determines the reactions’ outcome
(4) The addition of PhSeBr/PhSCl to dihalo-norbornenes gives rearranged
norbornanes