Homohalocyclization: Electrophilic Bromine-Induced Cyclizations of Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.5b01315

An efficient method for the halocyclization of cyclopropanes has been developed. The cyclopropanes undergo a 1,3-addition reaction to form homohalocyclization products compared to conventional alkene halocyclizations. The reaction can be induced by variou

Full text of DOI:10.1021/acs.orglett.5b01315

Letter
pubs.acs.org/OrgLett
Homohalocyclization: Electrophilic Bromine-Induced Cyclizations of
Cyclopropanes
Christian Rosner and Ulrich Hennecke*
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstr. 40, 48149 Munster, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: An efficient method for the halocyclization of
cyclopropanes has been developed. The cyclopropanes
undergo a 1,3-addition reaction to form homohalocyclization
products compared to conventional alkene halocyclizations.
The reaction can be induced by various electrophilic
halogenating agents including 1,3-dibromo-5,5-dimethylhydan-
toin and N-iodosuccinimide. In cyclopropane derivatives with
a preexisting stereocenter, excellent induced diastereoselectiv-
ities can be observed.
he rapid generation of complex molecules from simple
elemental halogens and related trihalogenids have been
Tstarting materials is a key goal of organic chemistry. required for those reactions limiting the general applicability.5,6
On the other hand cyclopropanes are important building blocks
in synthetic and medicinal chemistry.7 A range of methods for
their preparation are known, including asymmetric variants.8
Furthermore, due to the high ring strain, cyclopropanes can be
easily transformed, for example by reduction or, in the case of
donor−acceptor substituted cyclopropanes, by cycloadditions
and a range of other transformations.9 This includes the 1,3-
dihalogenation of donor−acceptor substituted cyclopropanes,
which is in many cases not taking place via an electrophilic
halogenation mechanism.10 In this manuscript we show that
cyclopropanes can also undergo typical halocyclizations such as
halolactonizations and halocycloetherifications. This trans-
formation can proceed with very high diastereoselectivity and
enable the rapid establishment of complex molecules by a
simple cyclopropanation/halocyclization sequence placing the
newly introduced groups in a 1,3-distance.
Halocyclizations such as iodolactonization generate two
stereocenters and a ring while introducing an additional
functional group (the halogen) in a single transformation.1,2
Therefore, this class of reactions is a powerful tool in organic
synthesis. In general, halocyclizations are electrophilic additions
to unsaturated C−C bonds such as alkenes, alkynes, or allenes.
This means that the newly generated functional groups are
placed vicinal (1,2) in the product (Scheme 1).
Scheme 1. Halocyclization of Alkenes and Cyclopropanes
Initial experiments into halocyclization reactions of cyclo-
propanes were conducted using phenyl-substituted cyclo-
propane derivative 1a (Table 1). Upon treatment with
elemental bromine in dichloromethane, 1a was converted
among other products into the 5-exo cyclization product 2a in
moderate yield (41%) (Table 1, entry 1). Switching to 2,4,4,6-
tetrabromo-2,5-cyclohexadienone (TBCO) as a brominating
agent, the yield was increased only marginally (Table 1, entry
2). However, by using N-bromosuccinimide (NBS) the yield
could be increased significantly to 60% (Table 1, entry 3). The
use of the very reactive brominating agent BDSB (BrSEt2·
SbCl5Br), developed by Snyder et al.,11 resulted in an excellent
yield of 79% (Table 1, entry 4). Nearly the same yield of 76%
was observed using 1,3-dibromo-5,5-dimethylhydantoin (1,3-
DBDMH) (Table 1, entry 5). For further optimization this
During our investigations on asymmetric halocyclizations,3
the question arose if halocyclizations are also possible using
cyclopropanes as starting materials leading to 1,3-substituted
products (Scheme 1). Due to the unusual bonding situation in
the highly strained cyclopropanes, these compounds often
show typical reactivity of unsaturated C−C bonds.4 This is also
true for the electrophilic addition of halogens and the 1,3-
dibromination of cyclopropanes, which has been described
previously.5 However, in general only a few examples have been
reported and very reactive halogenating agents such as the
Received: May 5, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01315
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Organic Letters
Letter
Table 1. Halocyclization of Cyclopropanol 1a: Optimization
of Reaction Conditions
Scheme 2. Scope of Haloetherification, Halolactonization,
and Haloamination
entry
reagent (1.2 equiv)
solvent
yield [%]
1
Br2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
41
47
60
79
76
39
49
14
69
8
2
TBCO
NBS
BrSEt2 ·SbCl5Br−
1,3-DBDMH
1,3-DBDMH
1,3-DBDMH
1,3-DBDMH
3
+
4
5
6
7
CH3CN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
a
9
1,3-DBDMH
10
11
12
NIS
BnMe3N+·ICl2
ICl
−
18
52
a
0.6 equiv of 1,3-dibromo-5,5-dimethylhydantoin (1,3-DBDMH).
reagent was chosen due to its low acquisition costs and simpler
handling. Attempts to increase the yield by using different
solvents led to no improvement, and yields in less (toluene)
and more polar solvents (THF, MeCN) were lower than in
dichloromethane (13−69%) (Table 1, entries 6−8). The yield
of product 2a was good (69%) but no longer excellent if only
0.6 equiv of 1,3-DBDMH were used (Table 1, entry 9). This
shows that both bromine atoms of 1,3-DBDMH do react, but
better yields are obtained if only the more reactive bromine is
required. The use of iodinating agents such as NIS or
iododichloride salts to induce iodocyclizations was also
possible; however, the reactions took much longer, and the
yield of iodocyclization product 2k after 24 h was low (Table 1,
entries 10, 11). Only with the very reactive iodine
monochloride high conversion was observed after 24 h and
the iodocyclization product 2k could be isolated in 52% yield
(Table 1, entry 12).
With the optimized reaction conditions in hand the scope of
the reaction was investigated (Scheme 2). Starting materials
bearing alkyl groups in the para-position on the aryl group led
to excellent yields [2b (96%), 2c (92%)]. Substrate 1d with an
even more electron-donating methoxy group was converted to
the product 2d in an even better yield (98%). With an electron-
withdrawing fluorine substituent in the para-position the
bromocyclization product 2e was produced in lower yield
(54%). Substituents in the meta- or ortho-position were well
tolerated including bulky substrate 1g, bearing a benzofurane
substituent. In both cases the cyclization products 2f and 2g
could be obtained in good yield (68% and 67%, respectively).
Furthermore, the linker between the cyclopropane and the
hydroxyl group can contain substituents such as two phenyl
groups (2h, 64%) or an additional CH2 group to give pyran
derivative 2i via a 6-exo cyclization (48%). As mentioned
before, the corresponding iodocyclizations are slower than the
bromocyclizations. Nevertheless, under slightly optimized
conditions (trifluoroethanol, 72 h) the iodocyclization product
2j was obtained in respectable yield (60%) using N-
iodosuccinimide as an iodinating agent. Finally, the reaction
was not limited to cycloetherifications and the hydroxyl group
can be replaced by other nucleophilic groups such as carboxyl
a
NBS (1.1 equiv) instead of 1,3-DBDMH in F3CCH2OH/CH2Cl2
b
1:1. NIS (1.2 equiv) instead of 1,3-DBDMH, reaction time 72 h,
F3CCH2OH instead of CH2Cl2. F3CCH2OH instead of CH2Cl2. 1,3-
DBDMH (1.7 equiv), reaction time 77 h. N-Iodopyrrolidin-2-one
(1.2 equiv) instead of 1,3-DBDMH, reaction time 72 h, addition of 2
mL of F3CCH2OH.
c
d
e
groups or tosyl amides. For example, compound 1k carrying a
tosylamide instead of a hydroxyl group could be cyclized to the
tosylated pyrrolidine 2k in good yield (60%) under the
standard conditions. Bromolactonizations of the cyclopropane
derivatives 1l, 1m, and 1n proceeded equally well and delivered
the γ-lactones 2l, 2m, and 2n in good to very good yields.
Again, the corresponding iodolactonization was slower and
required adjusted reaction conditions to give lactone 2o in
moderate yield (41%).
The similarity in reactivity of cyclopropanes to alkenes
suggests a mechanism related to conventional alkene
halocyclizations. For alkene halocyclizations, it is usually
assumed that a cyclic, three-membered halonium ion, a
haliranium ion, is formed as an intermediate explaining the
stereospecific anti-addition.12 However, whereas cyclic halo-
nium ions with a ring size of three and five are well-known,
examples with a four-membered ring, haletanium ions, have
only been observed in special cases or implicated as reaction
intermediates based on stereochemical grounds.13 This leads to
the question if the intermediate of the current transformations
is either a rare cyclic, four-membered bromonium ion,
brometanium ion A, or a benzylic carbocation B (Scheme 3).
For the dibromination of different cyclopropanes the reaction
B
DOI: 10.1021/acs.orglett.5b01315
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
onto the benzylic carbocation B. Nevertheless, it is clear that
further, more extended studies on the mechanism are necessary.
If the reaction is indeed taking place via the benzylic
carbocation B, this offers the possibility to control the relative
configuration by a substituent in the α-position to the
cyclopropane. In alkene halocyclization a substituent in this
position leads to very high diastereoselectivities.14 Furthermore,
for benzylic carbocations, Bach has also shown that very high
diastereocontrol can be obtained by substituents in this
position.15 To test this hypothesis α-substituted cyclopropane
derivatives 6a−c were prepared (Scheme 5). Upon treatment
Scheme 3. Possible Mechanism of the Bromocyclization of
Cyclopropanols
Scheme 5. Highly Diastereoselective Bromocyclization of α-
Substituted Cyclopropanes 7a−c
via a cyclic halonium ion as well as a carbocation has been
suggested.5 In our case, the higher yields obtained with starting
materials containing electron-rich aryl groups could point to a
benzylic carbocation B as an intermediate; however,
brometanium ion A would probably also be stabilized by an
electron-donating group. Nevertheless it should be possible to
distinguish between these scenarios based on the stereo-
chemistry of the cyclizations as the involvement of A should
lead to a stereospecific reaction whereas B should not.
To investigate this question for the present case, methyl-
substituted cyclopropane derivative 3 was prepared. Unfortu-
nately, it proved to be very difficult to prepare or isolate 3 as a
single diastereoisomer and only a mixture of cis-3 and trans-3
(79:21) could be obtained. Upon treatment with electrophilic
brominating agents such as 1,3-DBDMH or NBS cyclopropane
3 underwent bromocyclization. Depending on the reaction
conditions a product mixture was obtained containing two
different, regioisomeric cyclization products, each consisting of
two diastereoisomers. Additionally, aromatic bromination of
the cyclization products was observed. However, under
optimized conditions (NBS in CH2Cl2/TFE 1/1 at 0 °C)
aromatic bromination could be almost completely suppressed
and the bromcyclization product 4, which is formed by
bromination at the least hindered cyclopropane carbon, was
formed as the major regioisomer (Scheme 4). The diastereo-
with 1,3-DBDMH under standard conditions phenyl-substi-
tuted 6a underwent clean cyclization to the trisubstituted
tetrahydrofuran 7a in good yield (63%) and with excellent
diastereoselectivity (91:9 dr). The relative configuration of the
main product was established using NOESY experiments. The
substituent R is placed cis to the 2-bromoethyl group, which is
in agreement with an addition of the hydroxyl group to the
benzylic carbocation via a conformation with a minimized
allylic-1,3-strain.16 With alkyl substituents in the α-position,
similar high diastereoselectivites were observed. The methyl-
and ethyl-substituted tetrahydrofurans 7b and 7c could be
obtained in moderate yield and diastereoselectivities of 95:5
and 84:16 dr, respectively (Scheme 5).
In summary we have demonstrated that cyclopropane
derivatives can undergo halocyclizations in very much the
same way as alkenes, alkynes, and allenes. However, instead of
vicinal addition products, 1,3-addition products are obtained.
This means the combination of a cyclopropanation, which
could be a highly enantioselective metal-catalyzed variant,
followed by halocyclization leads to the formation of
homohalocyclization products with two new, neighboring
stereocenters. This two-step sequence is ideally suited for the
rapid generation of complex molecules from simple alkenes as
starting materials. Reagent-controlled asymmetric versions of
these reactions are currently under development in our
laboratory.
Scheme 4. Bromocyclization of a Trisubstituted
Cyclopropane
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for the preparation of all starting
materials and products including full spectroscopic data for all
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01315.
meric ratio (76:24 dr) was only slightly lower than in the
starting material. This effect was much more pronounced for
the minor regioisomer 5, resulting from bromination at the
more hindered cyclopropane carbon, which was formed in
52:48 dr, indicating a nonstereospecific reaction. Based on
these initial experiments we suggest a reaction via the benzylic,
tertiary cation B. The observed diastereoselectivity is probably
induced by the preexisting stereocenter during the cyclization
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ulrich.hennecke@uni-muenster.de.
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DOI: 10.1021/acs.orglett.5b01315
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Organic Letters
Letter
(11) Treitler, D. S.; Snyder, S. A. Angew. Chem., Int. Ed. 2009, 48,
7899−7903.
Notes
The authors declare no competing financial interest.
(12) Lenoir, D.; Chiappe, C. Chem.Eur. J. 2003, 9, 1036−1044.
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ACKNOWLEDGMENTS
The authors gratefully acknowledge the help of Christoph
Fricke (WWU Munster) in the preparation of compound 3.
■
̈
Financial support by the WWU Munster and the “Fonds der
Chemischen Industrie” is gratefully acknowledged.
̈
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