Ring-opening 1,3-dichlorination of donor-acceptor cyclopropanes by iodobenzene dichloride

Article abstract of DOI:10.1021/ol5029139

Donor-acceptor cyclopropanes are reacted with iodobenzene dichloride to afford ring-opened products bearing chlorine atoms in the 1- and 3-positions, adjacent to the donor and acceptor groups. A variety of different donors (e.g., alkyl, aryl, N, and O) and acceptor moieties (e.g., ketones, diesters, and dinitriles) are used.

Full text of DOI:10.1021/ol5029139

Letter
pubs.acs.org/OrgLett
Ring-Opening 1,3-Dichlorination of Donor−Acceptor Cyclopropanes
by Iodobenzene Dichloride
Lennart K. B. Garve, Philip Barkawitz, Peter G. Jones, and Daniel B. Werz*
†
̈
̈
Technische Universitat Braunschweig, Institut fur Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany
*
S Supporting Information
ABSTRACT: Donor−acceptor cyclopropanes are reacted with iodoben-
zene dichloride to afford ring-opened products bearing chlorine atoms in the
1
- and 3-positions, adjacent to the donor and acceptor groups. A variety of
different donors (e.g., alkyl, aryl, N, and O) and acceptor moieties (e.g.,
ketones, diesters, and dinitriles) are used.
he use of donor−acceptor (D−A) cyclopropanes as easily
Scheme 1. Enantioselective 1,3-Dichlorination Method of
Sparr and Gilmour for Aldehydes and Our Approach for a
Wider Range of Acceptor-Substituted Cyclopropanes
T
available building blocks in organic synthesis has
1
flourished in the recent past. Even though the groundwork
2
was performed by Wenkert and Reissig in the 1970s and
1
980s, the field has been enjoying a marked renaissance for the
3
,4
past decade. The capability of these highly polarized strained
systems to undergo cycloadditions, rearrangements, and
ring-opening reactions makes them attractive for heterocyclic
chemistry, natural product syntheses, and even medicinal
chemistry. Whereas cycloadditions and rearrangements of D−
5
6,7
8
9
A cyclopropanes commonly increase the complexity of the
compounds being utilized, ring-opening reactions transform the
cyclic moiety into an open-chain system. Formally, a 1,3-
addition of the reagent to the three-membered ring occurs.
Promoted by Lewis acids which coordinate to the acceptor,
nucleophiles commonly attack the emerging positive charge
1
next to the donor while ring-opening takes place. The resulting
negative charge associated with the acceptor substituent is
typically captured by a proton. A variety of heteroatoms as well
as carbon nucleophiles (e.g., phenols, amines, azides, and
10−13
indoles) have been successfully used for this purpose.
Only rare examples are known in which two non-hydrogen
substituents were attached to the 1- and 3-positions next to the
donor and acceptor.
intermediates (Scheme 1). We anticipated that a hypervalent
1
17
iodine reagent such as PhICl might be the reagent of choice
2
+
−
Of course, it has been known for more than 40 years that
elemental chlorine and bromine react with cyclopropanes in an
unselective reaction, leading to 1,3-disubstituted acyclic
products together with 1,2-substituted isomers obtained by
for this purpose, since it formally bears both Cl and Cl and in
addition displays Lewis acidic character. Radical pathways are
also often discussed for this compound.
17
At the outset of our studies, we employed D−A cyclo-
propane 5a to explore suitable conditions for the anticipated
ring-opening 1,3-dichlorination to yield 6a. We employed an
aliphatic ketone with a donor of minimal electron-donating
ability in order to test the desired reaction. Whereas DMF and
toluene only afforded traces of the product (Table 1, entries 1−
1
4
rearrangement. Recently, Sparr and Gilmour have cleverly
designed an enantioselective 1,3-dichlorination with cyclo-
15
propanes 1 bearing formyl groups (Scheme 1). The key to
this was a formal umpolung making use of a secondary amine in
order to use nucleophilic chloride for γ-functionalization to
afford intermediate 3 and electrophilic chlorine for α-attack.
After hydrolysis, the 1,3-dichlorinated aldehyde 4 was obtained.
Because of the obligatory enamine formation, this approach was
restricted to reactive formyl groups as substituents. Accord-
ingly, we have chosen to investigate a simple 1,3-dichlorination
3
), dichloromethane proved to be the solvent of choice for this
process. The best results were obtained using a slight excess of
the hypervalent iodine(III) reagent (1.2 equiv) at 45 °C with a
reaction time of 16 h (entry 5). Shorter reaction times at 45 °C
1
6
process that might be compatible with a wider range of
accepting moieties that are unable to generate enamine
Received: October 2, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5029139 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the PhICl -Mediated 1,3-
Dichlorination
Scheme 2. 1,3-Dichlorination of Donor−Acceptor
2
a
a
Cyclopropanes by Iodobenzene Dichloride
entry
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
toluene
toluene
DMF
60
120
100
45
45
45
rt
16
16
16
16
16
4
0
traces
0
b
CH Cl2
89
2
CH Cl2
93
43
11
2
CH Cl2
2
CH Cl2
48
2
a
Reaction conditions: 5a (0.2 mmol), PhICl (0.24 mmol), solvent
2
(
3 mL); yields represent isolated 1,3-dichlorinated products;
b
diastereomeric ratio 1:1. PhICl (0.4 mmol).
2
or reaction at room temperature (even with prolonged reaction
times) gave only poor yields (entries 6 and 7).
With our optimized conditions in hand, we probed the scope
of this 1,3-difunctionalization by changing both donor and
acceptor moieties. Besides ketones, we also employed
carboxylic esters and diesters as well as a nitroester and some
dinitriles as electron-withdrawing groups (Scheme 2). Not only
the weakly donating aliphatic groups were tested as donors, but
also various arene units differing strongly in electron-donating
ability, and also nitrogen and oxygen donors. In total, we
subjected 24 D−A cyclopropane derivatives to the reaction
conditions. The transformation proceeded smoothly, with
ketones furnishing the desired products in yields of 65−93%.
Since cyclopropyl ketones with strongly electron-donating
arene units or heteroatoms such as oxygen or nitrogen as
donors tend to rearrange easily to the five-membered ring
systems, we abstained from investigating the dichlorination
18
reaction with these systems. As a further type of electron-
withdrawing substituent, we employed carboxylic esters.
Whereas two ester groups as acceptors are commonly sufficient
to trigger the ring-opening process in concert with aromatic
and aliphatic groups, a perfluoroarene as a strongly electron-
withdrawing group completely prevents the scission of the
three-membered ring. This result can be rationalized in terms of
the donor/acceptor strength of the various residues. In
contrast, electron-withdrawing nitro and cyano groups attached
in the p-position are unable to completely counter the donating
ability of the arene moiety and do not significantly decrease the
yield. In contrast, the electron-withdrawing power of only one
ester group is not sufficient to polarize a cyclopropane to an
adequate extent for ring cleavage to take place. Oxygen and
nitrogen donors protected as imide moieties also act as
perfectly suitable residues to initiate the desired 1,3-
dichlorination, as examples 8m−8q demonstrate.
The last examples in Scheme 2 reveal that one of the two
ester groups can also be exchanged for a nitro functionality,
affording compound 8r in 74% yield. Since cyano function-
alities display the same oxidation state as carboxylic acids or
esters, we were keen to test also two examples of corresponding
dinitriles. Indeed, the reaction proceeded smoothly and yielded
the respective ring-opened chlorinated dinitriles 8s and 8t.
To prove the 1,3-dichlorination unambiguously, we obtained
a
b
All yields represent isolated 1,3-dichlorinated products. Mono-
chlorination of the aromatic ring could not be suppressed.
c
Methylester was used.
confirmed the anticipated structure involving a quaternary
carbon atom and another carbon bearing the nitrogen and the
1
9,20
single crystals of 8n. The X-ray crystallographic analysis
B
dx.doi.org/10.1021/ol5029139 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
second chlorine. The molecular structure of this compound is
depicted in Figure 1.
Scheme 4. Proposed Reaction Mechanism
available iodobenzene dichloride into the corresponding ring-
opened 1,3-dichlorinated compounds. Besides aliphatic resi-
dues, oxygen and nitrogen and also aromatic systems can be
successfully employed as donors, unless their electron-releasing
ability is too poor. As acceptors, a wide range of carbonyl
derivatives such as ketones, diesters, and dinitriles can be
utilized to initiate the process, whereas a single ester moiety
proved to be insufficient to trigger the process. It is expected
that such a simple 1,3-dichlorination reaction will inspire the
design of other ring-opening 1,3-difunctionalization reactions
using hypervalent iodine reagents.
Figure 1. Molecular structure (50% ellipsoid probability) of 8n in the
solid state. Oxygen atoms are shown in red, nitrogen atoms in blue,
20
and chlorine atoms in green.
In order to obtain insights as to whether a radical or an ionic
process takes place, we performed several experiments. Initial
screening results revealed that the reaction is much slower in
the dark. Thus, radical inhibitors such as TEMPO and BHT
were added to the reaction mixture. Both additives completely
inhibited the reaction, and starting material was reisolated. As a
side product of the latter reaction we were able to detect a BHT
dimer, implying that Cl radicals abstracted hydrogen, thus
paving the way for dimerization. In a further experiment
compound 7h was subjected to the typical conditions of our
ASSOCIATED CONTENT
Supporting Information
■
*
S
Detailed experimental procedures, analytical data for all new
compounds, and crystal data (CIF) for 8n. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
,3-dichlorination, but 1,4-cyclohexadiene was added to the
21
reaction mixture.
Because of facile aromatization this homoconjugated
compound is capable of delivering H radicals. Our notion
was to intercept a monochlorinated radical intermediate and to
elucidate which position is initially chlorinated. Indeed, besides
the dichlorinated product 8h a single monochlorinated species
AUTHOR INFORMATION
Corresponding Author
■
* E-mail: d.werz@tu-braunschweig.de.
9
h was unequivocally detected via GC-MS. Its fragmentation
pattern clearly indicated that Cl was located next to the donor
Scheme 3). The regioisomer 9h′ was not found.
Present Address
†
̈
̈
Technische Universitat Braunschweig, Institut fur Anorgani-
sche and Analytische Chemie, Hagenring 30, 38106 Braun-
schweig, Germany.
(
a
Scheme 3. Trapping Experiment with 1,4-Cyclohexadiene
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the German Research
Foundation (DFG, Emmy Noether and Heisenberg Fellow-
ships to D.B.W.) and by the Fonds der Chemischen Industrie
(Dozentenstipendium to D.B.W.).
a
Reaction conditions: 7h (0.11 mmol), PhICl (0.13 mmol), 1,4-
2
b
cyclohexadiene (0.13 mmol), CH Cl (3 mL), 45 °C, 16 h. Ratio
determined by GC-MS.
2
2
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D
dx.doi.org/10.1021/ol5029139 | Org. Lett. XXXX, XXX, XXX−XXX