Ring-opening 1,3-halochalcogenation of cyclopropane dicarboxylates

Article abstract of DOI:10.1021/acs.orglett.6b03375

Donor-acceptor cyclopropanes with two geminal carboxylic esters are reacted with chalcogenyl chlorides and bromides to afford ring-opened products bearing the halogen atoms in the 1-position, adjacent to the donor, and the chalcogenyl residue in the 3-pos

Full text of DOI:10.1021/acs.orglett.6b03375

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Letter
pubs.acs.org/OrgLett
Ring-Opening 1,3-Halochalcogenation of Cyclopropane
Dicarboxylates
†
†
‡
,†
Jan Wallbaum, Lennart K. B. Garve, Peter G. Jones, and Daniel B. Werz*
†
‡
Institut fu
̈
r Organische Chemie and Institut fu
̈
r Anorganische and Analytische Chemie, Technische Universitat
̈
Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
*
S Supporting Information
ABSTRACT: Donor−acceptor cyclopropanes with two gemi-
nal carboxylic esters are reacted with chalcogenyl chlorides and
bromides to afford ring-opened products bearing the halogen
atoms in the 1-position, adjacent to the donor, and the
chalcogenyl residue in the 3-position next to the two acceptor
groups. A variety of different donors (e.g., aryl, N, and O) are
used. The stereospecificity of the reaction is demonstrated by using a chiral starting material.
uring the past decade, donor−acceptor (D−A) cyclo-
Scheme 1. Ring-Opening 1,3-Dichlorination of Cyclopropane
Dicarboxylates and Our Extension to 1,3-Halochalcogenation
D
propanes have enjoyed a renaissance as easily available
1
building blocks. Although the basic chemistry in this field was
2
developed by Wenkert and Reissig in the 1970s and 1980s,
many groups have recently utilized the unique features of this
special class of three-membered rings. These highly polarized
3
strained systems easily undergo cycloadditions, rearrange-
4
,5
ments, and ring-opening reactions. Thus, they are an ideal
starting point for the synthesis of carbo- and heterocycles and
6
have been used in the preparation of natural products.
Cycloaddition and rearrangement reactions of D−A cyclo-
propanes commonly allow a rapid increase of complexity,
whereas ring-opening reactions decrease the complexity by
transforming the cyclopropane into an aliphatic chain. A variety
of heteronucleophiles such as phenols, amines, azides, or indoles
7
have been employed to open the ring. As a result, the
nucleophile is located next to the donor while the negative
charge next to the acceptor is captured by a proton. To further
weaken the bond between donor and acceptor and to promote
the attack, Lewis acids are commonly applied. Whereas the
transfer of a nucleophile to position 1 and a proton to position 3
has often been reported, only a few examples of ring-opening
reactions exist in which two non-hydrogen substituents were
attached to the 1- and 3-positions next to the donor and
nucleophilic part, next to the two acceptor moieties, would be
captured by the positively polarized chalcogen. This assumption
was corroborated by early work from Reissig and Reichelt that
led to 2-chalcogenyl-substituted 4-oxoesters when TMSO-
substituted cyclopropanes were treated with chalcogenyl
11
8
chlorides.
acceptor. Recently, we found that cyclopropane dicarboxylates 1
At the outset of our studies, D−A cyclopropane 1a was chosen
to explore suitable conditions for the expected process. As a
component to be added, we chose p-tolylsulfenyl chloride 3a,
which is easily available from the respective thiophenol and N-
react with Willgerodt’s reagent (PhICl ) to yield 1,3-dichlori-
2
9
nated compounds 2 (Scheme 1). Sparr and Gilmour even
performed enantioselective 1,3-dichlorinations of meso-cyclo-
10
propyl aldehydes using an organocatalytic approach.
12
chlorosuccinimide; as donor, we employed phthalimide.
After our initial attempts with the ring-opening 1,3-
dichlorination, we considered whether we might trigger other
ring-opening 1,3-additions of cyclopropane dicarboxylates using
strongly polarized bonds of the type RY−X. Prototypes of such
species are provided by the sulfenyl and selenyl halides 3, 5, and
Initial experiments using FeCl , which is known to act as
2
13
radical initiator in combination with sulfenyl chlorides, showed
no formation of the desired product (Table 1). Incorporation of
stronger Lewis acids such as Sc(OTf) (entry 2), Yb(OTf) , BF ·
3
3
3
OEt , or TiCl led to decomposition of the starting materials.
2
4
7. The higher electronegativity of the halogen in comparison to
that of the chalcogen efficiently polarizes the bond. Thus, we
envisioned that the electrophilic part of the cyclopropane, the
center next to the donor, might add the halide and that the
Received: November 11, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the 1,3-Chlorosulfenylation
donor phthalimide; thus, succinimide was also tested and
provided a 74% yield of 4b. Oxygens are other markedly
electron-releasing donors, and a phenoxy-substituted cyclo-
propane afforded the desired product 4c in 51% yield. Several
arene units differing in their electron-donating ability were
subjected to the reaction conditions. Transformations proceeded
smoothly and furnished desired products 4d−4g in yields of 74−
9
9%. Cyclopropanes with very electron-rich arene units such as
p-MeOPh underwent electrophilic aromatic substitution with a
sulfenium ion, resulting in a mixture of products.
entry
Lewis acid
3a (equiv)
t (h)
yield (%)
The scope of various sulfenyl chlorides was tested (Scheme 3).
Electron-poor (4h, 4o), electron-rich (4i), and fluoro-
1
2
3
4
5
6
FeCl2
1.1
1.1
1.1
1.1
1.1
1.5
24
24
24
3
−
Sc(OTf)3
FeCl3
decomp
b
complex mixture
Scheme 3. 1,3-Chlorosulfenylation of Phenyl- and Imido-
Substituted Cyclopropanes with Several Sulfenyl Chlorides,
ZnBr2
50 + byproducts
MgI2
0.5
0.08
81
91
a
ClS(CO)OMe, and ClSCN
MgI2
a
Reaction conditions: 1a (0.1 mmol), CH Cl (0.1 M, with respect to
2
2
the cyclopropane), 10 mol % of Lewis acid, ambient temperature.
b
Desired product was found in the mixture.
More promising results could be achieved with FeCl , indicating
3
that the desired product is formed, and ZnBr , giving rise to 50%
2
of 4a in addition to some unspecified byproducts. Finally,
utilization of 10 mol % of MgI as Lewis acid, combined with an
2
increase of the amount of sulfenyl chlorides to 1.5 equiv and a
shortening of the reaction time to 5 min, yielded 4a in 91% yield.
With optimized conditions in hand, the scope of this 1,3-
chlorosulfenation reaction was examined. We started with a
1
variation of the donor (R ) at the three-membered ring (Scheme
2). Optimization was originally performed with the nitrogen
Scheme 2. 1,3-Chlorosulfenylation of D−A Cyclopropanes
a
with p-Tolylsulfenyl Chloride
a
Reaction conditions: 1 (0.1 mmol), 3 (1.5−5.0 equiv), MgI (10
2
mol %), CH Cl (0.1 M), 15 min to 20 h. All yields represent isolated
1
2
2
b
,3-functionalized products. 0.2 mmol of 1 was used.
substituted (4j) aryl residues were compatible with the reaction.
Use of bulky o-tolyl sulfenyl chloride provided 4k in good yield of
8
3%. Aliphatic sulfenyl chlorides also participated in the reaction,
and a similar yield was obtained (77%). Even a thiocarbonate was
successfully introduced by the reaction of the cyclopropane with
ClS(CO)OMe, affording the respective product 4m in 90% yield.
The pseudohalogen ClSCN is easily available from the reaction
of lead(II) thiocyanate and sulfuryl chloride, and we therefore
employed this reagent too to affect a ring-opening under our
conditions; the transformation yielded the respective thiocyanate
4n in 96% yield. Since sulfur is still positively polarized,
thiocyanates were utilized as useful precursors for further
a
Reaction conditions: 1 (0.2 mmol), 3a (1.5−2.0 equiv), MgI (10
2
mol %), CH Cl (0.1 M), reaction time: 5 min − 3 h. All yields
represent isolated 1,3-functionalized products. 0.1 mmol of 1 was
2
2
b
used.
B
DOI: 10.1021/acs.orglett.6b03375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions with carbon nucleophiles with loss of cyanide (e.g.,
leading to thioalkynes).
Scheme 5. 1,3-Chloroselenylation of D−A Cyclopropanes
14
a
with Phenylselenyl Chloride
We addressed the question whether sulfenyl bromides also
react in an analogous way. These were obtained from the thiol
and a solution of N-bromosuccinimide. To precipitate the
resulting succinimide, the mixture was suspended with n-pentane
and filtered. Removal of the solvent in vacuo gave sulfenyl
bromide, which was used without further purification. Since
sulfenyl bromides are more sensitive than sulfenyl chlorides, we
employed only aryl sulfenyl bromides 5 and used more
equivalents than in the experiments described before. Scheme
4
depicts three examples of 1,3-bromosulfenation. Much longer
Scheme 4. 1,3-Bromosulfenylation of D−A Cyclopropanes
a
with Sulfenyl Bromide
a
Reaction conditions: 1 (0.1 mmol), 7 (0.15 mmol), MgI2 (10
mol %), CH Cl (0.1 M), 15 min to 5 h. All yields represent isolated
2
2
1
,3-functionalized products.
Scheme 6. Stereospecificity of the 1,3-Chlorosulfenylation
(
(
eq 1) and Transformation with S Cl to Dimeric Structures
eq 2)
2 2
a
Reaction conditions: 1 (0.1 mmol), 5 (3.0 equiv), MgI (10 mol %),
2
CH Cl2 (0.1 M), 20−24 h. All yields represent isolated 1,3-
2
b
c
functionalized products. 0.2 mmol of 1 used. 10 equiv of 5 used.
reactions times (20−24 h) were required for complete
conversion, which might be attributed to the much less
pronounced polarization of the S−Br bond. Yields of 6 ranging
from 32 to 70% were much lower than for the lighter
counterparts; nevertheless, even when the strongly electron-
withdrawing pentafluorophenyl residue was used as a donor, it
afforded 6c in 32% yield.
the sulfenium ion to give (R)-4h. We found that S Cl was also
able to undergo the reaction (Scheme 6, eq 2). Since both termini
2
2
Our reaction conditions were successfully extended to the
synthesis of 1,3-chloroselenated products. Phthalimide- and
phenyl-substituted three-membered rings were converted
smoothly with commercially available phenylselenyl chloride
of the S moiety react, we used (S)-1d to exclude the possibility
of generating a diastereomeric mixture. The desired product 10
was obtained in poor yield of 26% after 2 h; longer reaction times
2
furnished a product with an S chain (11) in much higher yield
4
(Scheme 5). The corresponding selenium-containing products
(
90%). For 10, X-ray crystallographic analysis confirmed the
were obtained in 66 and 83% yield. Formation of 8a was much
faster than 8b. Because of the relative instability of corresponding
aliphatic selenyl chlorides, we did not attempt transformations
with these reagents. Analogous experiments with phenylselenyl
bromide and thio- and selenocyanates showed no conversion,
and the starting material was recovered.
expected structure and demonstrated the inversion of the
stereocenter during the transformation. The molecular structure
of this compound is depicted in Figure 1.
In conclusion, we have developed novel 1,3-halochalcogena-
tion reactions of cyclopropane dicarboxylates. A variety of D−A
cyclopropanes were converted with either readily available
sulfenyl chlorides, sulfenyl bromides, or selenyl chlorides.
Oxygen and nitrogen and even aromatic systems can be
successfully employed as donors. Magnesium iodide proved to
be the Lewis acid of choice. Further work with other highly
polarized reagents to trigger other ring-opening 1,3-addition
processes is in progress in our laboratory.
Finally, we explored the stereospecificity of the ring-opening
1
,3-chlorosulfenation using enantioenriched (95% ee) phenyl-
substituted cyclopropane (S)-1d. p-Nitrophenylsulfenyl chloride
3b) reacted with almost complete stereospecificity, giving (R)-
h in quantitative yield and 88% ee as revealed by chiral HPLC
Scheme 6, eq 1, and Supporting Information). Mechanistically,
this process might be explained via S 2-like attack of the chloride
(
4
(
N
(from RSCl) to the cyclopropane, which then further reacts with
C
DOI: 10.1021/acs.orglett.6b03375
Org. Lett. XXXX, XXX, XXX−XXX

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15,16
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ASSOCIATED CONTENT
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*
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Crystal data for 10 (CIF)
Detailed experimental procedures, analytical data for all
new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: d.werz@tu-braunschweig.de.
ORCID
Daniel B. Werz: 0000-0002-3973-2212
Notes
(
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030−3039. (l) Ivanov, K. L.; Villemson, E. V.; Budynina, E. M.;
The authors declare no competing financial interest.
Ivanova, O. A.; Trushkov, I. V.; Melnikov, M. Y. Chem. - Eur. J. 2015, 21,
4975−4987. (m) Kang, Q.-K.; Wang, L.; Liu, Q.-J.; Li, J.- F.; Tang, Y. J.
Am. Chem. Soc. 2015, 137, 14594−14597. (n) Xia, Y.; Liu, X.; Zheng, H.;
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Lin, L.; Chang, F.; Fu, X.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2015,
ACKNOWLEDGMENTS
This research was supported by the European Research Council
ERC Consolidator Grant “GAINBYSTRAIN” to D.B.W.).
L.K.B.G. thanks the Studienstiftung des deutschen Volkes for a
Ph.D. Fellowship.
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Org. Lett. XXXX, XXX, XXX−XXX