A radical exchange process: Synthesis of bicyclo[1.1.1]pentane derivatives of xanthates

Article abstract of DOI:10.1039/c9cc07610g

Bicyclo[1.1.1]pentane (BCP) replacement as a bioisostere in drug molecules has an influence on their permeability, aqueous solubility and in vitro metabolic stability. Thus, the chemical installation of the BCP unit into a chemical entity remains a significant challenge from a synthetic point of view. Here, we have presented a new approach for the installation of the BCP unit on the xanthate moiety by means of a radical exchange process.

Full text of DOI:10.1039/c9cc07610g

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A radical exchange process: synthesis of
bicyclo[1.1.1]pentane derivatives of xanthates†
Cite this: Chem. Commun., 2019,
5, 14976
5
Saroj Kumar Rout, Gilles Marghem, Junjie Lan, Tom Leyssens and Olivier Riant
*
Received 30th September 2019,
Accepted 20th November 2019
DOI: 10.1039/c9cc07610g
rsc.li/chemcomm
Bicyclo[1.1.1]pentane (BCP) replacement as a bioisostere in drug
molecules has an influence on their permeability, aqueous solubility
and in vitro metabolic stability. Thus, the chemical installation of
the BCP unit into a chemical entity remains a significant challenge
from a synthetic point of view. Here, we have presented a new
approach for the installation of the BCP unit on the xanthate moiety
by means of a radical exchange process.
Structure–activity relationships have often facilitated the develop-
ment of small-ring three dimensional bioisosteres. The bicyclo-
[
1.1.1]pentane (BCP) unit is a unique isosteric replacement for
1
a phenyl ring, with similar geometrical characteristics. Intro-
duction of the BCP moiety into several drug candidates, such
as g-secretase inhibitors, mGlu1 receptor antagonists and
LpPLA2 inhibitors, significantly alters their physicochemical
2a
2b
2c
Scheme 1 BCP unit installation in small molecules.
2d
profiles in terms of aqueous solubility, membrane permeability Grignard reagent-mediated ring-opening of [1.1.1]propellane and
and in vitro metabolic stability. Many functionalized BCP deriva- Negishi coupling after transmetalation with ZnCl to synthesize
2
5b
tives have been obtained by the addition of groups across bis-arylated BCP moieties. Uchiyama/Kanazawa disclosed an Fe
3
the reactive central bond of a strained [1.1.1]propellane ring.
catalyzed multicomponent carboamination of [1.1.1]propellane
6
Considering that the background chemistry has now been well through a radical approach. Complementary to those studies,
established, and regarding the renewal in interest for such the Anderson group also synthesized highly functionalized 1-halo-
moieties in medicinal chemistry, the scientific community has 3-substituted bicyclo[1.1.1]pentanes through atom-transfer radical
7
been recently highly active in finding new methodologies for the addition and photoredox catalysis. Recently, the Walsh group
introduction of various functional groups on this unique and suggested a new protocol for the synthesis of BCP benzyl amine
fascinating hydrocarbon.
derivatives and intercepted anionic intermediates with iodo-
Recently, new approaches have been used to gain easy access benzene to evidence the formation of a BCP organolithium
8
to BCP containing molecules, as show in Scheme 1. The Baran intermediate. In addition to this, Brase et al. showed a
group solved a long standing problem for the synthesis of convenient approach for the synthesis of bicyclo[1.1.1]pentyl
9
amino-BCP derivatives, through a nucleophilic opening of sulfides through radical chemistry, using various thiols.
4
[
1.1.1]propellane by using ‘‘turbo-amides’’. Inspired by the
A pioneering study by the Zard group on the degenerative
Knochel and radical exchange of thiocarbonylthio derivatives and especially
3
b,5a
pioneer work of de Meijere and coworkers,
coworkers developed an elegant and practical method, combining on xanthates was one of the major breakthroughs in the field of
radical chemistry. The degenerative radical exchange allows the
Institute of Condensed Matter and Nanoscience. Molecular Chemistry, Materials
intermolecular addition of a wide range of xanthate derivatives
and Catalysis Division, Universit ´e Catholique de Louvain, 1348, Belgium.
on unactivated double bonds, with the potential further trans-
E-mail: olivier.riant@uclouvain.be; Fax: +91-3612690762
Electronic supplementary information (ESI) available. CCDC 1911714. For ESI
1
0
formation of the xanthate group. But so far, there has been
no precedence of BCP unit installation on a xanthate moiety.
In this study, we decided to study the possibility of incorporating
†
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc07610g
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a
Table 1 Screening of reaction conditions
Propellane DLP
Temperature Yield
Entry (equiv.)
(mol%) Solvent
(1C)
(%)
1
2
3
4
5
6
7
8
9
1
1.5
1.5
1.5
1.5
2.0
2.5
2.0
2.0
2.0
2.0
30
10
10
10
10
10
10
10
10
10
DCE
DCE
DCE
DCE
DCE
DCE
DCM
Toluene
Cyclohexane
Ethyl acetate
60
60
80
100
80
80
80
80
80
80
32
41
51
51
61
61
52
46
54
37
Fig. 1 Crystal structure of 4a.
After achieving the optimized conditions, this methodology
was applied to xanthates with various aryl and alkyl ketones on
the backbones of the xanthates (Schemes 2 and 3). At first,
the effects of substituents on the aryl ring of xanthates were
examined. The electron-donating aryl substituted (viz. o-Me (2b)
and p-OMe (2c)) xanthates reacted with (1) under optimized
conditions, and we successfully obtained the desired BCP
0
a
Reaction conditions: xanthate (1.0 equiv.), [1.1.1]propellane (2 equiv.),
DLP (0.1 equiv. unless stated substrates), DCE (2.0 M of xanthate after
the addition of diethyl solution of [1.1.1]propellane).
xanthate derivatives into a strained ring of [1.1.1]propellane to products (4b and 4c) in average yields of 44 and 53%, respectively.
obtain BCP O-ethyl carbonodithioate, using substoichiometric However, when the aryl ring contained electron-withdrawing
amounts of dilauroyl peroxide (DLP) as a radical initiator. With groups such as p-Br (2d) and di-F (2e), the reactions proceeded
this inspiration in mind, our initial investigation began by treating slightly better, to give their corresponding BCP products 4d and 4e
model xanthate 2a (1 equiv.) with [1.1.1]propellane (0.6–0.8 M in in 62% and 65% yields, as shown in Scheme 2.
2
Et O, 1.5 equiv.) and DLP (0.3 equiv.) at 60 1C in dichloroethane
A BCP moiety containing pyridine group (4g) was successfully
(DCE) in a sealed tube. To our delight, the BCP unit (4a) was prepared by the reaction of [1.1.1]propellane (1) with xanthate
isolated in 32% yield (entry 1, Table 1) along with some undesired (2g), in a moderate yield. Moving from aryl to alkyl xanthates,
product (competitive opening of propellane by decyl radicals). To to see the influence on reactivity, we then checked various groups
the best of our knowledge, the product is the first of its kind, a such as acetyl (3b), t-butyl (3c), cyclopropyl (3d) and cyclobutyl (3e)
BCP unit with a ketone moiety and a xanthate group, which can in the current protocol. Average to good yields up to 71% were
11
further modified to more useful products. Another appealing obtained in those cases with good reproducibility.
side to this methodology resides in the ability to form C–C and We then decided to check the variety of xanthate structures
C–S bonds across the reactive central bond of the strained with different functional groups in order to diversify the
1.1.1]propellane ring, without using a metal catalyst. Encouraged portfolio of available structures, as depicted in Scheme 3. First,
[
by this first result, other reaction parameters such as the quantity the scope was extended to the case of ester and substituted
of [1.1.1]propellane, the amount of radical initiator, temperature esters such as tert-butyl ester (6a), ethyl ester (6b) and a-methyl
and solvents were studied, to achieve the highest yield. To control
the formation of the undesired product, the loading of DLP was
decreased from 0.3 equiv. to 0.1 equiv., resulting in an improved
yield of 41% (entry 2, Table 1). To further improve the yield, the
temperature was increased from 60 1C to 80 1C to optimize the
fragmentation of the radical initiator (entry 3, Table 1).
A further increase in temperature from 80 1C to 100 1C did
not have any effect on the yield (entry 4, Table 1). Next, we
2
moved to the quantity of [1.1.1]propellane (0.6–0.8 M in Et O).
Increasing the quantity from 1.5 equiv. to 2.0 equiv. gave a good
yield of 61% (entry 5, Table 1). Increasing the quantity further
to 2.5 equiv. of (1) did not alter the yield of the reaction (entry 6,
Table 1). Screening of other solvents showed that DCM (52%),
toluene (46%), cyclohexane (54%), and ethyl acetate (37%) were
less productive than DCE (entries 7–10, Table 1).
Finally, it was found that the ideal conditions for this transfor-
mation were DLP (10 mol% for aromatic substrates and 20 mol%
for aliphatic substrates), [1.1.1]propellane to 2.0 equiv. in DCE at
Scheme 2 Scope of BCP moiety installation with xanthates 2a–3e.
Reaction conditions: xanthate (1.0 equiv.), [1.1.1]propellane (2 equiv.),
DLP (0.1 equiv., for aromatic ketones 2a–2g and 0.2 equiv. for aliphatic
ketones 3a–3e), DCE (2.0 M of xanthate after the addition of diethyl
80 1C in a sealed tube (entry 5, Table 1). Furthermore, the structure
of the BCP unit (4a) was confirmed by X-ray crystallography, Fig. 1. solution of [1.1.1]propellane) at 80 1C. Isolated yields.
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reaction was performed in the presence of TEMPO (E) to capture
the proposed intermediate in the catalytic cycle. Unfortunately,
we were not able to isolate any of the trapped intermediates, but
we were able to observe the formation TEMPO ether of the decyl
radical (F), along with the starting material.
In conclusion, we have developed an efficient method for
the synthesis of functionalized BCP derivatives with xanthate
moieties by means of a radical exchange process. This reaction
uses simple conditions and one-pot operations and tolerates
different functional groups present in the xanthate moiety.
Thus, it opens up a new avenue for medicinal chemistry. Work
Scheme 3 Scope of BCP moiety installation with xanthates 6a–11a.
Reaction conditions: xanthate (1.0 equiv.), [1.1.1]propellane (2.0 equiv.), is now in progress for studying the transformation of the
DLP (0.2 equiv.), DCE (2.0 M of xanthate after the addition of diethyl xanthate group for further transformations and implementing
solution of [1.1.1]propellane) at 80 1C. Isolated yields.
these new scaffolds.
We gratefully acknowledge financial support from the
Universit ´e Catholique de Louvain (UCL), FNRS (FRIA grant to
G. Marghem), FRS-FNRS (Charg ´e de recherches – CR, post-
ester (6c). All the esters yielded their corresponding products in
satisfactory yields (69–72%). The reaction was also successful
doctoral grant to S. Rout) and the Chinese Scholarship Council
with an acyloxazolidinone, yielding the corresponding adduct
(PhD grant to J. Lan).
(13a) in a more moderate 38% yield. We also aimed to demon-
strate that other functional groups could be introduced by this
method. Interestingly, xanthate 8a, previously described by
1
2
Conflicts of interest
Zard et al. for radical aminomethylation of alkenes, worked
well under our optimized conditions and gave the desired
product in a decent 53% yield. The unusual substrate 10a in
which the xanthate group is one carbon away from the ketone
gave the desired product (16a) in a moderate yield, suggesting
There are no conflicts to declare.
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Based on literature reports and mechanistic investigations,
a plausible mechanism for this transformation is depicted in
Scheme 4. A radical (B) is first formed by the reaction of the
xanthate with the decyl radical arising from the fragmentation/
decarboxylation of DLP. The alkyl radical (B) reacts then with 1
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1
0a
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3
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