Synthesis of Ortho-Functionalized 1,4-Cubanedicarboxylate Derivatives through Photochemical Chlorocarbonylation

Article abstract of DOI:10.1021/acs.orglett.1c01702

The cubane ring has received intense attention as a 3D benzene isostere and scaffold. Mono-and 1,4-disubstituted cubanes are well-described. Here we report a practical procedure for a direct radical-mediated chlorocarbonylation process initially reported by Bashir-Hashemi, to access a range of 2-substituted 1,4-cubanedicarboxylic ester derivatives. A subsequent regioselective ester hydrolysis to give fully differentiated 1,2,4-Trisubstituted cubanes is demonstrated.

Full text of DOI:10.1021/acs.orglett.1c01702

pubs.acs.org/OrgLett
Letter
Synthesis of Ortho-Functionalized 1,4-Cubanedicarboxylate
Derivatives through Photochemical Chlorocarbonylation
Diego E. Collin, Kristina Kovacic, Mark E. Light, and Bruno Linclau*
Cite This: Org. Lett. 2021, 23, 5164−5169
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ABSTRACT: The cubane ring has received intense attention as a 3D benzene isostere and scaffold. Mono- and 1,4-disubstituted
cubanes are well-described. Here we report a practical procedure for a direct radical-mediated chlorocarbonylation process initially
reported by Bashir-Hashemi, to access a range of 2-substituted 1,4-cubanedicarboxylic ester derivatives. A subsequent regioselective
ester hydrolysis to give fully differentiated 1,2,4-trisubstituted cubanes is demonstrated.
hether drug-like molecules with substantial sp3-rich
substructures could improve clinical success by
using oxone with (bipy)Cu(CF3)3 under blue light irradiation
was recently reported to allow direct CF3 introduction, albeit
in low yield (14%) despite using 6 equiv of 1.18
W
modulating their pharmacokinetics properties is a subject of
debate.1,2 However, sp3-rich sphere-like fragments are under-
represented in drug screening libraries,3 and 1,4-substituted
cubanes have received great interest as non-classical bio-
isosteres for para-substituted benzene structures in medicinal
chemistry.4−6 Further exciting opportunities to enter unex-
plored areas of chemical space can be envisaged with 1,2- and
1,3-substituted cubanes to replace ortho- and meta-substituted
benzenes (Figure 1A).5 In addition to bioisosteric applications,
cubanes could also be considered as a 3D benzene-like scaffold,
offering an opportunity to introduce substituents perpendicular
to the aromatic plane.6,7 However, accessing these cubane
motifs is still hampered by non-trivial synthetic access.
Eaton et al. pioneered ortho-lithiation of amidocubanes
(Figure 1B).8 While this requires the introduction of a
directing group and the use of strong bases, it is a versatile
methodology to introduce cubane substitution.9 Subsequently,
transmetalation, typically with Zn, enhances the nucleophilicity
and was shown to facilitate reaction with electrophiles.10
Direct C−H to C−C bond formation can also be achieved
using radical-based strategies, despite the strong cubane C−H
bond (Figure 1C).11 The C−H bond dissociation enthalpy of
1 is expected to be even higher than 104.7 kcal·mol−1 due to
the presence of electron-withdrawing groups.12,13 Indeed,
while tert-butoxyl radicals abstract hydrogen atoms from
cubane or mono-substituted cubanes, no cubyl radical
formation could be observed for 1.14 Nevertheless, based on
the work of Kharasch and Brown, Bashir-Hashemi reported a
photochemical radical chlorocarbonylation of dimethyl 1,4-
cubanedicarboxylate 1 with oxalyl chloride under light
irradiation.15−17 Radical-mediated cubane trifluoromethylation
Radical-mediated halogenation has also been reported to
subsequently enable C−C bond formation.10b,d Here,
regioselective hydrogen abstraction of monosubstituted
cubanes was shown to be challenging due to the small BDE
differences between the para-, meta-, and ortho-hydrogens.
Direct introduction of a carboxylic acid group in the
archetypical cubane starting material 1 is of high interest due
to the rich cubane decarboxylative functionalization chemistry
developed in recent years.19
Most of the reported aliphatic C−H bond carboxylations
rely on the use of transition metal complexes, photoredox
catalysis process, or both, usually in the presence of carbon
dioxide, and remain limited to allylic, benzylic, α-amino weak
C−H bonds.20 With the challenging cubyl radical formation in
mind, Bashir-Hashemi’s chlorine radical mediated cubane C−
H chlorocarbonylation remains of great interest despite the use
of the toxic and corrosive oxalyl chloride in very large excess,
and the use of a high-powered halogen lamp (≥275 W)
operating at very high temperatures.16 This method has
previously shown high potential to access molecular diversity
in the field of combinatorial chemistry.21 Recently, several
milder conditions for the generation of chlorine radical have
Received: May 20, 2021
Published: June 16, 2021
https://doi.org/10.1021/acs.orglett.1c01702
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5164−5169
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regulator led to clogging and was therefore abandoned.
Therefore, in order to keep the inherent benefits of the
photomicroreactor such as better light penetration, mixing, and
heat transfer25 despite the excessive gas generation, the
microreactor was used in a recirculating mode, enabling the
formed carbon monoxide to escape from the setup (Figure 2).
In this case, an ice−water bath was used in order to cool the
solution during the process.
Figure 2. Schematic representation and picture of the recirculating
flow microphotoreactor.
After some experimentation toward reducing the amount of
oxalyl chloride, irradiation of dimethyl 1,4-cubanedicarboxylate
1 with 20 equiv of oxalyl chloride for 3 h under a recirculating
flow rate of 0.2 mL·min−1, followed by quenching with
methanol, gave trimethyl 1,2,4-cubanetricarboxylate 3 in 23%
yield along with unreacted 1 (Table 1, entry 1). When the flow
rate was increased to 3 mL·min−1, the yield increased to 49%
and increasing the irradiation time to 4 h led to a 62% yield
with 7% of unreacted 1 (entries 2 and 3). Under similar
Figure 1. Context of the work.
3
been reported (for nickel mediated Csp −H cross-coupling or
Minisci-type reactions);22 however, a large excess of substrates
(5 to 20 equiv) is required, rendering these approaches
unattractive with the use of expensive 1.
Table 1. Optimization for the Ortho-Carboxylation of
a
Dimethyl-1,4-cubanedicarboxylate 1
Herein, we describe our efforts to develop safer, milder,
practical, and more efficient conditions to achieve the powerful
C−H chlorocarbonylation of 1 (Figure 1D) to give access to a
wide variety of 1,2,4-substituted cubane derivatives, exemplify
the synthetic opportunities offered by the introduction of the
corresponding carboxylic acid, and fully differentiate the three
substituents.
(COCl)2
[equiv]
Flow rate
Time
[h]
Yield
b
Entry
Light
UV-B
UV-B
UV-B
UV-B
UV-C
UV-A
Blue
LED
UV-B
UV-B
UV-B
None
[mL·min−1
]
[%]
Key considerations involved the excess of oxalyl chloride and
the irradiation source. Instead of using oxalyl chloride as the
solvent, dichloromethane was chosen, given the hydrocarbons
and ethers, the only other solvents compatible with oxalyl
chloride, are expected to undergo H-atom transfer (HAT) with
the cubyl radical. According to the reported photodissociation
mechanism of oxalyl chloride,23 we considered that a large part
of the emission spectrum of the previously used halogen or
mercury-vapor lamps remained unused, leading us to select
UV-irradiation to increase the energy efficiency. In addition,
the use of a microreactor was employed as a safe and more
efficient means for photochemical reactions, envisioning to
enable a drastic reduction in lamp power. A previously
reported24 home-made reactor setup using commercially
available parts and a low-powered 9 W bulb was used.
Our synthetic study began with UV-B irradiation of a 0.05 M
solution of 1 in a continuous manner. However, the formation
of carbon monoxide gas bubbles led to an uncontrolled flow
rate, and consequently a low conversion toward the formation
of chlorocarbonylated cubane 2. The use of a back pressure
c
1
2
3
4
5
6
7
20
20
20
20
20
20
20
0.2
3
3
3
3
3
3
4
4
4
4
8
23
49
62
60
c
c
d
de
,
32
49
c
3
3
f
0
8
9
10
11
40
10
20
3
3
3
3
4
4
4
3
61
55
8
g
20
0
a
Reaction conditions: Optimized on 0.6 mmol of 1 Internal Volume
b
(Vi) = 2 mL. 1H NMR yield with 1,4-dimethyl terephthalate as
c
internal standard. c = 0.05 M, CH2Cl2 (10.95 mL), (COCl)2 (20.0
equiv). c = 0.1 M, CH2Cl2 (5.0 mL), (COCl)2 (20.0 equiv).
Reactor fouling was observed (see Supporting Information for
details). Kessil A160WE Tuna Blue (40 W) lamp. Methyl
chlorooxoacetate (20.0 equiv).
d
e
f
g
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irradiation conditions, doubling the concentration of 1 does
not improve the yield (entry 4).
Scheme 1. In Situ Derivatization of Acyl Chloride
Intermediate 2
a
The use of UV-C and UV-A lamps was then investigated.
With a UV-C (λ = 100−280 nm) lamp, the yield was
decreased to 32% (entry 5). Considering reactor fouling was
also observed, no further optimizations were carried out with
UV-C (see Supporting Information for details). Under similar
conditions, replacing UV-B with UV-A (λ = 340−400 nm) also
led to a lower yield (49%) for the same irradiation time. Under
40 W blue LED (λ = 450 nm) light, no product could be
observed after 8 h of irradiation (Table 1, entry 7)
demonstrating that the visible region (λ = 400−700 nm) of
the emitted spectrum by halogen or mercury-vapor lamps
initially reported16,17 is not optimal. With regard to the large
excess of oxalyl chloride used originally, doubling the
concentration did not significantly increase the yield of 1
whereas decreasing the concentration 2-fold still gave trimethyl
1,2,4-cubanetricarboxylate 3 in 55% yield (entries 8 and 9).
Using the optimized conditions, replacing oxalyl chloride with
methyl chlorooxoacetate led to the desired product 3 in 8%
yield (entry 10). Finally, as expected, a control experiment
performed in the absence of light gave no product (entry 11).
Using the optimized conditions, the formed acid chloride
intermediate 2 was then trapped with various nucleophiles to
demonstrate further in situ derivatization while keeping the
two original ester groups intact. Several 1,2,4-tricarbonyl
cubane derivatives have been prepared (Scheme 1). Hydrolysis
of 2 gave the crude carboxylic acid 4 in 56% yield, similar to
that obtained by Irngartinger17 (cf. Figure 1). Doubling the
amount of 1 and increasing the reaction time to 8 h led to
isolation of 4 in 44% yield (Scheme 1). While 3 was obtained
subsequently by the addition of methanol after concentration
of the acyl chloride intermediate 2, attempting to trap the acyl
chloride similarly with more complex and bulkier alcohols at
room temperature did not lead to isolation of the
corresponding 1,2,4-triester cubanes, illustrating the hindered
nature of this acid chloride group. However, refluxing 2 in
toluene in the presence of 1 equiv or a slight excess of
(−)-menthol and bile acid methyl ester led to the
corresponding desired product 5 and 6 in 30% and 37%
yield respectively (Scheme 1). The use of hydroxyphthalamide
at room temperature enabled us to obtain the redox active
ester 7 in low yield. In most cases, excess triethylamine (5.0
equiv) was added in order to avoid protonation and
precipitation of the nucleophiles due to the formation of
hydrochloric acid during the photochemical step. Changing
alcohol for cyclohexyl mercaptan afforded 8 in 43% yield.
Trapping the acyl chloride 2 with ammonium chloride in the
presence of triethylamine led to the isolation of the
corresponding amide 9 in 22% yield. Primary amines such as
p-fluorobenzylamine and the bulky tert-butyl amine gave the
amides in 43−47% yield. Amide bond formation using the
para-anisidine cubane isostere19d led to 12 in reasonable yield.
Because aminocubanes are unstable,4 it was added as the
hydrochloric acid salt. Electron-poor and -rich anilines and
ampyrone gave the corresponding amides 13−15 in moderate
and good yields, respectively. Finally, secondary amides 16 and
17 obtained with morpholine and piperidine, which are
abundant drug substructures, were synthesized. Unfortunately,
attempts to form a carbonyl−carbon bond through Friedel−
Craft acylation in the presence of N-methyl-indole did not lead
to the corresponding ketone 19, probably due to the unlikely
a
Isolated yield based on 0.6 mmol of 1; 7−10% of 1 was recovered
after the reaction.
formation or stabilization of the corresponding cubyl acylium
ion.
With these 1,2,4-trisubstituted cubane derivatives in hand,
further transformations were explored. Starting from the ortho-
carboxylic acid 4, the redox-active ester 7 was obtained in 92%
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Letter
yield (Scheme 2). This can now be used for a range of
recirculating microreactor to enable continuous-flow condi-
tions despite excessive gas formation, and the significant
reduction in excess of oxalyl chloride by using a solvent,
leading to a safe and accessible platform. This allows for
convenient installation of the chlorocarbonyl group and,
through its hydrolysis, of the versatile carboxylic acid group,
with both exemplifying utility by ester and amide formations
and by ortho-arylation and alkylation via nickel catalysis,
showing their potential for the synthesis of diverse 1,2,4-
trisubstituted cubanes and, by extension, for cubane-derived
derivatives such as cyclooctatetraenes.28 In addition, regiose-
lective ester hydrolysis to access fully differentiated trisub-
stituted cubane derivatives is demonstrated.
decarboxylative coupling methodologies26 to establish Ccub
−
Scheme 2. Nickel-Catalyzed Ortho-Functionalization of
RAE 1,2,4-Cubane Diester 7
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01702.
Experimental procedures and compound characteriza-
tion, instructions for instrument setup, copies of NMR
spectra, X-ray crystallographic data (PDF)
3
2
Csp /sp ortho-cubane functionalization without the need to
introduce a directing amide group as previously reported.10c
By applying the Senge nickel catalyzed decarboxylative
procedure without further optimization, ortho-phenyl cubane
diester 20 was obtained in 32% yield from 7 in the presence of
4 equiv of phenyl zincate chloride.19 Similarly, Giese-type
reaction using benzyl acrylate as a Michael acceptor gave 21 in
20% isolated yield.27
Accession Codes
CCDC 1977608, 1986355, and 2057837 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
The presence of the substituent at the 2-position leads to a
differentiation of the two ester groups. Selective ester
hydrolysis will allow fully differentiated functionalization3
and can be used to further functionalize this position or,
through decarboxylation, give access to 1,2- or 1,3-substituted
cubane derivatives. Selective hydrolysis of the least hindered
ester group was achieved: by starting with 13, saponification
with 1 equiv of sodium hydroxide led to the isolation of the
corresponding carboxylic acid 22 in 84% yield in a 10:1 ratio
(1H NMR analysis) of the regiosiomers (Scheme 3).
Saponification of 15 enabled isolation of 23 with complete
regioselectivity (1H NMR analysis) in 74% isolated yield.
In conclusion, we have successfully developed a modified
protocol for the radical-mediated C−H chlorocarbonylation of
dimethyl 1,4-cubanedicarboxylate 1 using oxalyl chloride under
light irradiation. Key improvements include the use of an
adequate emission low-powered UV source, the use of a
AUTHOR INFORMATION
■
Corresponding Author
Bruno Linclau − School of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom;
orcid.org/0000-0001-8762-0170;
Email: Bruno.linclau@soton.ac.uk
Authors
Diego E. Collin − School of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom;
orcid.org/0000-0002-7389-6763
Kristina Kovacic − School of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom;
orcid.org/0000-0002-5180-9913
Mark E. Light − School of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom;
orcid.org/0000-0002-0585-0843
Scheme 3. Regioselective Saponification
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01702
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the ERDF
(LabFact: InterReg V project 121) and EPSRC (core
capability EP/K039466/1). K.K. thanks NZP for funding
and is grateful for a Denis Henry Desty PhD Scholarship.
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Role of Bond Energetics in C−H Activation/Functionalization. Chem.
Rev. 2017, 117 (13), 8622−8648.
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