Mild Darzens Annulations for the Assembly of Trifluoromethylthiolated (SCF3) Aziridine and Cyclopropane Structures

Article abstract of DOI:10.1021/acs.orglett.1c02204

We report mild new annulation approaches to trisubstituted trifluoromethylthiolated (SCF3) aziridines and cyclopropanes via Darzens inspired protocols. The products of these anionic annulations, rarely studied previously, possess attractive features rendering them valuable building blocks for synthesis platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF3 and bromine substituents in their α position were shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.1c02204

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Letter
Mild Darzens Annulations for the Assembly of
Trifluoromethylthiolated (SCF3) Aziridine and Cyclopropane
Structures
Michael D. Delost and Jon T. Njardarson*
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ABSTRACT: We report mild new annulation approaches to
trisubstituted trifluoromethylthiolated (SCF3) aziridines and cyclo-
propanes via Darzens inspired protocols. The products of these
anionic annulations, rarely studied previously, possess attractive
features rendering them valuable building blocks for synthesis
platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF3 and bromine substituents in their α position were
shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.
ith continued usage and development for well over a
Wcentury, the Darzens reaction has cemented itself as a
premier workhorse in the synthesis of 3-membered rings, most
notably oxiranes and aziridines.1 Cyclopropanes can be
similarly assembled by reacting Michael acceptors with alpha-
halo-esters or ketones. The Johnson−Corey−Chaykovsky
reaction,2,3 which is conceptually related to Darzens reactions,
offers a complementary approach to these strained rings. Both
these important [2 + 1] annulation canvases have been
successfully employed in obtaining 3-membered ring systems.
The success of fluorinated substituents in pharmaceutical4,5
and agrochemical products has catalyzed interest in new
reactions for synthesis of fluorinated strained rings. For
example, Xiao disclosed routes toward trifluoromethylated
oxiranes, aziridines and cyclopropanes though utilization of
2,2,2-(trifluoroethyl)diphenylsulfonium triflate.6 Koenigs later
expanded upon this approach with nitro-styrene electrophiles.7
More recently, Pace reported homologation strategies to access
fluorinated epoxides and aziridines8 and trifluoromethylated
aziridines.9 The juxtaposition of the trifluoromethylthiol
(SCF3) group, a moiety of modern importance,10−13 with
our interest in the Darzens reaction14−16 led us to ponder
whether a useful marriage could be forged between these?
There are very few reported methods to access SCF3-
containing aziridines and cyclopropanes. Only a single example
to access a disubstituted SCF3-containing aziridine has been
reported (Figure 1a), which involved direct aziridination of a
vinyl ketone containing an α-SCF3 group.17 No trisubstituted
Figure 1. Prior art and proposed studies for the synthesis of
routes have been reported to date. With regards to SCF3-
cyclopropanes, Haas and Hinsken introduced the first route in
1985 (Figure 1b).18 Their carbenoid approach utilized aryl-
mercury-halogen carbenes in conjunction with vinyl-SCF3
moieties. An alternative approach to access SCF3-cyclo-
propanes was developed by Stroech (Figure 1c),19 which
relies on trifluoromethanesulfenyl chloride (SCF3Cl) to install
trifluorothiomethylated aziridines and cyclopropanes.
Received: July 2, 2021
Published: July 22, 2021
https://doi.org/10.1021/acs.orglett.1c02204
Org. Lett. 2021, 23, 6121−6125
© 2021 American Chemical Society
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the SCF3 group followed by a base-mediated cyclization. A
major drawback of this route are toxicity concerns and
handling of SCF3Cl gas.20 Shen reported a silver-mediated
decarboxylative trifluoromethylthiolation, including two cyclo-
propane examples (Figure 1d).21 In this study, we describe the
development and investigations of mild annulation routes to
trisubstituted SCF3-containing aziridines and cyclopropanes
and an intriguing deacylation reaction to access disubstituted
SCF3-aziridines (Figure 1e).
Scheme 1. Scope of SCF3-Aziridine Synthesis
Our preliminary investigations commenced with the syn-
thesis of CF3SCH2X (where X = I, Br, and OTs) unsubstituted
nucleophiles. We were unable to reliably synthesize CF3SCH2I
and CF3SCH2Br, which we attribute to product stability issues.
CF3SCH2OTs on the other hand we did synthesize, but this
nucleophile did not possess the desired reactivity when reacted
with tosyl-imines and enones. We therefore turned our
attention to a nucleophile bearing an electron-withdrawing
group in lieu of a hydrogen, reasoning that deprotonation
could occur with a mild base. A ketone was chosen as the
electron-withdrawing group, as the pKa of its alpha-proton is
substantially lower than esters, amides, and sulfones. To that
end, we chose to synthesize and evaluate SCF3-substituted
bromo-acetophenone 1 (Table 1).22,23 The highly electrophilic
Table 1. SCF3-Aziridine Synthesis Optimization
entry
base
solvent, temp
yield (%)
b
1
2
3
4
5
6
7
8
9
LiHMDS
THF, 0 °C to rt
THF, 0 °C to rt
THF, 0 °C to rt
THF, 0 °C to rt
DMSO, rt
CHCl3, rt
DMF, rt
CH2Cl2, rt
CH3CN, rt
0
d
DBU
15
50
50
0
10
30
40
75
a
KOtBu
a
NaH
c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
a
a
a
Cs2CO3
a
1 (1 equiv) and 2 (1 equiv) added together over 30 min to base (2
b
c
equiv) and solvent. Base added last over 30 min. 1 and 2 added
together quickly. Base added last quickly.
d
2-nitro tosyl imine 2 was chosen for the optimization studies,
due to its enhanced reactivity in the first addition step and
decreased likelihood of the resulting Mannich adduct under-
going undesirable isomerization and hydride shift events,24,25
leading to enamines instead of aziridines. During our
optimizations we learned that base, solvent, and order of
addition were all determined to be critical for success. Strong
bases (Table 1, entries 1−4) did work, with yields as high as
50% when both substrates were added together last and slowly.
Cesium carbonate (entries 5−9) was shown to be the best
performing base for this anionic reaction cascade. Solvent
choice and the aforementioned addition order are decisive,
with acetonitrile along with slow addition of substrate resulting
in the target aziridine 3 being isolated in 75% yield and as a
single diastereomer.
The scope and limitations for our new synthesis of
trisubstituted SCF3-aziridines is presented in Scheme 1.
Optimized reaction conditions from Table 1 were used and
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diastereoselectivities (dr) were determined from integration of
1H NMR from crude reaction mixtures. All yields are isolated
yields. Highly reactive electron-poor sulfonyl imines have been
identified as the best reaction partners (3−15, Table 1), with
aryl-substituted nitro, cyano, fluoro, and trifluoromethyl groups
being performing best. Ortho-substitution has been shown to
produce slightly higher yields in these cases. The main
competing reaction pathway is a hydride shift to form an
enamide, which becomes the major product when appropriate
aryl deactivation is not present as exemplified by 4-bromo
product 19. Interestingly, a cyclopropyl imine is compatible for
the reaction cascade affording aziridine product 16. Beyond
phenyl, we have learned that electronics of the nucleophile
substituents are critical as well with the parent phenyl
performing the best (3) followed by 4-OMe (20), then 4-Br
(21) with 4-NO2 (22) failing to react.
Excitingly, a phenyl ester nucleophile works as well as the
phenyl ketone nucleophile (24). We were able to secure a
crystal structure of 24, which confirmed that the SCF3- and
aryl substituents are syn to each other. This ester product
opens the door significantly for expanded synthetic applica-
tions. Finally, an intriguing cyclic sulfamate aldimine has been
shown to form aziridine product 25.
Presumably, following aziridine ring opening the resulting
dipole undergoes a cyclization followed by loss of the N-tosyl
protecting group driven by aromatization and formation of the
oxazole product. Padwa first demonstrated this type of
rearrangement for N-alkyl and N-aryl aziridines using forcing
conditions (220 °C).26 The three reported N-sulfonyl
examples proceed under higher temperature and lower
yield.27 This is the first example of an SCF3-substituted ring
expansion case affording a rare example of an SCF3-substituted
oxazole. We have further demonstrated this ring expansion for
the synthesis of SCF3-oxazoles 27, 28, and 29. It is worth
noting that oxazoles are a prominent motif in pharmaceutical
architectures and our two-step route represents a novel entry
for their assembly.28,29
Unexpectedly, when we attempted a Horner−Wadsworth−
Emmons olefination of ketone 3 with trimethyl phosphonoa-
cetate (TMPA) none of the expected enoate (31) was
observed, but instead all cis-SCF3 disubstituted aziridine 30
was formed as the only product in 65% yield. Presumably, the
phosphonate anion adds to the ketone, which then undergoes a
deacylation to form an SCF3-stabilized aziridine carbanion and
then the product upon protonation. This is the first example of
a 1,2-disubstituted SCF3-aziridine being synthesized and a rare
example of a mild anion-mediated aziridine deacylation
reaction. We were eager to learn if we could replace the
phosphonate anion with a more affordable and readily available
carbanion for this anionic deacylation process. Our inves-
tigations have identified both ethyl acetate and dimethyl
malonate (DMM) as excellent replacements for TMPA.
Disubstituted SCF3-aziridines 32, 33, and 34 were also
synthesized as single syn-diastereomers employing ethyl
acetate as deacylation nucleophile.
We have identified two attractive applications for these
SCF3-aziridine products (Scheme 2 and Scheme 3). Aziridine
Scheme 2. SCF3-Aziridine Ring Expansion to Oxazoles
We next turned our attention to using this class of
nucleophiles for the synthesis of SCF3-substituted cyclo-
propanes. We rationalized that highly reactive enones with
limited stability would provide the best opportunity for the
tandem Michael-SN2 displacement to occur. To that end, we
chose phenyl vinyl ketone as our electrophile (Table 2). For
Table 2. SCF3-Cyclopropane Synthesis Optimization
Scheme 3. Synthesis of Disubstituted SCF3-Aziridines via an
Unexpected Anionic Deacylation Process
entry
base
solvent
yield (%), major:minor
a
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
CH3CN
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
CH3CN
THF
t-BuOH
THF
70, 1:25:1
65, 12.7:1
50, 5.3:1
60, 4.7:1
0
0
trace
0
0
a
a
a
K2CO3
a
Na2CO3
a
Li2CO3
a
Et3N
b c
,
LiHMDS
Proton sponge
a
9
a
10
11
12
DBU
10, 1.5:1
40, 6:1
20, 5.9:1
a
KOtBu
b c
,
NaH
a
Both substrates added together over 30 min to base and solvent.
b
c
3 undergoes a facile ring expansion under mild thermal
conditions to form SCF3-substituted oxazole 26 in 80% yield.
Base added last over 30 min. 0 °C to rt. Diastereomeric ratio was
1
based on integration of H NMR crude mixtures.
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our first attempt, we ran the reaction under the same optimized
conditions developed for SCF3-aziridine synthesis. We were
exhilarated to learn that the desired cyclopropane target
product (35) was formed in 60% yield as a 1.25:1 mixture of
diastereomers (Table 2, entry 1). Switching the solvent from
acetonitrile for chloroform (CHCl3), a more nonpolar solvent,
further increased the yield while more importantly drastically
increasing diastereoselectivity to 12.7:1 favoring major isomer
of 35 (entry 2). Perhaps unsurprisingly, the activated Cs2CO3
followed by K2CO3 (entry 4) were the only carbonate bases
which provided the cyclopropane with both Na2CO3 and
Li2CO3 (entries 5−6), failing to facilitate formation of any
cyclopropane products. This is attributed to the enhanced
solubility in organic solvents which Cs2CO3 provides.30 Of the
other reaction conditions tested, only potassium tert-butoxide
(KOt-Bu) in tert-butanol (t-BuOH) and NaH in THF
provided any remnants of cyclopropane formation. All other
reaction conditions led to recovered starting materials and
complex mixtures of degradations pathways.
Scheme 4. Scope of SCF3-Cyclopropane Synthesis
A variety of aryl vinyl ketones were evaluated with
nucleophile 1 (35−46, Scheme 4), employing the optimized
reaction conditions from Table 2. We were able to secure an X-
ray crystal structure analysis for cyclopropane 35, which
confirmed the syn-relationship between the two phenacyl
groups in the major diastereomer. Isolated yields were
remarkably uniform (58−70%) for these products with
diastereoselectivity ranging from 1.7:1 to 12.7:1. Interestingly,
when the phenyl group of the nucleophile was substituted in
the 4-position with bromide, methoxy, or nitro group, product
yields and diastereoselectivity were reduced in the case of
bromide (47) and methoxy (48) with no product formed for
the 4-nitro substituted nucleophile (49). Cyclopropane
product 51 is notable as it demonstrates that an ester
nucleophile is also compatible with this cascade, thus greatly
expanding synthetic application possibilities.
We have also evaluated the cyclopropane synthesis scope for
a variety of other Michael acceptors, affording tri- to
pentasubstituted cyclopropane products (Scheme 4). Doubly
activated Michael acceptors bearing one or two benzoyl group
performed well (53−56), with the 1,1-bis-acyl and 1,1-acyl-
ester acceptors affording the cyclopropanes in 82% (53) and
72% (54) yield, respectively, with lower yields observed for the
analogous sulfonate (55) and phosphonate (56) acceptors. By
using highly reactive acceptors, we were able to access
pentasubstituted cyclopropane products 57 and 58 as well as
fused cyclopropane 59 from an indanone precursor. Cyclo-
propane products 60 and 61 are particularly noteworthy, as
they are accessed from acrolein and its Ellman-imine analogue,
both of which are far less reactive Michael acceptors, to afford
intriguing cyclopropanes with useful functional group handles.
In conclusion, we have developed mild new approaches for
synthesizing trisubstituted SCF3-substituted aziridine and
cyclopropanes from the anionic union of SCF3-bearing
bromo-nucleophiles and imines and Michael acceptors,
respectively. We have expanded the cyclopropane scope and
demonstrated compatibility for other nucleophiles and the
Michael acceptors to deliver tetra- and pentasubstituted
cyclopropanes as well as fused ones. In the case of SCF3-
substituted aziridine we report a new synthesis of SCF3-
substituted oxazoles via a mild thermally promoted aziridine
ring expansion reaction. Finally, we designed the first synthesis
of disubstituted SCF3-aziridines via a deacylation protocol.
ASSOCIATED CONTENT
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Experimental procedures and characterization data for
all new compounds (PDF)
Accession Codes
CCDC 2087417 and 2092036 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
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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.
AUTHOR INFORMATION
Corresponding Author
■
Jon T. Njardarson − Department of Chemistry and
Biochemistry, University of Arizona, Tucson, Arizona 85721,
United States; orcid.org/0000-0003-2268-1479;
Email: njardars@arizona.edu
Author
Michael D. Delost − Department of Chemistry and
Biochemistry, University of Arizona, Tucson, Arizona 85721,
United States
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to acknowledge the National Science
Foundation (CHE-1855708) for supporting this program
and the purchase a new NMR spectrometer (MRI-grant
CHE-1920234), and Dr. Andrei Astaschkine (University of
Arizona, Department of Chemistry and Biochemistry) for
crystal structure data collection and analysis.
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