Phosphorus(III)-Mediated, Tandem Deoxygenative Geminal Chlorofluorination of 1,2-Diketones

Article abstract of DOI:10.1021/acs.orglett.0c01258

Tetrasubstituted carbon containing two different halogen substituents was constructed in a single-step operation by utilizing the carbene-like reactivity of dioxaphospholene through the tandem reaction of electrophilic and nucleophilic halogenating reagents. It was crucial to devise non-dealkylatable phosphoramidite, which enabled the efficient formation of geminal chlorofluorides from various 1,2-diketones with (PhSO2)2NF and n-Bu4NCl. In addition, selective functionalization of the chlorine substituent was demonstrated, and the absence of halogen scrambling was confirmed.

Full text of DOI:10.1021/acs.orglett.0c01258

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Letter
Phosphorus(III)-Mediated, Tandem Deoxygenative Geminal
Chlorofluorination of 1,2-Diketones
Garam Choi,† Ha Eun Kim,† Sunjoo Hwang, Hanna Jang, and Won-jin Chung*
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ABSTRACT: Tetrasubstituted carbon containing two different
halogen substituents was constructed in a single-step operation by
utilizing the carbene-like reactivity of dioxaphospholene through
the tandem reaction of electrophilic and nucleophilic halogenating
reagents. It was crucial to devise non-dealkylatable phosphor-
amidite, which enabled the efficient formation of geminal
chlorofluorides from various 1,2-diketones with (PhSO2)2NF and
n-Bu4NCl. In addition, selective functionalization of the chlorine
substituent was demonstrated, and the absence of halogen scrambling was confirmed.
he simultaneous introduction of two halogen substituents
onto organic molecules is generally accomplished via
T
vicinal dihalogenation of unsaturated functional groups, which
is one of the most extensively studied fundamental trans-
formations in organic chemistry.1 The scope of such reaction
has expanded greatly in recent years to culminate in the
development of enantioselective dihalogenation2a−d and
interhalogenation2e as well as stereochemically complementary
syn-dihalogenations.3 In contrast, geminal dihalogenation at
one carbon center has received much less attention probably
because such reactions usually do not involve interesting
selectivity issues. However, if the two halogen substituents are
different, it would lead to the construction of an unusual
tetrasubstituted stereocenter such as the chlorofluorinated
carbon in 1 (Figure 1A). This kind of geminal interhalide has
high synthetic utility.4,5 For example, 1 can be transformed
into a range of fluorinated organic molecules (2) typically via
SN2 displacement of the more reactive chlorine substituent as
demonstrated by the groups of Yamamoto and Shibatomi.4b,c
Geminal chlorofluoride has been synthesized most successfully
via sequential electrophilic halogenations of an activated
methylene such as 1,3-dicarbonyl compounds (3) (Figure
1B).4 However, because this process employs the same kind of
reactivity twice, it has to be a two-step operation. If the two
electrophilic reagents are present together, the starting material
will not be able to distinguish them. Moreover, it is often
difficult to avoid double incorporation of the same halogen,
and the resulting overhalogenated side product such as 5 is
very difficult to separate from the desired product 4.4a
Figure 1. Geminal interhalogenation.
Received: April 9, 2020
To solve these problems, the two halogenating reagents
must have different, distinguishable reactivities. Thus, it can be
postulated that the combined use of an electrophilic halenium
and a nucleophilic halide would allow the development of a
tandem, one-step geminal interhalogenation (Figure 1C). To
perform such a transformation, the reactant must be both
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© XXXX American Chemical Society
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A

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electrophilic and nucleophilic at the same carbon. This kind of
ambivalent reactivity is a characteristic of carbene. In recent
years, dioxaphospholene (6), also known as the Kukhtin−
Ramirez adduct, which can be conveniently derived from a 1,2-
dicarbonyl compound, has received attention as a highly useful
carbene surrogate that can react with an electrophile and a
nucleophile in a sequential manner.6,7 The addition of an
electrophile onto 6 leads to the formation of an oxaphospho-
nium species 7, which has an excellent leaving group that can
be easily displaced by a nucleophile to give the geminally
difunctionalized product 8. Here, we report a tandem, one-step
geminal chlorofluorination of 1,2-diketone with a halenium
and a halide by taking advantage of the carbene-like reactivity
of dioxaphospholene.
Because of the nucleophilic reactivity of the P(III) reagent,
the scope of a compatible electrophile in the Kukhtin−Ramirez
reaction is rather limited. In our case, the P(III) nucleophile
and the halogen electrophile will be consumed together in an
unproductive way by forming a halophosphonium adduct
unless the complete formation of dioxaphospholene is ensured
prior to the addition of a halenium reagent. A brief survey of
the P(III) reagent revealed that trialkyl phosphite is capable of
facile and complete production of dioxaphospholene with 1,2-
diketone.8 For example, the reaction of triethyl phosphite and
benzil afforded dioxaphospholene 6a quantitatively (Figure
2A). However, the subsequent halogenation was accompanied
kinetic stability of the two P−O bonds. The remaining site is
occupied by a secondary amino group, which is also difficult to
dealkylate. This newly designed P(III) reagent can be readily
prepared in one step from a commercially available
chlorophosphite. With 10, the reaction of benzil (11a)
produced the dioxaphospholene adduct 12a cleanly as
observed by ReactIR and 31P NMR spectroscopy. Gratifyingly,
the subsequent treatment with a fluorenium [(PhSO2)2NF,
NFSI] and a soluble chloride (n-Bu4NCl) afforded the geminal
chlorofluoride 13a in 76% yield without any detectable sign of
dealkylation (Figure 2C). A small portion of the dioxaphos-
pholene 12a reverted back to the starting material 11a, which
accounted for the mass balance. In addition, no reaction was
observed between 12a and n-Bu4NCl. Thus, the chlorofluori-
nation is clearly initiated by the electrophilic fluorination.
Encouraged by this promising preliminary result, we
evaluated several combinations of other halogenating reagents
prior to the substrate survey (Table 1). In contrast to the fairly
a
Table 1. Survey of Halogenating Reagents
b
b
entry
X+
X−
13a (%)
11a (%)
1
2
3
(PhSO2)2NF
Selectfluor
(PhSO2)2NF
(PhSO2)2NF
(PhSO2)2NF
NCS
n-Bu4NCl
n-Bu4NCl
LiCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NF
n-Bu4NF
78
3
15
26
0
13
26
45
39
0
c
4
5
d
6
7
0
2
11
18
PhthN-Cl
a
Reaction conditions: 11a (1.0 mmol), 10 (1.0 mmol), X+ (1.2
b
mmol), and X− (1.2 mmol) in CH2Cl2 (6.0 mL). Isolated yields after
column chromatography. With 2 equiv of 10. With 4 equiv of 10.
c
d
clean reaction with NFSI (entry 1), the use of another popular
electrophilic fluorinating reagent, Selectfluor, afforded a
complex mixture (entry 2). The mass balance was poor, and
only a trace amount of the desired product 13a was isolated.
Interestingly, when poorly soluble LiCl was employed, a
substantial amount of starting material was regenerated (entry
3). Because the displacement with Cl− is slow, a large portion
of fluorooxyphosphonium intermediate must have remained
unreacted and then been hydrolyzed to 1,2-diketone upon
aqueous workup. The use of an excess amount of 10 was not
beneficial. With 2 equiv of 10, product formation was
significantly attenuated (entry 4). Furthermore, the halogen-
ation was completely suppressed when 4 equiv of 10 was
employed (entry 5), and dioxaphospholene 12a remained as a
major component in the crude mixture. As mentioned above,
the excess P(III) reagent has probably consumed the
electrophilic fluorinating reagent. Switching the roles of
halenium and halide was found to be detrimental. A complex
mixture was obtained from the reaction with a chlorenium (N-
chlorosuccinimide or N-chlorophthalimide) and a fluoride (n-
Bu4NF), and the desired product formation was negligible
(entries 6 and 7). As proposed earlier, the introduction of a
small fluorine substituent at the initial electrophilic addition
step is beneficial for the subsequent nucleophilic displacement.
Figure 2. Design of the phosphorus(III) reagent.
by a serious side reaction. Instead of the desired SN2
displacement at the activated α-carbon, a nucleophilic
dealkylation took place at the alkoxy group of phosphite to
give phosphate 9, and no geminal chlorofluoride was obtained.
Thus, it turned out that two SN2 reactions are competing in
intermediate 7a. To facilitate the desired SN2 reaction at the α-
carbon, the steric hindrance around this center must be
alleviated by employing a small electrophilic halogen, i.e., F+.
In addition, to suppress the undesired dealkylation, we came
up with a neopentyl glycol-derived P(III) reagent 10 that
should be resistant to nucleophilic displacement (Figure 2B).
The bidentate nature of the diol moiety will also increase the
B
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Moreover, the strong leaving group ability of chlorine may
complicate the nucleophilic substitution step if chlorine is
installed first. The favorable binding of fluoride to electron-
deficient phosphorus may also be responsible for the lack of
the desired reactivity, as well.
With the optimized conditions (Table 1, entry 1) in hand, a
wide range of aryl−aryl 1,2-diketones (11) were surveyed
(Scheme 1). (The preparation of 11 is described in the
chlorofluorocarbon. To have a para oxygen substituent, the
electron-donating ability must be substantially attenuated.
Thus, by employing trifluoromethoxy groups, the product 13h
could be obtained in a high yield. An electron-rich
heteroaromatic substrate, 2,2′-furil (11i), was also tolerated
with only slightly diminished efficiency. Finally, unsymmetrical
aryl−aryl 1,2-diketones were examined. From the reaction of
an electronically biased substrate 11j, the geminal chloro-
fluorides 13j were isolated as an ∼7:3 mixture of constitutional
isomers in 52% yield. Although a slight preference for the
electron-poor site was observed, the selectivity was insignif-
icant. Steric hindrance by an ortho substituent (11k) was not a
sufficient controlling factor, either, resulting in essentially no
site selectivity. 1,2-Diketones with two ortho substituents could
not be prepared via the current synthetic route. The structure
of geminal chlorofluoride was unambiguously established by
single-crystal X-ray diffraction analysis of 13b.9
Scheme 1. Tandem Geminal Chlorofluorination of Aryl−
a
Aryl 1,2-Diketones
After slight modifications of reaction conditions, several
aryl−alkyl 1,2-diketones (14) were examined (Scheme 2).
Scheme 2. Tandem Geminal Chlorofluorination of Aryl−
a
Alkyl 1,2-Diketones
a
Reaction conditions: 11 (1.0 mmol), 10 (1.0 mmol), (PhSO2)2NF
(1.2 mmol), and n-Bu4NCl (1.2 mmol) in CH2Cl2 (6.0 mL). Isolated
b
yields after column chromatography are given. Decomposed on silica
c
gel. Yield based on 1H NMR analysis of the crude mixture with DMF
a
d
Reaction conditions: 14 (1.0 mmol), 10 (1.0 mmol), (PhSO2)2NF
as an internal standard. Isolated yield of the mixture of constitutional
e
1
(1.2 mmol), and n-Bu4NCl (2.0 mmol) in CH2Cl2 (6.0 mL).
isomers. Isomeric ratio based on H NMR analysis of the isolated
mixture.
b
c
Isolated yield after column chromatography. Isolated yield of a
d
mixture of isomers. Isomeric ratio based on 1H NMR analysis of the
e
f
isolated mixture. Reaction at room temperature. Decomposed on
g
silica gel. Yield based on 1H NMR analysis of the crude mixture with
Supporting Information.) The reaction tolerated electron-
withdrawing groups such as bromo, fluoro, and trifluoromethyl
groups to give the corresponding geminal chlorofluorides
(13b−d, respectively) in good yields. The slightly electron-rich
p-tolyl derivative (13e) was also a suitable substrate. However,
when the highly electron-donating methoxy group was
introduced, the product 13f became unstable. Even though
fairly clean formation of 13f was observed by 1H NMR analysis
of the crude mixture, the product was not isolable as it
decomposed quickly on silica gel probably via the extrusion of
the chlorine substituent. Nevertheless, the spectroscopic
estimation of yield with an internal standard indicated that
the reaction of the electron-rich substrate is equally efficient. A
meta substituent (13g) could also be attached without any
problem. In this case, methoxy groups were tolerated because
the electron density is not donated to the geminal
DMF as an internal standard.
(The preparation of 14 is described in the Supporting
Information.) In this case, a mixture of constitutional isomers
was generally obtained. The geminal chlorofluorination of
phenyl methyl 1,2-diketone (14a) took place more preferen-
tially at the benzylic carbon as it could be expected, providing
15a and 16a in 49% combined yield as an ∼2:1 isomeric
mixture. In contrast to the aryl−aryl series, steric hindrance has
a substantial influence on site selectivity. By employing a
secondary alkyl substrate 14b, the selectivity was greatly
improved to 95:5. Furthermore, a single constitutional isomer
15c was obtained from the reaction with a tertiary alkyl
substrate 14c. However, the rates were also significantly
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decreased at the same time, and unidentified side reactions that
seemed to arise from α-halogenation and elimination also took
place, resulting in low mass recovery. Interestingly, the
cyclopropyl group turned out to be the most suitable alkyl
group for this chemistry. The reaction of 14d afforded the
chlorofluoride products 15d and 16d in an increased 60%
combined yield as an ∼2:1 mixture of constitutional isomers.
The slightly improved yield and selectivity were obtained from
the reaction of an electron-poor substrate 14e. In the case of
electron-rich substrate 14f, decomposition of the product
during purification hampered the precise analysis, again. Thus,
chloride at the α-carbon affords the desired geminal
chlorofluoride product 13. On the other hand, the attack of
a nucleophile at the phosphonium center results in the
fragmentation to regenerate the 1,2-diketone starting material
11. On the basis of this mechanistic proposal, modulation of
steric and electronic property of phosphorus(III) reagents is
currently being investigated to prevent the reactant regener-
ation and thus to improve the conversion.
In attempts to expand the substrate scope, a few other types
of 1,2-dicarbonyl compounds were examined under the
optimized conditions (Scheme 4). The dioxaphospholene
1
the yields were measured by H NMR analysis of the crude
mixture with an internal standard. Comparable yields were
observed, and site selectivity was not affected by the electronic
nature of the substrate.
Scheme 4. Examination of Other 1,2-Dicarbonyl
Compounds
As demonstrated previously by many research groups,
geminal chlorofluorides are useful precursors to various
organofluorides. Accordingly, a selective nucleophilic displace-
ment of the chlorine substituent in our product 13a was
accomplished by the reaction with tetra-n-butylammonium
azide (Scheme 3).4c The resulting geminal azidofluoride 17
could then be readily converted to the corresponding triazole
18 via Cu-catalyzed azide−alkyne cycloaddition.
Scheme 3. Derivatization of Geminal Chlorofluoride
formation between α-keto ester 20 and 10 did not proceed
cleanly, and the subsequent treatment with halogenating
reagents afforded only a small amount of the desired geminal
chlorofluoride 21 in an impure form. α-Keto amide 22
remained mostly unreacted in the presence of 10. Further
investigation with α-keto carboxylic acid derivatives will be
reported in due course.
A major concern for the combined use of electrophilic and
nucleophilic halogens is the redox reaction between them,
which may cause the halogen scrambling to give an inseparable
mixture of geminal dihalides. Thus, the compatibility between
F+ and Cl− was examined (eq 1). Unexpectedly, the slow
In conclusion, we have developed an efficient synthetic
method that gives access to a tetrasubstituted carbon with two
different halogen substituents in a single step. The newly
designed phosphoramidite allows the formation of non-
dealkylatable dioxaphospholene as a suitable carbene surrogate
for the combined use of electrophilic halenium and
nucleophilic halide. This method can be applied to a variety
of aryl−aryl as well as aryl−cyclopropyl 1,2-diketones,
although the site selectivity is moderate for unsymmetrical
substrates. The structure of geminal chlorofluoride was
unambiguously established by single-crystal X-ray crystallog-
raphy. In addition, the more reactive chlorine substituent could
be selectively functionalized to give a tertiary alkyl fluoride.
Further studies of site selectivity control and development of
enantioselective variants are currently ongoing in our
laboratories.
conversion of NFSI to phenylsulfonyl fluoride was observed in
the presence of n-Bu4NCl, and no sign of the oxidation of
chloride was detected. This result explains the lack of halogen
scrambling as well as the requirement of a slight excess of
NFSI.
A reaction mechanism is proposed for the product formation
and the starting material regeneration (Figure 3). Electrophilic
fluorination of dioxaphospholene 12 generates an activated
cationic intermediate 19, which has two competing electro-
philic sites. The subsequent nucleophilic displacement by
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01258.
Experimental details, characterization data, and copies of
NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 1964847 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Figure 3. Proposed reaction mechanism.
D
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̈
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AUTHOR INFORMATION
Corresponding Author
■
Won-jin Chung − Department of Chemistry, Gwangju Institute
of Science and Technology, Gwangju 61005, Republic of Korea;
orcid.org/0000-0003-3050-4798; Email: wjchung@
gist.ac.kr
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Authors
Garam Choi − Department of Chemistry, Gwangju Institute of
Science and Technology, Gwangju 61005, Republic of Korea
Ha Eun Kim − Department of Chemistry, Gwangju Institute of
Science and Technology, Gwangju 61005, Republic of Korea
Sunjoo Hwang − Department of Chemistry, Gwangju Institute
of Science and Technology, Gwangju 61005, Republic of Korea
Hanna Jang − Department of Chemistry, Gwangju Institute of
Science and Technology, Gwangju 61005, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01258
Author Contributions
†G.C. and H.E.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Basic Science Research
Program through the National Research Foundation of
Korea (NRF) funded by the Ministry of Education (NRF-
2018R1D1A1B07049889). The authors thank Prof. Junseong
Lee at Chonnam National University for the X-ray crystallo-
graphic analysis of 13b.
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(8) The most commonly employed P(III) reagent, P(NMe2)3, was
also examined. Although dioxaphospholene formation was efficient,
the treatment with halogenating reagents resulted mainly in
decomposition, and the geminal chlorofluoride was obtained in only
32% yield. Additionally, P(OPh)3 and PPh3 do not form
dioxaphospholene with benzil. Thus, these P(III) reagents were not
suitable for geminal dihalogenation.
(9) CCDC 1964847 contains the supplementary crystallographic
data for this study. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
F
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Org. Lett. XXXX, XXX, XXX−XXX