Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gem-Difluoroolefins

Article abstract of DOI:10.1021/acs.orglett.5b03159

Cross-coupling between difluorocarbene and carbene-derived intermediates generated from diazocompounds was developed to give gem-difluoroolefins, which constitutes a fast practical pathway to achieve hindered gem-difluoroolefins. The cross-coupling between difluorocarbene and aryl diazoacetates proceeded smoothly in the presence of a copper source, whereas its coupling with diaryl diazomethanes occurred well under metal-free conditions. A mechanism involving a copper-difluorocarbene complex was proposed.

Full text of DOI:10.1021/acs.orglett.5b03159

Letter
pubs.acs.org/OrgLett
Cross-Coupling between Difluorocarbene and Carbene-Derived
Intermediates Generated from Diazocompounds for the Synthesis of
gem-Difluoroolefins
Jian Zheng,† Jin-Hong Lin,† Liu-Ying Yu,‡ Yun Wei,‡ Xing Zheng,‡ and Ji-Chang Xiao*,†
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
‡Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study,
University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
S
* Supporting Information
ABSTRACT: Cross-coupling between difluorocarbene and
carbene-derived intermediates generated from diazocom-
pounds was developed to give gem-difluoroolefins, which
constitutes a fast practical pathway to achieve hindered gem-
difluoroolefins. The cross-coupling between difluorocarbene
and aryl diazoacetates proceeded smoothly in the presence of a
copper source, whereas its coupling with diaryl diazomethanes occurred well under metal-free conditions. A mechanism involving
a copper−difluorocarbene complex was proposed.
ecent decades have witnessed significant advances in the
chemistry of difluorocarbene.1 The singlet difluorocarbene
of gem-difluoroolefins, it is reasonable to speculate that the
most straightforward synthetic protocol might be the cross-
coupling between difluorocarbene and another carbene.
However, this strategy has never been considered or
successfully achieved. In this paper, we demonstrate a
successfully fast cross-coupling reaction of difluorocarbene
with other carbene precursors such as aryl diazoacetates and
diaryl diazomethanes (Scheme 1), giving the corresponding
gem-difluoroalkenes. Interestingly, homocoupling of diazocom-
pounds or difluorocarbene was suppressed in this trans-
formation.
R
is stabilized by π-donation from fluorine and is destabilized by
the negative inductive effect of the highly electronegative
fluorine. Because of these stabilizing and destabilizing effects of
fluorine, difluorocarbene shows moderate electrophilicity.1e As
a valuable intermediate, it has been applied to a wide variety of
organic transformations, including trifluoromethylation,2 di-
fluoromethylation of the X−H bond (X = N, O, S),1h,3 [2 + 1]
cycloaddition with multibonds,1f,h,4 homocoupling to produce
tetrafluoroethylene (TFE),5 and coordination with transition
metals.6 The homocoupling reaction is one of the most
important industrial applications of difluorocarbene. Although
the homocoupling reaction has been well studied, cross-
coupling of difluorocarbene with other carbenes, allowing
access to gem-difluoroolefins, remains a significant challenge.
gem-Difluoroolefins have received a great deal of attention in
organic synthesis and medicinal chemistry because of the
unique chemical and biological properties of gem-difluorovinyl
functionality.7 Consequently, determined efforts have been
devoted to the exploration of efficient approaches for the
preparation of gem-difluoroolefins. Traditional synthetic
methods include gem-difluoroolefination of carbonyl com-
pounds such as the Wittig reaction,1c,7g,8 the Julia−Kocienski
reaction,7f and the Horner−Wadsworth−Emmons reaction,9
and the incorporation of gem-difluorovinyl-containing building
blocks into the target molecules.10 Recently, Hu and co-workers
described a novel approach of gem-difluoroolefination11
utilizing the Rupert−Prakash reagent (TMSCF3)12 via a β-
fluoride eliminationaion in 10 h. This transformation can be
applied to Ar1Ar2CN2. However, its application for the
conversion of diazoacetate (a very common diazo com-
pound)13 has been less successful. On the basis of the structure
We have shown that difluoromethylene phosphobetaine
(Ph3P+CF2CO2 , PDFA) is an efficient difluorocarbene reagent
−
because decarboxylation of PDFA and subsequent dissociation
of the P−CF2 bond can readily take place.2d,4,7g,8c,14 Owing to
its stability, facile accessibility, and ease of handling, PDFA was
selected as the difluorocarbene source for the cross-coupling
Scheme 1. Synthesis of gem-Difluoroolefins
Received: November 1, 2015
© XXXX American Chemical Society
A
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Letter
with phenyldiazoacetate (1a). After screening various reaction
conditions [Table 1 in the Supporting Information (SI)], we
found that the cross-coupling employing CuBr proceeds
fluently in a mixed solvent (Vp‑xylene: Vdioxane = 1 mL: 0.5 mL)
at 90 °C with 1a and PDFA (molar ratio 1:1.4) for just 10 min.
To explore the scope of this Cu-mediated cross-coupling
reaction, the optimized conditions were applied to the
conversion of a variety of aryl diazoacetates. As shown in
Scheme 2, the reactions occurred very fast to give the desired
With the reaction conditions optimized, we then investigated
the substrate scope for the metal-free cross-coupling of
difluorocarbene with diaryl diazomethanes (Scheme 3). The
Scheme 3. Metal-Free Cross-Coupling of Difluorocarbene,
Showing Isolated Yields
Scheme 2. Cu-Mediated Cross-Coupling of Difluorocarbene,
Showing Isolated Yields
reaction conditions could tolerate various functional groups and
afforded corresponding gem-difluoroolefins. The examination of
electronic effects of the substituents indicated that electron-
donating groups were more favorable for this conversion (4a−j
vs 4k−m). The dramatic difference between yields for 4g
(41%) and 4f (88%) suggests that steric hindrance had a clear
side effect. The compatibility of the Br (Cl, F) substituent with
this protocol also provides possibilities for further trans-
formations (4k−m).
a
Determined by 19F NMR.
More experimental evidence was collected to elucidate the
mechanism for the coupling with aryl diazoacetates (Scheme
4). It was found that CuBr can significantly accelerate the
dissociation of PDFA. After the mixture of PDFA and CuBr
was stirred at 90 °C for 10 min, PDFA was completely
consumed as determined by 19F NMR spectroscopy (eq 1). 1a
was added into this system, and the resulting mixture was
further stirred at the same temperature for 10 min. Desired
product 2a was not detected, indicating that the intermediate
obtained from the reaction of PDFA with CuBr is highly
reactive or is not an intermediate for the coupling reaction (eq
1). As is well-known, Cu-mediated homocoupling of diazo
compounds proceed well to give olefins.15 However, the
reaction of olefin 5 with PDFA did not furnish product 2a,
suggesting that 2a is not produced from olefin 5 (eq 2).
Considering that the dissociation of PDFA would release Ph3P,
we envisioned that Ph3P may play an important role in the
reaction. This hypothesis was supported by the successful
conversion of PDFA with the intermediate obtained from the
reaction of Ph3P, substrate 1a, and CuBr (eq 3). For the
reaction of substrate 1a with PDFA under optimal reaction
conditions, phosphonium salt 6 was detected by LC−MS (eq
products. The ester moiety showed no side steric effect on this
reaction (2a−d), as evidenced by the good yield obtained for
product 2c featuring an isopropyl group. Various functional
groups on the phenyl ring were compatible with this coupling
process, and the corresponding products were obtained in
moderate to good yields (2e−k). Notably, the Br (Cl)
substituent remained intact under these conditions, providing
possibilities for further transformations (2j, 2k). The utility of
this cross-coupling was demonstrated by the development of a
short route to a derivative of testosterone phenylacetate (2n).
Unexpectedly, the reaction was not applicable to diphenyl
diazomethane (3a), which might be because 3a is more reactive
and is not compatible with the copper(I) complex even at room
temperature. And it was found that both the aryl ring and the
ester group are significant to this reaction (2l, 2m).
The successful cross-coupling of difluorocarbene with aryl
diazoacetates prompted us to screen more reaction conditions
for the conversion of diphenyl diazomethane. The screening of
reaction conditions showed that 1.3:1 of 3a to PDFA at 70 °C
for 35 min in THF were the optimal reaction conditions (see
SI, Table 2).
B
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Letter
ocarbene produced from PDFA to intermediate B furnishes
Cu−difluorocarbene C. An equilibrium between intermediates
B (C) and ylide 7 may be established. Subsequently, migratory
insertion of difluorocarbene to the Cu−C bond in species C
leads to the formation of a new Cu species D, reductive
elimination of which gives the final product 2. Another
possibility is that intermediate C might be formed from Cu−
difluorocarbene species E (path II). Species E may be initially
produced, and its reaction with diazo compound 1 gives
intermediate F. Subsequent electrophilic attack at PPh3 also
generates intermediate C.
Scheme 4. Experimental Evidence for the Coupling with Aryl
Diazoacetate
A Cu−difluorocarbene complex has been proposed,16 but it
has never been observed. Much effort has been made to isolate
or characterize intermediate C, but all attempts were frustrated.
We then tried to stabilize species E by coordination with an
appropriate ligand. With the use of 1,10-phenanthroline as the
ligand, carbene species E′ may be formed (Scheme 6).
Scheme 6. Stabilization of Cu−Difluorocarbene Species
a
The yields were determined by 19F NMR spectroscopy using
trifluoromethylbenzene as the internal standard. In all reactions, the
loadings of all reagents were as established for optimal conditions.
Solv. = p-xylene (1 mL) + 1,4-dioxane (0.5 mL).
Although the isolation of E′ by flash column chromatography
was unsuccessful, difluoromethane (CH2F2) was detected by
19F NMR spectrometry in the eluents (ethyl acetate and
petroleum ether). CH2F2 was not observed before the
attempted isolation of intermediate E′. Its formation may be
due to the hydrolysis of intermediate E′ during isolation (a
similar process has been previously reported).17
4). Salt 6 may be produced from its corresponding
phosphonium ylide 7. Ylide 7 can react with PDFA to give
product 2a in the presence of CuBr, meaning that ylide 7 may
be involved in the cross-coupling reaction (eq 5). Without
CuBr, product 2a was not observed, further suggesting that a
copper source is necessary for this reaction (eq 5).
Because both PDFA and substrate 1 can react rapidly with
CuBr, we propose that the cross-coupling reaction may proceed
via two pathways (Scheme 5). Copper carbene A may be
readily formed and then be trapped by Ph3P generated from
PDFA to give intermediate B (path I). Hydrolysis of
intermediate B by trace water present in the reaction system
affords phosphonium salt 6. The coordination of difluor-
The proposed mechanism for the cross-coupling reaction
with diaryl diazomethanes is shown in Scheme 7. The reactive
Scheme 7. Proposed Mechanism for the Cross-Coupling
with Diaryl Diazomethanes
Scheme 5. Proposed Reaction Mechanism for the Cross-
Coupling with Aryl Diazoacetate
substrate 3a may undergo denitrogenation to produce carbene
G, which is trapped by PPh3 produced from PDFA to give ylide
I. Another possibility is the reaction of PPh3 with substrate 3a
to generate intermediate H, which undergoes denitrogenation
to furnish ylide I. The nucleophilic attack of ylide I at
difluorocarbene generated from PDFA affords intermediate J.
β-PPh3 elimination of this intermediate gives the final product
4.18 Of course, :CF2 could also react directly with Ar2CN2.
As an electrophile, it could add at the C end of the polar C−
+
N2 bond. The intermediate thus formed would then lose N2
with the formation of Ar2CCF2.
The proposed mechanism shown in Scheme 7 was further
supported by experimental evidence. The reaction of substrate
3a with PPh3 did occur albeit giving some unknown side
products. For the coupling of 3a with PDFA, phosphonium salt
C
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Letter
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8 was detected in the reaction system by LC−MS (Scheme 8).
Salt 8 is likely formed from ylide I via hydrolysis.
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Scheme 8. Observation of Phosphonium Salt 8
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In summary, we have described the fast cross-coupling of
difluorocarbene with carbene generated from diazo compounds
to give gem-difluoroolefins. Interestingly, the coupling with aryl
diazoacetate proceeded smoothly in the presence of a copper
source, whereas the coupling with diaryl diazomethanes
proceeded under metal-free conditions. The copper−difluor-
ocarbene complex may be involved in this coupling reaction.
This work represents the first protocol for the synthesis of gem-
difluoroolefins via cross-coupling of difluorocarbene.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03159.
Experimental procedures, analytical data for products,
NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jchxiao@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation (21172240, 21421002, 21472222,
81273537, 21502214), National Basic Research Program of
China (2015CB931900, 2012CBA01200), the Chinese Acad-
emy of Sciences (XDA02020105, XDA02020106), and
Zhengxiang scholar program of the University of South China.
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