gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors

Article abstract of DOI:10.1021/jacs.5b09888

A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF₃) or TMSCF₂Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N₂. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF₃, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF₃, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.

Full text of DOI:10.1021/jacs.5b09888

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Article
gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br:
Transition-Metal-Free Cross-Coupling of Two Carbene Precursors
Mingyou Hu, Chuanfa Ni, Lingchun Li, Yongxin Han, and Jinbo Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09888 • Publication Date (Web): 26 Oct 2015
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gem-Difluoroolefination of Diazo Compounds with TMSCF3 or
TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene
Precursors
Mingyou Hu,† Chuanfa Ni,† Lingchun Li,† Yongxin Han,‡ and Jinbo Hu*†
† Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sci-
ences, 345 Ling-Ling Road, Shanghai, 200032, China.
‡ Boston-Kenilworth LO Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts,
02115, United States
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Supporting Information Placeholder
ABSTRACT: A new gem-difluoroolefination protocol by transition-metal-free cross-coupling of two carbene fragments
arising from two different sources, namely a non-fluorinated carbene fragment resulting from a diazo compound and a
difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This
olefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by
elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with
TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo
compounds and in situ generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to
various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as
arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile
transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in
organic synthesis.
Scheme 1. Pathways of C=C Bond Formation with Di-
azo Compounds
1. Introduction
1,1-Difluoroalkenes are structurally unique organic
compounds in medicinal chemistry, which are usually
explored in drug design as mechanism-based enzyme
inhibitors yet with remarkable metabolic stability against
P-450 family enzymes.1,2 Moreover, 1,1-difluoroalkenes are
versatile building blocks in organic synthesis and the
gem-difluorovinyl group can be transformed to many val-
uable functionalities.3,4 To date, numerous approaches to
synthesize 1,1-difluoroalkenes have been developed,3 as
represented by carbonyl olefination methods such as Wit-
tig type and Julia-Kocienski type reactions.5 However,
most of these approaches need strong bases and suffer
from disadvantages such as limited substrate scope and
low efficiency.3,5 Considering the wide applications of the
difluorinated olefins, highly efficient and operationally
simple approaches are still urgently desired.
Difluorocarbene is the most stable dihalocarbene and
readily reacts with a series of both electron-rich and elec-
tron-poor substrates.6 Traditional synthetic applications
Diazo compounds have found wide applications in
modern organic synthesis due to their capability in con-
structing structurally diverse molecules.9 In their trans-
formations, diazo compounds can serve as carbene pre-
cursors,10 carbon nucleophiles,11 and N-heterocyclic pre-
cursors.12 In recent years, the construction of C=C bonds
with diazo compounds, which relies on transition-metal-
carbene species-involved coupling reactions, has attracted
much attention.1ob,13,14 These olefination processes are
mainly achieved in two manners: (1) a diazo compound is
of difluorocarbene include: (1) homo-coupling at very
high temperature to produce tetrafluoroethylene (TFE);7
(2) reacting with heteroatom- and carbon-nucleophiles to
afford difluoromethylation products;6 and (3) undergoing
[2+1] cycloaddition with alkynes or alkenes.6 However, the
direct reaction of difluorocarbene with a carbon nucleo-
phile followed by β-elimination to give the 1,1-
difluoroalkenes is rare.8
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converted to a transition metal−carbene species, which
Table 1. Survey of Reaction Conditions Between Di-
azoacetate 1a and TMSCF3a
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undergoes
a
migratory insertion followed by β-
elimination (Scheme 1, eq (a));10b,13 and (2) a nucleophilic
attack of a diazo compound on a transition met-
al−carbene species followed by β-elimination (Scheme 1,
eq (b)).14
Based on a Cu-carbene migratory insertion mechanism,
we
have
developed
a
copper-catalyzed
gem-
difluoroolefination of diazo compounds with Ruppert-
Prakash reagent (TMSCF3) (Scheme 1, eq (c)).15 However,
the substrate scope of this difluoroolefination reaction is
narrow, and it is only efficient for the synthesis of 1,1-
diaryl-2,2-difluoroalkenes.15 This limitation intrigued our
interest in searching for new synthetic protocols to
broaden the scope of this diazo gem-difluoroolefination
method. We envisioned that diazo compounds, which
contain a nucleophilic carbon center, may react directly
with the electrophilic difluorocarbene to furnish the gem-
difluoroolefins (Scheme 1, eq (d)). To our knowledge,
cross-coupling reactions between diazo compounds and
difluorocarbene species under transition-metal-free con-
ditions have never been reported.16 Herein, we report our
success in the gem-difluoroolefination of diazo acetates,
diaryl diazomethanes, as well as diazirines (the diazo
compound surrogates) with two difluorocarbene reagents,
TMSCF3 and TMSCF2Br, in the absence of transition met-
als.17
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a All reactions were performed with 0.5 mmol of 1a. b The yields of
2a and 3a were determined by 19F NMR with PhCF3 as an internal
standard, and the yields of 3a are given in parentheses.
Table 2. Survey of Reaction Conditions Between Di-
azoacetate 1a and TMSCF2Bra
2. Results and Discussion
a All reactions were performed with 0.5 mmol of 1a. b The yields of
2a and 3a were determined by 19F NMR with PhCF3 as an internal
standard, and the yields of 3a are given in parentheses.
We began our study using a stabilized diazo compound,
phenyl diazoacetate 1a as a model substrate (Table 1),
which had been found difficult to undergo efficient gem-
difluoroolefination by TMSCF3 under copper catalysis,
presumably due to the low reactivity of α-diazoacetates
towards CuCF3 in situ generated under such conditions.15
Since TMSCF3 is not only a trifluoromethylation reagent,18
but also is able to generate difluorocarbene species under
transition-metal-free conditions at a wide range of tem-
difluorocarbene (Table 1, entry 2).20 Moreover, raising or
lowering the temperature did not enhance the yield (Ta-
ble 1, entries 3 and 4), and reducing the quantities of NaI
initiator also resulted in a decrease of yield (Table 1, entry
5). Among several ethereal solvents tested, THF proved to
be the best solvent (Table 1, entries 2, 5 and 6; see SI for
more details).
o
peratures (–50 to 110 C),19 we first chose this reagent as
the difluorocarbene source. By employing nonmetallic
fluoride source tetrabutylammonium triphenyldifluorosil-
icate (TBAT) that had been used for the difluorocyclopro-
panation of electron-rich alkenes at low temperatures,
diazoacetate 1a, however, did not react to give the desired
difluoroolefin probably due to the relatively low nucleo-
philicity of the stabilized diazo compound towards
difluorocarbene at such temperatures. As a result, the
fluoride-induced fast self-decomposition of TMSCF3 over-
took the desired olefination (Table 1, entry 1). When the
less basic activator sodium iodide (NaI) was used instead
of TBAT, a relatively slower release of difluorocarbene
from TMSCF3 was beneficial for the olefination reaction.
By using a stoichiometric amount (2.2 equiv) of NaI as the
initiator, the reaction proceeded smoothly at 60 oC to give
difluoroolefin 2a in 74% yield, with only 1% yield of tetra-
fluorocyclopropane as the side product, which arose from
the further [2+1] cycloaddition between product 2a and
To find more evidence to support the difluorocarbene
pathway for this novel gem-difuoroolefination process, we
examined the reaction of diazoacetate 1a with TMSCF2Br
(Table 2), a known difluorocarbene reagent that is less
likely to directly introduce a bromodifluoromethyl group
under non-equilibrium conditions.21 By using tetrabu-
tylammonium bromide (TBAB) as the initiator, reaction
of 1a at 110 oC in toluene gave 36% yield of gem-
difluoroolefination product 2a and a trace amount of tet-
rafluorocyclopropanation side product 3a (2% yield) (Ta-
ble 2, entry 1). An investigation of the solvent effect once
again showed that the ethereal solvents were better than
the other solvents and tetrahydrofuran (THF) gave the
highest yield (Table 2, entries 1, 2, 3, 5 and 6). Since diazo
compounds are generally susceptible to high tempera-
tures, decreasing the reaction temperature from 110 oC to
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Table 3. gem-Difluoroolefination of α-Diazoacetatesa
bene source. The electron-donating and withdrawing
1
groups substituted on the phenyl ring, such as methoxy,
fluorine, chlorine, bromine and trifluoromethyl groups,
had no significant effects on the yields (Table 3, 2f–2m),
whereas the strong electron-withdrawing nitro group led
to only a moderate yield when using TMSCF2Br, and no
product at all when using TMSCF3 (Table 3, 2n). Further-
more, compared with reactions using TMSCF3, reactions
using TMSCF2Br usually afforded somewhat higher yields
of tetrafluorocyclopropanation side products 3a, presum-
ably due to the higher reaction temperature and pro-
longed reaction time required, especially in the cases of
relatively electron-rich diazo acetates. The steric bulki-
ness of the ester group adjacent to the carbenic carbon
had little influence on the reaction, and a change from
the methyl to ethyl to isopropyl esters gave similar yields
of the corresponding 1,1-difluoroalkenes (Table 3, 2a-2c);
however, the substitution pattern of the aryl group adja-
cent to the carbenic carbon had a remarkable effect on
the reaction. For example, 1-naphthyl and 2-tolyl substi-
tuted diazo acetates gave very low yields (Table 3, 2d and
2e). It is worthwhile noting that benzyl diazoacetates
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generally
gave
higher
yields
in
this
gem-
difluoroolefination than those in previously reported
copper-promoted trifluoromethylation,22 and no alkenes
that arose from 1,2-H shift of carbene intermediates were
observed,
which
suggests
that
this
gem-
difluoroolefination should proceed via a reaction between
diazo compounds and difluorocarbene (as depicted in
Scheme 1, eq (d)) rather than a direct cross-coupling of
two different carbenes.
To extend the synthetic application of this transition-
metal-free olefination protocol, we further investigated
the reaction of diaryl diazomethanes (Table 4). Because
these substrates are more thermally labile than the diazo-
acetates and their gem-difluoroolefination products are
more reactive towards difluorocarbene, their reaction
a All reactions were performed on 0.5 mmol scale. Unless
otherwise noted, the yields given refer to the isolated yields
of 2. The data in the parentheses refer to the yields of side
product 3 as determined by 19F NMR analysis of the reaction
mixture using PhCF3 as an internal standard. b The yields of
the products were determined by 19F NMR using PhCF3 as an
internal standard.
o
with TMSCF2Br at high temperatures (80 C to 110 oC)
gave only moderate yields of diaryldifluoroolefins 5, ac-
companying with a substantial amount of tetrafluorocy-
clopropanation side products 6 (see SI for more details).
When TMSCF3 was used instead of TMSCF2Br, a control of
the release of difluorocarbene by using a substoichio-
metric amount of NaI and conducting the reaction at
room temperature converted a variety of diaryl diazome-
thanes 4 into diaryldifluoroolefins 5 in good to excellent
yields, with minimized amounts of side products 6. Not
only the halogen substituents, such as fluorine, chlorine
and bromine were amenable to the reaction (Table 4, 5h-
5p, and 5r), but also the electron-donating methoxy
group and electron-withdrawing nitro group were com-
patible (Table 4, 5f, 5g, and 5q). Note that the ortho-
substituted diaryl diazomethanes also reacted smoothly
to give good yields of difluoroolefins (Table 4, 5h and 5l).
In contrast to the previously developed copper-catalyzed
gem-difluoroolefination with TMSCF3,15 this NaI-catalyzed
olefination process precluded the transition-metal-
carbene complexes-involved side reactions, thus largely
improved the yield of diaryldifluoroolefins.
80 oC gave a better result (Table 2, entry 3); however, fur-
o
ther lowering the temperature (such as 60 C) led to a
decrease of the yield of 2a due to a slower generation of
difluorocarbene species from TMSCF2Br (Table 1, entry 4).
In addition, increasing the amount of initiator TBAB did
not benefit the reaction (Table 1, entry 8; see SI for more
details).
With the two optimized conditions in hand (Table 1,
entry 2 and Table 2, entry 3), we investigated the scope of
α-diazo acetates, and the results are shown in Table 3.
Generally, aryl-, benzyl-, and simple alkyl-substituted
diazoacetates reacted smoothly to give 1,1-difluoroalkenes
2 in moderate to good yields. Reactions with both elec-
tron-neutral and electron-deficient aryl-substituted di-
azoacetates prefer TMSCF2Br as the difluorocarbene
source, while reactions with electron-rich aryl, benzyl,
and alkyl diazoacetates prefer TMSCF3 as the difluorocar-
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Table 4. gem-Difluoroolefination of Diaryl Diazome-
thanesa
Table 5. gem-Difluoroolefination and Tetrafluorocy-
clopropanation of Diazirinesa
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a Conditions: for compounds 8a-8h, 7/TMSCF2Br = 2:1; for
compounds 9a-9h, 7/TMSCF2Br = 1:2.2. All reactions were
performed on 0.5 mmol scale.
a All reactions were performed on 0.5 mmol scale. Unless
otherwise noted, the yields given refer to the isolated yields
of 5. The data in the parentheses refer to the yields of side
product 6 as determined by 19F NMR analysis of the reaction
this gem-difluoroolefination reaction, and both electron-
deficient and electron-rich aryl substituents are amenable.
On the other hand, simply changing the ratio of diazir-
ines to TMSCF2Br from 2:1 to 1:2.2 resulted in the predom-
inant formation of cyclopropanation products, with the
b
mixture using PhCF3 as an internal standard. 1.3 equiv of
TMSCF3 were used. c 3.0 equiv of TMSCF3 were used and the
yields of the products were determined by 19F NMR with
d
PhCF3 as an internal standard. 0.8 equiv of NaI and 2.0
tetrafluorocyclopropanes
9
derived
from
1,1-
equiv of TMSCF3 were used.
difluoroalkenes 8 as the major products, along with gem-
difluorocyclopropanes derived from non-fluorinated al-
kenes as the minor products (Table 5, 9a–9h). Taking the
reaction of 7a as an example, a 19F NMR analysis of the
reaction mixture showed that the tetrafluorocyclopropane
9a and difluorocyclopropane 10a were formed in 88% and
12% yields, respectively (eq 1), which indicates that the
reaction of acyclic arylalkyl diazomethanes with difluoro-
carbene is much faster than its denitrogenative rear-
rangement to alkenes. Interestingly, cyclic diazirine com-
pound 7i readily underwent the denitrogenative 1,2-
hygrogen shift reaction to give 1,2-dihydronaphthalene
rather than the gem-difluoroolefination product, as was
evidenced by the isolation of its difluorocyclopropanation
product 10i in 76% yield when excess TMSCF2Br was used
(eq 2).
Encouraged by the high efficiency of this olefination
protocol,
we
next
investigated
the
gem-
difluoroolefination of less stabilized diazo compounds,
namely arylalkyl diazomethanes (Table 5). Since such
compounds are inherently unstable and challenging to
prepare,10 we used the stable diazirines as their surrogates,
which can isomerize to the less stable diazo compounds
upon heating.23 In this case, the combination of
TMSCF2Br/TBAB(cat.) was chosen as the optimal olefina-
tion system, which was expected to produce the difluoro-
carbene species with a reaction rate comparable to that of
the in-situ formation of arylalkyl diazomethanes under
thermal conditions. To avoid the further [2+1] addition
between the relatively electron-rich 1,1-difluoroalkene
products and difluorocarbene (see SI for more details),
TMSCF2Br was used as the limiting reactant, and the reac-
tion between acyclic diazirines 7 and TMSCF2Br (in 2:1
molar ratio) under the catalysis of 15 mol% of TBAB in
toluene as solvent at 100 oC afforded gem-difluoroolefins 8
as the sole fluorinated products in 66 - 91% yields (Table 5,
8a–8h). The competitive denitrogenative 1,2-hygrogen
shift of diazo compounds to alkenes did not interfere with
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As for the mechanism of this gem-difluoroolefination,
difluorocarbene reagents and versatile transformations of
1,1-difluoroalkenes, this method is expected to find wide
applications in organic synthesis. This type of intriguing
C=C bond formation reaction is currently under further
investigation in our laboratory.
1
2
3
4
5
6
7
8
in addition to the initially mentioned nucleophilic reac-
tion pathway (Scheme 2a, Path a), the other pathway in-
volving the cross-coupling of two carbenes could not be
ruled out at this stage because diazo compounds can re-
lease carbene under thermolysis24 (Scheme 2a, Path b). To
better understand the mechanism, we carried out the
reaction of aryldiazoacetate 1a, a substrate that is stable
toward diazo decomposition under common laboratory
conditions,10a with TMSCF3/NaI at room temperature. As
shown in Scheme 2b, the olefination proceeded smoothly
to afford 1,1-difluoroalkene 2a in moderate yield, albeit
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.xxxxxx.
Tables of reaction condition development, full experimental
protocols, and characterization data for all new compounds
(PDF) .
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somewhat lower than the reaction performed at 60 C.
This result suggests that a direct carbenecarbene cross-
coupling (Scheme 2a, Path b) is less likely to occur as the
major pathway.
AUTHOR INFORMATION
Corresponding Author
*jinbohu@sioc.ac.cn
Scheme 2. Proposed Mechanism for gem-
Difluoroolefination of Diazo Compounds with
Difluorocarbene
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Basic Research
Program of China (2015CB931900, 2012CB821600), the Na-
tional Natural Science Foundation of China (21372246,
21421002, 21472221), Shanghai Science and Technology pro-
gram (15XD1504400), MSD China R&D Postdoc Fellowship
(M.H.) and the Chinese Academy of Sciences.
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3. Conclusion
In conclusion, we have developed
a new gem-
difluoroolefination protocol by transition-metal-free
cross-coupling of two carbene fragments arising from two
different sources, a non-fluorinated carbene fragment
resulting from a diazo compound and a difluorocarbene
fragment derived from TMSCF3 or TMSCF2Br. This ole-
fination
proceeds
through
the
direct
C-
difluoromethylenation of diazo compounds by electro-
philic difluorocarbene followed by β-elimination of N2.
Compared to previously reported Cu-catalyzed gem-
difluoroolefination of diazo compounds with TMSCF3,15
which possesses a narrow substrate scope due to a de-
manding requirement on the reactivity of diazo com-
pounds and in situ generated CuCF3, this protocol affords
a general and efficient approach to various disubstituted
1,1-difluoroalkenes, including difluoroacrylates, dia-
ryldifluoroolefins, as well as arylalkyldifluoroolefins. Con-
sidering the ready availability of diazo compounds and
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