Reaction of Diazo Compounds with Difluorocarbene: An Efficient Approach towards 1,1-Difluoroolefins

Article abstract of DOI:10.1002/anie.201509711

A transition-metal-free difluoromethylenation of diazo compounds that proceeds under mild conditions has been developed and is based on the use of TMSCF₂Br as the difluoromethylene source and tetrabutylammonium bromide (TBAB) as the promoter. T

Full text of DOI:10.1002/anie.201509711

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International Edition: DOI: 10.1002/anie.201509711
German Edition: DOI: 10.1002/ange.201509711
Difluorocarbene
Hot Paper
Reaction of Diazo Compounds with Difluorocarbene: An Efficient
Approach towards 1,1-Difluoroolefins
Zhikun Zhang, Weizhi Yu, Chenggui Wu, Chengpeng Wang, Yan Zhang, and Jianbo Wang*
Abstract: A transition-metal-free difluoromethylenation of
diazo compounds that proceeds under mild conditions has
been developed and is based on the use of TMSCF2Br as the
difluoromethylene source and tetrabutylammonium bromide
(TBAB) as the promoter. The chemoselective formal carbene
dimerization reaction is achieved owing to the electronic
properties and the relative stability of the difluorocarbene
intermediate.
D
iazo compounds are versatile intermediates in organic
synthesis that have most commonly been employed as
carbene precursors in transition-metal-catalyzed reactions.[1]
They are ambiphilic reagents as the carbon atom bearing the
diazo group has a partial negative charge and is thus
nucleophilic. In the presence of a catalyst (typically late
transition metals, such as RhII and CuI), metal carbene species
can be generated from diazo compounds through coordina-
tion of the negatively polarized carbon atom to the empty
d orbital of the metal followed by dinitrogen extrusion.
Interestingly, the metal carbene species generated in most
catalytic reactions have an electron-deficient carbene center
and thus are Fischer carbene complexes. The highly reactive
metal carbene species further undergo typical carbene trans-
=
Scheme 1. Chemoselective carbene dimerization for C C bond con-
struction.
an efficient approach towards the synthesis of functionalized
alkenes, although the inevitable problems associated with
chemo- and stereoselectivity have to be addressed. Early
explorations of carbene dimerization focused on intramolec-
ular carbene dimerizations for the construction of ring
systems.[2,3] For example, Doyle and co-workers explored
RhII-catalyzed reactions of bis(diazocarbonyl) compounds to
construct macrocycles.[3c] Che and co-workers achieved sim-
À
formations, such as C H insertion, cyclopropanation, and
ylide formation. Aside from these common transformations,
formal carbene dimerizations are also frequently encoun-
tered. Mechanistically, carbene dimerization is attributed to
the reversal of the polarity of the carbon atom bearing the
diazo group in the process of metal carbene formation. The
negatively polarized carbon atom of a diazo substrate could
attack the electron-deficient carbene carbon atom of the
metal carbene, which is then followed by the release of
dinitrogen and the metal catalyst to generate a double bond
(Scheme 1a).
ilar cyclizations with their RuII porphyrin catalyst.[3d]
A
related strategy has also been explored by our group for the
synthesis of polycyclic aromatic compounds with bis(N-
tosylhydrazones).[4] Chemo- and stereoselective carbene
dimerization reactions of two different diazo substrates are
obviously more challenging.[5,6] In this context, the groups of
Davies[5a] and Sun[5b–e] have recently reported successful
examples of intermolecular carbene dimerizations. Their
approaches were based on fine-tuning the reactivity of two
different diazo substrates. Furthermore, we have reported the
reaction of diazo compounds (in situ generated from N-
tosylhydrazones) with Cr0 Fischer carbene complexes under
catalyst-free conditions (Scheme 1b).[7]
Among free carbene species, difluorocarbene possesses
several special properties that are attributed to the fluorine
substituents.[8] On the one hand, difluorocarbene is electro-
philic in nature owing to the strongly electron-withdrawing
nature of the fluorine substituents. On the other hand,
fluorine is an excellent p-electron donor and could stabilize
the singlet difluorocarbene. In terms of its electronic proper-
ties and stability, difluorocarbene is considered to be some-
what similar to a Fischer carbene.[9] Therefore, it is conceiv-
able that nucleophilic diazo compounds may react with
Formal carbene dimerizations are normally considered as
unwanted side reactions. However, they also show potential in
[*] Z. Zhang, W. Yu, C. Wu, C. Wang, Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education
College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509711.
electron-deficient difluorocarbene in
a chemoselective
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manner to generate double bonds. Herein, we report our
investigations along this line. The developed reaction pro-
vides a unique approach towards the synthesis of 1,1-
difluoroolefins (Scheme 1c).[10]
First, we examined the reaction of diphenyldiazomethane
(1a) as the diazo substrate, TMSCF2Br (2), a difluorocarbene
precursor introduced by Hu and co-workers,[11] as the source
of difluorocarbene, and tetrabutylammonium bromide
(TBAB) as the initiator to generate difluorocarbene in 1,2-
dichloroethane (DCE). Gratifyingly, in the initial experiment,
product 3a was isolated in 38% yield, whereas TMSCF2Br (2)
remained largely unchanged as observed by 19F NMR spec-
troscopy (Table 1, entry 1). Encouraged by this result, we
Scheme 2. Difluoromethylenation with diaryl diazomethanes. The reac-
tions were run on 0.2 mmol scale (1/2=1.5:1). Yields of isolated
products after column chromatography on silica gel are given.
Table 1: Optimization of the reaction conditions.[a]
the other hand, the reaction efficiency was also affected by
steric effects, as a more sterically hindered diazo substrate
resulted in diminished yield (3i).
Entry
1a/2
TBAB [mol%]
T [8C]
Yield[b] [%]
To further expand the substrate scope, we next examined
diazo compounds bearing electron-withdrawing ester groups.
As shown in Scheme 3, when alkyl diazoester 4a was used as
1
2
3
4
5
6
1:2
20
20
20
10
30
20
25
50
50
50
50
50
38
70
81
40
28
92[c]
1.2:1
1.5:1
1.5:1
1.5:1
1.5:1
[a] The reactions shown in entries 1–5 were run on 0.1 mmol scale, and
the reaction in entry 6 was run on 0.2 mmol scale. [b] Unless otherwise
noted, yields were determined by 19F NMR spectroscopy (300 MHz) with
trifluorotoluene as the internal standard. [c] Yields of isolated products
after column chromatography. TBAB=tetrabutylammonium bromide,
DCE=1,2-dichloroethane.
proceeded to further optimize the reaction conditions. The
reaction was significantly affected by the reaction temper-
ature. At 508C, the desired product was formed in 70% yield
while 18% of the TMSCF2Br remained unchanged (as
determined by 19F NMR spectroscopy; entry 2). Increasing
the loading of the diazo substrate further improved the yield
to 81% yield (19F NMR; entry 3). The TBAB loading also
significantly affected the reaction, and 20 mol% of TBAB
afforded the best results (entries 3–5). Finally, the reaction
was run on 0.2 mmol scale, and the desired product was
isolated in 92% yield (entry 6).
With the optimized reaction conditions in hand, the
substrate scope of this reaction was investigated with a series
of diaryl diazomethanes. As illustrated in Scheme 2, various
diaryl diazomethanes reacted smoothly with TMSCF2Br to
afford the corresponding 1,1-difluoroolefins in good to
excellent yields. The electronic nature of the substituents on
the aromatic ring moderately affected the yields. The
reactions of substrates bearing electron-withdrawing sub-
stituents afforded the products in excellent yields (3d, 3e, 3h,
3j). However, substrates bearing electron-donating substitu-
ents gave the corresponding products in only moderate yields
(3b, 3c, 3g). The variation in yields was attributed to the
stability of the diazo substrates. Diaryl diazomethanes with
electron-donating substituents are less stable than their
counterparts bearing electron-withdrawing substituents. On
Scheme 3. Difluoromethylenation with diazoesters. Unless otherwise
noted, the reactions were run on 0.2 mmol scale (4/2=1.5:1). Yields
of isolated products after column chromatography on silica gel are
given. For 4a–4c and 4e–4h, the reaction temperature was 508C; all
other reactions were run at 708C. [a] 4/2=1:1.5. [b] 4/2=1:2.0; yields
determined by 19F NMR spectroscopy (300 MHz) with trifluorotoluene
as the internal standard.
the substrate, the corresponding 1,1-difluoroolefination prod-
uct 5a could be isolated in 87% yield. Encouraged by this
result, we further studied other alkyl diazoesters. Diazoesters
with various alkyl substituents afforded the corresponding
1,1-difluoroolefins in good yields (5b, 5c, 5e). Double bonds,
which easily undergo cyclopropanation with difluorocar-
bene,[8] are compatible with the current reaction conditions
(5g, 5h).
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Diazoacetates 4d and 4i–4k were also examined in this
hydrazone (10a) was subjected to the above reaction
transformation. With benzyl diazoacetate 4d as the substrate,
the corresponding product 5d was obtained in about 30%
yield (19F NMR) under identical reaction conditions. The
diminished yield may be attributed to the fact that these
diazoesters (4d, 4i–4k) are less nucleophilic than the diazo
substrates 1a–1j, 4a–4c, and 4e–4h. As these diazo substrates
are more stable, the reaction temperature was then raised
from 508C to 708C. Under the modified reaction conditions,
product 5d could be obtained in 90% yield. The reaction also
proceeded efficiently with other diazoacetates (Scheme 3, 4i–
4k).
Next, we examined aryl diazoesters (Scheme 3, 4l–4p),
which are relatively stable donor–acceptor diazoesters that
are widely explored in transition-metal-catalyzed carbene
transfer reactions.[12] The initial reaction with phenyldiazo-
acetate 4l at 708C afforded the desired product 5l, but the
product contained an inseparable chlorination side product.
As the chlorine should originate from the solvent (DCE), we
screened other solvents. However, our experiments indicated
that DCE still afforded the best results in terms of the yield of
the desired product. Therefore, we examined the reactions of
aryl diazoesters 4m–4p under the original reaction condi-
tions. The corresponding products 5m–5p were obtained in
moderately high yields as determined by 19F NMR spectros-
copy (300 MHz). However, in all cases, the products con-
tained minor amounts of inseparable chlorinated side prod-
ucts.
conditions, but the desired product 11a could not be detected
[Eq. (3)]. We reasoned that the high temperature needed for
the conversion of the N-tosylhydrazone into the diazo
compound might not be compatible with the current reaction.
Indeed, when the conversion of N-tosylhydrazone 10b into
the diazo intermediate was carried out before the addition of
TMSCF2Br and TBAB, the desired product 11b could be
obtained in approximately 20% yield [19F NMR; Eq. (4)].
Furthermore, we explored the use of benzophenone hydra-
zone (12) as a precursor that could generate diphenyl
diazomethane by treatment with an oxidant at low temper-
ature. The solution containing the diazo substrate was clean
upon filtration. Treatment of this solution with TMSCF2Br
and TBAB afforded product 3a in 65% yield [Eq. (5)].
The stable b-keto a-diazoester 6 was also subjected to the
above reaction conditions. However, only trace amounts of
the desired product 7 could be detected by 19F NMR
spectroscopy [Eq. (1)]. The low yield was attributed to the
Furthermore, a series of hydrazones, 13a–13e, were
subjected to the reaction with TMSCF2Br under identical
conditions to those shown in Eq. (5). The reactions afforded
the corresponding 1,1-difluoroolefination products 14a–14e
in moderate to good yields (Scheme 4).
low nucleophilicity of the carbon atom that bears the diazo
group in the substrate. On the other hand, the reaction with
diazo substrate 8, which bears an electron-withdrawing CF3
substituent, afforded the corresponding polyfluorinated 1,1-
difluoroolefin 9 in good yield [Eq. (2)].
N-Tosylhydrazones are bench-stable and easily prepared.
They have been widely explored as precursors of diazo
compounds, especially for the in situ generation of non-
stabilized diazo compounds.[13] Thus we proceeded to exam-
ine whether N-tosylhydrazones are suitable substrates for the
current transformation. 4-Biphenylcarboxaldehyde N-tosyl-
Scheme 4. Difluoromethylenation with hydrazones. The reactions were
run on 0.2 mmol scale (13/2=3.0:1.0). Yields of isolated products
after column chromatography on silica gel are given. [a] The second
step was carried out at 608C.
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reaction, gram-scale experiments were carried out with diazo
substrates 1a and 4a [Eq. (6) and (7)]. Under the optimized
reaction conditions, the desired 1,1-difluoroolefination prod-
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the diazo substrate to difluorocarbene as shown in Sche-
me 1c. However, alternative mechanisms may also be oper-
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the detailed reaction mechanism.
In summary, we have developed an efficient method for
the synthesis of 1,1-difluoroolefins. The transition-metal-free
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Acknowledgements
This project was supported by the National Basic Research
Program of China (973 Program, 2012CB821600) and the
NSFC (21472004 and 21332002).
Keywords: carbenes · diazo compounds · difluorocarbene ·
fluorine · hydrazones
How to cite: Angew. Chem. Int. Ed. 2016, 55, 273–277
Angew. Chem. 2016, 128, 281–285
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Received: October 16, 2015
Published online: November 19, 2015
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