Difluoroacetaldehyde N-Triftosylhydrazone (DFHZ-Tfs) as a Bench-Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

Article abstract of DOI:10.1002/anie.202000119

Despite the growing importance of volatile functionalized diazoalkanes in organic synthesis, their safe generation and utilization remain a formidable challenge because of their difficult handling along with storage and security issues. In this study, we developed a bench-stable difluoroacetaldehyde N-triftosylhydrazone (DFHZ-Tfs) as an operationally safe diazo surrogate that can release in situ two low-molecular-weight diazoalkanes, diazoacetaldehyde (CHOCHN₂) or difluorodiazoethane (CF₂HCHN₂), in a controlled fashion under specific conditions. DFHZ-Tfs has been successfully employed in the Fe-catalyzed cyclopropanation and Doyle–Kirmse reactions, thus highlighting the synthetic utility of DFHZ-Tfs in the efficient construction of molecule frameworks containing CHO or CF₂H groups. Moreover, the reaction mechanism for the generation of CHOCHN₂ from CF₂HCHN₂ was elucidated by density functional theory (DFT) calculations.

Full text of DOI:10.1002/anie.202000119

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Accepted Article
Title: Difluoroacetaldehyde N-Triftosylhydrazone (DFHZ-Tfs) as a
Bench-Stable Crystalline Diazo Surrogate for Diazoacetaldehyde
and Difluorodiazoethane
Authors: Xihe Bi, Yi Gai, Xinyu Zhang, Yuanqing Dong, Paramasivam
Sivaguru, Yingying Wang, Bhoomireddy Rajendra Prasad
Reddy, Giuseppe Zanoni, and Yongquan Ning
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000119
Angew. Chem. 10.1002/ange.202000119
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Angewandte Chemie International Edition
10.1002/anie.202000119
RESEARCH ARTICLE
Difluoroacetaldehyde N-Triftosylhydrazone (DFHZ-Tfs) as a
Bench-Stable Crystalline Diazo Surrogate for Diazoacetaldehyde
and Difluorodiazoethane
§
§
§
§
Yongquan Ning, Xinyu Zhang, Yi Gai, Yuanqing Dong, Paramasivam Sivaguru, Yingying Wang,
Bhoomireddy Rajendra Prasad Reddy, Giuseppe Zanoni and Xihe Bi*
[
5]
Abstract: Despite the growing importance of volatile functionalized
functionalized diazomethanes are largely underdeveloped.
[6]
diazoalkanes in organic synthesis, their safe generation and
Diazoacetaldehyde (CHOCHN
(CF HCHN )
2 2
2
)
and difluorodiazoethane
are two valuable low-molecular-weight diazo
compounds that have shown to act as formylating (CHO) and
difluoromethylating (CF H) reagents, respectively. Nevertheless,
in stark contrast to the remarkable achievement in the utility of
[7]
utilization remain
a
formidable challenge due to their difficult
handling along with storage and security issues. In this study, we
developed a bench-stable difluoroacetaldehyde N-triftosylhydrazone
2
(
DFHZ-Tfs) as an operationally safe diazo surrogate that can in situ
release two low-molecular-weight diazoalkanes, diazoacetaldehyde
CHOCHN ) or difluorodiazoethane (CF HCHN ), in a controlled
[8]
trifluorodiazoethane (CF
3
CHN
2
) in organic synthesis, the broad
remain in infancy,
(
2
2
2
applicability of CF HCHN
2
2
and CHOCHN
2
fashion under specific conditions. DFHZ-Tfs has been successfully
employed in the Fe-catalyzed cyclopropanation and Doyle–Kirmse
reactions, thus highlighting the synthetic utility of DFHZ-Tfs in the
efficient construction of molecule frameworks containing CHO or
suffering from difficulties associated with practical generation,
storage, and reaction operation.
[
7a][7c]
Despite the several attempts since 1971,
2 2
the CF HCHN
was first prepared in situ in 2015 by Mykhailiuk by heating a
solution of commercially available difluoroethylamine with tert-
butyl nitrite under oxidative acidic conditions (Figure 1b, right
CF
2
H groups. Moreover, the reaction mechanism for the generation
from CF HCHN was elucidated by density functional
of CHOCHN
2
2
2
[7b]
[9a]
theory (DFT) calculations.
side).
Jamison
CF HCHN
Subsequently, the research groups of Koenigs
and
[
9b]
have improved the technology by generating the
2
using continuous-flow technology. Later, Han and
2
Chen group described an ex-situ generation of CF
the double champer system. In 2018, Ma group developed an
2
HCHN
2
using
Introduction
[9c]
alternative masked CF
difluorodiazoethane (PhSO
since the first discovery of CHOCHN
are two protocols are known for their preparation: 1) acylation of
diazomethane with either formyl fluoride
2
HCHN
CF CHN
2
reagent, phenylsulfone
Diazo compounds are versatile building blocks for numerous
[9d]
2
2
2
).
On the other hand,
[1]
chemical transformations. However, the safe generation and
utilization of low-molecular-weight diazo compounds remain a
formidable challenge owing to their volatility, explosiveness, and
2
in 1966 by Meloy, there
[6a]
or acetic formic
[2]
carcinogenicity. Diazomethane (CH
2
2
N ), the simplest and well-
[6b]
anhydride (Figure 1b, left side);
toluenesulfonyl azide with
2) by heating excess p-
known volatile diazo compound, was first discovered by
[6c]
β-N-methylanilinoacrolein.
[
3]
Pechmann in 1894. Since then, it has been exploited as a
versatile reagent in organic synthesis. The diazo group has rich
and tunable reactivity patterns; therefore, chemists have
derivatized the parent diazomethane with one or two functional
groups to construct functionalized diazomethanes, and then
introduce functional groups into organic molecules by virtue of
Nevertheless, the generation and utilization of CF
2
HCHN
2
and
CHOCHN remains problematic, for example, the CF
2
2
HCHN
2
generation methods requiring oxidative acidic conditions or flow
conditions/two-chamber system, and the practicality of
CHOCHN generation being restricted by the use of explosive
2
diazomethane, giving a crude mixture, and/or requiring multi-
step process. Therefore, the development of new methods for
the safe generation and handling of these two species is a key
to their practical utilization.
[1a][4]
the highly reactive diazo functionality (Figure 1a).
However,
the routine utilization of functionalized diazomethanes in organic
[
1]
synthesis is mostly limited to stable diazoesters,
[
1]
[4]
diazoketones, or aryl diazomethanes. In sharp contrast, the
synthetic applications of volatile low-molecular-weight
A promising solution for the safe and scalable generation and
use of these volatile diazo compounds is the controlled release
of the diazo species in situ from a bench-stable diazo surrogate.
With this in mind, and our continued interest in low-temperature
decomposition of N-sulfonylhydrazones for the in situ generation
[*] Dr. Y. Ning, X. Zhang, Y. Gai, Y. Dong, Dr. P. Sivaguru, Y. Wang, Dr.
[
10]
B. R. P. Reddy, Prof. X. Bi
Department of Chemistry
Northeast Normal University, Changchun 130024, China
E-mail: bixh507@nenu.edu.cn
of diazo compounds,
we herein report difluoroacetaldehyde
N-triftosylhydrazone (DFHZ-Tfs) as a new, bench-stable, and
operationally safe diazo surrogate for in situ divergent release of
Homepage: http://www.bigroup.top/
CHOCHN
2
and CF
2
HCHN
2
under specific conditions.
Prof. X. Bi
Furthermore, these in situ-generated diazo species displayed
remarkable carbene reactivity in the Fe(III)-catalyzed
cyclopropanation and Doyle–Kirmse reactions, affording a wide
variety of formyl- and difluoromethyl-containing organic
molecules in a regio- and stereoselective manner (Figure 1c).
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071, China
Prof. G. Zanoni
Department of Chemistry, University of Pavia, Viale Taramelli 12,
27100, Pavia, Italy.
[
§] These authors equally contributed to this work
1
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RESEARCH ARTICLE
Figure 1. a) The functionalized diazomethane strategy for introducing functional groups into organic molecules by virtue of the reactivity of diazo functionality. b)
Previous approaches to the generation of two important volatile functionalized diazomethanes. c) Our strategy for the in situ safe and divergent generation and
reactions of diazoacetaldehyde and difluorodiazoethane from DFHZ-Tfs.
Scheme 1. a) Preparation of difluoroacetaldehyde N-sulfonylhydrazones (DFHZ). b) Fe-catalyzed cyclopropanation with p-methylstyrene.
Results and Discussion
with sulfonyl hydrazides, affording corresponding DFHZ-Tfs,
DFHZ-Ns, and DFHZ-Ts in excellent yields (Scheme 1a). These
products are bench-stable crystalline solid that can be stored at
ambient conditions for at least three months without significant
degradation. With these novel reagents in hand, we first
examine their reactivity in the cyclopropanation with alkenes.
Three difluoroacetaldehyde N-sulfonylhydrazones (DFHZ) with
different sulfonyl groups were readily prepared from
commercially available ethyl difluoroacetate in two-steps, which
4
involving a sequential reduction with LiAlH and condensation
2
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RESEARCH ARTICLE
The cyclopropane motif is an important target to organic
chemists because it is widespread in natural products and
the trans isomer. The electronic properties and position of the
substituents on the phenyl ring did not influence the reaction
efficiency (3a–3k) and stereoselectivity observed in the
reactions of fused aryl (3l) and heteroaryl (3m) substrates. The
reaction exhibited excellent chemoselectivity with conjugated
dienes and enynes, rendering the terminal cyclopropanation
products 3n and 3o in 79% and 97% yields, respectively. While
[
11]
synthetic bioactive agents,
and its elaboration with fluorine
represents an opportunity for discovering novel compounds with
[
12]
new or increased activity.
group can also act as
Particularly, the difluoromethyl
bioisostere for carbinol, thiol,
a
[
13]
hydroxamic acid, and amide groups.
Surprisingly, our initial
study on the reaction of p-methylstyrene 1a with DFHZ-Tfs by
iron catalysis in alkaline aqueous conditions exclusively afforded
a cyclopropane carboxaldehyde 2a in 91% yield with high
diastereomeric ratio (9:1), rather than the expected
difluoromethylated cyclopropane (Scheme 1b). This result
suggests that the exclusive formation of a diazoacetaldehyde
species (For conditions optimization, see SI, Table S1). By
comparison with DFHZ-Ns and DFHZ-Ts, DFHZ-Tfs afforded the
best results regarding the product yield and the diastereomeric
ratio.
a decrease in stereoselectivity was observed for methyl-
substituted conjugated diene (3p) and enyne (3q). This result
demonstrates that steric hindrance is not a major determinant of
the stereoselectivity of this transformation. Likewise, various 1,1-
disubstituted alkenes also delivered the corresponding products
3r–3t with moderate diastereoselectivity. Notably, 1,1-
diphenylethylene was smoothly converted into the desired
product 3u in 97% yield with high diastereoselectivity. Besides,
spiro[2.n] compounds 3v and 3w could be easily obtained from
cyclic 1,1-disubstituted alkenes. The incorporation of the
difluoromethylcyclopropyl motif into a ferrocene (3x) is a novel
derivatization of this scaffold. Finally, a derivative of Estrone
Attracted by the widespread importance of cyclopropane
[14]
carboxaldehyde in organic synthesis,
we then turned our
attention to investigate the reaction scope (Scheme 2a). The
protocol demonstrated excellent functional group tolerance, as
substrates bearing methoxy, halogen, trifluoromethyl, nitro,
cyano, and acyl groups on the benzene ring were converted to
desired products 2a–2k in moderate to high yields and high
diastereomeric ratios. p-Divinylbenzene, a substrate with more
than one vinyl group, also smoothly underwent cyclopropanation
to give monocyclopropanated product 2l in 87% yield. Alkenes
bearing heterocycles, such as 3-benzothiophene and 3-indole
groups were converted into corresponding products 2m and 2n,
respectively, in good yields and with good diastereoselectivities.
2
gave the corresponding Estrone-CF in 90% yield without a
decrease in reactivity.
To further explore the synthetic versatility of DFHZ-Tfs, we
studied the Doyle–Kirmse reaction — a unique method for
3
constructing C(sp )–S and C–C bonds through [2,3]-sigmatropic
[
20]
rearrangements.
A survey of the literature revealed that
and CF HCHN
2
Doyle–Kirmse reactions involving CHOCHN
2
2
had not been explored. In this context, we first evaluated the
Doyle–Kirmse reaction of DFHZ-Tfs with allyl sulfide under the
aqueous conditions (3 mol% FeTPPCl as the catalyst in aq.
NaOH/DCE mixture, details see SI, Table S3) (Scheme 3a,
conditions A). A range of aryl allyl sulfides with either electron-
donating or electron-withdrawing groups, heteroaryl and alkyl
allyl sulfides afforded α-sulfenylated carbonyl compounds 5a–5p
in moderate to good yields. Note that the reaction efficiency was
The reaction with
chemoselectively afforded terminal cyclopropanation products
o and 2p in 95% and 74% yields, respectively, with a
decreased diastereomeric ratio for 2p. 1,1-Disubstituted alkenes
a
conjugated diene or an enyne
2
were also converted into formyl cyclopropanated products 2q–2t, not determined by the electronic properties or the positions of
albeit in relatively lower diastereoselectivities. In stark contrast,
,1-diphenylethylene was transformed into 2u in 93% yield with
excellent diastereoselectivity. Interestingly, spiro[2.n]
compounds 2v and 2w were readily obtained from cyclic 1,1-
the substituents on the aromatic ring. Similarly, cinnamyl and
crotyl sulfides were also excellent reaction partners, delivering
the desired products 5q and 5r in 87% and 85% yields,
respectively, albeit with no measurable diastereoselectivity.
Notably, the α-sulfenylated carbonyl compounds and structural
motifs obtained by this process are found in pharmaceutically
1
[
15]
disubstituted alkenes.
Further, applying this protocol to
alkenes containing ferrocene (2x) and Estrone (Estrone-CHO)
moieties demonstrated the synthetic utility of this methodology.
To the best of our knowledge, this is the first general and
practical catalytic method for accessing cyclopropane
[
21]
active molecules,
biotransformations to produce chiral β-hydroxysulfoxides, and
used as starting materials in
[
22]
[
23]
reactive intermediates in a variety of organic transformations.
carboxaldehydes in
a
single step from CHOCHN
2
and
In particular, our synthetic approach offers an attractive
alternative to the existing multistep synthetic approaches for α-
sulfenylated carbonyl compounds that use toxic reagents and/or
[
14a][16]
alkenes.
The benefits of CF
force for the booming development of difluoromethylating
2
H incorporation have been a major driving
[
23a][24]
expensive transition metal catalysts.
[
17]
reagents.
To achieve the desired difluoromethylated
Next, we assessed the synthetic utility of DFHZ-Tfs as a
difluoromethyl source in the Doyle–Kirmse reaction. After further
optimization of the difluoromethylcyclopropanation reaction
conditions (details see SI, Table S4), the conditions of FeTPPCl
cyclopropanation reaction, a systematic survey of the reaction
parameters were carried out (details see SI, Table S2), and we
eventually found the non-aqueous conditions capable of
releasing CF
2
HCHN
2
and affording difluoromethylated
(3 mol%) as the catalyst and Cs
provides the best reaction (Scheme 3b, conditions B). The α-
difluoromethyl sulfide (-SCH CF H) moiety in the resulting
2 3
CO as the base in THF
cyclopropanes by iron catalysis (Scheme 2b). Then, the reaction
scope was evaluated with a set of alkenes. Various terminal
alkenes proved to be suitable for this reaction, affording
products 3a–3x in high to excellent yields (up to 98%).
2
2
difluoromethylated homoallyl and α-allenyl sulfides is a recurring
structural motif in compounds proposed as pest control
[
18]
[25]
[26]
Compared to the approach used by Koenigs et al.,
and Lin
to prepare difluoromethylated cyclopropanes
they observed no or poor diastereomeric ratios), our strategy
exhibited excellent stereoselectivities (up to > 20:1 dr) in favor of
agents, and treatments of dilated cardiomyopathy. Various
aryl, heteroaryl, and alkyl allyl sulfides reacted smoothly with
[
19]
and Xiao et al.
(
CF
2
HCHN
2
to provide the corresponding difluoromethyl
homoallyl sulfides 6a–6m in moderate to good yields.
3
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RESEARCH ARTICLE
Scheme 2. a) Scope of formyl cyclopropanation. Reaction conditions: alkene (0.3 mmol), DFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%), aq. NaOH (5.0 wt%)/toluene,
0 °C, 22 h, N atmosphere. b) Scope of difluoromethylcyclopropanation. Reaction conditions: alkene (0.3 mmol), DFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%),
CO (0.9 mmol), 1,4-dioxane, 40 °C, 22 h, N
6
2
K
2
3
2
atmosphere. Yields refer to isolated products. dr = diastereomeric ratio. *At 0 °C.
4
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The electronic properties and the position of the substituents
on the benzene ring had no significant impact on the reaction
outcome. Variations in the substitution pattern of the allyl group
did not hamper the reactivity, as demonstrated by cinnamyl and
crotyl sulfides, thus resulting in the related products (6n and 6o)
with modest diastereomeric ratio.
sulfides 8a–8f in moderate to good yields. Finally, a multi-gram
scale synthesis was carried out leading to the product 6a in a
yield comparable to that of a smaller scale; further oxidation of
6a by mCPBA afforded a sulfone derivative (6a') (Scheme 3c).
Collectively, a range of novel difluoromethylated homoallylic
thioethers and α-allenyl sulfides were obtained by Doyle–Kirmse
reaction of DFHZ-Tfs and allyl/propargyl sulfides, which are
Next, the reactivity of propargyl sulfides 7 was examined
under the same conditions, and resulted in a variety of α-allenyl
[27]
interesting building blocks for the synthesis of fluorochemicals.
Scheme 3. Scope of Doyle-Kirmse Reaction: a) 4 (0.3 mmol), DFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%), NaOH aq. (5.0 wt%)/DCE, 40 °C, 18 h, N
b) 4 or 7 (0.3 mmol), DFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%), Cs CO (0.9 mmol), THF, 40 °C, 12 h, N atmosphere. c) Gram-scale synthesis and further
transformation of 6a: 4a (10.0 mmol), DFHZ-Tfs (20.0 mmol), FeTPPCl (1 mol%), Cs CO (30.0 mmol), THF, 40 °C, 48 h, N atmosphere; 6a (0.5 mmol), mCPBA
1.25 mmol), DCM, 0 °C, 4 h, air atmosphere. Yields refer to isolated products. *Yield based on recovered starting material.
2
atmosphere;
2
3
2
2
3
2
(
5
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RESEARCH ARTICLE
Considering the widespread importance of functionalized
(2bc), amine (2bd), nitrile (2be), propargyl alcohol (2bf), gem-
difluoroalkene (2bg), alkyne (2bh), and alkene (2bi). The
structure of cyclopropane carboxylic acid 2ba was
unambiguously confirmed by single-crystal X-ray diffraction
analysis.
[
28]
cyclopropanes,
the functional group interconversions of
cyclopropane carboxaldehyde was explored. As summarized in
Scheme 4, diverse functionalized cyclopropanes were readily
obtained from 2b, such as acid (2ba), alcohol (2bb), oxime
Scheme 4. Functional group transformations of cyclopropane carboxaldehydes: Reaction conditions: (a) oxidation: 2b (0.5 mmol), Ag
10.0 wt%), 60 °C, 30 min; (b) reduction: 2b (0.5 mmol), LiAlH (0.75 mmol), THF, 25 °C, 10 h, N atmosphere; (c) oximation: 2b (1.0 mmol), NaOH (2.6 mmol),
O, reflux, 18 h; (d) amination: 2bc (0.5 mmol), LiAlH (1.1 mmol), THF, reflux, 2 h, N atmosphere; (e) cyanation: 2b (0.5 mmol),
OH·HCl (0.75 mmol), NMP, 100 °C, 2 h; (f) addition: 2b (0.5 mmol), BrMgC≡CH (0.5 mmol), THF, 25 °C, 12 h; (g) difluoroalkenylation: 2b (0.5 mmol), PPh
CO Na (0.75 mmol), NMP, 100 °C, 2 h; (h) alkynylation: i) 2b (0.5 mmol), PPh (2.0 mmol), CBr (1.0 mmol), DCM, 0 °C, 3 h; ii) n-BuLi (1.4
mmol), THF, −78 °C, 12 h; (i) alkenylation: 2b (0.5 mmol), Ph PCH I (0.6 mmol), n-BuLi (0.6 mmol), THF, 25 °C, 4 h. Yields refer to isolated products.
2
O (0.5 mmol), NaOH aq.
(
4
2
NH
NH
2
OH·HCl (1.6 mmol), EtOH/H
2
4
2
2
3
(0.6 mmol), ClCF
2
2
3
4
3
3
To clarify the transformation mechanism of CF
CHOCHN under aqueous conditions, we performed DFT
calculations starting from the in situ generated CF HCHN at the
According to
the calculations, the cooperative effect of base NaOH and water
via hydrogen bonding was found to play a critical role. The
transformation could be divided into three steps: the C–F bond
2
HCHN
2
into
ion to vinyl carbocation leads to 2-diazo-1-fluoroethanol Int3 with
a barrier of only 2.2 kcal/mol (via TS2) with respect to Int2.
Considering the experimentally existing of a strong NaOH base
in the system and inspired by the recent report by Zhang and
Houk et al. about the hydroxylation and deprotonation of
2
2
29]
2
[
M06-2X/6-31+G(d,p) level of theory (Figure 3).
[
30]
difluorocarbene compound,
we first investigated the
deprotonation of Int3 by NaOH to form the sodium alkoxide
intermediate Int4, and this step is exergonic by 18.5 kcal/mol.
The substituent F, which is on the same carbon as the sodium in
Int4, is a potential leaving group; therefore, in the last step the
elimination of NaF with the assistance of 2 molecules of water
activation by NaOH-H
to vinyl carbocation, and the elimination of HF with the
assistance of NaOH-H O. In the first step, the NaOH only and
the NaOH with 1~3 H O molecules were considered in the
activation of C–F bond (See SI, Figure S1). It was found that the
mode catalyzed by NaOH-3H O (TS1, 15.9 kcal/mol) is most
favored, which is 13.3 kcal/mol lower than that of NaOH only
TS1', 29.2 kcal/mol). In TS1, water enhances the nucleophilic
2
O, nucleophilic addition of hydroxy group
2
2
(TS3, 0.5 kcal/mol) occurs to afford the CHOCHN
intermediate Int3 may also undergo another pathway to produce
CHOCHN , the direct C–F bond activation of Int3 by NaOH (see
2
. The key
2
2
(
SI, Figure S2). Conclusively, the NaOH acts as the base to
extract fluorine and the weakly acidic water enhances the
electrophilicity of Na ion through the hydrogen bonding to
promote the hydration reaction.
activity of base NaOH through the bridged hydrogen bonding,
thereby promoting the C–F bond activation by NaOH. In the
following step, the nucleophilic addition of dissociative hydroxyl
6
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RESEARCH ARTICLE
2 2 2
Figure 2. Free energy profiles of the conversion of CF HCHN into CHOCHN .
Financial support by NSFC (21871043, 21961130376),
Department of Science and Technology of Jilin Province
Conclusion
(
20180101185JC, 20190701012GH), and the Fundamental
We have demonstrated DFHZ-Tfs to be an operationally safe
and bench-stable diazo surrogate of two important, volatile
Research Funds for the Central Universities (2412019ZD001).
functionalized diazomethanes, CF
2
HCHN
2
2
and CHOCHN ,
which could be independently generated in situ under specific
conditions. This strategy circumvents direct human exposure to
toxic and explosive diazo reagents and reduces the risk of rapid
accumulation of explosive diazo compounds. Furthermore,
successful applications of DFHZ-Tfs to cyclopropanation and
Doyle–Kirmse reactions demonstrated its great synthetic utilities.
The discovery described here represents a significant advance
in diazo chemistry, as it has opened up an avenue to the
exploration of two classes of important functionalized diazo
compounds. In view of the remarkable stability and operational
simplicity, as well as the mild and controlled decomposition
conditions, DFHZ-Tfs would find wide applications in organic
synthesis.
Keywords: difluoroacetaldehyde N-triftosylhydrazone •
diazoacetaldehyde • difluorodiazoethane • cyclopropanation •
Doyle–Kirmse reaction
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
RESEARCH ARTICLE
Yongquan Ning, Xinyu Zhang, Yi Gai,
Yuanqing Dong, Paramasivam Sivaguru,
Yingying Wang, Bhoomireddy Rajendra
Prasad Reddy, Giuseppe Zanoni and
Xihe Bi*
Page No. – Page No.
Difluoroacetaldehyde N-
Triftosylhydrazone (DFHZ-Tfs) as a
Bench-Stable Crystalline Diazo
Surrogate for Diazoacetaldehyde and
Difluorodiazoethane
Two from One: An operationally safe and bench-stable crystalline diazo surrogate,
difluoroacetaldehyde N-triftosylhydrazone (DFHZ-Tfs) was developed for in situ
2 2 2
divergent release of two volatile diazo species, CHOCHN and CF HCHN . The
synthetic utility of these reagents was successfully demonstrated in the Fe-catalyzed
cyclopropanation and Doyle–Kirmse reactions. The reaction mechanism for the
formation of CHOCHN
2
from CF
2
HCHN
2
was elucidated by DFT calculations.
9
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