β-Diazocarbonyl Compounds: Synthesis and their Rh(II)-Catalyzed 1,3 C?H Insertions

Article abstract of DOI:10.1002/anie.202015077

Herein, we describe the first electrophilic diazomethylation of ketone silyl enol ethers with diazomethyl-substituted hypervalent iodine reagents that gives access to unusual β-diazocarbonyl compounds. The potential of this unexplored class of diazo compounds for the development of new reactions was demonstrated by the discovery of a rare Rh-catalyzed intramolecular 1,3 C?H carbene insertion that led to complex cyclopropanes with excellent stereocontrol.

Full text of DOI:10.1002/anie.202015077

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: β-Diazocarbonyl compounds: synthesis and their Rh(II)-catalyzed
1,3 C-H insertions
Authors: Liyin Jiang, Zhaofeng Wang, Melanie Armstrong, and Marcos
G. Suero
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
β-Diazocarbonyl compounds: synthesis and their Rh(II)-catalyzed
1,3 C-H insertions
Liyin Jianga, Zhaofeng Wanga, Melanie Armstronga, and Marcos G. Sueroa*
Dedicated to the memory of Professor Kilian Muñiz
[a]
Dr. L. Jiang, Dr. Z. Wang, M. Armstrong, Prof. M. G. Suero
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology
Av. Països Catalans 16 – 43007 Tarragona (Spain)
E-mail: mgsuero@iciq.es
Supporting information for this article is given via a link at the end of -the document.
Abstract: Herein, we describe the first electrophilic diazomethylation
of ketone silyl enol ethers with diazomethyl-substituted hypervalent
iodine reagents that gives access to unusual β-diazocarbonyl
compounds. The potential of this unexplored class of diazo
compounds for the development of new reactions was demonstrated
by the discovery of a rare Rh-catalyzed intramolecular 1,3 C–H
carbene insertion that led to complex cyclopropanes with excellent
stereocontrol.
starting materials was not reported. The authors also showed that
this diazo compound class can be used in classic intermolecular
Rh(II)-catalysed carbene transfer reactions for alkene
cyclopropanation, O–H insertion, as well as arylation with phenyl
boronic acid.
Taking into account the impact of α-diazocarbonyl
compounds in chemical science and the potential untapped
synthetic applications of β-diazocarbonyl derivatives, we sought
to develop a general strategy relying on the coupling of ketones,
via the corresponding enol/enolate, with an electrophilic
diazomethyl source (Scheme 1c). In contrast to the Barluenga
strategy that relied in vinyl diazo derivatives, the disconnection
proposed would be convergent and conceptually the simplest
possible. It would rely on the use of ketone building blocks, which
are one of the most structurally diverse, useful and commercially
available starting materials. If successful, this simple protocol
would give immediate access to unexplored β-diazocarbonyl
compounds to the broad synthetic community working in reaction
discovery and development, natural product synthesis and
(bio)catalysis.
Introduction
Since Curtius reported the synthesis of ethyl diazoacetate
for the first time in 1883,[1] α-diazocarbonyl compounds have
found broad applications in chemical synthesis,[2] chemical
biology[3] as well as in the directed evolution of enzymes (Scheme
1a).[4] The long-lasting success of α-diazocarbonyl reagents has
been underpinned by the discovery and development of general
and efficient synthetic routes for their preparation.[2e],[5]
A key feature of α-diazocarbonyl compounds is their ability
to generate reactive free carbenes or transition-metal-
carbene(carbenoid) species, upon thermal, photonic or transition-
metal catalyst activation. Some of the most important advances
in the field of C–H functionalization rely on the use of dirhodium
paddlewheel complexes and α-diazocarbonyl compounds to
catalytically generate Rh-carbene species, which showed efficient
site- and stereoselective C–H functionalization of simple and
complex molecules.[6]
In contrast, β-diazocarbonyl compounds have been
underexplored and overlooked for years, mainly due to the lack of
synthetic procedures (Scheme 1a). In fact, to the best of our
knowledge, only one synthetic protocol has been reported by
Barluenga, López and co-workers in 2011 and is based on a
Cu(II)-catalyzed oxidative rearrangement of vinyl diazo
derivatives with iodosylbenzene (Scheme 1b).[7] The products
obtained are functionalized with an ester group at the β position,
which enables stability to the diazo function. The method is
particularly efficient in the synthesis of β-diazocarbonyl
compounds unsubstituted in alfa position. However, lower yields
or no reaction is observed for the synthesis of mono or
disubstituted derivatives, respectively. In addition, an study of the
functional group tolerance of the process and the synthesis of β-
diazocarbonyl compounds from complex natural products as
Recently, our group reported the synthesis of a new class of
cyclic and pseudocyclic hypervalent iodine reagents substituted
with diazomethyl groups and exploited them in photocatalytic
arene C–H bond diazomethylations via diazomethyl radicals;[8]
and in the catalytic cleavage of C–C double bonds with Rh-
carbynoids.[9],[10] In 1994, the group of Weiss reported the
synthesis of the parent linear hypervalent iodine derivate and
demonstrated its ability to react with nucleophiles such as sulfides,
phosphines or amines.[11] More recently, the groups of Bonge-
Hansen[12] and Gaunt[13] demonstrated applications of the linear
hypervalent iodine reagents in nucleophilic halogenations and in
a
methionine bioconjugation of peptides and proteins,
respectively.[14]
Considering that this unusual class of hypervalent iodine
reagents can serve as an electrophilic diazomethyl source, we
anticipated that silyl enol ethers derived from ketones could be
suitable nucleophiles. In fact, silyl enol ethers are known to react
with hypervalent iodine reagents and deliver α-substituted
carbonyl compounds.[15] Herein, we present the successful
execution of this concept for a new synthesis of β-diazocarbonyl
compounds. The synthetic method is general, simple to perform,
relatively fast, occurs at room temperature and does not require a
transition-metal catalyst (Scheme 1d). In addition, we found that
β-diazocarbonyl compounds can be converted into cyclopropanes
1
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
by an unusual diastereoselective 1,3 C–H carbene insertion with
Rh(II) catalysis.
38% 1H-NMR yield when using the more electrophilic linear
reagent 2d (entry 8).
a-diazocarbonyl compounds
a
After this, we observed a significant increment on efficiency
by degasifying the reaction mixture (entry 9) and among the
solvents screened, CH3CN was the best so far (entry 10-17). We
then screened a range of carboxylate, phosphate or carbonate
additives (entry 18-25) and found that Na2CO3 provided better
yields (entry 25). Control experiments showed the necessity of
using an additive in the reaction (entry 26), since we proved in a
control experiment that TMSOTf decomposed the diazo product
3a. Finally, we observed a positive effect in the efficiency of the
reaction when we scaled-up from 0.20 mmol to 0.60 mmol of 2d.
3a was obtained in 81% isolated yield after purification by flash
chromatographic column (entry 27).[16]
b-diazocarbonyl compounds
O
O
N2
N2
widely used
well-established synthetic methods
unexplored
only one synthetic method
b
Previous work: Cu(II)-catalyzed oxidative rearrangement
CO2Et
O
CO2Et
N2
2 mol% Cu(OTf)2
PhIO
N2
R2
R1
CH3CN, 5-10 min
room temperature
R1
vinyl diazo reagents
R2
8 examples
c
can we develop a new strategy by using readily available ketones ?
Table 1. Optimization studies.[a]
O
O
O
CO2Et
N2
OTMS
Me
CO2Et
N2
additive, catalyst
I(III)
+
Electrophilic
diazomethylation
Ph
solvent
room temperature
2 hours
(-)
nucleophile
Ph
(+)
Me
3a
N2
1a
2
ketones
electrophile
Entry
2
catalyst
solvent
Additive
Yield 3a
[%][b]
O
CO2Et
N2
1
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CPh
NaO2CCH2Ph
NaO2CC6H4(p-OH)
NaOAc
0
0
OTMS
CO2Et
N2
Na2CO3, CH3CN
Ph
2
Zn(OTf)2
+
TfO
I
Ph
room temperature
2 hours
3
Zn(NTf2)2
0
Ph
Me
Me
71% yield
4
Sc(OTf)3
0
b-diazocarbonyl
compound
silyl enol ether hypervalent I(III) reagent
5
ReO3Me
0
O
6
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0
CO2Et
Ph
1 mol % Rh2(OAc)4
7
0
CH2Cl2
8
38
2 hours, 0 °C
Me
9
59[c]
19[c]
27[c]
32[c]
20[c]
23[c]
0[c]
95% yield dr >20:1
exclusive 1,3 C-H insertion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Scheme 1. General synthesis of β-diazocarbonyl compounds by electrophilic
diazomethylation and their use in cyclopropane synthesis by Rh2-catalyzed 1,3
C–H carbene insertion (a-c).
acetone
DMF
Et2O
Results and Discussion
EtOAc
toluene
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0[c]
The feasibility of the envisaged coupling was initially
evaluated with propiophenone silyl enol ether 1a (1.25 equiv.) with
benziodoxolone-based hypervalent iodine reagent 2a (1 equiv.) in
acetonitrile at room temperature and sodium benzoate (1 equiv.)
was added as additive to quench TMSOTf sub-product (Table 1).
After 2 hours, conversion to 3a was not observed and longer
reaction times conducted to decompositions of the silyl enol ether
1a (entry 1). It is well-known that the electrophilicity of
benziodoxolone-based reagents can be enhanced with Lewis
acid catalysts.[10e] In fact, we reported that Zn(NTf2)2 catalyst had
23[c]
24[c]
48[c]
57[c]
27[c]
44[c]
69[c]
0[c]
KOAc
K3PO4
K2CO3
Cs2CO3
a
crucial role in our photocatalytic arene C–H bond
diazomethylation with 2a.[8] However, we did not observe any
conversion to 3a when using zinc catalysts as well as with
scandium or rhenium catalysts (entry 2-5). Then, we turned our
efforts to evaluate whether the structural nature of the hypervalent
iodine core would be key in the reaction. Neither benziodoxole-
based reagent 2b nor pseudo-cyclic derivative 2c were
successful (entries 6,7). In contrast, we observed a promising
Na2CO3
72[c]
24c]
85(81)[c],[d]
-
Na2CO3
[a] Reaction conditions: 1a (0.25 mmol), 2a-d (0.20 mmol), additive (0.20 mmol),
catalyst (10 mol %), solvent (1 mL). [b] 1H-NMR yields calculated using
mesitylene as internal standard. [c] the reaction mixture was degassed under
2
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
argon. [d] Yield of the isolated product 3a using 1a (0.60 mmol), 2d (0.50 mmol),
Na2CO3 (0.60 mmol), CH3CN (2 mL).
molecules. The key for success has been basically due to the
convergent coupling strategy based on the unique reactivity of the
diazomethyl-substituted hypervalent iodine reagents and the
employment of ketone silyl enol ethers as nucleophiles.
Furthermore, the diversity and availability of the latter reagents,
that can be made by robust synthetic protocols, is in sharp
contrast with vinyl diazo compounds.[2e]
CO2Et
N2
OTf
CO2Et
N2
CO2Et
N2
O
I
TfO
I
O
I
O
CO2Et
RO
O
I
2a
Me
Me
N2
2d
2c R = CH2CO2Et
2b
Two possible mechanisms can be envisaged for the
diazomethylation reaction of silyl enol ethers (Scheme 2). The first
possibility could involve a ligand exchange of the triflate anion with
the silyl enol ether to form int-1 and then a subsequent reductive
elimination would form the product and iodobencene. This
possibility is aligned with a widely accepted mechanism for
coupling of nucleophiles and hypervalent iodine reagents.[10] The
second mechanism would involve a SN2-type nucleophilic
reaction of the silyl enol ether at the diazo carbon via int-2 with
concomitant elimination of PhI and triflate.[12] We proposed also
this possibility based on the DFT calculations performed by the
group of Bonge-Hansen with the same class of linear hypervalent
iodine reagents and neutral or charged nucleophiles. The
calculations showed that the nucleophilic addition can occur
directly at the diazo carbon by a SN2-type mechanism (with Me2S
and Et3N) or by a carbonyl-like addition−elimination reaction (with
bromide).[20] At present, we do not have any evidence that support
one of the above mentioned mechanisms.[21]
With the optimized reaction conditions, we evaluated the
scope of the electrophilic diazomethylation using non-terminal
ketone silyl enol ethers and reagent 2d (Table 2). We were
delighted to find that our protocol permitted access to β-
diazocarbonyl compounds substituted in α position with simple
alkyl chains (3b-e) as well as with a range of useful functionalities,
including alkene, alkyne, phenyl, alcohol, chlorine and esters (3f-
l). The use of tetrasubstituted silyl enol ethers led to the formation
of β-diazocarbonyl compounds which are doubly-substituted at α
position (3m-q,3s). In addition, cyclic silyl enol ethers derived
from benzocyclopentanone were well tolerated (3r,s). It is worth
highlighting that compound 3s exemplifies the ability of this
method to reach diazo compounds α-substituted with all-carbon
quaternary stereogenic centers. Such structural motifs are hardly
inaccessible by classical or modern diazo synthesis.[17]
On the other hand, the substitution of the aromatic ring of
the silyl enol ether in (3t-w) or the use of heterocycles such as
furane (3z) did not influence the efficiency of the electrophilic
diazomethylation. Terminal silyl enol ethers worked well (3y-ah)
and β-diazocarbonyl compounds from acetone, 3-pentanone and
cyclohexanone could be obtained albeit in lower yields (3ai,
3aj,3ak). Unfortunately, silyl enol ethers derived from esters or
aldehydes did not work under the optimized reaction conditions.
However, we were able to introduce the versatile Donohoe
pentamethylphenyl (Ph*) acyl protecting group (3x), which could
be derivatized into esters, aldehydes, alcohols, amides,
carboxylic acids or aldehydes under relative mild conditions.[18]
Then, we explored the scope of the linear hypervalent iodine
reagents 2. We successfully demonstrated the introduction of
alternative alkyl substituents in the ester group such as benzyl, t-
butyl, 2,2,2-trichloroethyl and (–)-menthyl [3al-n,(±)-3ao].
Importantly, we were able to synthesize β-diazocarbonyl
compounds substituted with ketone, phosphonate, trifluoromethyl
and sulphonate groups (3ap-au). These results clearly underline
the high modularity of our approach to the synthesis of β-
diazocarbonyl compounds.
-OTf
ligand
exchange
reductive
elimination
TMS
1R
+
O
R4
Ph
I
R3 R2
int-1
TMSOTf
PhI
1 +
2
3
OTMS
R2
SN2-type
nucleophilic
addition
1R
R3
TfO
R4
N2
I
Ph
int-2
Scheme 2 Mechanism proposals
In 2018, our group demonstrated the late-stage radical C–H
bond diazomethylation of drug molecules/natural products and its
application in the construction of chiral centers, by exploiting a
broad range of known catalytic carbene insertion reactions.[8] The
installation of a substituted diazomethyl group at the β position of
complex ketone derivatives may be of utility for streamlining the
synthesis of libraries of analogues.[19] Here we show four
examples of an electrophilic diazomethylation reaction using
flavanone, testosterone, jasmone and donezepil derivative (3av-
ay).
Our methodology in comparison with the Barluenga
rearrangement of vinyl diazo compounds demonstrated to be a
more general approach.[7] Our new process surpasses the main
limitations of the Barluenga protocol with regards to the (1)
generality, (2) substitution patterns, (3) functional group tolerance,
(4) late-stage functionalization of natural products and drug
3
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Scope of the electrophilic diazomethylation of ketone silyl enol ethers 1 with hypervalent iodine reagents 2.[a]
R4
O
OTMS
R2
R4
N2
Na2CO3, CH3CN
+
TfO
I
1R
1R
N2
R3 R2
room temperature, 2 hours
R3
Ph
1
2
3
enol ether scope
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
3b R = Et, 88%
O
CO2Et
N2
Ph
Ph
Ph
Ph
Ph
3c R = n-propyl, 71%
3d R = iso-propyl, 65%
3e R = iso-pentyl, 79%
Ph
R
OTBS
Cl
3f 61%
3g 70%
3h 66%
3i 74%
3j 64%
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
O
Me Me
OMe
3k 71%
OMe
3l 60%
3m 66%
3n 74%
3o 84%
3p 64%
3q 62%
CO2Et
O
O
CO2Et
N2
Me
O
CO2Et
N2
O
CO2Et
N2
R
O
CO2Et
N2
I
3t R = OMe, 75%
3u R = Me, 78%
3v R = Cl, 77%
Me
Me
N2
O
S
Bu
Et
Me
O
Et
Me
O
O
R
Me
3x 77%
3r R = H, 84%
3w 53% [x-ray]
3y 63%
3s R = Me, 76%
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
Ph
Me
MeO
OMe
O
Me
3z 79% (71%)[b]
3aa 81%
3ab 75%
3ac 85%
3ad 69%
3ae 77%
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
O
CO2Et
N2
Me
Me
Me
O
S
3af 88%
3ag 70%
3ah 73%
3ai 60%
3aj 44%
3ak 25%
reagent scope
late-stage functionalization
Me
O
OTMS
Me
O
O
CO2Et
N2
Me
Me
3al R = CO2Bn, 82%
3am R = CO2tBu, 81%
O
CO2R
N2
CO2Et
O
Me
H
O
3av 62% (8:1)
from flavanone
(±)-3aw 44% (1:1)
from testosterone
Ph
O
3an R = CO2CH2CCl3, 67%
N2
Me
(±)-3ao 84%
N2
Ph
(1:1)
Me
O
CO2Et
N2
O
Ph
N2
O
O
PO(OMe)2
N2
O
CF3
N2
O
SO3Et
N2
O
MeO
CO2Et
N2
Me
3ax 33%
from jasmone
3ay 27%
Ph
Ph
Ph
Ph
from donezepil
MeO
Me
R
R
Me
3ap 92%
3aq R = Me, 91%
3ar R = Pr, 87%
3as R = Me, 82% 3au 71%
3at R = Pr, 77%
N
Me
Boc
[a] Reaction conditions: silyl enol ether 1 (0.50 mmol), reagent 2d (0.60 mmol), Na2CO3 (0.60 mmol), CH3CN (2 mL), room temperature, 2 hours. Reported yields
are of isolated product after purification by flash chromatographic column with silica gel. [b] Yield in parenthesis of isolated product using 1.4 grams of acetophenone
trimethylsilyl enol ether and 2.8 grams of 2d.
4
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
temperatures (–78 ºC).[26] We generally did not observe β-hydride
migration and this might be due to the electron-withdrawing
character of the carbonyl group in 3. It is worth mentioning that
Barluenga did not observed β-hydride migration in classic Rh-
catalyzed transformations showed for β-diazocarbonyl
compounds. In our case, the only example that showed such
migration from the β-diazocarbonyl compounds tested is 3a
(Table 3C) with Rh2(OAc)4 as catalyst. We found that the reaction
led to cyclopropane 4m and to olefin 6 in significant yield. The β-
hydride migration in int-4 can now be observed probably because
the 1,3 C–H insertion occurs in the less reactive methyl C–H bond.
However, we were able to mitigate the β-hydride migration
pathway by using Rh2(TPA)4 at –60 ºC. Olefin 6 was formed in 4%
yield and cyclopropane 4m was obtained with even higher
efficiency.
On the other hand, another competitive pathway found to
the 1,3 C–H insertion was the 1,2-alkyl shift rearrangement.
Benzocyclopentane 3s conducted to spirocycle 4m as the minor
product when Rh2(OAc)4 was used. The major product found was
naphtol 7 formed by a cyclopentane ring-expansion in int-5 via
selective 1,2-migration of the carbonyl group. This migration was
fully suppressed by using Rh2(TPA)4 and 4m was obtained as the
only reaction product. In contrast to this, no 1,3 C–H insertion was
observed when using derivative 3n. Both catalysts, Rh2(OAc)4
and Rh2(TPA)4, enabled the synthesis of cyclobutene 8 by a well-
known cyclopropyl carbene ring-expansion of int-6.[27]
The new stereoselective cyclopropane synthesis represents
a new strategy to construct cyclopropane cores from α & β C–H
bonds in aliphatic ketones.[28] The use of two C–H bonds as
functional groups for the synthesis of this privileged core is
relative unusual.[29] This is in sharp contrast with the large variety
of synthetic methods based on metal-catalyzed C–H bond
functionalization that access larger cyclic molecules.[30]
Cyclopropanes 4 show a cis disposition of the carbonyl
function from the ketone with the electron-withdrawing group
(ester, CF3, phosphate) alfa to the diazo functionality, and that
relative configuration has been confirmed by single-crystal x-ray
diffraction analysis (4i,k; Table 3). Our process complement more
direct cyclopropane synthesis substituted with two electron-
withdrawing groups from α,β-unsaturated carbonyls via Corey-
Chaykovsky processes as well as with diazo compounds.[31]
Interestingly, those strategies generally conduct to trans isomer
cyclopropane with the exception of the Macmillan
cyclopropanation, which lead to cis cyclopropanes via
enantioselective organocatalysis.[31b] Recently, Rovis developed
a Rh(III)-cyclopropanation reaction using N-enoxyphthalimides
able to reach also cis cyclopropane isomers from moderate to
high diastereomerio ratios.[29c],[29f]
The intramolecular carbene C–H insertion with diazo
compounds catalyzed by paddlewheel dirhodium carboxylate
catalysts has been of great importance in the effective
construction of complex carbocycles.[2] Diazo compounds
substituted with a free-rotation linear carbon chain often conduct
to five-membered rings via 1,5 C–H insertion.[22] We wondered
whether the β-diazocarbonyl compounds 3 could be transformed
in complex cyclopentanes using Rh2 catalysis. To our surprise,
when we performed a reaction using 3c and simple Rh2(OAc)4 in
dichloromethane at 0 ºC, we found the exclusive formation of
cyclopropane 4a with excellent yield and as
a single
diastereoisomer via 1,3 C–H insertion (Table 3A, 95% yield,
>20:1). Interestingly, a similar outcome was observed when we
used more electrophilic catalysts such as Rh2(TFA)4 (TFA =
trifluoroacetate) or the bulkier Rh2(TPA)4 (TPA = triphenylacetate).
The 1,3 C–H carbene insertion is a rare behavior and has
only been observed in structurally rigid diazo compounds,[23] and
to the best of our knowledge, only one report is described for a
freely rotating chain system.[24] We believe that formation of
cyclopropane 4a as single isomer where both carbonyl functions
are in cis disposition, may involve the generation of the reacting
conformation int-3, where the ester at C1 and the propyl
substituent at C3 are displayed in pseudo-axial and pseudo-
equatorial, respectively, to prevent steric clashes. In conformation
int-3 the Rh-carbene and the pseudo-equatorial C–H bond at C3
are in close proximity and that could be explaining the excellent
levels of regio and diastereoselectivity.
This 1,3 C–H insertion also occurred in β-diazocarbonyl
compounds substituted with shorter carbon chains and the
cyclopropanes were generally obtained with high efficiency and
excellent diasteroselectivities (4b-f). However, we observed that
compound 3e substituted with a longer carbon chain led to an
equimolecular ratio of 1,3 and 1,5 C–H insertion products (4g,5).
We rationalized that the use of a bulkier catalysts may hamper the
1,5 C–H insertion and in consequence favors the 1,3 C–H
insertion. In this sense, when we used Rh2(TPA)4, we were
delighted to see a dramatic increment of the ratio in favor of the
1,3 C–H insertion and efficiency of the process (82%, 4f:5
12:1).[25]
After this, we explored substrates containing functionalities
that could potentially intercept the corresponding electrophilic
Rh2-carbene intermediate through well-known transformations
such as alkene cyclopropanation, Buchner reaction, arene C–H
insertions or ylide generation by carbonyl addition. However, we
were glad to not observe those processes and instead, the
exclusive formation of cyclopropanes 4h-j. The latter results
clearly suggest that those processes are unfavored due to the
reacting conformations analogous to int-3 that favors the 1,3 C–
H insertion process. In addition, the use of β-diazocarbonyl
compounds substituted with trifluoromethyl and phosphate group
conducted to valuable cyclopropane rings 4k,l.
On the other hand, β-hydride migration is a well-known
process observed for α-alkyl-substituted α-diazo compounds
under Rh2 catalysis that conducts to olefins. β-hydride migration
can be generally suppressed by the use of sterically demanding
carboxylate ligands in the Rh2 catalyst and low reaction
5
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10.1002/anie.202015077
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RESEARCH ARTICLE
Table 3. Rh-catalyzed stereoselective 1,3 C−H insertion of β-diazocarbonyl compounds 3.[a]
discovery of a 1,3 C-H insertion
R
1,3 C-H insertion
1,5 C-H insertion
CO2Et
O
R
CO2Et
O
CO2Et
N2
O
O
O
O
H
5´
O
(1 mol%)
1
O
Rh
CO2Et
Ph
Rh2
Rh
Ph
O
Ph
H
3
O
CH2Cl2, 0 °C
2 hours
R
H
O
O
Et
5
H
Me
3c
(not observed)
cyclopropane 4a
R
int-3
Rh2 catalyst
1H-NMR yield of 4a
Rh2(OAc)4 R = Me
97% (>20:1)
Rh2(TFA)4 R = CF3
Rh2(TPA)4 R = CPh3
92% (>20:1)
70% (>20:1)
95% isolated yield
cyclopropane scope
Me
O
O
O
O
O
Me
Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
O
Ph
Ph
Ph
Me
Me
Me Me
Me
Me
Me
Cl
4b 72% (>20:1)[b]
4c 72% (>20:1)[b]
4d 91% (>20:1)[b]
4e 52% (>20:1)[b]
4f 91% (19:1)[b]
O
O
CO2Et
CO2Et
O
O
O
O
Ph
Me
Me
Me
Ph
CO2Et
CO2Et
CO2Et
R
+
Ph
Ph
Ph
Ph
Ph
CO2Me
4j 72% (13:1)[c]
Et
Me
4g
5
4h 74% (>20:1)[c]
4i 60% (>20:1)[c]
[x-ray]
4k R = CF3, 89% (>20:1)[c] [x-ray]
4l R = PO(OMe)2 35% (>20:1)[d],[e]
69% (>20:1)
82% (>20:1)
29% (>20:1)
5% (>20:1)
Rh2(OAc)4
Rh2(TPA)4
1,3 C-H insertion vs b-hydride migration
1,2-alkyl shift
O
O
CO2Et
N2
O
O
O
CO2Et
Rh2
H
int-4
O
CO2Et
N2
1 mol % Rh2 catalyst
CH2Cl2, 0 °C, 2 hours
CO2Et
+
Ph
COOEt
Ph
Ph
Ph
Ph
Me
Me
Me
3n
4m
6
Rh2(OAc)4
Rh2(TPA)4
69% (>20:1)
85% (>20:1)
29% (1.4:1)
4% (1:1)
CO2Et
Rh2
3a
Ph
1,3 C-H insertion vs 1,2-alkyl shift
int-6
OH
CO2Et
O
O
Me
O
CO2Et
Me
1 mol % Rh2 catalyst
O
CO2Et
+
N2
CO2Et
Ph
CO2Et
Rh2
CH2Cl2, 0 °C, 2 hours
4n
7
Me
8
int-5
26% (>20:1)
80% (>20:1)
72%
0%
Rh2(OAc)4
Rh2(TPA)4
Rh2(OAc)4
Rh2(TPA)4
72%
81%
3s
[a] See Supporting Information for experimental details. Diastereomeric ratios are shown in parenthesis and were determined by 1H NMR analysis of the crude
reaction mixture. [b] Rh2(OAc)4 was used. [c] Rh2(TPA)4 was used. [d] Rh2(TFA)4 was used. [e] 40% of 3ar was recovered.
After this, we wondered whether we could develop a one-pot
protocol for the synthesis of cyclopropanes 4 from the electrophilic
diazomethylation reaction of silyl enol ethers and the Rh-
catalyzed stereoselective 1,3 C−H insertion. If successful, this
process would avoid the isolation and purification of the
corresponding diazo compound, and that may be of utility when
dealing with sensitive diazo derivatives. We explored this
possibility with silyl enol ether 1c and reagent 2d and found that
cyclopropane 4d could in fact be obtained with excellent efficiency
considering that isolation of diazo intermediate 3c was avoided
(Scheme 3a). For the one-pot protocol, we had to increase the Rh
catalyst loading (2 mol%) and the reaction time in the C–H
insertion process (12 hours) to enable conversion of 3c. This
might be due to the fact that the reaction is carried out in CH3CN
(instead of CH2Cl2), which is known
to
formed
Rh2(OAc)4(CH3CN)2 complexes.[32] Finally, we wanted to exploit
the utility of the Donohoe acyl protecting group in cyclopropane
4c. By using the reported protocol for the synthesis of amides,[18h]
we were pleased to find that 4c could be transformed into
cyclopropyl amide 8 in a reasonable good yield. (Scheme 3b). The
latter result further illustrates the versatility of our new approach
for the synthesis of cyclopropane rings.
6
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10.1002/anie.202015077
Angewandte Chemie International Edition
RESEARCH ARTICLE
2861; c) M. M. Díaz-Requejo, P. J. Pérez, Chem. Rev. 2008, 108, 3379;
d) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110,
704; e) A. Ford, H. Miel, A. Ring, C. N. Slattery, A. R. Maguire, M. A.
McKervey, Chem. Rev. 2015, 11 5, 9981; f) Y. Xia, D. Qiu, J. Wang,
Chem. Rev. 2017, 117, 13810; g) H. M. L. Davies, K. Liao, Nat. Rev.
Chem. 2019, 3, 347.
a
O
Na2CO3, CH3CN
room temperature,
2 hours
OTMS
CO2Et
N2
CO2Et
Ph
TfO
I
Me
Ph
then
Ph
Et
2 mol% Rh2(OAc)4
room temperature
12 hours
[3]
[4]
K. A. Mix, M. R. Aronoff, R. T. Raines, ACS Chem. Biol. 2016, 11, 3233.
For selected examples: a) P. S. Coelho, E. M. Brustad, A. Kannan, F. H.
Arnold, Science 2013, 339, 307; b) Z. J. Wang, H. Renata, N. E. Peck,
C. C. Farwell, P. S. Coelho, F. H. Arnold, Angew. Chem. Int. Ed. 2014,
53, 6810; Angew.Chem. 2014, 126, 6928; c) P. Bajaj, G. Sreenilayam, V.
Tyagi, R. Fasan, Angew. Chem. Int. Ed. 2016, 55,16110; Angew. Chem.
2016, 128, 16344; d) R. K. Zhang, K. Chen, X. Huang, L. Wohlschlager,
H. Renata, F. H. Arnold, Nature 2019, 565, 67.
1c
2
4a 73% (>20:1)
b
Me
O
MeO2C
Ph
O
Br2, CH2Cl2 -20 ºC
then i-Pr2NEt
Me
Me
CO2Et
CO2Et
N
H
Me
Me
Me
9 63% (1:1)
Me
CO2Me
NH2.HCl
room temperature
16 hours
Ph
[5]
[6]
G. Maas, Angew. Chem. Int. Ed. 2009, 48, 8186; Angew. Chem. 2009,
121, 8332
4c
a) K. Liao, S. Negretti, D. G. Musaev, J. Bacsa, H. M. L. Davies, Nature
2016, 533, 230; b) K. Liao, T. C. Pickel, V. Boyarskikh, J. Bacsa, D. G.
Musaev, H. M. L. Davies, Nature 2017, 551, 609; c) K. Liao, Y.-F. Yang,
Y. Li, J. N. Sanders, K. N. Houk, D. G. Musaev, H. M. L. Davies, Nat.
Chem. 2018, 10, 1048; d) J. Fu, Z. Ren, J. Bacsa, D. G. Musaev, H. M.
L. Davies, Nature 2018, 564, 395. See also: e) A. Caballero, E.
Despagnet-ayoub, M. M. Díaz-requejo, A. Díaz-rodríguez, M. E.
González-núñez, R. Mello, B. K. Muñoz, W. Ojo, G. Asensio, M. Etienne,
P. J. Pérez, Science 2011, 332, 835; f) S. F. Zhu, Q. L. Zhou, Natl. Sci.
Rev. 2014, 1, 580; g) L. Liu, J. Zhang, Chem. Soc. Rev. 2016, 45, 506;
h) Ł. W. Ciszewski, K. Rybicka-Jasińska, D. Gryko, Org. Biomol. Chem.
2019, 17, 432.
Scheme 3 One-pot synthesis of cyclopropane 4a (a) and amidation of Donohoe
protecting group (b).
Conclusion
In summary, we have developed a general synthesis of β-
diazocarbonyl compounds by the coupling of readily available
ketone silyl enol ether with hypervalent iodine reagents as
electrophilic diazomethyl sources. The scope of our
diazomethylation reaction has been demonstrated in a broad
range of silyl enol ethers derived from simple ketones, natural
products and drug molecules as well as from different hypervalent
iodine reagents, that permitted to introduce esters, ketones,
phosphate, trifluoromethyl and sulfonate groups. To date, this is
the most general process for the synthesis of this diazo compound
class. In addition, we have proven the synthetic utility of β-
[7]
[8]
[9]
J. Barluenga, G. Lonzi, L. Riesgo, M. Tomás, L. A. López, J. Am. Chem.
Soc. 2011, 133, 18138.
Z. Wang, A. G. Herraiz, A. M. del Hoyo, M. G. Suero, Nature 2018, 554,
86.
Z. Wang, L. Jiang, P. Sarró, M. G. Suero, J. Am. Chem. Soc. 2019, 141,
15509.
[10] For selected reviews of hypervalent iodine reagents: a) V. V. Z. Zhdankin,
P. J.Stang, Chem. Rev. 1996, 66, 243; b) T. Wirth, Hypervalent iodine
chemistry: modern developmentsin organic synthesis, Vol. 224, Springer,
New York, 2003; c) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108,
5299; d) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48,
9052; Angew. Chem. 2009, 121, 9214 e) J. Charpentier, N. Frꢀh, A.
Togni, Chem. Rev. 2015, 115, 650; f) Y. Li, D. P. Hari, M. V. Vita, J.
Waser, Angew. Chem. Int. Ed. 2016, 55, 4436; Angew. Chem. 2016, 128,
4512.
diazocarbonyl compounds by the discovery of
a
new
cyclopropane synthesis enabled by a Rh-catalyzed intramolecular
1,3 C−H insertion, that occurs with excellent diastereoselectivity.
This new synthetic strategy that construct cyclopropane cores
and uses α & β C–H bonds as functional groups in aliphatic
ketones, represent
cyclopropanation process employing α,β-unsaturated carbonyl
a
complementary approach to other
[11] R. Weiss, J. Seubert, F. Hampel, Angew. Chem. Int. Ed. 1994, 33, 1952;
Angew. Chem. 1994, 106, 2038.
compounds.
[12] C. Schnaars, M. Hennum, T. Bonge-Hansen, J. Org. Chem. 2013, 78,
7488.
[13] M. T. Taylor, J. E. Nelson, M. G. Suero, M. J. Gaunt, Nature 2018, 562,
563.
Acknowledgements
[14] R. Zhao, L. Shi, Angew. Chem. Int. Ed. 2020, 59, 12282; Angew.Chem.
2020, 132, 12378.
We thank ICIQ and the Agencia Estatal de Investigación (AEI) of
the Ministerio de Ciencia e Innovación (CTQ2016-75311-P,
[15] a) K. Chen, G. F. Koser, J. Org. Chem. 1991, 56, 5764; b) M. V. Vita, J.
Waser, Org. Lett. 2013, 15, 3246; c) M. Pushpak, W. Thomas, Angew.
Chem. Int. Ed. 2014, 53, 5993; Angew.Chem. 2014, 126, 6103; d) Y.
Kobayashi, S. Masakado, Y. Takemoto, Angew. Chem. Int. Ed. 2018, 57,
693; Angew.Chem. 2018, 130, 701.
PID2019-104101GB-I00, FEDER-EU
&
Severo Ochoa
Excellence Accreditation 2020-2023 -CEX2019-000925-S) for
financial support. We also thank the European Union for a Marie
Skłodowska-Curie Individual Fellowship (794815) (to L.J.), a
Marie Curie-COFUND postdoctoral fellowship (to Z.W.) and La
Caixa Foundation for a ICIQ Summer Fellowship (to M.A.). Pau
Sarró is gratefully acknowledged for proofreading.
[16] Reagent 2d must be stored at –30 ºC (–20 ºC possible) to prevent
decompositions over the time but can be handle at room temperature.
We have never observed any explosion when making or working with 2d
at the scale indicated. DCS analysis of reagent 2d is provided in the
Supporting Information.
[17] Recently, the group of Brewer have reported the synthesis of diazo
compounds with achiral β quaternary centers: J. Fang, E. M. Howard, M.
Brewer, Angew. Chem. Int. Ed. 2020, 59, 12827; Angew. Chem. 2020,
132, 1292.
Keywords: diazo compounds • hypervalent iodine reagents •
Rh-carbenes • cyclopropanes • C–H insertion
[18] a) J. R. Frost, C. B. Cheong, W. M. Akhtar, D. F. J. Caputo, N. G.
Stevenson, T. J. Donohoe, J. Am. Chem. Soc. 2015, 137, 15664; b) W.
M. Akhtar, C. B. Cheong, J. R. Frost, K. E. Christensen, N. G. Stevenson,
T. J. Donohoe, J. Am. Chem. Soc. 2017, 139, 2577; c) W. M. Akhtar, R.
[1]
[2]
T. Curtius, Ber. Dtsch. Chem. Ges. 1883, 16, 2230.
For selected reviews: a) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998,
98, 911; b) H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103,
7
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RESEARCH ARTICLE
J. Armstrong, J. R. Frost, N. G. Stevenson, T. J. Donohoe, J. Am. Chem.
Soc. 2018, 140, 11916; d) D. S. Chung, J. S. Lee, H. Ryu, J. Park, H.
Kim, J. H. Lee, U. Bin Kim, W. K. Lee, M. H. Baik, S. gi Lee, Angew.
Chemie. Int. Ed. 2018, 57, 15460; Angew. Chemie. 2018, 130, 15686; e)
R. J. Armstrong, W. M. Akhtar, T. A. Young, F. Duarte, T. J. Donohoe,
Angew. Chemie. Int. Ed. 2019, 58, 12558; Angew. Chem. 2019,
131,12688; f) D. M. J. Cheang, R. J. Armstrong, W. M. Akhtar, T. J.
Donohoe, Chem. Commun. 2020, 56, 3543; g) C. B. Cheong, J. R. Frost,
T. J. Donohoe, Synlett. 2020, 31, 1824; h) S. Wꢀbbolt, C. B. Cheong, J.
R. Frost, K. E. Christensen, T. J. Donohoe, Angew. Chem. Int. Ed. 2020,
59, 11339; Angew. Chem. 2020, 132, 11435.
P. Antonchick, Angew. Chem. Int. Ed. 2015, 54, 14845; Angew. Chem.
2015, 127, 15058; k) Z.-Z. Zhang, Y.-Q. Han, B.-B. Zhan, S. Wang, B.-F.
Shi, Angew. Chem. Int. Ed. 2017, 56, 13145; Angew. Chem. 2017, 129,
13325; l) A. Clemenceau, P. Thesmar, M. Gicquel, A. Le Flohic, O.
Baudoin, J. Am. Chem. Soc. 2020, 142, 15355.
[30] M. Gulías, J. L. Mascareñas, Angew. Chem. Int. Ed. 2016, 55, 11000;
Angew. Chem. 2016,128, 11164.
[31] For selected examples of cyclopropanation of α,β-unsaturated
carbonyls: a) E. J. Corey, M.Chaykovsky, J. Am. Chem. Soc. 1965, 87,
1353; b) R. K. Kunz, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
3240; c) C. D. Papageorgiou, M. A. Cubillo De Dios, S. V. Ley, M. J.
Gaunt, Angew. Chemie. Int. Ed. 2004, 43, 4641; Angew.Chem. 2004,
116, 4741; d) Y. Chen, J. V. Ruppel, X. P. Zhang, J. Am. Chem.
Soc. 2007, 129, 12074; e) H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am.
Chem. Soc. 2007, 129, 10886; f) S. L. Riches, C. Saha, N. F. Filgueira,
E. Grange, E. M. McGarrigle, V. K. Aggarwal, J. Am. Chem.
Soc. 2010, 132, 7626; g) L. Gao, G. S. Hwang, D. H. Ryu, J. Am. Chem.
Soc. 2011, 133, 20708; h) H. Wang, D. M. Guptill, A. Varela-Alvarez, D.
G. Musaev, H. M. L. Davies, Chem. Sci. 2013, 4, 2844; i) V. N. G.
Lindsay, D. Fiset, P. J. Gritsch, S. Azzi, A. B. Charette, J. Am. Chem.
Soc. 2013, 135, 1463.
[19] T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem.
Soc. Rev. 2016, 45, 546.
[20] An SN2-type mechanism has been also proposed with alkenyliodonium
reagents: M. Ochiai, S. Yamamoto, K. Sato, Chem. Commun. 1999,
1363.
[21] A reaction carried out with 1a and 2d in the presence of TEMPO (1.1
equiv.) under the standard conditions led to 3a in 77% isolated yield.
TEMPO adducts formed from a radical radical coupling were not
detected (GC/MS; NMR). Since TEMPO had not influence in the reaction
outcome, a radical pathway seems to be unlikely.
[22] a) D. F. Taber, R. E. Ruckle, J. Am. Chem. Soc. 1986, 108, 7686; b) M.
P. Doyle,L. J. Westrum, W. N. E. Wolthuis, M. M. See, W. P. Boone, V.
Bagheri, M. M. Pearson, J. Am. Chem. Soc. 1993, 115, 958; c) D. F.
Taber, K. K. You, A. L. Rheingold, J. Am. Chem. Soc. 1996, 118, 547.
[23] a) P. Yates, S. Danishefsky, J. Am. Chem. Soc. 1962, 84, 879. b) J.
Wrobel, K. Takahashi, V. Honkan, G. Lannoye, J. M. Cook, S. H. Bertz,
J. Org. Chem. 1983, 48, 139.
[32] a) V. M. Miskowski, W. P. Schaefer, B. Sadeghi, B. D. Santarsiero, H. B.
Gray, Inorg. Chem. 1984, 23, 1154; b) J. W. Trexler, A. F. Schreiner, F.
Albert Cotton, Inorg. Chem. 1988, 27, 3265; c) E. Warzecha, T. C. Berto,
C. C. Wilkinson, J. F. Berry, J. Chem. Educ. 2019, 96, 571.
[24] The group of Jianbo Wang observed a preferential 1,3 C-H carbene
insertion with β-tosyl α-diazocarbonyl compounds under Rh(II) catalysis.
The authors hypothesized that the intramolecular 1,3 C-H insertion is
likely to be due to conformational factors and the inhibition of the 1,2-
hydride migration may be due to the strongly electron-withdrawing tosyl
group. W. Shi, B. Zhang, J. Zhang, B. Liu, S. Zhang, J. Wang, Org. Lett.
2005, 7, 3103.
O
S
Ar
CO2Et
N2
O
S
1 mol %
Rh2(TFA)4
CO2Et
+
Ar
1
O
S
CO2Et
Me
O
Ar
O
3
DCE
75% yield
86:14
O
Me
5
Me
major
minor
Ar = pMe-C6H4
[25] For more experiments using other Rh(II) catalysts, see the Supporting
Information.
[26] A. DeAngelis, R. Panish, J. M. Fox, Acc. Chem. Res. 2016, 49, 115.
[27] For examples of ring-expansion of diazo compounds under metal
catalysis, see: a) H. Xu, W. Zhang, D. Shu, J. B. Werness, W. Tang,
Angew. Chem. Int. Ed. 2008, 47, 8933; Angew. Chem. 2008, 120, 9025.
b) S. Chen, Y. Zhao, J. Wang, Synthesis 2006, 2, 1705; c) A. M. Jadhav,
V. V. Pagar, R. S. Liu, Angew. Chem. Int. Ed. 2012, 51, 11809; Angew.
Chem. 2012, 124, 11979.
[28] For selected reviews in cyclopropane synthesis: a) H. Lebel, J. F.
Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977. b) C.
Ebner and E. M. Carreira, Chem. Rev. 2017, 117, 11651. c) W. Wu, Z.
Lin, H. Jiang, Org. Biomol. Chem. 2018, 16, 7315. d) A. G. Herraiz, M. G.
Suero, Synthesis 2019, 51, 2821.
[29] For examples of cyclopropane ring formation using one C–H bond: a) Y.
Oonishi, Y. Kitano, Y. Sato, Angew. Chem. Int. Ed. 2012, 51, 7305;
Angew. Chem. 2012, 124, 7417; b) J. Mao, S. Q. Zhang, B. F. Shi, W.
Bao, Chem. Commun. 2014, 50, 3692; c) T. Piou, T. Rovis, J. Am. Chem.
Soc. 2014, 136, 11292; d) W. Du, Q. Gu, Z. Li, D. Yang, J. Am. Chem.
Soc. 2015, 137, 1130; e) C. M. Weinstein, G. P. Junor, D. R. Tolentino,
R. Jazzar, M. Melaimi, G. Bertrand, J. Am. Chem. Soc. 2018, 140, 9255;
f) T. Piou, F. Romanov-Michailidis, M. A. Ashley, M. Romanova-
Michaelides, T. Rovis, J. Am. Chem. Soc. 2018, 140, 9587; g) C.
Duchemin, N. Cramer, Chem. Sci. 2019, 10, 2773. For examples of
cyclopropane ring formation using two C–H bonds: h) R. Giri, M. Wasa,
S. P. Breazzano, J. Q. Yu, Org. Lett. 2006, 8, 5685; i) P. Cotugno, A.
Monopoli, F. Ciminale, A. Milella and A. Nacci, Angew. Chem. Int. Ed.,
2014, 53, 13563; Angew. Chem. 2014, 126, 13781; j) S. Manna and A.
8
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Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Insert graphic for Table of Contents here.
O
CO2Et
N2
OTMS
Na2CO3, CH3CN
CO2Et
N2
Ph
+
TfO
I
room temperature
2 hours
Ph
Ph
Me
Me
71% yield
hypervalent I(III) reagent
b-diazocarbonyl
compound
silyl enol ether
O
CO2Et
Ph
1 mol % Rh2(OAc)4
cyclopropane
CH2Cl2
2 hours, 0 °C
Me
95% yield dr >20:1
exclusive 1,3 C-H insertion
Text for Table of Contents here: A general synthesis of underexploited β-diazocarbonyl compounds has been developed by the
electrophilic diazomethylation of silyl enol ethers. The synthetic utility of β-diazocarbonyl compounds was demonstrated with the
discovery of a cyclopropane synthesis enabled by an unusual Rh-catalyzed intramolecular 1,3 C−H insertion.
Institute and/or researcher Twitter usernames: @MarcosGSuero
9
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