Copper-catalyzed oxyvinylation of diazo compounds

Article abstract of DOI:10.1021/acs.orglett.0c01150

A copper(I)-catalyzed vinylation of diazo compounds with vinylbenziodoxolone reagents (VBX) as partners is reported. The transformation tolerates diverse functionalities on both reagents delivering polyfunctionalized vinylated products. The strategy was successfully extended to a three-component/intermolecular version with alcohols. The obtained products contain synthetically versatile functional groups, such as an aryl iodide, an ester, and an allylic leaving group, enabling further modification.

Full text of DOI:10.1021/acs.orglett.0c01150

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Letter
Copper-Catalyzed Oxyvinylation of Diazo Compounds
Guillaume Pisella, Alec Gagnebin, and Jerome Waser*
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ABSTRACT: A copper(I)-catalyzed vinylation of diazo compounds with
vinylbenziodoxolone reagents (VBX) as partners is reported. The trans-
formation tolerates diverse functionalities on both reagents delivering
polyfunctionalized vinylated products. The strategy was successfully extended
to a three-component/intermolecular version with alcohols. The obtained
products contain synthetically versatile functional groups, such as an aryl
iodide, an ester, and an allylic leaving group, enabling further modification.
etal carbenes obtained from diazo compounds have been
relationship between the nucleophile and the vinyl group. We
considered a reverse approach to develop an unprecedented 1,1-
oxyvinylation: Addition of an oxygen nucleophile first, followed
by reaction with an electrophilic hypervalent iodine vinylation
reagent (Scheme 1C). Our group established an efficient
copper-catalyzed 1,1-oxyalkynylation of diazo compounds based
on the use of electrophilic ethynylbenziodoxolone (EBX)
hypervalent iodine reagents.8,9 To develop the first direct
vinylation of diazo compounds, we envisaged the use of the
corresponding vinylbenziodoxolone (VBX) reagents recently
reported by Olofsson and co-workers.10
In this work, we report a copper-catalyzed insertion of diazo
compounds into VBX reagents proceeding with broad scope at
room temperature. The transformation was successfully
extended to the synthesis of allylic ethers using alcohols as
external nucleophiles.
M
extensively used in synthetic chemistry,1 and their gem-
difunctionalization is a powerful method to access complex
products (Scheme 1A).2 The formation of at least one new C−C
bond in this process has been realized for alkylation, arylation
and alkynylation reactions using palladium,3 copper4 and
rhodium5 catalysis. The most successful approaches involve
cross-coupling through carbene migratory insertion (path a),2b
or trapping of transient ylides with carbon electrophiles (path
b).2a
The introduction of an olefin in such processes has been
limited to the formation of a C-alkenyl and a C−H bond,6 with
the exception of a palladium-catalyzed cross-coupling combin-
ing vinylhalides and nucleophiles (Scheme 1B).7 The reaction
proceeds via a π-allyl palladium species, resulting in a 1,3
Scheme 1. General Difunctionalization of Metal Carbenes
(A) and Vinylation of Diazo Compounds (B and C)
We started our optimization by reacting Ph-VBX (1a) with
ethyl diazoacetate (2a) (Table 1; see the Supporting
Information for other tested conditions, Table S1). No desired
product was isolated without copper catalyst or ligand (entries 1
and 2). Allylic ester 4a was formed in 90% yield when
Cu(CH3CN)4BF4 (4 mol %) was used in combination with
diimine 3a (5 mol %) (entry 3).8a A lower yield was obtained
with more electron-rich VBX 1c (entry 4). No reaction occurred
using the alkyl-substituted substrate 1j even at a higher
temperature (entry 5). We therefore investigated bisoxazoline
(BOX) ligands, which had also been successful in our previous
work.8b Using tBu-BOX ligand 3b, the reaction could be
performed in one hour at room temperature to give 4a in 95%
yield as a racemate (entry 6). The nonchiral ligand 3c gave a
similar result (entry 7). These conditions performed well with
Received: March 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01150
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Table 1. Optimization of the Insertion of Diazo Compounds 2a and 2b into VBX (1)
b
entry
ligand
diazo R1 =
VBX R2 =
product
temp
time
yield
c
1
3a
none
3a
3a
3a
3b
3c
3c
3c
3c
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Ph (2b)
Ph (2b)
Ph (1a)
Ph (1a)
Ph (1a)
PMP (1c)
Cy (1j)
Ph (1a)
Ph (1a)
PMP (1c)
Cy (1j)
Ph (1a)
Ph (1a)
4a
4a
4a
4b
4j
4a
4a
4b
4j
40 °C
40 °C
40 °C
60 °C
60 °C
25 °C
25 °C
25 °C
25 °C
40 °C
40 °C
4 h
4 h
4 h
24 h
24 h
1 h
1 h
4 h
4 h
4 h
0%
<5%
90%
50%
<5%
95%
95%
81%
99%
<5%
2
3
4
5
6
d
7
d
8
d
9
10
11
5a
5a
3a
4 h
b
80%
c
a
Reactions on 0.10 mmol scale with 2.0 equiv of 2, 4 mol % Cu(CH3CN)4BF4, 5 mol % ligand in DCE (0.04 M). Isolated yields. Without
Cu(CH3CN)4BF4. On 0.20 mmol scale. Ph = phenyl, Cy = cyclohexyl, PMP = para-methoxyphenyl.
d
a
a
Scheme 2. Scope of VBX Reagents
Scheme 3. Scope of Diazo Compounds 2
a
Reactions using Ph-VBX (1a) (0.2 mmol) and 2 (0.4 mmol) in DCE
b
c
(0.04 M). 3c as ligand at 25 °C. 3a as ligand at 40 °C.
(entry 10). Product 5a could be obtained in 80% yield using
ligand 3a (entry 11). In all reactions, only the E-olefin was
obtained.
Diverse aryl-substituted VBXs were then explored with ethyl
diazoacetate (2a) (Scheme 2A).11 Electron donating ether and
alkyl groups on the arene afforded products 4b,c in 81% and 92%
yields, respectively. Fluorinated compounds 4d and 4e were
obtained in 72% and 66% yields, respectively. A naphthyl-
substituted VBX led to the formation of 4f in 81% yield. A
slightly diminished yield was obtained for thiophene-substituted
4g (76% yield). Both electron-rich and -poor substituents on the
benziodoxolone backbone were tolerated, affording 4h and 4i.
Next, we turned our attention to alkyl-substituted VBX reagents
(Scheme 2B). VBXs bearing aliphatic chains (Cy, Bn, and nPr)
a
Reactions using VBX 1 (0.2 mmol) and 2a (0.4 mmol) in DCE
(0.04 M).
the more electron-rich and aliphatic substrates (entries 8 and 9),
but were not successful for substituted diazo compound 2b
B
https://dx.doi.org/10.1021/acs.orglett.0c01150
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a
Scheme 4. Extension to Three-Component Reaction
Scheme 5. Scale-up Synthesis and Product Modifications
a
Reaction conditions: (a) LiAlH4 (3.00 equiv), THF, 0 °C to rt, 1 h,
91%; (b) DBU (10 equiv), MeOH, 50 °C, 6 h, 93%; (c) allyl-TMS
(1.5 equiv), TiCl4 (1.05 equiv), DCM, 0 °C, 15 min, 83%; (d)
propargyl-TMS (2.0 equiv), TiCl4 (1.05 equiv), DCM, −78 to 0 °C,
59%; (e) TMSN3 (1.5 equiv), TiCl4 (1.05 equiv), DCM, −20 to 0 °C,
12/12′ 70:30, 86%; (f) methyl acrylate (5.0 equiv), PdCl2(PPh3)3 (5
mol %), PPh3 (5 mol %), Et3N, 80 °C, 24 h, 66%; (g) H2, Pd/C (10
mol %, 10% w/w), DABCO (10 equiv), MeOH, rt, 10 min, 77%; (h)
fac-Ir(ppy)3 (2.5 mol %), NBu3 (10 equiv), HCO2H (10 equiv), blue
LED, MeCN, 40 °C, 18 h, 82%.
a
Reactions using VBX (1v−z) (0.3 mmol) and R3OH (0.9 mmol) in
DCM (0.075 M). Diazo 2 (0.6 mmol, 0.6 M in DCM) added via
syringe pump over 1 h.
provided allylic esters 4j−l in 90−99% yield. The incorporation
of an ester (4m) or a chloride (4n) group could also be achieved.
Trisubstituted alkene 4o was accessed in 97% yield. VBXs with
amines, silyl ethers, and chlorides in the allylic position delivered
the corresponding products 4p−r. A lower yield was obtained
for 4p and 4r, maybe due to the low solubility of the
corresponding VBX reagents in DCE. π-Conjugated systems
were readily incorporated (Scheme 2C). An isoprene skeleton
was introduced to give 4s in 82% yield. Conjugated diene 4t and
enyne 4u were also successfully synthesized.
We next investigated the scope of the acceptor substituent on
the diazo compounds (Scheme 3A). Various esters such as tBu
or BHT were tolerated giving 5b and 5c in quantitative yield.12
Product 5d bearing a benzyl group was obtained in 92% yield
and 5e with an allyl group in 91%. 2-Diazo-N,N-diethylaceta-
mide provided 5f in 94% yield. Weinreb amide derivative 5g was
isolated in 99% yield. Sulfonate- and phosphonate-diazo
compounds were efficient coupling partners, generating
products 5h and 5i in quantitative yields.13 Unfortunately,
diazoketones underwent degradation through Wolff rearrange-
ment (5j) and no conversion was obtained using trimethylsi-
lyldiazomethane (5k, 0% yield). However, compound 5l
incorporating a trifluoromethyl group was isolated in
quantitative yield. Organofluorine compounds are important
for the pharmaceutical, agrochemical, and materials industries.14
Other less stable diazo compounds lacking an electron-
withdrawing group were not yet investigated. Finally, the
reaction of disubstituted diazo compounds was investigated
using diimine ligand 3a (Scheme 3B). Products 5a and 5m with
tertiary allylic centers were formed in 71 and 89% yield. A
second electron-withdrawing group suppressed the reactivity
(5n, 0% yield). A cyclic diazo compound afforded the desired
product 5o in 90% yield. Diene product 5p could be obtained in
good yield when starting from a vinyl diazo precursor. Attack of
the nucleophile at the vinylogous center was favored.15
We then investigated an enantioselective version of the
reaction. Testing various substrates, chiral ligands, and reaction
conditions, we achieved a maximum of 75:25 er with ligand 3d
for the formation of 5c (see Table S3 for details).16 Interestingly,
1
with tert-amyl alcohol as the cosolvent, we observed H NMR
signals tentatively assigned to allylic ether product 6a in the
crude reaction mixture, in addition to expected 4a for the
reaction of VBX 1a and 2a (Scheme 4A).
To favor the three-component reaction, we used less
nucleophilic bis-trifluoromethyl benziodoxole VBX 1′ and
removed the ligand (see Table S2 for details).17 With 3 equiv
of alcohol, the three-component products were obtained in 23−
72% yield (Scheme 4B). Primary, secondary, and tertiary
alcohols were combined with different VBXs and diazo
compounds leading to functionalized allylic ethers bearing
esters (6b, 6c, and 6e), phosphonate (6d), chloride (6f), furan
(6c), indanyl (6e), adamantyl (6c), or trifluoromethyl (6e and
6f) groups. The vinylation of cholesterol was achieved in 61%
yield affording 6g with a trifluoromethyl and a phthalimide
group.
Product 4a was synthesized on the 2.0 mmol scale using a
lower catalyst loading at higher concentration (Scheme 5A).
The ester groups in 4a were readily reduced with LiAlH4 to
produce diol 8 (Scheme 5B). Butenolide 9 resulting from the
formation of an α-keto ester followed by dimerization was
formed under basic conditions. Treatment of 4a with TiCl4 and
C
https://dx.doi.org/10.1021/acs.orglett.0c01150
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Letter
allyl-TMS led to the formation of conjugated ester 10.
Propargyl-TMS could also be used as nucleophile giving
allene-containing product 11. The introduction of an azide
was accomplished using TMSN3 to form 12, which isomerizes
spontaneously.18 A Heck reaction between 5m and methyl
acrylate afforded 13 in 66% yield. Hydrogenolysis of the
iodoarene was achieved with hydrogen and poisoned Pd/C to
give product 14 in 77% yield. Visible light photoredox catalysis
gave access to the deiodinated product 15 in 82% yield with E to
Z isomerization of the olefin.
Based on literature precedence and our work on the copper-
catalyzed oxy-alkynylation reaction,8a−c a tentative reaction
mechanism would involve an electrophilic copper-carbene
generated from the diazo compound (see Scheme S1 in the
Supporting Information). Nucleophilic attack of the carboxylate
part of the VBX reagent or the alcohol nucleophile would
generate an ylide intermediate, which is then vinylated.
In summary, we have developed a copper-catalyzed insertion
of diazo compounds into vinylbenziodoxolone (VBX) reagents.
The transformation provides access to a broad scope of
functionalized allylic esters.19 Extension of the strategy to a
three-component reaction with alcohol nucleophiles allowed the
synthesis of structurally diverse allylic ethers. The obtained
products can be further modified to give important building
blocks. Ongoing research is focused on the elucidation of the
reaction mechanism and the development of the asymmetric
version of the transformation based on our preliminary results.
Alec Gagnebin − Laboratory of Catalysis and Organic Synthesis,
́
Institut des Sciences et Ingenierie Chimique, Ecole Polytechnique
́
́
Federale de Lausanne, CH-1015 Lausanne, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01150
Notes
The authors declare no competing financial interest.
Raw NMR, IR, and MS data is available at zenodo.org, DOI:
10.5281/zenodo.3764827.
ACKNOWLEDGMENTS
■
We thank ERC (European Research Council, Starting Grant
iTools4MC, Number 334840) and the Swiss National Science
Foundation (SNSF, Grant 200020_182798). We thank Dr. R.
Scopelliti and Dr. F. F. Tirani from ISIC at EPFL for X-ray
analysis. We thank Dr. Durga Prasad Hari (University of Bristol)
for insightful discussions during the project.
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The Supporting Information is available free of charge at
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Supplementary tables (Tables S1 and S2: details for
optimization of the reactions, Table S3: attempts towards
an enantioselective reaction), and scheme (Scheme S1:
proposal for the reaction mechanism), experimental
procedures, and characterization data (NMR, IR, MS,
X-ray) (PDF)
Accession Codes
CCDC 1993681 and 1897009 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Corresponding Author
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Jerome Waser − Laboratory of Catalysis and Organic Synthesis,
́
Institut des Sciences et Ingenierie Chimique, Ecole Polytechnique
́
́
Federale de Lausanne, CH-1015 Lausanne, Switzerland;
orcid.org/0000-0002-4570-914X; Email: jerome.waser@
epfl.ch
Authors
Guillaume Pisella − Laboratory of Catalysis and Organic
́
Synthesis, Institut des Sciences et Ingenierie Chimique, Ecole
́
́
Polytechnique Federale de Lausanne, CH-1015 Lausanne,
Switzerland
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(16) This result contrasts with the excellent er obtained in the
corresponding alkynylation using a very similar catalyst system.
Nevertheless, this is not so surprising, considering that the geometries
of the alkenyl and the alkynyl reagents, as well as in a lesser measure
E
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their reactivity, are very different, leading to different interactions with
the ligands in the transition state. Obviously, another type of ligand will
be needed to achieve high enantioinduction in this case.
(17) This approach was also successful for the development of the first
three-component oxylalkynylation of diazo compounds (ref 8c).
(18) Sawama, Y.; Nagata, S.; Yabe, Y.; Morita, K.; Monguchi, Y.; Sajiki,
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(19) This part of the work has previously appeared in a preprint:
Pisella, G.; Gagnebin, A.; Waser, J. Copper-Catalyzed Insertion of
Diazo Compounds into Vinyl Hypervalent Iodine Reagents to
Generate Allylic Esters. ChemRxiv, March 2, 2019, ver. 1,
DOI: 10.26434/chemrxiv.7892513.v1.
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