Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds with Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/jacs.6b00278

Alkynes have found widespread applications in synthetic chemistry, biology, and materials sciences. In recent years, methods based on electrophilic alkynylation with hypervalent iodine reagents have made acetylene synthesis more flexible and efficient, but they lead to the formation of one equivalent of an iodoarene as side-product. Herein, a more efficient strategy involving a copper-catalyzed oxy-alkynylation of diazo compounds with ethynylbenziodoxol(on)e (EBX) reagents is described, which proceeds with generation of nitrogen gas as the only waste. This reaction is remarkable for its broad scope in both EBX reagents and diazo compounds. In addition, vinyl diazo compounds gave enynes selectively as single geometric isomers. The functional groups introduced during the transformation served as easy handles to access useful building blocks for synthetic and medicinal chemistry.

Full text of DOI:10.1021/jacs.6b00278

Communication
pubs.acs.org/JACS
Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds with
Hypervalent Iodine Reagents
Durga Prasad Hari and Jerome Waser*
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Fed
Lausanne, Switzerland
́ ́
erale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015
S
* Supporting Information
Scheme 1. Alkynylation Strategies and Multicomponent
Reactions Using Diazo Compounds
ABSTRACT: Alkynes have found widespread applica-
tions in synthetic chemistry, biology, and materials
sciences. In recent years, methods based on electrophilic
alkynylation with hypervalent iodine reagents have made
acetylene synthesis more flexible and efficient, but they
lead to the formation of one equivalent of an iodoarene as
side-product. Herein, a more efficient strategy involving a
copper-catalyzed oxy-alkynylation of diazo compounds
with ethynylbenziodoxol(on)e (EBX) reagents is de-
scribed, which proceeds with generation of nitrogen gas
as the only waste. This reaction is remarkable for its broad
scope in both EBX reagents and diazo compounds. In
addition, vinyl diazo compounds gave enynes selectively as
single geometric isomers. The functional groups intro-
duced during the transformation served as easy handles to
access useful building blocks for synthetic and medicinal
chemistry.
he carbon−carbon triple bond is among the most valuable
Tfunctional groups in organic chemistry because of its
versatile reactivity.1 Alkynes are broadly applied as chemical
building blocks for the synthesis of fine chemicals.2 In past years,
they have also gained a lot of interest for applications in
biochemistry or material sciences.1,3 As a result of this growing
importance of alkynes, developing more efficient and versatile
methods for their synthesis is of fundamental importance.
Alkynes are often accessed by the addition of acetylides on
electrophilic positions of molecules.4 However, introducing triple
bonds only to electrophilic positions strongly limits the flexibility
and efficiency of alkyne synthesis. Major efforts have therefore
been made to develop electrophilic alkynylation methods, relying
on the umpolung of the innate reactivity of acetylenes (Scheme
1A).5
Hypervalent iodine reagents such as alkynyliodonium salts
have been particularly successful for the electrophilic alkynylation
of nucleophiles.6 However, the use of alkynyliodonium salts is
limited due to their low stability. Recently, ethynylbenziodoxol-
(on)es (EBX)7a,b have been introduced as excellent electrophilic
reagents for the alkynylation of ketoesters,7c thiols,7d and
aromatic C−H bonds using transition metal catalysis,7e−g
among many other successful transformations.7h Nevertheless,
the developed methods are often restricted to the transfer of one
type of acetylenes (either silyl-, aryl-, or alkyl- substituted).
Furthermore, 2-iodobenzoic acid is usually obtained as a
stoichiometric byproduct after alkynylation, resulting in low
atom economy.8 Recently, Greaney and co-workers9a and
Dauban and co-workers9b reported more atom economical
transformations based on the use of the formed aryl iodides in
cross-coupling reactions with aryliodonium salts and PhI(OPiv)2,
respectively. With EBX reagents, progress in this area has been
limited to a report of Yoshikai and co-workers on the palladium-
catalyzed reaction of imines with alkynylbenziodoxolones to give
furan derivatives.10
To develop more efficient transformations with EBX reagents,
we intended to make use of the nucleophilic properties of the
formed iodobenzoate side products. In this context, metal
carbene species are interesting reactive intermediates, as they
display both nucleophilic and electrophilic reactivity on a single
carbon atom and can be easily generated from α-diazo carbonyl
compounds.11 They have been used in a broad range of
transformations such as X−H bond insertions, cyclopropanation,
ylide formation, and 1,2- migration reactions and have been
successfully applied in total synthesis.12 Recently, research in the
area has focused on the development of multicomponent
reactions to afford products with high structural diversity,
complexity, and atom economy (Scheme 1B).13 The only
Received: January 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b00278
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Journal of the American Chemical Society
Communication
approach for the synthesis of alkynes from diazo compounds has
been reported by Wang and co-workers for a reaction involving
metal carbene migratory insertion with nucleophilic alkynes.14
We envisioned a different strategy making use of the carboxylate
of the EBX reagent as a nucleophile, and the alkyne as an
electrophile.
Herein, we report the successful implementation of this
strategy, resulting in a highly efficient and atom economical oxy-
alkynylation of diazo compounds under mild conditions using a
nonexpensivecoppercatalyst(Scheme1C). Thereactionexhibits
a broad scope toward both diazo compounds and EBX-reagents
and tolerates many functional groups. It provides access to both
secondary and tertiary propargylic alcohol derivatives and can be
used for the synthesis of silyl-, aryl-, and alkyl-substituted
acetylenes. The iodine atom, the ester, and the triple bond of
the product can serve as versatile handles for further trans-
formations. Interestingly, whenvinyldiazo compounds wereused
as starting materials, only 1,4-addition to give enynes was
observed.
in60%yieldwhentheconcentrationofthereactionwasdecreased
to 0.05 M (Table 1, entry 11). Finally, a major improvement was
obtained when using 2.5 mol % of 1,2 diimine 4a as ligand:15 the
yield increased to 86% and the reaction could be performed at
room temperature (Table 1, entry 12). In contrast, the reaction
did not take place when using 1,10-phenanthroline (4b) as ligand
(Table 1, entry 13). In the absence of Cu(CH3CN)4BF4, no
product was obtained, demonstrating that the copper catalyst is
necessary for the reaction (Table 1, entry 14).
The scope of the reaction was first examined using TIPS-EBX
(2a) and a variety of α-diazo compounds (Figure 1A). tert-Butyl
and benzyl diazoacetates provided the oxy-alkynylation products
3b and 3c in high yields. The transformation was also successful
fordisubstituteddiazocompounds,leadingtoproducts3d−fwith
tertiary propargylic centers. Noteworthy, a cyclic diazo
compound also afforded the desired product 3g in 80% yield.
Derivatives of α-hydroxy-alkynyl lactones are present in
pharmaceutical molecules16 but have never been synthesized
directly from lactones to the best of our knowledge. In addition to
α-diazo esters, several other diazo compounds including 2-diazo-
N,N-diethylacetamide, ethyl diazomethanesulfonate, and diethyl
(diazomethyl)phosphonate underwent the desired transforma-
tion in good to high yields (products 3h−j). We then turned our
attention to the scope of R-EBX reagents (Figure 1B). Electron-
donating and -withdrawing groups were well tolerated on the aryl
ring of TIPS-EBX (2a) (products 3k−m). EBX reagents bearing
aryl substituents on the alkyne worked efficiently in this
transformation, giving products 3n−p in 80−84% yield. Bro-
mide-substituted product 3p, which is useful for further chemical
transformations, could be isolated in 83% yield. Several aliphatic
EBXreagents bearingfunctionalgroups suchas achloro, anazido,
and an ether also gave the desired products in moderate to high
yields (products 3q−t). A cyclopropyl derived EBX reagent can
also be used in this reaction (product 3u). A TMS-alkyne
substituted EBX reagent gave product 3v in 75% yield. In
addition, ethyl 2-diazopropanoate can also be oxy-alkynylated
successfully with aryl-substituted EBX reagents to furnish
products 3w and 3x with tertiary propargylic centers in 78%
and 72% yield, respectively.
Next, the developed method was applied to the oxy-
alkynylation of vinyl diazo compounds (Figure 1C). Controlling
the selectivity in the reaction of nucleophiles with vinyl diazo
compounds is challenging, as they display electrophilic reactivity
at both the carbenoid and the vinylogous center.17 Gratifyingly,
only vinylogous product 6a was obtained as a single geometric
isomer when using (E)-methyl 2-diazopent-3-enoate (5a) with
TIPS-EBX (2a). We were pleased to see that (E)-methyl 2-
diazohex-3-enoate (5b) and cyclic diazo compounds 5c and 5d
could be used to give the desired vinylogous products 6b, 6c, and
6d in good to high yields.18 Various R-EBX reagents were then
examined. TIPS-EBX reagents having substituents on the
aromatic ring led to the desired products 6e and 6f in high yields.
The reaction was also successful with aryl-substituted EBX
reagents, and products 6g and 6h were obtained in 82% and 75%
yield, respectively. Substituents containing a long alkyl chain, a
chloro, and a cyclopropyl functional group were well tolerated in
this reaction (products 6i−k). A TMS-alkyne substituted EBX
reagent gave the vinylogous product 6l in 72% yield.
We first attempted the oxy-alkynylation of ethyl diazoacetate
(1a)with1-[(triiso-propylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-
one (TIPS-EBX, 2a) using 5 mol % of Rh2(OAc)4 in DCM at 40
°C, but did not obtain the desired product 3a (Table 1, entry 1).
a
Table 1. Optimization of the Reaction Conditions
entry
catalyst (×mol %)
solvent (conc.) time/T (°C) yield
1
2
3
4
5
6
7
8
Rh2(OAc)4 (5.0)
DCM (0.1 M)
DCM (0.1 M)
DCM (0.1 M)
DCM (0.1 M)
DCM (0.1 M)
DCM (0.1 M)
DCM (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.05 M)
DCE (0.05 M)
DCE (0.05 M)
DCE (0.05 M)
20 h/40
20 h/40
20 h/40
20 h/40
20 h/40
2 h/40
<5%
19%
24%
<5%
<5%
<5%
<5%
30%
46%
54%
60%
86%
<5%
<5%
Cu(OTf)2 (5.0)
Cu(CH3CN)4BF4 (5.0)
CuCl (5.0)
Cu(OAc)2 (5.0)
PdCl2(PPh3)2 (5.0)
AuBr3 (5.0)
18 h/40
2 h/65
Cu(CH3CN)4BF4 (5.0)
Cu(CH3CN)4BF4 (5.0)
Cu(CH3CN)4BF4 (2.0)
Cu(CH3CN)4BF4 (2.0)
Cu(CH3CN)4BF4 (2.0)
Cu(CH3CN)4BF4 (2.0)
no catalyst
b
9
1 h/65
b
10
1.5 h/65
2.5 h/65
1 h/RT
20 h/RT
20 h/65
b
11
bc
,
12
13
14
bd
,
b
a
Reaction conditions: 0.30 mmol ethyldiazoacetate (1a), 0.25 mmol
TIPS-EBX (2a). The reaction was run for 20 h or until full conversion
of the EBX reagent. Yield after purification by column chromatog-
b
c
d
raphy. With 0.50 mmol 1a. With 2.5 mol % of 4a. With 2.5 mol %
of 4b.
ReplacingRh2(OAc)4 withCu(OTf)2 gavethedesiredproduct3a
in 19% yield after 20 h at 40 °C (Table 1, entry 2). Product 3a was
obtained in 24% yield when Cu(CH3CN)4BF4 was used (Table 1,
entry 3), whereas the use of other metal catalysts such as CuCl,
Cu(OAc)2, PdCl2(PPh3)2, and AuBr3 did not lead to the
formation of the desired product 3a (Table 1, entries 4−7). Use
of DCE as a solvent at 65 °C gave 3a in 30% yield (Table 1, entry
8). With two equivalents of 1a, the yield could be raised to 46%
(Table 1, entry 9). Decreasing the catalystloading to2mol%gave
3a in 54% yield (Table 1, entry 10). Alkyne 3a was then obtained
Modification of steroidal drugs provides an efficient route for
the fine-tuning of their biological activity. Therefore, our method
was applied to the late-stage oxy-alkynylation of diazo derivatives
7 and 8 of steroids,19 which could be smoothly converted to the
desired products 9 and 10 in 82% and 75% yield, respectively
B
DOI: 10.1021/jacs.6b00278
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Journal of the American Chemical Society
Communication
Figure 1. Scope of the copper-catalyzed oxy-alkynylation of diazo compounds with EBX reagents.
(Scheme 2A). This transformation highlights the chemo-
selectivity of the method in the presence of carbon−hydrogen
bonds, olefins, and carbonyls, which can react with carbene
intermediates.20
The obtained products contain three valuable functional
groups: an alkyne, an iodide, and an ester. Oxy-alkynylated
products 3a, 3d, and 3w were synthesized on gram scale in 91%,
84%, and 79% yield, respectively. Ester 3d could be readily
hydrolyzed, affording the alkyne substituted α-hydroxy acid 11 in
94% yield (Scheme 2B). Copper-catalyzed cycloaddition of
terminal alkyne3y, obtainedbydesilylationof3d, withbenzyland
phenylazidesgavetriazoles12and13inhighyields. Deiodination
of 3y was achieved using visible light photoredox catalysis to give
product 14 in 82% yield.21 Isocoumarin derivative 15 could be
synthesized using a domino carbopalladation/Suzuki cascade
reaction22 in 60% yield from 3w. Tetra-substituted allene 16 was
also obtained as a side product in the coupling reaction. Finally, a
domino carbopalladation/Heck cascade reaction was also
possible to furnish product 17 in 24% yield from 3w.
a
Scheme 2. Late Stage Reaction and Product Modifications
Based on literature reports5,13,17 and our own results, we
propose a tentative mechanism for the reaction (Scheme 3A).
The Cu(I) catalyst I first reacts with diazo compound 1 to form
copper-carbene intermediate II. Then the carboxylate group of
EBX reagent 2 adds to carbene intermediate II to form
organocopper species III. Finally, intramolecular alkyne transfer
gives product 3. For vinyl diazo compound 5, conjugate addition
on the formed carbene intermediate would give organocopper
species IV, which affords enyne product 6 as a single geometric
isomer after alkyne transfer. For the alkyne transfer step, several
mechanisms could be envisaged (Scheme 3B): nucleophilic
attack on either the α or β position of the alkynyliodonium salt
(pathways a and b), or oxidative alkyne transfer to copper
(pathway c). In the case of α-addition, β-elimination of the iodine
wouldled directlytotheproduct from theformed intermediate V.
Alternatively, a concerted reaction could also be envisaged.7d
However, β-addition would furnish first a vinylidene intermediate
via α-elimination on addition product VI. A fast 1,2-silicon shift
would then lead to product 3.
a
Reaction conditions: (a) K2CO3, EtOH; (b) R1N3, 20 mol % CuSO4·
When 13C labeled TIPS-EBX reagent 2a′ was used in the
reaction, product 3′ without 1,2-shift of the silyl group was
obtained exclusively, which indicated that addition on the β
position is less probable. However, oxidative alkyne transfer to
5H2O, sodium ascorbate, triazole ligand, tBuOH/H2O; (c) 2.5 mol %
fac-Ir(ppy)3, NBu3, HCO2H, blue LED, MeCN; (d) 5 mol %
Pd(PPh3)4, K2CO3, PhB(OH)2, DMF; (e) ethyl acrylate, 5 mol %
Pd(PPh3)4, NEt3, DMF.
C
DOI: 10.1021/jacs.6b00278
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Journal of the American Chemical Society
Communication
Scheme 3. Proposed Mechanism for Oxy-Alkynylation
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.6b00278.
■
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Experimental procedures (PDF)
Analytical data (CIF)
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AUTHOR INFORMATION
Corresponding Author
*jerome.waser@epfl.ch
Notes
■
The authors declare no competing financial interest.
(22) Guo, L.-N.; Duan, X.-H.; Hu, J.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M.
Eur. J. Org. Chem. 2008, 2008, 1418.
ACKNOWLEDGMENTS
■
We thank European Research Council (ERC; Starting Grant
iTools4MC, number 334840) and the EPFLfor financial support.
We thank Dr. Scopelliti Rosario from ISIC-EPFL for the X-ray
studies.
D
DOI: 10.1021/jacs.6b00278
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX