Ethynyl-1,2-benziodoxol-3(1H)-one (EBX): An exceptional reagent for the ethynylation of keto, cyano, and nitro esters

Article abstract of DOI:10.1002/chem.201001539

Hot alkyne! The in situ generation of ethynyl-1,2-benziodoxol-3(1H)-one (EBX) from a silyl-protected reagent by using TBAF is reported. EBX displayed exceptional acetylene transfer ability onto stabilized enolates (see scheme), even at -78 □°C. The mild reaction conditions allowed the first ethynylation reactions of linear keto, cyano, and nitro esters in high yields to give all-carbon quaternary centers or non-natural amino acids after selective reduction of the nitro group.

Full text of DOI:10.1002/chem.201001539

COMMUNICATION
DOI: 10.1002/chem.201001539
Ethynyl-1,2-benziodoxol-3ACTHNUTRGNE(NUG 1H)-one (EBX): An Exceptional Reagent for the
Ethynylation of Keto, Cyano, and Nitro Esters
Davinia Fernꢀndez Gonzꢀlez, Jonathan P. Brand, and Jꢁrꢂme Waser*[a]
The chemistry of acetylenes has been extensively used in
organic synthesis.[1] In recent decades, the functionalization
of the triple bond by using metal catalysis has complement-
ed classical acetylene chemistry, providing numerous addi-
tion, cyclization, and cycloaddition reactions for the con-
struction of organic molecules.[2] The exceptional properties
of acetylenes have also found widespread application in
neighboring fields, such as materials science and biochem-
istry.[1] To respond to this ever increasing demand for struc-
turally diverse acetylenes, the development of new methods
for their synthesis is an important task for organic chem-
ists.[3]
are still limited. In particular, ethynylation reactions would
be highly desirable, as they would allow further direct func-
À
tionalization of the alkyne C H bond without the need for
the removal of protecting groups. To our knowledge, the
one-step a-ethynylation of carbonyl groups has been realiz-
ed in only a few examples that use lead reagents[7a] or alky-
nyliodonium salts,[8b,e] and the scope reported for these reac-
tions was limited. As a result, these methods have not been
broadly adopted by the organic chemistry community and
reported applications are scarce.
Recently, we discovered the exceptional reactivity of 1-
[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3ACTHNUGTRNEUNG(1H)-one
À
Acetylene transfer reactions constitute an efficient
method for the introduction of the triple bond. The sp hy-
(TIPS–EBX, 1) for the metal-catalyzed alkynylation of C H
bonds and olefins.[10] Herein, we report the in situ genera-
À
bridization increases the acidity of the alkyne C H bond, al-
tion of the parent reagent, ethynyl-1,2-benziodoxol-3ACHTUNGTRENNUNG(1H)-
lowing the easy generation of acetylide anions or metal in-
termediates, which have been used extensively in addition
reactions to carbonyls or imines[4] and in cross-coupling (So-
nogashira) reactions.[5] In contrast, electrophilic alkynyl syn-
thons have been much less well developed,[6–8] and discon-
nections based on this umpolung reactivity are not usually
considered when planning syntheses. This constitutes a seri-
ous limitation in the syntheses with acetylenes, as, for exam-
ple, all-carbon quaternary centers containing a triple bond
cannot be easily accessed by using acetylide nucleophiles.
Reported methods for the generation of electrophilic
acetylene synthons are based on the use of halogen acet-
one (EBX, 3) from the corresponding trimethylsilyl-protect-
ed benziodoxolone 2 (TMS–EBX) and its exceptional acety-
lene-transfer ability with soft enolates (Scheme 1). The
simple procedure and mild reaction conditions, which use
ACHTUNGTRENNUNG
ylenes,[6] lead acetylide reagents,[7] or alkynyliodonium
Scheme 1. Alkynylation of soft enolates with EBX (3).
salts.[8] Although recent progress has been made for the
[9]
À
functionalization of aromatic C H bonds, the methods for
the conceptually simple a-alkynylation of carbonyl groups
tetrabutylammonium fluoride (TBAF) both as an activating
agent and a base, allowed high yields and a broad substrate
scope, including cyano and nitro esters, two classes of com-
pounds that have never been reported before. Finally, a
proof of concept for asymmetric induction has been ach-
ieved.
[a] D. Fernꢀndez Gonzꢀlez, J. P. Brand, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢁdꢁrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
Fax : (+41)21-693-9700
Prior to our work, the few methods describing the ethyny-
lation of carbonyl compounds that use hypervalent iodine
reagents were all based on the use of alkynyliodonium
E-mail: jerome.waser@epfl.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001539.
AHCTUNGTRENNUNG
salts.[8b,e] In these reports, the enolate was formed in the
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presence of a strong base before the addition of the iodine
reagent, probably to prevent its decomposition in presence
of the base. Benziodoxolone-based reagents were not used
in these works.[11] As TIPS–EBX (1) has proven to be very
stable to both base and moisture, we first investigated
whether milder, one-pot, phase-transfer conditions were
possible for the alkynylation of keto ester 4a (Table 1,
reaction was run under previously reported conditions with
an alkynyliodonium salt, which reacts via formation of the
sodium enolate of 4a,[8b] alkyne 5a was isolated in only 69%
yield (Table 1, entry 10).
The scope of the reaction was examined next (Table 2).
Cyclic keto esters 4a–c and diethyl phenylmalonate (6) gave
moderate to excellent yields in the alkynylation reaction
Table 2. Scope of the alkynylation of activated carbonyls.
Table 1. Alkynylation of keto ester 4a.
Entry
1
Substrate
Product
Isolated
yield [%][a]
98
94
Entry
Reaction conditions[a]
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
1, sat. K2CO3, Me4N+ClÀ, 08C
2, sat. K2CO3, Me4N+ClÀ, 08C
2, sat. KF, Me4N+ClÀ, 08C
2, TBAF, 08C
toluene
toluene
toluene
toluene
toluene
Et2O
iPrOH
CH2Cl2
THF
n.r.[b]
<80[c]
87
2
decomp[d]
71
2, TBAF, À78 to 108C, 12 h
2, TBAF, À78 to 108C, 12 h
2, TBAF, À78 to 108C, 12 h
2, TBAF, À788C, 3 h
49
<90[c]
78
3
4
50[b]
95[c]
2, TBAF, À788C, 1.5 h
98
69
10
Ochiaiꢃs conditions[8b]
THF
[a] Reactions under phase-transfer conditions (entries 1–3): substrate
(0.3 mmol), Me4N+ClÀ (10 mol%), reagent (1 or 2; 1.3 equiv), toluene/
saturated base solution (5 mL/1.5 mL). Reactions with TBAF: substrate
(0.4 mmol), TBAF (1.3 equiv), 2 (1.3 equiv), solvent (3.3 mL). [b] n.r.=
no reaction. [c] Product 5a could not be separated from unidentified im-
purities. [d] decomp=decomposition of the starting materials.
5
6
7
R=Me (8a)
R=Et (8b)
R=Bn (8c)
9a
9b
9c
90
63[b]
77
entry 1). However, no reaction was observed with this re-
agent. We then turned to the potentially more reactive
TMS–EBX (2). In this case, alkynylation was observed, but
the deprotected product 5a was obtained as the major prod-
uct (Table 1, entry 2). A control experiment showed that
this deprotection did not occur at the product stage under
these reaction conditions. Consequently, we speculated that
EBX (3) itself was responsible for the observed ethynylation
reaction. Although both TIPS–EBX (1) and TMS–EBX (2)
are bench-stable reagents, we were unable to isolate EBX
(3), as all attempts towards silyl removal resulted in decom-
8
9
10
R=Me (8d)
R=Bn (8e)
R=allyl (8 f)
9d
9e
9 f
83
93[b,c]
88[b]
11
12
R=Bn (10a)
R=4-Br-Bn (10b)
11a
11b
90
75
13
14
15
16
R1 =Me, R2 =Et (12a)
R1 =Bn, R2 =Et (12b)
R1 =Ph, R2 =Me (12c)
R1 =Ph, R2 =tBu (12d)
13a
13b
13c
13d
75
93
80
85
position. If KF was used as the base, free acetACHTNUTRGNEyNUG lene product
5a was obtained exclusively in 87% yield (Table 1, entry 3).
Although these reaction conditions worked well for cyclic
keto esters, much lower yields were obtained with other
classes of substrate (vide infra). We then turned to TBAF as
a fluoride source, but extensive decomposition of the re-
agent was observed at 08C (Table 1, entry 4). A significantly
improved yield was obtained by starting the reaction at
À788C and slowly warming up to 108C (71%, Table 1,
entry 5). Different solvents were then examined (Table 1,
entries 5–9) and alkyne 5a was obtained in 98% yield in
only 1.5 h at À788C in THF (Table 1, entry 9). This result
demonstrates the exceptional reactivity of EBX (3), which
allowed the alkynylation reaction to proceed under mild
conditions with use of a simple procedure. When the same
[a] Reaction conditions: substrate (0.4 mmol), TBAF (1.3 equiv),
2
(1.3 equiv), at À788C or from À788C to 108C, 1–20 h, THF (3.3 mL; see
Supporting Information for the exact reaction time and temperature)
[b] The reagent was slowly added as a solution (THF/CH2Cl2; 5:1) over
10 h. [c] The reaction was run with 1.8 equiv of 2.
(Table 2, entries 1–4). In contrast to cyclic keto esters and
malonates, only the alkynylation of acyclic keto esters by
lead reagents has been reported,[7a,c] and there are no exam-
ples of the ethynylation of these more challenging sub-
strates. Gratifyingly, the desired acetylene products were ob-
tained in 63–93% yield for keto esters 8a–f, giving quater-
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Ethynylation
COMMUNICATION
[14,15]
À
nary centers with four different carbon substituents (Table 2,
entries 5–10). Both methyl and phenyl ketones (Table 2, en-
tries 5–10) with several different a-alkyl substituents, includ-
ing an allyl group, could be used, which provided access to
the versatile 1,5-enyne product 9 f (Table 2, entry 10). Cyano
and nitro esters (Table 2, entries 11–16) were also good sub-
strates for the reaction. Importantly, the alkynylation of
theses two classes of compounds has never been reported
before. The nitro substrates in particular are very sensitive
compounds and the mild conditions developed were crucial
to obtaining good yields.[12] A practical issue with the ethy-
nylation reaction is caused by the similar polarity of the
starting materials and products, which makes their separa-
tion by thin layer or column chromatography nearly impos-
sible. Consequently, complete conversion was required to
allow purification of the products. For slow reacting sub-
strates, a better conversion was achieved if reagent 2 was
added slowly at À788C by using a syringe pump.
ported conditions for the reduction of the N O bond.
If
Zn dust was used under more forcing conditions, allyl amine
16 was obtained in 57% yield.[16] Gratifyingly, we found that
À
selective reduction of the N O bond in 15 was possible by
using SmI2 in THF/tBuOH.[17] Purification of the free amine
was difficult, but quenching the reaction with trifluoroacetic
anhydride (TFAA) allowed the isolation of the correspond-
ing trifluoro amide (17) in good yield and purity. The ob-
tained protected alkynyl amino acids display interesting bio-
logical activities and few methods have been reported for
their synthesis.[18]
During optimization of the reaction, we speculated that
EBX (3) was the alkynylating agent. As it was not possible
to isolate this reagent, we decided to monitor its formation
by 1H and 13C NMR at low temperature. Treating TMS–
EBX (2) with TBAF at À788C led to immediate conversion
to a new compound, the spectrum of which was in full
agreement with the structure of EBX (3).[19] The H NMR
1
The obtained propargylic nitro and cyano products con-
taining an ester group are new structures that have never
before been synthesized. In particular, propargylic nitro
compounds with a free acetylene are a very rare class of
compounds and their properties have never been studied in
detail. Consequently, we decided to examine the synthetic
potential of product 13b more intensively (Scheme 2).
spectrum remained unchanged when the solution was
heated up to À208C. At this point, EBX (3) gradually de-
composed to generate several as yet unidentified products.
If a substrate was added to the EBX (3) solution, the only
signals observed belonged to EBX (3), 2-iodobenzoic acid,
the substrate and the ethynylation product; no other inter-
mediates were observed.[20]
In principle, two reaction pathways can be envisaged for
this reaction (Scheme 3): addition of the enolate to the
iodine atom followed by reductive elimination (pathway A)
Scheme 2. Scaled-up synthesis and functionalization of 13b. Reaction
conditions: a) 2 (1.3 equiv), TBAF (1.3 equiv), THF, À788C, 77%;
b) BnN3 (1 equiv), CuSO4 (5 mol%), sodium ascorbate (10 mol%),
tBuOH/H2O (1:1), 608C, 65%; c) Zn, HCl/AcOH (1 n), 08C, 57%;
d) Zn, NH4Cl, EtOH/H2O (1:1), 08C, 94%; e) SmI2, THF, tBuOH, then
TFAA, 67%.
Scheme 3. Possible mechanisms for the ethynylation reaction and labeling
experiment (Ar=phenyl-2-carboxylate).
or conjugate addition to the alkyne, followed by an elimina-
tion and 1,2-hydride shift (pathway B). For both pathways,
initial interaction with the carbonyl oxygen could also be en-
visaged. The use of 13C-labeled reagent 18[21] led to product
20, which is only consistent with the 1,2-hydride-shift path-
way. This mechanism has also been proposed in the case of
alkynyliodonium salts.[8b] Interestingly, the opposite result
was obtained in the case of metal-catalyzed alkynylation re-
actions that used TIPS–EBX (1).[10]
The use of benziodoxolone-based reagents for the ethyn-
AHCTUNGTREGyNNNU lation reaction allowed us to increase the scope and effi-
ciency of the reaction. Nevertheless, the obtained products
are racemic and an asymmetric method would be highly de-
The ethynylation of 12b proceeded with a yield of 77%
on a 4.7 mmol scale to give 13b. The Cu-catalyzed [3+2] cy-
cloaddition of 13b with BnN3 gave the corresponding tria-
zole (14) in 65% yield.[13] This constitutes the first example
of a [3+2] cycloaddition reaction of a propargyl nitro com-
pound. Reduction of the nitro group to the amine was at-
tempted next. To the best of our knowledge, there is only
one report of the reduction of a propargylic nitro compound
to the amine, which proceeds through the corresponding hy-
droxylamine.[14] Although reduction to hydroxylamine 15
with Zn dust worked well, it was not possible to use the re-
Chem. Eur. J. 2010, 16, 9457 – 9461
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9459

J. Waser et al.
sirable. The only reported enantioselective method for the
alkynylation of enolates is limited to carbonyl substituted
acet
Keywords: alkynylation · hypervalent compounds · iodine ·
quaternary carbon atoms · umpolung
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ylenes.[6i] Preliminary investigations by using the phase-
transfer conditions developed by Jørgensen[6i] led to moder-
ate asymmetric induction (Scheme 4). Interestingly, the use
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Scheme 4. An asymmetric ethynylation reaction.
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products in this case, highlighting a further advantage of
EBX (3) as an electrophilic ethynylation reagent.
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ACHTUNGTRENNUNGynylation of activated carbonyl compounds. The reactive
EBX (3) was generated from bench-stable TMS–EBX (2) in
the presence of TBAF under mild conditions. The high acet-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
acyclic keto and cyano esters was achieved, which gave
access to quaternary centers with four different carbon sub-
stituents, a synthetically challenging class of compounds in
organic chemistry. Unprecedented alkACTHNUTRGNEUNGyne substituted nitro
esters were synthesized and methods for their transforma-
tion to the corresponding protected amino acids were devel-
oped. The reaction was shown to proceed through a 1,2-hy-
dride-shift mechanism similar to the one proposed for alk-
ACHTUNGTRENNUNGynyliodonium salts. Finally, we demonstrated that asymmet-
ric induction was possible under phase-transfer conditions.
The simplicity of the reported method, as well as its broad
scope, greatly enhance the usability of electrophilic alkyne
synthons in organic chemistry and is expected to stimulate
chemists to more routinely use an umpolung approach for
the synthesis of acetylenes. The application of benziodoxo-
lone reagents for the alkynylation of other nucleophiles, as
well as the improvement of the asymmetric induction are
currently under investigation in our laboratory.
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EPFL and SNF (grant number: 200021_119810) are acknowledged for fi-
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preparation of starting materials.
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Ethynylation
COMMUNICATION
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À
[19] In particular, an acetylene C H signal was now visible at d=
3.50 ppm. See Figure S1 in the Supporting Information.
[20] In the case of slower-reacting substrates, partial decomposition of
EBX was also observed.
[21] For reasons of synthetic accessibility, the labeled TIPS–EBX reagent
18 was used. Generally, TIPS–EBX (1) was as efficient as TMS–
EBX (2) as the reagent precursor, although the silyl-group removal
was slightly slower.
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Received: May 6, 2010
Published online: July 19, 2010
Chem. Eur. J. 2010, 16, 9457 – 9461
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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