1
COMMUNICATION
DOI: 10.1002/chem.200((will be filled in by the editorial staff))
Ethynyl BenziodoXolone (EBX): An Exceptional Reagent for the Ethynylation of
Keto-, Cyano- and Nitro- Esters.**
Davinia Fernández González, Jonathan P. Brand and Jérôme Waser *
[a]
Dedication ((optional))
The chemistry of acetylenes has been extensively used in organic
synthesis.
[1]
In the last decades, the functionalization of the triple
bond using metal catalysis has complemented classical acetylene
chemistry with numerous addition, cyclization and cycloaddition
reactions for the construction of organic molecules.
[2]
The
exceptional properties of acetylenes have also found widespread
applications in neighboring fields, such as material sciences and
biochemistry.
[1]
To answer to this ever increasing demand for
structurally diverse acetylenes, the development of new methods
for their synthesis is an important task for organic chemists.
[3]
Acetylene transfer reactions constitute an efficient method for
the introduction of the triple bond. The SP hybridization increases
the acidity of the alkyne C-H bond, allowing the easy generation
of acetylide anions or metal intermediates, which have been
extensively used for additions to carbonyls or imines
[4]
or for
cross-coupling (Sonogashira) reactions.
[5]
In contrast,
electrophilic alkynyl synthons have been much less developed,
[6-8]
and disconnections based on this Umpolung are usually not
considered when planning synthesis. This constitutes a serious
limitation for the synthesis of acetylenes, as for example all-
carbon quaternary centers bearing a triple bond cannot be easily
accessed using acetylide nucleophiles.
Reported methods for the generation of electrophilic acetylene
synthons are based on the use of halogen acetylenes,
[6]
lead
acetylide reagents
[7]
or alkynyliodonium salts.
[8]
Whereas recent
progress has been achieved for the functionalization of aromatic
C-H bonds,
[9]
the methods for the conceptually simple -
alkynylation of carbonyl groups are still limited. In particular,
ethynylation reactions would be highly desirable, as they would
allow direct further functionalization of the alkyne C-H bond
without removal of protecting groups. To the best of our
knowledge, the one-step -ethynylation of carbonyl groups has
been realized only in few examples using lead reagents
[7a]
or
alkynyliodonium salts,
[8b,8e]
and the scope reported for these
reactions 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-3(1H)-one (TIPS-
EBX (1)) for metal-catalyzed alkynylation of C-H bonds and
olefins.
[10]
Herein, we would like to report the in situ generation
of the parent reagent, Ethynyl-1,2-BenziodoXol-3(1H)-one (EBX,
(3)) from the corresponding TMS protected benziodoxolone 2 and
its exceptional acetylene-transfer ability to soft enolates (Scheme
1). The simple procedure and mild reaction conditions using
TBAF both as activating agent and base allowed high yields and a
broad scope of substrates, including cyano and nitro esters, two
classes of compounds which were never reported before. Finally,
a first proof of concept for asymmetric induction has been
achieved.
Scheme 1.
Prior to our work, the few methods describing the
ethynylation of carbonyl compounds using hypervalent iodine
reagents were all based on alkynyliodonium salts.
[8b,8e]
In these
reports, the enolate was formed in the presence of a strong base
before addition of the reagent, probably to prevent decomposition
of the reagent in presence of the base. Benziodoxolone-based
reagents were never used in these works.
[11]
As TIPS-EBX (1) has
proven to be very stable to base and moisture in our hand, we first
investigated if milder, one-pot phase-transfer conditions were
possible for the alkynylation of keto-ester 4a (Table 1, Entry 1).
However, no reaction was observed with this reagent. We then
decided to turn to the potentially more reactive TMS-EBX (2). In
this case, alkynylation was observed, but the deprotected product
5a was obtained as the major product (Entry 2). A control
experiment showed that deprotection did not occur at the product
[a] D. Fernández González, J. P. Brand and Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
E-mail: jerome.waser@epfl.ch
Homepage: http://isic.epfl.ch/lcso
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author.
This is the peer reviewed version of the following article: Chem. Eur. J. 2010, 16, 9457, which has been
published in final form at http://onlinelibrary.wiley.com/doi/10.1002/chem.201001539/abstract. This article may
be used for non-commercial purposes in accordance With Wiley-VCH Terms and Conditions for self-archiving
2
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 into
decomposition only. When KF was used as a base, free acetylene
product 5a was obtained exclusively in 87% yield (Entry 3).
Although these reaction conditions worked well with cyclic keto-
esters, much lower yields were obtained with other classes of
substrates (vide infra). We then turned to TBAF as a fluoride
source, but extensive decomposition of the reagent was observed
at 0 °C (Entry 4). A significantly improved yield was obtained by
starting the reaction at –78 °C and slowly warming up to 10 °C
(71%, Entry 5). Different solvents were then examined (Entries 5-
9) and alkyne 5a was obtained in 98% yield in only 1.5 h at –
78 °C in THF (Entry 9). This result demonstrated the exceptional
reactivity of EBX (3), which allowed the alkynylation reaction to
proceed under mild conditions using a simple procedure. When
the same reaction was run under reported conditions with an
alkynyliodonium salt via formation of the sodium enolate of
4a,
[8b]
alkyne 5a was isolated in 69% yield only (Entry 10).
Table 1.
The scope of the reaction was examined next (Table 2).
Cyclic keto esters 4a-c and phenyl-diethylmalonate (6) gave
moderate to excellent yields in the alkynylation reaction (Entries
1-4). In contrast to cyclic keto-esters or malonates, the
alkynylation of non-cyclic keto-esters has been reported only
using lead reagents,
[7a,7c]
and there is no example of ethynylation
for these more challenging substrates. Gratifyingly, the desired
acetylene products were obtained in 63-93% yield for keto-esters
8a-f, giving quaternary centers with four different carbon
substituents (Entries 5-10). Both methyl (Entries 5-7) and phenyl
(Entries 8-10) ketones could be used with several -alkyl
substituents, including an allyl group, which gave access to the
versatile 1,5-enyne product 9f (Entry 10). Cyano (Entries 11-12)
and nitro (entries 13-16) esters were also good substrates for the
reaction. Importantly, the alkynylation of theses two classes of
compounds had never been reported before. The nitro substrates
in particular were very sensitive compounds, and the mild
conditions developed were crucial to obtain good yields.
[12]
A
practical issue with the ethynylation reaction is the similar
polarity of the starting materials and the products, which makes
their separation via thin plate or column chromatography nearly
impossible. Consequently, complete conversion was required to
allow purification of the products. For slow reacting substrates, a
better conversion was achieved when reagent 2 was added slowly
at –78 °C using a syringe pump.
The obtained propargylic nitro and cyano products bearing an
ester group are new structures, which have never been synthesized
before. In particular, propargylic nitro compounds with a free
acetylene are generally a very rare class of compounds, and their
properties have never been studied in details. We consequently
decided to examine the synthetic potential of product 13b more
intensively (Scheme 2).
Table 2.
The ethynylation of 12b proceeded in 77% yield on a 4.7
mmol scale. The Cu-catalyzed [3+2] cycloaddition of 13b with
BnN
3
gave the corresponding triazole 14 in 65% yield.
[13]
This
constituted the first example of [3+2] cycloaddition reaction of a
propargyl nitro compound. Reduction of the nitro group to the
amine was attempted next. To the best of our knowledge, there is
only one report about the reduction of a propargylic nitro
compound to the corresponding amine proceeding via the
corresponding hydroxylamine 15.
[14]
Although reduction to
hydroxylamine 15 with Zn dust worked well, it was not possible
to use the reported conditions for the reduction of the N-O
bond.
[14,15]
Allyl amine 16 was obtained in 57% yield when Zn
dust was used under more forcing conditions.
[16]
Gratifyingly, we
found that selective reduction of the N-O bond was possible by
using SmI
2
in THF/tBuOH.
[17]
Purification of the free amine was
difficult, but quenching the reaction with trifluoro acetic
anhydride (TFAA) allowed the isolation of the corresponding
trifluoro amide 17 in good yield and purity. The obtained
protected alkynyl amino acids display interesting biological
activities, and only few methods have been reported for their
synthesis.
[18]
Scheme 2.
When optimizing the reaction, we had speculated that EBX
(3) was the alkynylating agent. As it was not possible to isolate
this reagent, we decided to monitor its formation by
1
H and
13
C
NMR at low temperature. Treating TMS-EBX (2) with TBAF at –
78 °C led to the immediate conversion to a new compound, which
spectra were in full agreement with the structure of EBX (3).
[19]
The
1
H NMR spectrum remained unchanged when the solution
was heated up to –20 °C. At this point, EBX (3) gradually
decomposed under the generation of several not yet identified
products. When a substrate was added to the EBX (3) solution,
the only signals observable belonged to EBX (3), 2-iodo benzoic
acid, the substrate and the ethynylation product: no further
intermediate could be observed.
[20]
In principle, two reaction pathways could be envisaged
(Scheme 3): Addition of the enolate to the iodine atom followed
by reductive elimination (pathway A) or conjugate addition to the
alkyne, followed by a elimination and 1,2- hydride shift (pathway
B). For both pathways, initial interaction with the carbonyl
oxygen could also be envisaged. The used of
13
C labeled reagent
18
[21]
led to product 20, which is consistent with the 1,2-shift
pathway. This mechanism had also been proposed in the case of
alkynyliodonium salts.
[8b]
Interestingly, the opposite result was
obtained in the case of metal-catalyzed alkynylation reactions
using TIPS-EBX (1).
[10]
The use of benziodoxolone-based reagents for the
ethynylation reaction allowed us to increase the scope and
efficiency of the reaction. Nevertheless, the obtained products are
racemic, and an asymmetric method would be highly desirable.
The only reported enantioselective method for the alkynylation of
enolates is limited to carbonyl substituted acetylenes.
[6i]
Preliminary investigations using the phase-transfer conditions
developed by Jørgensen
[6]
in fact led to a moderate asymmetric
induction (Equation 1). Interestingly, the use of alkynyliodonium
salts led to the formation of racemic products in this case,
highlighting a further advantage of EBX (3) as electrophilic
ethynylation reagent.
3
Scheme 3.
Equation 1.
In conclusion, we have reported the first use of
benziodoxolone-based hypervalent iodine reagents for the
ethynylation of activated carbonyl compounds. The reactive EBX
(3) was generated from the bench-stable TMS-EBX (2) in the
presence of TBAF under mild conditions. The high acetylene
transfer ability of 3 resulted in good yield for ethynylation
reactions. For the first time, acetylene transfer to non-cyclic keto-
and cyano- esters was achieved, which gave access to quaternary
centers with four different carbon substituents, a synthetically
challenging class of compounds in organic chemistry.
Unprecedented alkyne substituted nitro esters were synthesized,
and methods for their transformation to the corresponding
protected amino acids were developed. The reaction was shown to
proceed via a 1,2-shift mechanism similar to the one proposed for
alkynyliodonium salts. Finally, we demonstrated that asymmetric
induction was possible under phase-transfer conditions. The
simplicity of the reported method, as well as its broad scope,
greatly enhances the utility of electrophilic alkyne synthons in
organic chemistry and is expected to stimulate chemists to use
more routinely an Umpolung approach for the synthesis of
acetylenes. Application of benziodoxolone reagents for the
alkynylation of other nucleophiles, as well as improvement of the
asymmetric induction are currently under investigation in our
laboratory.
Acknowledgements
EPFL and SNF (grant number 200021_119810) are acknowledged for
financial support. Miss Raha Sedigh-Zadeh (EPFL) is acknowledged for the
preparation of starting material.
Keywords: Alkynylation · Hypervalent Iodine · Reactivity
· Umpolung · Quaternary Center.
[1] F. Diederich, P. J. Stang, R. R. Tykwinski, Acetylene Chemistry: Chemistry,
Biology and Material Science; Wiley-VCH, Weinheim, 2005
[2] a) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079. b) E.
Jimenez-Nunez, A. M. Echavarren, Chem. Commun. 2007, 333. c) J. F. Lutz,
Angew. Chem. 2007, 119, 1036; Angew. Chem., Int. Ed. 2007, 46, 1018. d) S.
M. Abu Sohel, R. S. Liu, Chem. Soc. Rev. 2009, 38, 2269.
[3] L. Brandsma, Synthesis of Acetylenes, Allenes and Cumulenes: Methods and
Techniques (Best Synthetic Methods Series), Academic Pr Inc 2003.
[4] B. M. Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351, 963.
[5] R. Chinchilla, C. Najera, Chem. Rev. 2007, 107, 874.
[6] a) S. I. Miller, J. I. Dickstein, Acc. Chem. Res. 1976, 9, 358. b) A. S. Kende,
M. Benechie, D. P. Curran, P. Fludzinski, W. Swenson, J. Clardy,
Tetrahedron Lett. 1979, 4513. c) A. S. Kende, P. Fludzinski, Tetrahedron
Lett. 1982, 23, 2373. d) A. S. Kende, P. Fludzinski, J. H. Hill, W. Swenson, J.
Clardy, J. Am. Chem. Soc. 1984, 106, 3551. e) R. Sauvetre, J. F. Normant,
Tetrahedron Lett. 1982, 23, 4325. f) M. Arisawa, R. Amemiya, M.
Yamaguchi, Org. Lett. 2002, 4, 2209. g) Y. Nishimura, R. Amemiya, M.
Yamaguchi, Tetrahedron Lett. 2006, 47, 1839. h) J. W. Sun, M. P. Conley, L.
M. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2006, 128, 9705. i) T. B.
Poulsen, L. Bernardi, J. Aleman, J. Overgaard, K. A. Jorgensen, J. Am. Chem.
Soc. 2007, 129, 441.
[7] a) M. G. Moloney, J. T. Pinhey, E. G. Roche, J. Chem. Soc. Perkin Trans. 1
1989, 333. b) C. J. Parkinson, T. W. Hambley, J. T. Pinhey, J. Chem. Soc.
Perkin Trans. 1 1997, 1465. c) S. I. Hashimoto, Y. Miyazaki, T. Shinoda, S.
Ikegami, J. Chem. Soc. Chem. Commun. 1990, 1100. d) R. Ciochina, R. B.
Grossman, Org. Lett. 2003, 5, 4619.
[8] For some selected examples, see: a) F. M. Beringer, S. A. Galton, J. Org.
Chem. 1965, 30, 1930. b) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, M.
Kunishima, S. Tani, Y. Nagao, J. Chem. Soc. Chem. Commun. 1990, 118. c)
P. J. Stang, A. M. Arif, C. M. Crittell, Angew. Chem., Int. Ed. Engl. 1990, 29,
287. d) M. D. Bachi, N. Barner, C. M. Crittell, P. J. Stang, B. L. Williamson,
J. Org. Chem. 1991, 56, 3912. e) M. D. Bachi, N. Barner, P. J. Stang, B. L.
Williamson, J. Org. Chem. 1993, 58, 7923. f) T. Kitamura, K. Nagata, H.
Taniguchi, Tetrahedron Lett. 1995, 36, 1081. g) T. Kitamura, T. Fukuoka, L.
Zheng, T. Fujimoto, H. Taniguchi, Y. Fujiwara, Bull. Chem. Soc. Jpn. 1996,
69, 2649. h) B. Witulski, T. Stengel, Angew. Chem. 1998, 110, 495; Angew.
Chem., Int. Ed. 1998, 37, 489. i) B. Witulski, M. Gössmann, Chem. Commun.
1999, 1879. For reviews, see: j) V. V. Zhdankin, P. J. Stang, Tetrahedron
1998, 54, 10927. k) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299.
l) M. Ochiai In Chemistry of Hypervalent Compounds; K. Akiba, Ed.; Wiley-
VCH: New York, NY, 1999; Chapter 12; p. 359-389. m) T. Wirth, M. Ochiai,
V. V. Zhdankin, G. F. Koser, H. Tohma, Y. Kita, Top. Curr. Chem.:
Hypervalent Iodine Chemistry: Modern Developments in Organic Synthesis,
Vol. 224, Springer, Berlin, 2003. n) K. S. Feldman, Arkivoc 2003, 179. o) E.
A. Merritt, B. Olofsson, Angew. Chem. 2009, 121, 9214; Angew. Chem., Int.
Ed. 2009, 48, 9052.
[9] a) T. de Haro, C. Nevado, J. Am. Chem. Soc. 2010, 132, 1512. b) Y. Wei, H.
Q. Zhao, J. Kan, W. P. Su, M. C. Hong, J. Am. Chem. Soc. 2010, 132, 2522.
c) A. S. Dudnik, V. Gevorgyan, Angew. Chem. 2010, 122, 2140; Angew.
Chem., Int. Ed. 2010, 49, 2096. And references cited therein.
[10] a) J. P. Brand, J. Charpentier, J. Waser, Angew. Chem.. 2009, 121, 9510;
Angew. Chem., Int. Ed. 2009, 48, 9346. b) S. Nicolai, S. Erard, D. Fernández
González, J. Waser, Org. Lett. 2010, 12, 384.
[11] Kitamura reported the use of an hypervalent iodine reagent derived from 2-
iodo benzoic acid, but he used the triflate salt, and not the benziodoxolone
reagent.
[8e]
For the use of benziodoxol(on)es for CF3-transfer, see: a) P.
Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579; b) I.
Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768; Angew.
Chem., Int. Ed. 2007, 46, 754; c) R. Koller, K. Stanek, D. Stolz, R. Aardoom,
K. Niedermann, A. Togni, Angew. Chem. 2009, 121, 4396; Angew. Chem.,
Int. Ed. 2009, 48, 4332.
[12] When the ethynylation of substrate 12b was done using an alkynyliodonium
salt following a reported procedure,
[8b]
only 46% yield of 13b was obtained.
Using phase-transfer conditions reported in Entry 3, Table 1 for substrate 12c
gave 13c in only 24% yield.
[13] W. D. Sharpless, P. Wu, T. V. Hansen, J. G. Lindberg, J. Chem. Educ. 2005,
82, 1833. No attempt was made to optimize the reaction conditions.
[14] C. Y. Jin, J. P. Burgess, J. A. Kepler, C. E. Cook, Org. Lett. 2007, 9, 1887.
[15] Y. Nambu, M. Kijima, T. Endo, M. Okawara, J. Org. Chem. 1982, 47, 3066.
[16] W. Oppolzer, O. Tamura, J. Deerberg, Helv. Chim. Acta 1992, 75, 1965.
[17] a) E. Dumez, J. P. Dulcere, Chem. Commun. 1998, 479. b) G. E. Keck, T. T.
Wager, S. F. McHardy, Tetrahedron 1999, 55, 11755.
[18] a) P. Casara, B. W. Metcalf, Tetrahedron Lett. 1978, 1581. b) P. J. Colson, L.
S. Hegedus, J. Org. Chem. 1993, 58, 5918. c) P. Meffre, L. Gauzy, E.
Branquet, P. Durand, F. LeGoffic, Tetrahedron 1996, 52, 11215. d) P. Meffre,
F. LeGoffic, Amino Acids 1996, 11, 313.
[19] In particular, a acetylene C-H signal was now visible at 3.50 ppm. See Figure
S1 in supporting information.
[20] In case of slower reacting substrates, partial decomposition of EBX was also
observed.
[21] For reason of synthetic accessibility, the labeled TIPS-EBX reagent 18 was
used. Generally, TIPS-EBX (1) was as efficient as TMS-EBX (2) as reagent
precursor, although silyl group removal was slightly slower.
Received: ((will be filled in by the editorial staff))
Revised: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
4
Scheme and figure legends:
Scheme 1. Alkynylation of Soft Enolates with EBX (3).
Scheme 2. Scale up of the synthesis and functionalization of 13b. Reaction conditions: a) 1.3 equiv 2, 1.3 equiv TBAF, THF, -78 °C, 77%; b) 1 equiv BnN
3
, 5 mol % CuSO
4
, 10
mol % Na ascorbate,
tBuOH/H
2
O 1:1, 60 °C, 65%; c) Zn, 1 N HCl/AcOH, 0 °C, 57%; d) Zn, NH
4
Cl,
EtOH/H
2
O 1:1, 0°C, 94%; e) SmI
2
, THF, tBuOH, then TFAA, 67%.
Scheme 3. Possible mechanisms for the ethynylation reaction and labeling experiment (Ar = phenyl-2-carboxylate).
Equation 1.
Tables:
Table 1. Alkynylation of Keto-Ester 4a.
Entry
Reaction conditions
[a]
Solvent
Yield
1
1, sat. K
2
CO
3
, Me
4
N
+
Cl
-
, 0 °C
toluene
n.r.
[b]
2
2, sat. K
2
CO
3
, Me
4
N
+
Cl
-
, 0 °C
toluene
<80%
[c]
3
2, sat. KF, Me
4
N
+
Cl
-
, 0 °C
toluene
87%
4
2, TBAF, 0 °C
toluene
dec.
5
2, TBAF, –78 to 10 °C, 12 h
toluene
71%
6
2, TBAF, –78 to 10 °C, 12 h
Et
2
O
49%
7
2, TBAF, –78 to 10 °C, 12 h
i
PrOH
<90%
[c]
8
2, TBAF, –78 °C, 3 h
CH
2
Cl
2
78%
9
2, TBAF, –78 °C, 1.5 h
THF
98%
10
Ochiai’s conditions
[8b]
THF
69%
[a] Reactions under phase-transfer conditions (Entries 1-3): 0.3 mmol substrate, 10 mol % Me
4
N
+
Cl
-
, 1.3 equiv reagent, toluene/saturated base solution (5 mL/1.5 mL). Reactions
with TBAF: 0.4 mmol substrate, 1.3 equiv TBAF, 1.3 equiv reagent, solvent (3.3 mL). [b] n.r. = no reaction. [c] Product 5a could not be separated from non-identified impurities.
Table 2. Scope of the Alkynylation of Activated Carbonyls
5
Entry
Substrate
Product
Isolated Yield
[a]
1
98%
2
94%
3
50%
[b]
4
95%
[c]
5
R = Me (8a)
9a
90%
6
R = Et (8b)
9b
63%
[b]
7
R = Bn (8c)
9c
77%
8
R = Me (8d)
9d
83%
9
R = Bn (8e)
9e
93%
[b,c]
10
R = allyl (8f)
9f
88%
[b]
11
R = Bn (10a)
11a
90%
12
R = 4-Br-Bn (10b)
11b
75%
13
R
1
= Me, R
2
= Et (12a)
13a
75%
14
R
1
= Bn, R
2
= Et (12b)
13b
93%
15
R
1
= Ph, R
2
= Me (12c)
13c
80%
16
R
1
= Ph, R
2
=
t
Bu (12d)
13d
85%
[a] 0.4 mmol substrate, 1.3 equiv TBAF, 1.3 equiv reagent 2, at –78 °C or from –78 °C to 10 °C, 1-20 h, solvent (3.3 mL) (see supporting information for exact reaction time and
temperature) [b] The reagent was slowly added as a solution (THF/CH
2
Cl
2
5:1) over 10 h. [c] The reaction was run with 1.8 equiv of reagent 2.
Table of Contents:
