OH-directed alkynylation of 2-vinylphenols with ethynyl benziodoxolones: A fast access to terminal 1,3-enynes

Article abstract of DOI:10.1002/anie.201412148

The first direct alkynylation of 2-vinylphenols was developed. The rationally optimized hypervalent iodine reagent TIPS-EBX in combination with [(CpRhCl₂)₂] as a C-H-activating transition metal catalyst enables the construction of a variety of highly substituted 1,3-enynes in high yields of up to 98 %. This novel C-H activation method shows excellent chemoselectivity and exclusive (Z)-stereoselectivity, and it is also remarkably mild and tolerates a variety of functional groups. Furthermore, synthetic modifications of the resulting 1,3-enynes were demonstrated. To our knowledge, this is the first example for an OH-directed C-H alkynylation with hypervalent iodine reagents.

Full text of DOI:10.1002/anie.201412148

Angewandte
Chemie
DOI: 10.1002/anie.201412148
À
C H Activation
OH-Directed Alkynylation of 2-Vinylphenols with Ethynyl
Benziodoxolones: A Fast Access to Terminal 1,3-Enynes**
Peter Finkbeiner, Ulrich Kloeckner, and Boris J. Nachtsheim*
Abstract: The first direct alkynylation of 2-vinylphenols was
developed. The rationally optimized hypervalent iodine
reagent TIPS-EBX* in combination with [(Cp*RhCl2)2] as
tron-rich phenols by using GaCl3 as the catalyst and
triethylsilylchloroethyne as the electrophilic alkyne transfer
reagent (Scheme 1a).[13] However, despite its importance, this
method has major drawbacks, such as limited substrate scope
À
a C H-activating transition metal catalyst enables the con-
struction of a variety of highly substituted 1,3-enynes in high
À
yields of up to 98%. This novel C H activation method shows
excellent chemoselectivity and exclusive (Z)-stereoselectivity,
and it is also remarkably mild and tolerates a variety of
functional groups. Furthermore, synthetic modifications of the
resulting 1,3-enynes were demonstrated. To our knowledge,
À
this is the first example for an OH-directed C H alkynylation
with hypervalent iodine reagents.
À
T
ransition-metal-catalyzed C H activation is an efficient
approach for the construction of molecular complexity from
barely substituted precursors.[1] The direct alkynylation of
À
(hetero)aryl and olefinic C H bonds is of particular interest
because the resulting (hetero)aryl alkynes and 1,3-enynes are
privileged structural motifs in a variety of biological active
compounds and single-emitting components.[2–4] Furthermore,
they are valuable precursors for the synthesis of a variety of
Scheme 1. Phenol alkynylations. DIPEA=N,N-diisopropylethylamine,
TIPS=triisopropylsilyl.
carbo- and heterocycles.[5–7] Key to success for an efficient C
À
H bond activation is the existence of a metal-coordinating
directing group, under the guidance of which only one
À
particular C H bond is activated in a highly regioselective
and very harsh reaction conditions (1608C, nBuLi as a base).
Furthermore, this reaction must be seen as a Lewis acid
mediated addition/elimination cascade rather than a true
OH-directed alkynylation reaction with terminal alkynes
manner.[8] For direct C H alkynylation reactions, this has led
À
to efficient protocols for the chemoselective synthesis of 2-
alkynyl substituted heteroarenes.[9] For the direct alkynylation
of aromatic carbocycles or alkenes, additional nitrogen-
containing directing groups such as amides, pyridines, pyr-
azoles, oxazolines, or N-oxides have frequently been used.[10]
In general, a free hydroxyl functionality as part of a phenol or
naphthol ring is unsuitable as a directing group in alkynyla-
tions. The OH group can act as a nucleophile and directly
react with the electrophilic alkyne reagent or further react in
À
under C H-activating conditions. To the best of our knowl-
edge such a reaction has not been described so far.
Hypervalent alkynyl iodine compounds are versatile
electrophilic reagents that have recently been applied in
a variety of alkyne transfer reactions.[14] In particular, 1-
silylethynyl-1,2-benziodoxol-3(1H)-ones (silyl-EBX) have
been utilized in such transformations owing to their fast and
reliable synthesis and a well-balanced stability/reactivity
ratio.[15] Very recently, there have been reports of their use
À
a cyclization cascade after initial C H alkynylation to give
oxygen-containing hetero- or spirocycles.[11,12] In a seminal
study, Yamaguchi and co-workers developed the first, and so
far only, protocol for the direct ortho-alkynylation of elec-
À
in direct alkynylation reactions under C H-activating con-
ditions with transition metal catalysts, in particular RhIII.[16]
Herein, we report their application in a rhodium(III)-cata-
À
lyzed direct C H alkynylation of 2-vinylphenols with perfect
[*] P. Finkbeiner, U. Kloeckner, Jun.-Prof. Dr. B. J. Nachtsheim
Institut fꢀr Organische Chemie
stereo- and chemoselectivity (Scheme 1b). This reaction
affords fast and efficient access to highly substituted 1,3-
enynes and,[17] to the best of our knowledge, is a very rare
Eberhard Karls Universitꢁt Tꢀbingen
Auf der Morgenstelle 18 (Germany)
E-mail: boris.nachtsheim@uni-tuebingen.de
À
example of an OH-directed alkynylation under C H-activat-
ing conditions.
Initially, we investigated the oxidative coupling of 2-(1-
methylvinyl)phenol 1a with TIPS-EBX. When 1a was treated
[**] We thank the DFG (NA 955/1-1), the Fonds der Chemischen
Industrie (Sachkostenzuschuss) and the Carl-Zeiss-Stiftung (PhD-
scholarship for PF) for financial support.
À
with [(Cp*RhCl2)2] as a C H-activating transition metal
catalyst and AgOAc, 2a was isolated in 59% yield (Table 1,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412148.
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III
À
Table 1: Optimization of the reaction conditions.
benzoate (5a) through an ortho C H insertion of a (Rh Cp*)
complex into benzoic acid.[18] In our reaction, this pathway
could lead to the undesired formation of 5b from 2-iodo
benzoic acid, which is formed from TIPS-EBX after alkyne
transfer. To prevent insertion of the RhIII catalyst into the
À
H6 C6 bond of 2-iodo benzoic acid and to sterically hinder
the formation of 3, we modified the alkynyl benziodoxolone
and synthesized the ortho-CH3-substituted derivative TIPS-
EBX*. Furthermore, Waser and co-workers reported TIPS-
EBX* to be significantly more reactive in gold(I)-catalyzed
alkynylations of indoles than TIPS-EBX.[15b] To our delight,
this change led to the formation of 2a in an excellent yield of
91% (Table 1, entry 4). Decreasing the catalyst loading to
1 mol% (Table 1, entry 5) had a negative impact on product
yield (81%). Finally, a variety of solvents were investigated,
however, this did not lead to further improvement of the
reaction performance (Table 1, entries 6–8).
Entry[a]
Iodane
Base[c]
Solvent
T
[8C]
t
[h]
Yield
[%]
1[b]
2[b]
3
TIPS-EBX
TIPS-EBX
TIPS-EBX
TIPS-EBX*
TIPS-EBX*
TIPS-EBX*
TIPS-EBX*
TIPS-EBX*
–
MeCN
MeCN
MeCN
MeCN
MeCN
DCE[e]
40
6
4
4
2
3
2
6
6
59
65
75
91
81
79
59
21
With the optimal reaction conditions in hand, we inves-
tigated the substrate scope of this transformation (Scheme 2).
Electron-poor 2-(1-methylvinyl)phenols, in particular 4- and
5-halogen-substituted derivatives, as well as a 4-nitro-substi-
tuted derivative, reacted well to give products 2b–2 f in
excellent yield (86–93%). 4,6-Dichloro-substituted 2-(1-
methylvinyl)phenol showed outstanding reactivity and gave
2g in 98% yield. Electron-rich derivatives bearing a 4-methyl
or a 4-methoxy substituent gave compounds 2h and 2i in 92%
and 87% yield, respectively. We then changed the substitution
pattern of the exocyclic double bond. When 2-vinylphenol
(R2 = H) was used as the substrate, the reaction was sluggish
and the desired product 2j could only be isolated in
a moderate yield of 40% after 72 h. However, introducing
an ethyl side chain restored reactivity to give 2k in 78% yield.
A variety of 2-(1-phenylvinyl)phenols (R2 = Ph) reacted well
to give compounds 2l–2n in 77–84% yield. Next, we varied
the aryl group of the 1-arylvinyl side chain (2o–2s). 4-
Fluorophenyl and 3,5-bis(trifluoromethyl)phenyl substituents
gave 2o and 2p in 71% and 90% yield, respectively. For 2p,
the solvent was changed from acetonitrile to 1,2-dichloro-
ethane because of solubility problems. The same change was
necessary for the 4-cyanophenyl derivative, which finally gave
2q in 78% yield. Heterocyclic substituents, such as benzo[d]-
[1,3]dioxoles and 2,5-dimethyl thiophenes, gave the desired
products 2r and 2s in 77% and 95% yield, respectively. When
a b-alkyl substituent was introduced, no alkynylated product
(2t) was observed. Finally, we showed that the 2-hydroxy
functionality is crucial for reactivity. 3-(1-methylvinyl)phenol
does not give the desired alkynylated product 2u. O-
Methylation of 2-(1-methylvinyl)phenol also inhibits this
transformation (2v) completely. In all of these cases (2t–
2v), no conversion into the corresponding products was
observed and significant amounts (> 80%) of the starting
materials were recovered.
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
RT
RT
RT
RT
RT
RT
RT
4
5[d]
6
7
8
Toluene
DMF[e]
[a] Reactions were conducted with 0.2 mmol of 1a and 0.24 mmol of the
iodane. [b] 10 mol% AgOAc was added. [c] 1.5 equiv of base were added.
[d] Reaction was performed with 1 mol% of the RhIII catalyst.
[e] DCE=1,2-dichloroethane, DMF=N,N-dimethylformamide.
entry 1). By adding DIPEA as a base, the reaction could be
significantly accelerated and even performed at room temper-
ature to give 2a in 65% yield (Table 1, entry 2). We then
realized that the reaction proceeded even in the absence of
a cocatalyst to yield 2a in 75% (Table 1, entry 3).
However, we still detected significant side-product for-
mation by NMR analysis of the crude product. The two most
abundant side products were identified as being the benzoic
acid esters 3 (4% yield) and 4 (5% yield). The latter is the
result of a subsequent OH alkynylation followed by hydrol-
ysis of the triple bond (Figure 1).[11] Neither the correspond-
ing ortho-alkynylated phenol derivative nor the correspond-
ing E-configured stereoisomer could be detected, which
demonstrates the perfect chemo- and stereoselectivity of
this chelate-assisted transformation. On performing an
À
intense literature search for rhodium(III)-mediated C H
insertions, we found a report by Maitlis and co-workers from
1987. It describes the formation of a cyclometallated rhodium
Finally, we investigated the principle reactivity of the
obtained 1,3-enynes (Scheme 3). Compound 2a was inves-
tigated as a model substrate. Treating 2a with the cationic AuI
catalyst [(MeCN)AuPPh3]SbF6 led to 6-exo-dig cyclization to
give 2H-chromene 6 in 84% yield. For further derivatization
of the triple bond, protection of the free OH group was
necessary. Methylation of 2a followed by removal of the TIPS
Figure 1. Analysis of the side products.
2
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Scheme 3. Derivatization of model compound 2a. TBAF=tetra-n-butyl-
ammonium fluoride, NBS=N-bromosuccinimide.
reaction as shown in Scheme 4.[12a,b,16a,d] Base-assisted ligand
À
exchange with 1a followed by C H bond activation through
an addition/elimination cascade leads to the formation of
rhodacycle A. Insertion of the triple bond adjacent to the
hypervalent iodine of TIPS-EBX* gives rhodacycle B, which
undergoes elimination of 2-iodo-6-methylbenzoate to give the
rhodium vinylidene complex C. 1,2-Migration of the vinylic
moiety followed by a ligand exchange finally releases the
desired product 2a and regenerates the rhodium(III) catalyst.
In summary, we have developed a mild and highly
effective method for the electrophilic alkynylation of 2-
vinylphenols by using modified TIPS-EBX* under rhodium-
(III) catalysis. This reaction merges an OH-directed reaction
with an electrophilic alkyne transfer reagent and is charac-
terized by mild reaction conditions and ease of preparation.
The corresponding products are obtained in excellent yields
Scheme 2. Reactions were carried out at room temperature with
0.2 mmol 1, 0.24 mmol TIPS-EBX*, 0.30 mmol Hꢀnig’s base, and
2.5 mol% [(Cp*RhCl2)2] in 2 mL of MeCN. Cp*=pentamethylcyclopen-
tadiene. [b] The reaction was performed in 1,2-dichlorethane as
solvent.
protecting group yielded the terminal 1,3-enyne 7 in 86%
yield. Starting from this intermediate, Sonogashira coupling
under standard conditions with iodobenzene gave bis-
(aryl)enyne 8 in 88% yield. Copper-catalyzed Huisgen-type
cycloaddition gave triazole 9 in 72% yield and reaction with
the Schwartz reagent and NBS gave the corresponding diene
10 in 70% yield.
Considering mechanistic studies and proposals by other
À
groups working in the field of rhodium(III)-catalyzed C H
bond activation, we propose a mechanism for the underlying
Scheme 4. Proposed reaction mechanism.
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Communications
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Received: December 18, 2014
Revised: January 14, 2014
Published online: && &&, &&&&
À
Keywords: alkynes · C H activation · enynes · iodine · rhodium
.
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Communications
À
C H Activation
P. Finkbeiner, U. Kloeckner,
B. J. Nachtsheim*
&&&& — &&&&
OH-Directed Alkynylation of 2-
Vinylphenols with Ethynyl
Benziodoxolones: A Fast Access to
Terminal 1,3-Enynes
TIPS and tricks for alkynylation: The first
direct alkynylation of 2-vinylphenols was
developed. The rationally optimized
hypervalent iodine reagent TIPS-EBX*
(see scheme)in combination with
tion metal catalyst enables the construc-
tion of a variety of highly substituted 1,3-
enynes in high yield under mild condi-
tions and with excellent chemo- and
stereoselectivity.
À
[(Cp*RhCl2)2] as a C H-activating transi-
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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These are not the final page numbers!