Palladium-catalyzed regio- and stereoselective cross-addition of terminal alkynes to ynol ethers and synthesis of 1,4-enyn-3-ones

Article abstract of DOI:10.1002/anie.201411261

Conjugated enynes, enol ethers, and enynones are versatile building blocks that can be elaborated by a wide variety of synthetic transformations. The selective synthesis of such units is a prerequisite for their effective utilization. The synthesis of conjugated 2-phenoxyenynes through a palladium-catalyzed cross-addition of terminal alkynes to phenylethynyl ethers (hydroalkynylation) is now presented. The reaction is highly regio-, stereo-, and chemoselective, and shows excellent tolerance toward functional groups. The addition further features very mild reaction conditions (room temperature) and an inexpensive catalytic system (without a ligand and with a cheaply available Pd catalyst). The thus synthesized enynyl ethers with allylic hydroxy tethers, which survived the reaction, were shown to be ready precursors for valuable 1-en-4-yn-3-ones. Alkyne plus alkyne: The hydroalkynylation of phenoxy alkynes was achieved with high regio-, chemo-, and stereoselectivities. A catalytic amount of [Pd(PPh₃)₂Cl₂] with 2.5equiv. of NEt₃ could mediate the reaction without the need for a ligand, or a Cu catalyst for the activation of the terminal alkyne. The products with allylic hydroxy tether are convenient precursors for useful enynones. pTSA=p-toluenesulfonic acid.

Full text of DOI:10.1002/anie.201411261

Angewandte
Chemie
DOI: 10.1002/anie.201411261
Synthetic Methods
Palladium-Catalyzed Regio- and Stereoselective Cross-Addition of
Terminal Alkynes to Ynol Ethers and Synthesis of 1,4-Enyn-3-ones**
Madala Hari Babu, Vikas Dwivedi, Ruchir Kant, and Maddi Sridhar Reddy*
Abstract: Conjugated enynes, enol ethers, and enynones are
versatile building blocks that can be elaborated by a wide
variety of synthetic transformations. The selective synthesis of
such units is a prerequisite for their effective utilization. The
synthesis of conjugated 2-phenoxyenynes through a palladium-
catalyzed cross-addition of terminal alkynes to phenylethynyl
ethers (hydroalkynylation) is now presented. The reaction is
highly regio-, stereo-, and chemoselective, and shows excellent
tolerance toward functional groups. The addition further
features very mild reaction conditions (room temperature)
and an inexpensive catalytic system (without a ligand and with
a cheaply available Pd catalyst). The thus synthesized enynyl
ethers with allylic hydroxy tethers, which survived the reaction,
were shown to be ready precursors for valuable 1-en-4-yn-3-
ones.
G
iven the importance of conjugated enynes and enol ethers
as subunits in bioactive molecules as well as valuable
synthetic intermediates,[1] a number of efforts have been
made toward their synthesis. Alkyne–alkyne cross-addition
was developed as a practical and atom economical means to
obtain conjugated enynes,[2–5] with couplings ranging from
dimerization to polymerization. After the pioneering studies
by Trost et al. on the homodimerization of terminal alkynes
(Scheme 1A)[2] and the selective coupling of terminal alkynes
with electron-deficient conjugated alkynes (Scheme 1B),[3]
many groups investigated the selective synthesis of enynes
through this pathway. However, most of these studies were
limited to the homodimerization of terminal alkynes,[2] which
do not have extensive use in organic synthesis.
Scheme 1. Alkyne–alkyne cross-addition.
with regioselectivities and undesired homodimerizations.
Although considerable efforts have been made on the
heterodimerization of acceptor alkynes (alkynes with elec-
tron-withdrawing groups), surprisingly, there are hitherto no
precedents on the reactivity of electron-rich alkynes, such as
ynol ethers and ynamines.
As part of our ongoing search for reactions of activated
alkynes,[6] we investigated (Scheme 1E) the selective cross-
coupling of terminal alkynes with ynol ethers to produce
enynes with a phenoxy group tether. Furthermore, we showed
the products we obtained to be convenient precursors for
synthetically highly valuable enynones.[7]
The cross-addition of two different alkynes is rather
limited (Scheme 1B–D) because of the difficulties associated
In an attempt to achieve an alkynylative Meyer–Schuster
rearrangement, we treated substrate 1a[6a] with phenyl
acetylene (2a) under the Sonogashira reaction conditions
(Scheme 2). We hypothesized that the PdII species would
react with the electron-rich b-carbon atom of the ynol ether in
an SN2 fashion before undergoing a metal–ligand exchange
with the Cu–acetylide, and the resultant intermediate would
undergo 1,3-hydroxy migration and reductive elimination to
give 3. Surprisingly, the reaction produced 4aa, along with the
coupled dimer of 2a (Glaser–Hay coupling), through a regio-
selective cross-addition (hydroalkynylation) in a syn manner.
Apart from the importance of 4aa as a selectively substituted
enyne with an enol ether substructure, it appeared, with its
allylic hydroxy group, to be a ready starting material for the
synthesis of the useful enynone 5a through an acid-mediated
migration of the allylic hydroxy group. Additionally, these
two products, which feature a polarized olefin with a tethered
[*] M. Hari Babu, V. Dwivedi, Dr. M. Sridhar Reddy
Medicinal & Process Chemistry Division
CSIR-Central Drug Research Institute
Lucknow, 226031 (India)
E-mail: msreddy@cdri.res.in
R. Kant
Molecular & Structural Biology Division
CSIR-Central Drug Research Institute
Lucknow, 226031 (India)
[**] This work was supported by CSIR-THUNDER (BSC0102), New
Delhi. We are thankful to SAIF, CSIR-CDRI, for providing the
analytical facilities and Dr. Tejender S. Thakur, Molecular and
Structural Biology Division, CSIR-CDRI, for supervising the collec-
tion of X-ray data and the determination of the structure of
compound 4af. M.H.B. and V.D. thank CSIR for the fellowships.
CSIR-CDRI communication no 8886.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411261.
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Table 1: Optimization of the cross-addition.[a]
Entry
Catalyst
Co-catalyst
Base
Solvent Additive Yield
[%][b]
1
2
3
4
5
6
7
8
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
Pd(OAc)2
CuI
CuI
CuI
CuI
CuI
–
–
–
–
–
–
–
–
–
–
–
–
K2CO3
Na2CO3
TEA
py
THF
THF
THF
THF
THF
THF
THF
MeCN
toluene
THF
THF
THF
THF
THF
THF
THF
THF
–
–
–
–
–
–
–
–
50
40
48
–
Scheme 2. Cross-addition of phenyl acetylene to 1a.
DBU
K2CO3
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
–
35
65
85
80
60
82
78
80
72
80
–
alkynyl group, might be attractive substrates for the synthesis
of novel building blocks. We thus began our search for ideal
conditions for the effective addition of 2a to 1a.
9
–
PPh3
dppe
dppf
–
–
–
–
–
10
11
12
13
14
15
16
17
In fact, some recent reports showed that the cross-
addition of terminal alkynes with propargyl alcohols can be
achieved in a regioselective manner (alkyne coupling on the
proximal carbon atom to the propargyl hydroxy group,
Scheme 1D).[5] However, the present work offers a complete
reversal of the regioselectivity (alkyne coupling on the distal
carbon atom to the propargyl hydroxy group) by yielding to
the inherent polarization of the alkyne rather than to the
inductive effect of the propargyl hydroxy group.
[Pd(PPh3)4]
Pd(TFA)2
–
–
–
[Pd(PPh3)2Cl2]
[a] 1a (1.0 mmol), 2a (1.2 mmol), base (2.5 mmol), and catalyst
(10 mol%) in the indicated solvent (anhydrous) at RT for 12 h. [b] Yields
of isolated products. dppf=1,1’-bis(diphenylphosphanyl)ferrocene,
dppe=bis(diphenylphosphanyl)ethane. The entry in bold marks the
optimized reaction conditions.
The optimization studies for the conversion of 1a to 4aa
are presented in Table 1. Initially, we screened various
inorganic (entries 1–2) and organic bases (entries 3–5) with
the same catalytic system ([Pd(PPh3)2Cl2] and CuI) in THF.
None of these reactions led to an improvement in the yield of
4aa. Surprisingly, the yield increased considerably when CuI
was not added (entry 6). Additionally, the undesired homo-
coupling (Glaser–Hay coupling) of 2a was mostly suppressed,
suggesting that the cross-addition actually did not require the
copper catalyst, which in fact hampered the intended reaction
by assisting the unwanted homo-coupling. To our delight,
changing the base to TEA resulted in the formation of 4aa in
85% yield (entry 7). The variation of the solvent (entries 8
and 9), the addition of a phosphorous ligand (entries 10–12),
or the change of the catalyst (entries 13–15) led to the
formation of 4aa only in decreased yields. The optimized
reaction conditions thus included the use of [Pd(PPh3)2Cl2] as
the catalyst and TEA as the base in THF at room temper-
ature. However, the transformation did not occur in the
absence of the catalyst or the base (entries 16 and 17).
With the optimized conditions established, we investi-
gated the scope of the reaction of phenoxy propargyl alcohol
1a with various alkynes (Scheme 3). Similar to 2a, electron-
poor phenyl acetylenes 2b–e smoothly reacted with 1a to
produce 4ab–ae in 71–82% yields. Electron-rich alkynes 2 f–h
were equally reactive (producing 4af–ah in 79–81% yields),
thus indicating that the electronic nature of the alkyne has no
significant effect on the cross-addition. The structure of 4af
was unambiguously confirmed by single-crystal X-ray analy-
sis.[8]
Scheme 3. Cross-addition of acetylenes 2a–o to 1a. Reaction condi-
tions: 1.0 mmol of 1a, 1.2 mmol of 2, 2.5 equiv of TEA, and 0.1 mmol
of [Pd(PPh3)2Cl2] in THF at RT.
was produced in 76% yield. Propargyl compounds 2n and 2o
showed moderate activity (4an and 4ao were obtained in 54
and 61% yield, respectively), partially because of a compet-
itive homo-coupling.
We next focused our attention on the scope of the reaction
with regard to different phenoxy propargyl alcohols 1.[6a]
Various tertiary and secondary propargyl alcohols bearing
a wide range of substitution patterns (alkyl, aryl, vinyl, and
Aliphatic alkynes such as 2i and 2j, and enyne 2k also
readily underwent the cross-addition to produce the corre-
sponding products 4ai–ak in 69–72% yields. The formyl
group in alkyne 2l was tolerated by the reaction to give 4al.
Heteroaryl acetylene 2m showed similar reactivity and 4am
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Scheme 5. Scope of phonoxy alkynes other than propargyl alcohols.
Scheme 4. Scope of phenoxy propargyl alcohols in the cross-addition
with 2a.
hydroxy functionality does not have any role in the course in
the reaction. Next, substrate 1v, bearing no further functio-
nality,[1m] was subjected to the reaction. Various electron-rich
and electron-poor phenyl acetylenes (2a, 2c–d, 2g–h, 2n–o,
Scheme 5B) successfully reacted with 1v under the standard
reaction conditions, but in the alternative solvent CH3CN
(entry 8, Table 1). The reaction of 1v with the protected
propargyl alcohol 2n and propargyl amine 2o afforded the
corresponding products in moderate yields of 51% and 49%,
respectively. To further broaden the scope of the reaction,
conjugated substrate 1w was successfully coupled with 2a, 2d,
and 2 f to obtain triphenyl-substituted adducts 4wa, 4wd, and
4wf, respectively. To our delight, the phenoxy enyne 1x[6a]
could also be coupled with 2a to furnish dienyne 4xa in 76%
yield (Scheme 5C). Because 1v–x required a change of the
solvent under the reactions conditions, we confirmed one of
the structures, 4wa, by X-ray crystallography.[8]
After we had established the highly general hydroalky-
nylation of phenoxy acetylenes, we investigated the trans-
formation of the products to useful enynones through an acid-
mediated migration of the allylic hydroxy group (Sche-
me 1E). After some experiments with a few Bronsted acids
(HCl, H2SO4, trifluoroacetic acid (TFA), and p-toluenesul-
fonic acid (pTSA)), we realized the conversion of 4 to 5 in
excellent yields at room temperature in THF using 30 mol%
pTSA (Scheme 6). Thus, various adducts obtained from
benzophenone (4aa, 4af, 4ah, 4aj, 4ak and 4am) were
converted to the corresponding 1,1-symmetrically substituted
products (5a–f) in excellent yields (90–96%), irrespective of
the substitution at the alkyne terminus. Similarly, 1,1-
dimethyl-substituted enynone 5g was obtained in 91%
yield. We next investigated aldehyde-originating substrates,
which may elaborate to two different isomers (cis and trans).
Promisingly, upon exposure to 30% pTSA in THF, 4pa
cleanly produced the trans isomer 5h[7a] as the sole product in
89% yield. Similarly, the methoxyphenyl-substituted trans
enynone 5i was obtained as the only isomer in 94% yield.
Pleasingly, substrates originating from aliphatic aldehydes
also gave the single enynone adducts 5j–k selectively in
alkynyl) were synthesized and subjected to the addition
reaction with 2a to show the generality of the reaction
(Scheme 4). Substrates 1b and 1c, prepared from the
corresponding benzophenones, were cleanly converted (67
and 86% yield, respectively) to the corresponding products
4ba and 4ca, respectively, with the halogen functionalities
intact (which might have reacted in an equally possible
Sonogashira coupling). Phenoxy propargyl alcohols (1d and
1e) derived from aryl alkyl ketones also smoothly underwent
the targeted hydroalkynylation (4da and 4ea in 81 and 78%
yield, respectively). Similarly, nonbenzylic propargyl alcohols
1 f/1g and 1h/1i, prepared from acyclic and cyclic ketones,
respectively, reacted equally well in the reaction to give 4 fa–
ia in good yields (69–79%). Notably, both terminal and
internal alkenyl groups (as in 1j and 1k) were tolerated in the
synthesis of 4ja and 4ka. Very pleasingly, the addition proved
to be highly chemoselective by discriminating the phenoxy
ethynyl group from the phenyl ethynyl group in 1l to
selectively produce 4la in 76% yield.
Next, we chose various secondary propargyl alcohols for
the selective addition of 2a. Substrates 1m–o, obtained from
aliphatic aldehydes, were smoothly transformed to the
corresponding products 4ma–oa in 76–79% yields. Similarly,
1p–s and 1t, prepared from various benzaldehydes and
cinnamaldehyde, respectively, also reacted in the hydroalky-
nylation to furnish 4pa–ta in 66–82% yields.
Although the reaction can be predicted (from the
previous studies)[2–4] to occur through a concerted syn
addition of the hydroalkynyl palladium species to the
alkyne using the intrinsic polarization for the regioselectivity,
we were interested in finding any possible involvement of the
hydroxy functionality in the assembly of the metal–substrate
complex. Furthermore, we wanted to expand the scope of the
reaction to nonpropargyl substrates to further improve the
generality of the approach. Initially, we subjected the MOM-
protected propargyl substrate 1u to the cross-addition with 2a
(Scheme 5A). This reaction cleanly furnished the correspond-
ing product 4ua in 71% yield, thus demonstrating that the
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Scheme 6. Conversion of enynols 4 to enynones 5.
similar yields (90–92%). Furthermore, the substrate obtained
from cinnamaldehyde was neatly transformed to the di-trans
dienynone 5l in 88% yield. To our pleasure, acetophenone-
and propiophenone-based substrates 4da and 4ea, respec-
tively, also produced the corresponding products 5m–n as
single isomers, thus indicating that the conjugation played
a key role in the selectivity. Finally, the cinnamyl ketone based
substrate 4ka gave 5o in 87% yield as a 3:2 mixture of
stereoisomers, probably because of a weaker conjugation, the
effect of which could not completely dominate over the steric
bulk of the methyl group.
In conclusion, we have demonstrated the cross-addition of
terminal alkynes with ynol ethers in a highly stereo- and
regioselective manner for the synthesis of conjugated 2-
phenoxy-Z-enynes with various functional groups. The reac-
tion neither required a copper catalyst or a ligand to assist
catalysis by the readily available [Pd(PPh3)2Cl2], nor did it
need elevated temperatures. The thus synthesized compounds
with tethered allylic hydroxy groups were ready precursors
for the stereoselective synthesis of useful enynones. With the
high functionalization around the enyne, both substrate
classes should find uses in future synthetic endeavors.
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Received: November 20, 2014
Published online: && &&, &&&&
Keywords: enol ethers · enynes · enynones · hydroalkynylation ·
.
stereoselectivity
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[8] See the Supporting Information for details.
4
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Synthetic Methods
M. Hari Babu, V. Dwivedi, R. Kant,
M. Sridhar Reddy*
&&& — &&&
Palladium-Catalyzed Regio- and
Stereoselective Cross-Addition of
Terminal Alkynes to Ynol Ethers and
Synthesis of 1,4-Enyn-3-ones
Alkyne plus alkyne: The hydroalkynylation
of phenoxy alkynes was achieved with
high regio-, chemo-, and stereoselectivi-
ties. A catalytic amount of [Pd(PPh3)2Cl2]
with 2.5 equiv. of NEt3 could mediate the
reaction without the need for a ligand, or
a Cu catalyst for the activation of the
terminal alkyne. The products with allylic
hydroxy tether are convenient precursors
for useful enynones. pTSA=p-toluene-
sulfonic acid.
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