Gold-catalyzed intermolecular [4+2] and [2+2+2] cycloadditions of ynamides with alkenes

Article abstract of DOI:10.1002/anie.201105921

As good as gold: Gold-catalyzed intermolecular [4+2] cycloadditions of 2-arylynamides with alkenes and gold-catalyzed [2+2+2] cycloadditions of terminal ynamides with enol ethers have been developed (see scheme). The [4+2] cycloaddition is compatible with a range of alkenes and arylynamides and the [2+2+2] cycloaddition can also accommodate a variety of different arylynamide and enol ether substrates.

Full text of DOI:10.1002/anie.201105921

Angewandte
Chemie
DOI: 10.1002/anie.201105921
Synthetic Methods
Gold-Catalyzed Intermolecular [4+2] and [2+2+2] Cycloadditions of
Ynamides with Alkenes**
Ramesh B. Dateer, Balagopal S. Shaibu, and Rai-Shung Liu*
Gold-catalyzed cycloisomerizations of 1,5- and 1,6-enynes
represent important advances in modern catalysis.[1] These
reactions provide unusual and diverse carbocyclic compounds
that are not readily synthesized by common methods.
Importantly, such cycloisomerizations allow facile access to
naturally occurring compounds.[2,3] As gold-catalyzed enyne
cycloisomerizations occur exclusively under intramolecular
conditions, little effort has been devoted to the study of
intermolecular reactions between alkynes and alkenes.[4,5]
Hashmi et al. studied the gold-catalyzed reaction of phenyl-
acetylene with excess 2,5-furan, which gave the desired 2-
phenyl-3,5-dimethylphenol in a low yield (Scheme 1).[4] Very
recently, Echavarren and co-workers reported the efficient
synthesis of cyclobutene derivatives by gold-catalyzed inter-
molecular [2+2] cycloadditions of phenylacetylenes with
alkenes.[5] Intermolecular reactions of alkynes with alkenes
can also be performed with nickel and cobalt complexes to
give acyclic butene or butadiene derivatives.[6,7] We inves-
tigated new intermolecular reactions of alkynes with alkenes
catalyzed by gold complexes. Herein, we report [4+2] cyclo-
additions of 2-arylynamides with alkenes, and [2+2+2] cyclo-
additions of arylynamides with enol ethers (Scheme 1). To our
knowledge, there are no analogous inter- or intramolecular
reactions for this type of [2+2+2] cycloaddition.[7]
Recently, there has been considerable interest in the
electrophilic activation of ynamides and alkynyl ethers. Such
substrates are studied because they are more electrophilic
than other, more common alkynes in reactions catalyzed by
gold compounds.[8–10] These effects arise from the polarized p-
alkyne character of the substrate–catalyst complex (I, which
can also be drawn as the ketene resonance structure (II),
Scheme 2) and can control the regioselectivity of reactions.
Scheme 2. Resonance structures of gold–alkyne complexes. XR2 =OR,
NR2.
Table 1 shows the outcome of the intermolecular [4+2]
cycloaddition of ynamide 1a to 4-methoxyphenylethene
(2 equiv) catalyzed by various gold complexes. Echavarren
and co-workers have reported intramolecular [4+2] cyclo-
additions of arylynes with alkenes.[11] The success of this
intermolecular reaction relies on a suitable gold catalyst and
solvent. The use of [(PPh3)AuCl]/AgNTf2 and [LAuCl]/
AgNTf2 (L = (tBu)2(o-biphenyl)P; Tf = trifluoromethanesul-
fonate) in dichloroethane (DCE) at 258C resulted in the
recovery of unreacted 1a in 62% and 58% yield, respectively
(Table 1, entries 1 and 2). A significant amount of the alkene
underwent dimerization during the long reaction time. The
use of [(IPr)AuCl]/AgNTf2 (IPr= 1,3-bis(diisopropylphenyl)
imidazol-2-ylidene) in DCE gave the desired cycloadduct 2a
in 88% yield after 1 h. (Table 1, entry 3). Table 1, entries 4
and 5 show the effects of the changing the silver salt on the
yield of the reaction. Changing the catalytic system to
[(IPr)AuCl]/AgOTf or [(IPr)AuCl]/AgSbF6 reduced the
yield of 2a to 46% and 57%, respectively. Degradation of
1a also occurred in these two reactions. The use of AgNTf2
alone led to complete decomposition of 1a (Table 1, entry 6).
This cycloaddition is sensitive to solvents: Running the
reaction in dichloromethane gave 2a in 62% yield, whereas
no 2a was formed in nitromethane (Table 1, entries 7 and 8).
The initial step in the formation of 2a is attack of the alkene at
the C1 position of the alkyne, because the gold–alkyne
complex has a ketene-like character (II, Scheme 2). The
Scheme 1. Gold-catalyzed intermolecular alkyne/alkene reactions.
EWG=electron-withdrawing group.
[*] R. B. Dateer, B. S. Shaibu, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: rsliu@mx.nthu.edu.tw
[**] We thank the National Science Council, Taiwan for financial support
of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105921.
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Table 1: [4+2] Cycloadditions of arylynamides and alkenes catalyzed by
gold complexes.[a]
Table 2: Scope of [4+2] cycloadditions with various electron-rich
alkenes.[a]
Ent. Alkene[b]
Time [h] Product
Yield [%][c]
1)
8
78
Entry
[Au][b]
Solvent
Time [h]
Yield [%]
1a[c]
2a[c]
1
2
3
4
5
6
7
8
[PPh3AuCl]/AgNTf2
[LAuCl]/AgNTf2
[(IPr)AuCl]/AgNTf2
[(IPr)AuCl]/AgOTf
[(IPr)AuCl]/AgSbF6
AgNTf2
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
CH3NO2
24
24
1
62
58
–
–
–
–
–
72%
–
–
2)
3)
5
1
84
81
88
46
57
–
62
–
10[d]
3[d]
10[d]
1.5[d]
24
[(IPr)AuCl]/AgNTf2
[(IPr)AuCl]/AgNTf2
[a] Concentration of 1a=0.1m, Ar=4-MeOC6H4. [b] IPr=1,3-bis(diiso-
propylphenyl)-imidazol-2-ylidene, L=P(tBu)2(o-biphenyl). [c] Yields are
reported after purification. [d] Reaction time corresponds to complete
consumption of 1a.
4)
5)
8
2
61
91
intermediate cyclopropyl gold carbenoid III is then attacked
by the tethered phenyl group.
To test the scope of the reaction, we examined the
cycloaddition of 1a with various alkenes (Table 2). The
reactions were performed with [(IPr)AuCl]/AgNTf2
(5 mol%) in DCE at 258C. The cycloadditions of ethoxy-
ethene, 2-methylethoxyethene, (E/Z = 1:1.2) and 2-phenyl-
ethoxyethene (E/Z = 1.1:1) to 1a gave 2-aminonaphthalenes
2b’–2d’ after the loss of ethanol (Table 2, entries 1–3). In
contrast, 2e, which is derived from a cyclic enol ether, was
obtained in 61% yield (Table 2, entry 4). The 1H NMR NOE
spectrum of 2e confirmed its cis-fused configuration.[11] The
reaction of (E)-1-methoxy-4-(prop-1-enyl)benzene with 1a
afforded 2 f in 91% yield (Table 2, entry 5), and the reactions
of 2,4-dimethoxyphenylethene, 3,4-dimethoxyphenylethene,
and 2-thienylethene with 1a gave 2g, 2h, and 2i in high yields
(Table 2, entries 6–8).
6)
1
78
Scheme 3 shows the compatability of the catalytic system
with ynamides 1 that have various aryl substituents (Ar’). The
reactions were performed with 4-methoxyphenylethene
(2 equiv) and [(IPr)AuCl]/AgNTf2 (5 mol%) in DCE at
258C. The reactions of ynamide substrates which contain
electron-rich Ar’ groups, such as 4-methoxyphenyl, 3,5-
dimethoxyphenyl, or benzo[d][1,3]dioxole, gave the corre-
sponding products 3a, 3b, and 3c in high yields. We obtained
satisfactory yields of products 3d–3 f from reactions with
ynamide substrates which contain the electron-deficient Ar’
groups 4-fluorophenyl, 4-chlorophenyl, and 3,5-difluoro-
phenyl. The cycloaddition reactions also work well for
alkyne substrates that contain 3-thienyl, 3-benzothienyl, and
3-benzofuryl substituents. In these cases, the corresponding
products 3g, 3h, and 3i were obtained in 78–94% yields.
7)
0.5
86
8)
5
82
[a] Concentration of 1a=0.1m, IPr=1,3-bis(diisopropylphenyl)imida-
zol-2-ylidene). [b] 2.0 equiv of alkene were used [c] Product yields are
reported after purification.
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Table 3: Gold-catalyzed intermolecular [2+2+2] cycloaddition reaction.[a]
Entry
[Au][b]
Solvent
(time)[b]
Product
(yields [%])[c]
1
2
3
4
5
6
7
[(IPr)AuCl]/AgNTf2
LAuCl/AgNTf2
LAuCl/AgSbF6
LAuCl/AgOTf
DCE (12 h)
4a (56), 5a (14)
5a (83)
DCE (5 min)
DCE (10 min)
DCE (10 min)
DCE (15 min)
CH2Cl2 (8 min)
CH3CN (17 min)
5a (70), 6 (10)
5a (62), 6 (14)
5a (69), 6 (11)
5a (73), 6 (9)
5a (33), 6 (18)
PPh3 AuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgNTf2
[a] Concentration of 4a=0.1m. [b] IPr=1,3-bis(diisopropylphenyl)-imi-
dazol-2-ylidene, L=P(tBu)2(o-biphenyl). [b] Reaction time corresponds
to complete consumption of 4a. [c] Product yields are reported after
purification.
cycloisomerizations. The catalytic system is compatible with
various substituents on the ynamide group, as well as several
different enol ethers (Scheme 4). The cycloadducts 5b–5j
were produced with a high diastereoselectively (diastereomer
ratio greater than 20:1). Products 5b–5g were obtained in 79–
83% yield from reactions with ynamides that contain differ-
ent substituents (EWG = methansulfonyl, toluenesulfonyl, or
Scheme 3. Cycloadditions of 4-methoxyphenylethene with various aryl-
ynamides. Concentration of substrate=0.1m, Ar=4-MeOC6H4. Reac-
tion times and yields are given in parentheses. Yields are reported
after purification.
We also studied the reaction of terminal ynamide 4a with
ethoxyethene (4 equiv) in dichloroethane at 258C (Table 3).
In the presence of [(IPr)AuCl]/AgNTf2 (5 mol%), this
reaction afforded a 14% yield of compound 5a and unreacted
4a in 56% yield (Table 3, entry 1). In contrast, the reaction
with [LAuCl]/AgNTf2 as the catalyst gave compound 5a as a
single diastereomer in 83% yield (Table 3, entry 2). The use
of other gold catalysts [LAuCl]/AgSbF6, [LAuCl]/AgOTf, and
[PPh3AuCl]/AgNTf2 (Table 3, entries 3–5) resulted in lower
yields of compound 5a because small amounts of by-product 6
were also formed. The undesired product 6 was also obtained
in 9% and 18% yield with [LAuCl]/AgNTf2 in dichloro-
methane or acetonitrile, respectively (Table 3, entries 6–7).
The stereochemistry of compound 5a was determined by
1H NMR NOE spectroscopy.[12]
Scheme 4. Scope of gold-catalyzed [2+2+2] cycloaddition. Concentra-
tion of 4=0.1m, EWG=electron-withdrawing group, L=P(tBu)2(o-
biphenyl). Yields are given in parentheses and are reported after
purification.
To our knowledge, there is no analogue of the [2+2+2]
cycloaddition, even in gold-catalyzed intramolecular enyne
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phenylsulfonyl; R1 = n-butyl, benzyl, or phenyl). Compounds
5h, 5i, and 5j were obtained from the reaction of ynamide 4a
with n-butoxyethene, tert-butoxyethene, and 1-methyl-1-
methoxyethene, respectively. The yields of these reactions
were between 52–81%.
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rationalized in Scheme 5. Our calculations indicate that 5a is
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Scheme 5. Synthesis of 5a by [2+2+2] cycloaddition.
more likely to proceed through the intermediate cyclopropyl
gold-carbenoid A than resonance structure B because struc-
ture B will give a [2+2] cycloadduct.[14] In our experiments we
did not obtain any of the [2+2] cycloadducts, which indicates
that the role of structure B in the reaction is insignificant. We
postulate that species A reacts further with the second alkene
to give an oxonium species that may have two conformations
(C and C’, Scheme 4) in the final cyclization. The product of
the reaction is 5a, which suggests that the steric interactions
between the equatorial oxonium moiety and the gold catalyst
of conformation C’ are more hindered than the 1,3-axial
interaction between the amino group and the oxonium moiety
in conformation C. Therefore, the less-hindered conformation
will control the stereoselectivity of the cyclization.
In conclusion, prior to this study there were very few
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alkynes with alkenes.[1,4,5] This study describes gold-catalyzed
[4+2] cycloadditions of 1-amino-2-aryl-1-ynes with alkenes.[15]
The reaction has a wide scope and can accommodate various
alkenes, as well as ynamides which are substituted with
different aryl groups. The reactions of terminal ynamides with
enol ethers resulted in highly stereoselective [2+2+2] cyclo-
additions.
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Keywords: cycloaddition · enynes · gold · ynamides
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[12] 1H NMR NOE spectra of the key compounds are provided in the
Supporting Information.
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[13] Procedures for the calculations are described in the Supporting
Information.
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