Gold-Catalyzed [4+2]- and [3+3]-Annulations of Ynamides with 1-Yn-3-ols to Access Six-Membered Carbocycles and Oxacycles via Three Distinct Cyclizations

Article abstract of DOI:10.1002/adsc.201700784

Three distinct strategies for catalytic annulations between ynamides and 1-yn-3-ols are described; the resulting carbo- and heterocycles were produced efficiently in one-pot operations using a gold catalyst. The chemoselectivities of these annulations are controlled by variations of the substituents of the ynamides and the 1-yn-3-ols. This reaction sequence involves initial alkoxylations of ynamides, followed by Claisen rearrangement of propargylic enol ethers, and ends with 6-endo-trig cyclizations of 1-allenyl-5-amide intermediates. Among these cascade annulations, the cyclizations of 5-allenyl-1-amides to yield 5,6-dihydro-2-pyranones and 6-alkylenecyclohex-2-ene-1-carboxamides are unprecedented in the literature. (Figure presented.).

Full text of DOI:10.1002/adsc.201700784

Title: Gold-catalyzed [4+2]- and [3+3]-Annulations of Ynamides with
1-Yn-3-ols to Access Six-Membered Carbo- and Oxacycles via
Three Distinct Cyclizations
Authors: Rai-Shung Liu and Sovan Sundar Giri
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700784
Link to VoR: http://dx.doi.org/10.1002/adsc.201700784

10.1002/adsc.201700784
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gold-catalyzed [4+2]- and [3+3]-Annulations of Ynamides with
1-Yn-3-ols to Access Six-Membered Carbo- and Oxacycles via
Three Distinct Cyclizations
Sovan Sundar Giria and Rai-Shung Liua,*
a Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, ROC
E-mail: rsliu@mx.nthu.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
can implement three key steps, involving (i) initial
between ynamides and 1-yn-3-ols are described; resulting alkyne alkoxylations, (ii) a Claisen rearrangement of
Abstract. Three distinct strategies for catalytic annulations
carbo- and heterocycles were produced efficiently in one-
pot operations using a gold catalyst. The chemoselectivities
of these annulations are controlled by variations of the
substituents of ynamides and 1-yn-3-ols. This reaction
sequence involves initial alkoxylations of ynamides,
followed by Claisen rearrangement of propargylic enol
ethers, and ended with 6-endo-trig cyclizations of 1-allenyl-
5-amide intermediates. Among these cascade annulations,
the cyclizations of 5-allenyl-1-amides to yield 5,6-dihydro-
2-pyranones and 6-alkylenecyclohex-2-ene-1-carboxamides
are unprecedented in the literature.
propargylic enol ethers, and (iii)
a catalytic
cyclization of 1-allenyl-5-amide intermediates. Three
distinct cyclizations of 5-allenyl-1-amides are
achieved with varying the substituents of the
ynamides. As depicted in eqs 3 and 4, common
ynamides and alkyl-substituted 3-yn-1-ols (R3
=
alkyl) deliver 5,6-dihydro-2-pyranones. Distinct 1,4-
dihydronaphthalene-1-carboxamides were obtained
using ynamides bearing R2 = very electron-rich aryl.
Alternatively, 3-en-1-ynamides and common 3-yn-1-
ols afford 6-alkylenecyclohex-2-ene-1-carboxamides
using the same gold catalyst.
Keywords: propargylic alcohols; carbo & oxacycles;
pyranones; 3-en-1-ynamides; gold catalysis
Gold
catalysis
has
accelerated
new
functionalization of alkynes with diverse nucleophiles
to produce functionalized molecules that are not
readily available from common methods.[1] Gold-
catalyzed reactions of alkynes with propargylic
alcohols (1-yn-3-ols) represent one prominent
example; the resulting 1,5-allenylketones serve as
versatile building blocks in many organic reactions.[2-
3]
The initial work on these reactions was conducted
initially by Saucy and Marber,[2] and extensively
further by Hsung and others[3]. In the context of
ynamides, their reactions with 3-yn-1-ols were
catalyzed by Au(I), Ag(I), Zn(II) and Brønsted
acids;[3] the resulting 1,5-allenylamides were
transformed into furan[3e] and indene[3d] derivatives
using Pd(II) and Pt(II) catalysts respectively. The
overall transformations operated in two steps with
two catalysts such as Zn(II)/Pd(II)[3e] and
Ag(I)/Pt(II)[3d] respectively.
Table 1 shows the effects of gold catalysts on
the reaction chemoselectivity. We employed alkyl-
substituted 1-yn-3-ol (R3 = alkyl) to avoid the
formation of an indene product[3d] as depicted in eq 2.
The reaction of ynamide 1a with 1-yn-3-ol 2a with
p(t-Bu)2(o-biphenyl)AuCl/AgOTf in dichloroethane
(DCE, 25 °C, 8 h) yielded 1-allenyl-5-amide 4 in 76%
yield (entry 1). To enable the cyclization of this 1-
To highlight the new utility of such alkyne
functionalizations, we develop one-pot cascade
[4+2]- and [3+3]-annulations of ynamides with 3-yn-
1-ols to access six-membered carbo- and oxacycles.
Notably, in these annulations, a single Au(I) catalyst
1
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10.1002/adsc.201700784
Advanced Synthesis & Catalysis
allenyl-5-amide, we changed the catalyst to
IPrAuCl/AgOTf and PPh3AuCl/AgOTf; the former
gave a mixture of four isolable products (entry 2)
whereas the latter implemented a clean reaction to
afford 5,6-dihydro-2-pyranone 3a in 80% yield (entry
3). Alternatively, desired 3a was obtained in 78%
These gold-catalyzed reactions were tested with
various ynamides and 1-yn-3-ols to demonstrate the
reaction generality; the results are summarized in
Table 2. Common alkyl- and aryl-substituted
ynamides and alkyl-substituted 1-yn-3-ols were
compatible with the reactions, highlighting the
effective scope of reactions. For phenyl-substituted
ynamides 1b-1d (X = Cl, OMe, Me, entries 1-3), their
catalytic annulations with 1-yn-3-ol 2a proceeded
smoothly to afford desired pyranones 3b-3d in
satisfactory yields (64-82%, entries 1-3). Entries 4-7
showed additional examples for the reactions of
ynamide 1a with various alkyl-substituted 3-yn-1-ols
2b-2e to afford desired compounds 3e-3h in moderate
yields (46-54%, entries 4-7); here, undesired
byproducts like 5, 5’ and 1a-H (Table 1) were also
present and not further isolated. p-Nitrophenyl-
substituted 1-yn-3-ol 2f was also compatible with this
reaction to afford desired 3i in 61% yield (entry 8).
The reactions were extensible to 1-yn-3-ols 2g
bearing R2, R2= cyclohexyl, yielding the compounds
3j and 3k in 52% and 56% yields respectively
(entries 9-10). 2-Furyl-1-ynamide 1e reacted well
with 1-yn-3-ol 2a to produce pyranone 3l in 66%
yield (entry 11). We tested the reactions involving all
alkyl-substituted ynamides 1f-1g and 1-yn-3-ols 2a,
2c and 2e to produce desired products 3m-3o in 46-
51% yields (entries 12-14). Among these pyranone
products, the molecular structures of two
representatives 3b and 3i were determined with x-ray
diffraction studies.[4]
0
yield in a hot DCE solution (65 C, 4 h). We isolated
no furan product as reported in the literature[3d-3e] (eq
2). With PPh3AuCl, other silver salts such as AgNTf2
and AgSbF6 were troubled with competitive alkyne
hydration to produce amide 1a-H in 67-68% yields
(entries 4-5). As depicted in entries 6-9,
PPh3AuCl/AgOTf in dichloromethane (DCM) and
toluene afforded desired 3a in 74% and 58% yields
respectively, whereas MeCN and THF were
inappropriate for this pyranone synthesis. The
treatment
of
1,5-allenylamide
4
with
PPh3AuCl/AgOTf in DCE (8 h) afforded target 3a in
18
81% yield (eq 6). In the presence of H2 O (97 %, 2
equiv), the reactions of ynamide 1a with 3-yn-1-ol 2a
in hot DCE (65 C, 8 h) yielded lactone 3a (M+ =
°
258) bearing only one 18O atom with a mass
distribution of 258 : 260 : 262 = 1.0 : 0.41 : 0. The IR
of compound 3a showed two  (C=O) bands at 1688
and 1662 cm-1 respectively, due to the oxygen isotope
effect (see SI). This information indicates that water
is the oxygen source of the carbonyl group of
pyranone 3a.
Table 1. Synthesis of 5,6-dihydro-2-pyranone with gold
catalysts.
Table 2. Scope of one-pot synthesis of pyranones.
[a][1a]= 0.15M. [b]Product yields are reported after
separation from a silica column. L = p(t-Bu)2(o-biphenyl),
IPr = 1,3-bis(diisopropylphenyl)-imidazol-2-ylidene, Ms =
methanesulfonyl.
[a][1]= 0.15M. [b]Product yields are reported after
separation from a silica column. [c]Reaction temperature
65 °C.
We
tested
the
chemoselectivity
of
phenylproparygylic alcohol 2i that afforded indene
2
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10.1002/adsc.201700784
Advanced Synthesis & Catalysis
derivative 3-in through a gold-catalyzed cyclization
of allenylbenzene moiety as depicted in eq 2. The
molecular structure of compound 3-in was
determined by X-ray diffraction.[4]
In the case of benzodioxole derivative 6g, two regio-
isomeric products 7i and 7i’ were separated in 63%
and 12% yields respectively (entry 10). The
molecular structure of indole-fused cyclohexene 7g
was confirmed by X-ray diffraction.[4]
We developed new gold-catalyzed [3+3]-
annulations of 3-en-1-ynamides[5,6] with various 1-yn-
3-ols (R’ = alkyl and aryl), giving distinct 6-
alkylenecyclohex-2-ene-1-carboxamide derivatives
10, as depicted in Table 4. The reactions of 3-methyl-
3-en-1-ynamide 9a with phenyl-substituted 3-yn-1-
ols (X = H, OMe and Cl) afforded the annulation
products 10a-10c in 56-73% yields (entries 1-3).
Alkyl-substituted 3-yn-1-ols 2a and 2b were also
applicable substrates to yield desired 10d and 10e in
71% and 40% yields respectively (entries 4-5).
Electron-rich 2-thiophene- and 2-furan-containing 3-
yn-1-ols 2l-2m retained high efficiency to deliver 6-
alkylenecyclohex-2-ene derivatives 10f and 10g in
satisfactory yields (61-76%, entries 6-7); herein, we
isolated no indene product that might exist in the
reaction, according to eq 2.[3d] For 3-butyl 3-en-1-
ynamide 9b, cyclohexene derivative 10h was isolated
in 55% yield (dr = 4:5) in toluene (entry 8); the yield
of 10h became 53% when DCE was the solvent.
Interestingly, ynamides bearing electron-rich
aryl groups altered the chemoselectivity to deliver
distinct 1,4-dihydronaphthalene-1-carboxamides
7
together with 2H-pyranones 8 in minor proportions;
the results are summarized in Table 3. When 2H-
pyranones 8 were obtained in significant amount (>
20%), we employed MS 4Ǻ (condition A) to improve
the yields of desired carbocycles 7. 3-(thien-3-yl)-1-
ynamide 6a underwent smooth [3+3]-annulations
with alkyl-substituted 1-yn-2-ols in DCE to afford
4,7-dihydrobenzo[b]thiophenes 7a-7c in 63-94%
yields (entries 1-3). The same operation on 3-(thien-
2-yl)-1-ynamide 6b and 1-yn-3-ol 2a afforded
analogous product 7d and 2H-pyranone 8d in 72%
and 22% yields respectively (entry 4). In the absence
of MS 4Ǻ, the yields of 7d and 8d in DCE became
35% and 61% yields respectively (entry 5). We
prepared 4-ynamides 6c-6f bearing 3-benzothiophene,
3,4-dimethoxybenzene, N-tosyl 3-indolyl and 3,5-
dimethylbenzene, yielding desired annulation
products 7e-7h in 46-65% yields together with 2H-
pyranones 8e-8h in small yields (5-18%, entries 6-9).
Table 4. Synthesis of 6-alkylenecyclohex-2-ene-1-
carboxamides.
Table 3. Synthesis of arene-fused cyclohexene derivatives.
[a][9]= 0.15M. [b]Product yields are reported after
separation from a silica column. [c]Reaction performed in
DCE.
Notably, these 6-alkylenecyclohexene products
10 were produced from a kinetic reaction control
because a treatment of compound 10f with DBU (10
mol%) in hot THF delivered two 1,3-cyclohexadienes
11a’ and 11a” that are separable from a silica column
(eq 8).
[a][6]= 0.15M. [b]Product yields are reported after
separation from a silica column. [c]Reaction temperature
65 °C.
3
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10.1002/adsc.201700784
Advanced Synthesis & Catalysis
In the preceding [4+2]- or [3+3]-annulations, we
An important feature of these cyclizations is the
coordination of LAu+ with allene to generate an
allylic cation like species A; the formation of this
allyl cation is known to be more pronounced with
highly substituted allenes. The difficult cyclization of
species 11a is hence not attributed to the Thorpe-
Ingold effect.[13]
employed 3-yn-1-ols 2 bearing a tertiary alcohol to
achieve a subsequent cyclization of 1-allenyl-5-
amides. To understand this steric effect, we prepared
a secondary alcohol 2n to afford 1-allenyl-5-amide
11a in 86% yield (eq 9). Heating this mixture in hot
°
DCE (70 C, 20 h) failed to induce a cyclization; in
contrast, gold-catalyzed reaction between 3-(thien-3-
yl)-1-ynamide 6a and this alcohol afforded desired
product 11b in 82% yield and dr = 8:1 (eq 10). In the
case of 3-en-1-ynamide 9a, the same reaction
sequence gave no 1-allenyl-5-amide intermediate, but
afforded an unknown carbocycle 11c that cannot be
structurally elucidated because of
rearrangement (eq 11).
a
skeletal
One-pot [3+3]-annulations of ynamides with 3-
yn-1-ols are unprecedented in the literature, but a
cyclization of 5-allenyl-1-amides in the second
annulation, as depicted in Table 3, follows a reported
process as shown in eq 12.[7] Although 5,6-dihydro-2-
pyranones were available from catalytic cyclizations
of allenyl acids or esters (eq 13),[8] such oxacycles in
this work likely proceeded through a new mechanism
because an amide is not easily hydrolyzed. We
postulate that initially resulting 1-allenyl-5-amides 4
are coordinated with LAu+ to generate gold-allyl
cation intermediates,[9,10] which are in turn attacked
by the amide oxygen of its enol form B to induce a
cyclization, yielding 2H-pyran C. These oxacyclic
species are prone to gold-catalyzed hydrolysis to
afford the observed 5,6-dihydro-2-pyranones 3 via
intermediate D. This proposed mechanism
rationalizes well that water is the oxygen source of
the carbonyl group of pyranone products 3.
Scheme1. Postulated mechanism.
In summary, we report new gold-catalyzed
[4+2]- and [3+3]-annulations of ynamides[14,15] with
3-yn-ols to yield useful carbo- and oxacycles in one-
pot operations. Their chemoselectivities are
controlled with variations of the substituents of
ynamides and 3-yn-1-ols using a single gold catalyst.
Among these cascade annulations, the cyclizations of
1-allenyl-5-amide intermediates to yield 5,6-dihydro-
2-pyranones
3
and 6-alkylenecyclohex-2-ene-1-
carboxamides 10 are unprecedented in the literature.
The experimental data indicate that compounds 10
arose from a kinetically controlled process; these
compounds were convertible to two stable 1,3-
cyclohexadienes through a facile isomerization.
Particularly notable is the formation of
6-
alkylenecyclohex-2-ene-1-carboxamides 10 of which Experimental Section
the two olefins are not conjugated with the amide
group. After the cyclization of intermediate E,
Synthesis of 4-butyl-6,6-dimethyl-3-phenyl-5,6-dihydro-
resulting carbocation F is expected to lose a proton at
the acidic –CH(C=O) site to yield a conjugate diene.
We envisage that a non-classical carbocation F’[11,12]
is likely to form, enabling the methyl group being
deprotonated to yield observed products 10 from a
kinetically controlled process. An isomerization of
compound 10 with DBU lead to formation of
cyclohexadienes 11’ and 11”, as shown by eq 8.
2H-pyran-2-one (3a).
A suspension of PPh3AuCl (0.023 g, 0.046 mmol) and
AgOTf (0.012 g, 0.046 mmol) in dry DCE (2 mL) was
fitted with N2 balloon and to this solution was added a
DCE
(1
mL)
solution
of
N-methyl-N-
(phenylethynyl)methanesulfonamide 1a (0.1 g, 0.47 mmol)
and 2-methyloct-3-yn-2-ol 2a (0.134 g, 0.96 mmol) at
room temperature. The resulting mixture was stirred for
8.5 h. after completion of the reaction it was filtered over a
short celite bed. The solvent was evaporated under reduced
4
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10.1002/adsc.201700784
Advanced Synthesis & Catalysis
pressure, and the residue was purified on a silica gel
column using ethyl acetate/hexane (15:85) as eluent to give
compound 3a (0.098 g, 0.38 mmol, 80%) as off-white solid.
[4] Crystallographic data of compound 3b, 3i, 3-in & 7g
were deposited at Cambridge Crystallographic Data
Center: 3b, CCDC 1549338; 3i, CCDC 1549344; 3-in,
CCDC 1563068; 7g, CCDC 1549350.
Synthesis of 5-butyl-N,7,7-trimethyl-N-(methylsulfonyl)
- 4,7- dihydrobenzo[b]thiophene-4-carboxamide (7a).
[5] For catalytic 1,4- and 1,2-functionalizations of 3-en-
ynamides developed by this laboratory, see: a) A. M.
Jadhav, D. B. Huple, R. R. Singh, R. S. Liu, Adv. Synth.
Catal. 2016, 358, 1017-1022; b) A. M. Jadhav, S. A.
Gawade, D. Vasu, R. B. Dateer, R. S. Liu, Chem. Eur.
J. 2014, 20, 1813-1817; c) S. A. Gawade, D. B. Huple,
R. S. Liu, J. Am. Chem. Soc. 2014, 136, 2978-2981; d)
A. M. Jadhav, V. V. Pagar, D. B. Huple, R. S. Liu,
Angew. Chem. 2015, 127, 3883-3887; Angew. Chem.
Int. Ed. 2015, 54, 3812-3816; e) R. R. Singh, R. S. Liu,
Adv. Synth. Catal. 2016, 358, 1421-1427.
A suspension of PPh3AuCl (0.023 g, 0.046 mmol) and
AgOTf (0.012 g, 0.046 mmol) in dry DCE (2 mL) was
fitted with N2 balloon and to this solution was added a
DCE (1 mL) solution of N-methyl-N-(thiophen-3-
ylethynyl)methanesulfonamide 6a (0.1 g, 0.46 mmol) and
2-methyloct-3-yn-2-ol 2a (0.130 g, 0.93 mmol) at room
temperature. The resulting mixture was stirred for 10 h.
after completion of the reaction it was filtered over a short
celite bed. The solvent was evaporated under reduced
pressure, and the residue was purified on a silica gel
column using ethyl acetate/hexane (10:90) as eluent to give
compound 7a (0.155 g, 0.44 mmol, 94%) as brown oil.
[6] For [4+2]- and [4+1]-annulations of 3-en-1-ynamides,
see a) J. R. Dunetz, R. L. Danheiser, J. Am. Chem. Soc.
2005, 127, 5776-5777; b) C. Shu, Y. H. Wang, C. H.
Shen, P. P. Ruan, X. Lu, L. W. Ye, Org. Lett. 2016, 18,
3254-3257; c) R. B. Dateer, K. Pati, R. S. Liu, Chem.
Commun., 2012, 48, 7200-7202.
Acknowledgements
The authors wish to thank the National Science Council, Taiwan
for supporting this work.
[7] a) Y. Qiu, J. Zhou, J. Li, C. Fu, Y. Guo, H. Wang, S.
Ma, Chem. Eur. J. 2015, 21, 15939-15943; b) J.
Barluenga, E. C. Gomez, A. Minatti, D. Rodriguez, J.
M. Gonzalez, Chem. Eur. J. 2009, 15, 8946-8950; c) T.
Watanabe, S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2007,
9, 4821-4824; d) J. Mo, P. H. Lee, Org. Lett. 2010, 12,
2570-2573.
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10.1002/adsc.201700784
Advanced Synthesis & Catalysis
7118; d) A. M. Echavarren, N. Jiao, V. Gevorgyan,
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[15] We have examined the reaction of a different ynamide
1h that appeared be less efficient because the key
allenyamide intermediate became an inactive diene
intermediate 5h that was difficult to obtain in pure form.
6
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Advanced Synthesis & Catalysis
COMMUNICATION
Gold-catalyzed [4+2]- and [3+3]-Annulations of
Ynamides with 1-Yn-3-ols to Access Six-
Membered Carbo- and Oxacycles via Three
Distinct Cyclizations
Adv. Synth. Catal. Year, Volume, Page – Page
Sovan Sundar Giria and Rai-Shung Liua,*
7
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