Mutual Cooperation in the Formal Allyl Alcohol Nucleophilic Substitution and Hydration of Alkynes for the Construction of γ-Substituted Ketones

Article abstract of DOI:10.1002/chem.201600248

Mutual cooperation in the formal allyl alcohol nucleophilic substitution reaction and hydration of an alkyne has been utilized in the presence of a gold catalyst to give a series of γ-functionalized ketones with high to excellent yields. This reaction actually involved an intramolecular O-H insertion cyclization of an alkyne to form the dihydrofuran intermediate, which was followed by the nucleophilic addition ring-opening of a dihydrofuran to give the target compound.

Full text of DOI:10.1002/chem.201600248

DOI: 10.1002/chem.201600248
Communication
&
Organic Synthesis
Mutual Cooperation in the Formal Allyl Alcohol Nucleophilic
Substitution and Hydration of Alkynes for the Construction of
g-Substituted Ketones
Kaimeng Huang,[a] Hongkai Wang,[a] Lingyan Liu,*[a] Weixing Chang,[a] and Jing Li*[a, b]
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alkoxylation of internal alkynes.[8] Directing-group strategies
have been employed to control hydration of both alkyl- and
aryl-substituted alkynes.[8a,d] For example, Hammond and co-
workers developed an AuIII-catalyzed hydration of 3-alkynoates
to provide g-ketoesters in high yields with high regioselectiv-
ity.[8d] They proposed that the regioselectivity was dependent
on the initial intramolecular attack of the ester group to the
neighboring alkyne group, which is a favored 5-endo-dig cycli-
zation rather than the alternative 4-exo-dig process. Hydrolysis
of the resulting oxonium ion and protodeuration would then
form the desired g-ketoesters. In a similar fashion, another ex-
ample showed that the aldehyde or ketone carbonyl group
can act as the directing group for the hydration of an internal
alkyne to generate dicarbonyl products with high regioselectiv-
ity.[9] Moreover, no reaction occurred when using the substrate
bearing no directing group. Additionally, the nucleophile was
limited to water in these reports.[8d,9] For the tethered alcohol
nucleophile,[1g,7e,8a,10] Genet and co-workers have reported the
gold-catalyzed intramolecular hydroalkoxylation of terminal al-
kynes by utilizing bis(homopropargylic) diols substrates, open-
ing a door to an interesting family of strained acetals.[10b]
Krause and co-workers reported that the pendent alcohol
group is an excellent directing group for the intramolecular hy-
droalkoxylation of internal alkynes, which furnished a five-
membered acetal in the presence of an external nucleophile
and Brønsted acid catalyst.[10f]
Abstract: Mutual cooperation in the formal allyl alcohol
nucleophilic substitution reaction and hydration of an
alkyne has been utilized in the presence of a gold catalyst
to give a series of g-functionalized ketones with high to
excellent yields. This reaction actually involved an intra-
molecular OÀH insertion cyclization of an alkyne to form
the dihydrofuran intermediate, which was followed by the
nucleophilic addition ring-opening of a dihydrofuran to
give the target compound.
Transition-metal-catalyzed allyl substitution of unactivated allyl
alcohol substrates has attracted increasing interest due to the
possibility of forming new CÀX (X=O, N, C) bonds;[1] this reac-
tion has broad application prospects for the synthesis of natu-
ral products or pharmaceutical intermediates.[1,2] From the
atom/step economic and environmental perspective, the direct
use of readily available allyl alcohol instead of its derivatives as
substrates undoubtedly represents an improved process as
water is the sole generated byproduct. However, due to the
poor leaving capability of the hydroxyl group, the direct nucle-
ophilic substitution of allyl alcohol is disfavored and challeng-
ing, and thus the hydroxyl groups are usually changed to
better leaving groups, such as halides, carboxylates, or sulfo-
nates.[3] A variety of catalytic systems, such as Brønsted
acids,[1c,4] Lewis acids, transition-metal complexes, Pd, Pt, Mo,
Bi, Ru, Ir, and Au[1,2] or iodine, have been developed to achieve
this transformation.[5] Recently, there are also some reports on
the direct nucleophilic substitution of allyl alcohol; however,
either a high reaction temperature is required or a promoter
must be added to enhance the leaving ability of the hydroxy
group.[1a,b,e]
Considering the above and as a continuation of our ongoing
work, (Scheme 1a),[11] we herein chose the unprotected 1,5-
enynol 2 as a substrate, which includes three functional
groups, such as a double bond, triple bond, and a hydroxy
group. As a result, an unexpected g-functionalized ketone 3
was mainly obtained in high yields by the addition of external
nucleophiles. Herein, a new CÀO, CÀN, or CÀC bond is simulta-
neously formed besides the hydration of the alkyne. Obviously,
this new ketone product was generated from an initial formal
5-endo-dig cyclization of the homopropargyl alcohol activated
by the gold catalyst, and subsequently formal nucleophilic ad-
dition ring-opening of the vinyl dihydrofuran (Scheme 1b). To
the best of our knowledge, this type of ring-opening of vinyl
dihydrofuran was unprecedented and it was the first time that
the mutual cooperation of hydration of alkyne and formal nu-
cleophilic substitution of allyl alcohol were successfully achiev-
ed in one pot. This interesting result intrigued us to further in-
vestigate this cascade reaction.
On the other hand, the addition of an oxygen nucleophile
(water or alcohol) to the alkyne group, known as hydration or
hydroalkoxylation of alkynes, is a well-developed powerful tool
to convert alkynes into carbonyl or acetal compounds. Various
metal catalysts, such as Pd, Rh, Ru, and Pt, as well as other
metals have been developed for this transformation to avoid
using the toxic Hg salt, which has been known for more than
a century in the hydration of alkynes.[6] More recently, the
gold-catalyzed hydration or hydroalkoxylation of alkynes with
high efficiency has attracted the increasing attention of chem-
ists.[7] Despite of these great achievements, developing
a highly efficient catalytic system is desirable and challenging,
especially with regards to regioselective hydration and hydro-
In our initial study, we used (E)-1,6-diphenylhex-1-en-5-yn-3-
ol as a model substrate. In a DCM/MeOH (10:1) mixture,[12]
a new compound 3a was generated almost quantitatively in
the presence of a cationic gold(I) complex of [(Ph3P)AuCl]/
AgNTf2 (Table 1, entry 1).[13] Other catalysts and reaction param-
eters were further screened. It was found that whether using
AuI (entries 1, 2, 5) or AuIII (entry 6), the reaction could smooth-
ly proceed and afford the corresponding product 3a in high to
excellent yield. But to our surprise, when using only
[(Ph3P)AuCl], no catalytic activity was observed, whereas when
using only AgNTf2 the reaction gave a moderate yield of g-me-
thoxy ketone 3a with part of the starting material recovered
over a long reaction time (entry 3 vs. 4). Both platinum(II) chlo-
[a] K. Huang, H. Wang, Prof. L. Liu, W. Chang, Prof. J. Li
The College of Chemistry
the State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Wiejin Road 94#, Tianjin 300071 (P. R. China)
E-mail: lijing@nankai.edu.cn
liulingyan@nankai.edu.cn
[b] Prof. J. Li
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600248.
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However, no desired product was obtained in CHCl3
solvent when using [Pd(PPh3)4] or SnCl2 even when
prolonging the reaction time for 24 h (entries 9 and
10). However, a trace of allyl alcohol etherification
product 5a was obtained in the presence of SnCl2 in
toluene/methanol at 808C (entry 11). Interestingly,
upon changing PtCl2 to PtI2, the reaction afforded
the vinyl tetrahydrofuranyl ether 6a in 89% isolated
yield with a d.r. value of 52:48 in toluene at 458C
(entry 12).[10b,14] Krause and co-workers have report-
ed that an analogue of 6a could be generated with
the necessity of TsOH except when using gold cata-
lyst. Moreover, 6a could be slowly converted herein
to the desired product 3a under the same reaction
conditions by prolonging the reaction time. When
using 5 mmol% [Ir(cod)Cl]2 (cod=1,5-cycloocta-
diene), the substrate 2a gave the product 3a and
6a in 14 and 21% isolated yield, respectively, after
24 h (entry 13).[10e] In summary, the combination of
5 mol% [(PPh3)AuCl] with AgNTf2 was the best cata-
lytic system and gave the highest yield, whereas
using AuCl3 (5 mol%) as the catalyst consumed the
shortest reaction time.
Scheme 1. Cascade reactions of 1,5-enyne alcohols.
Under the optimized reaction conditions, we next
examined various aryl-substituted 3-hydroxy-1-en-5-
ynes 2 with methanol as an external nucleophile. As
shown in Table 2, two methods A (shown in blue)
and B (shown in red) were applied to 3-hydroxy-1-
en-5-ynes with various aryl groups at the terminal of
the alkene and alkyne, respectively. It was found
that all reactions could afford the corresponding g-
methoxylation ketones isomers 3 in high or excellent
yields (3/4>20:1), and method A was generally suit-
able for the substrates with various aryl groups at
the terminal of the alkyne (3a–e), whereas method B
was more efficient for those substrates with various
substituted aryl or alkyl groups at the double bond
(3 f–k). Nevertheless, in the case of 1,5-enynols with
a heteroaromatic group thiophenyl or steric hin-
drance naphthyl on the terminal of alkyne, only
method B was applicable. Namely, these two reac-
tants were successfully transformed to g-methoxyke-
tones by using 5 mol% AuCl3 salt (3l and 3m). In
addition, for the substrates with p-MeO and p-F-sub-
stituted aryls at the terminal of the alkyne as well as
the reactant with m-Me-substituted phenyl on the
double bond, two methods were both effective (3c–
e). In comparison, the [(Ph3P)AuCl]/AgNTf2 (5 mol%)
catalytic system needed a longer reaction time than
AuCl3 in these three cases (Table 2, 3c–e).
Table 1. Optimization studies of the nucleophilic substitution of 2a.[a]
Entry
Catalyst (mol%)
Conditions
Yield [%][b]
1
2
3
4
[(PPh3)AuCl] (5), AgNTf2 (5)
[(X-phos)AuCl] (5), AgNTf2 (5)
[(PPh3)AuCl] (5)
AgNTf2 (5)
DCM, rt, 2 h
DCM, rt, 2 h
DCM, rt, 48 h
DCM, rt, 48 h
99
90
–
50
5
6
7
8
AuCl (5)
AuCl3 (5)
PtCl2 (20)
PdCl2 (30)
[Pd(PPh3)4] (20)
SnCl2 (30)
SnCl2 (30)
PtI2 (5) N-phenylmaleimide (50)
[Ir(cod)Cl]2 (5)
DCM, rt, 30 min
DCM, rt, 30 min
toluene, 808C,1.5 h
toluene, 808C, 2 h
CHCl3, 608C, 24 h
CHCl3, 608C, 24 h
toluene, 808C, 2 h
toluene, 458C, 4 h
MeOH, rt, 24 h
80
91
73
87
–
–
9
10
11
12
13
trace (5a)
89 (6a)
14 (3a)+21 (6a)
[a] Standard procedure: under an N2 atmosphere, catalyst and solvent (2 mL) were
added into the Schlenk tube, [(PPh3)Au]NTf2 (5% mol) was prepared in situ by stirring
a mixture of [(PPh3)AuCl] (5 mol%), AgNTf2 (5 mo%l) in dry (2 mL) solvent for 20 min.
After the addition of MeOH (0.2 mL) and the substrate (0.1 mmol), the reaction was
carried out under the given reaction conditions and the products were subsequently
detected by TLC. [b] Isolated yield.
Meanwhile, we also attempted to apply this meth-
odology to other nucleophiles (Table 3). For exam-
ple, various O-, C-, and N-nucleophiles were all inves-
tigated with 1,5-enynol 2a by using 5 mol%
[(Ph3P)AuCl]/AgNTf2 in DCM (2 mL) at room tempera-
ride and palladium(II) chloride could also effectively promote
this reaction in toluene at a high temperature (entries 7 and 8).
ture. Apparently, all kinds of O-nucleophiles, including all kinds
of alcohols, acid, and water, could react with 1,5-enynol 2a to
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Table 2. The allyl methoxylation of various aryl-substituted 1,5-enynols.[a]
Table 3. The scope of nucleophilic reagents attacking the 1,5-enynols.[a]
[a] Standard procedure: Under a N2 atmosphere, the reactions were con-
ducted with substrate on a 0.1 mmol scale in the presence of [(Ph3P)AuCl]
(5 mol%) and AgNTf2 (5 mol%) or AuCl3 in dry DCM/MeOH=10:1 (2 mL)
at room temperature, and the products were subsequently detected by
TLC.
give the corresponding g-alkoxy, carboxylic and hydroxyl ke-
tones (3a, 3n–t) as major products in good to high yields, re-
spectively. Among them, for the glycol, AuCl3 displayed higher
catalytic activity than [(Ph3P)AuCl]/AgNTf2, resulting in g-alkoxy-
ketone in 65% yield (3q). The reactions of carboxylic acids
with 2a gave lower yields of g-functionalized ketones than
that of alcohols and water. In the examples of C-nucleophiles,
we chose three types of compounds, 1,3,5-trimethoxybenzene,
1-methyl-1H-indole, and 2,4-pentanedione. As a result, two re-
gioselective products, g- and e-functionalized ketones were ob-
tained at the same time in good yields (3u–w, 4u–w). Apart
from that, the p-nitroaniline and m-bromoaniline could also
react with1,5-enyol 2a and give the corresponding g-arylamino
ketone or e-arylaminoketone with a prolonged reaction time
(4x and 4y). Notably, the regioselectivity of N-nucleophiles
was completely different from the O- and C-nucleophiles. The
reason remained unclear at present, and this reaction was very
sluggish when using p-methylaniline (4z).
[a] Standard procedure: Under a N2 atmosphere, [(PPh3)Au]NTf2(5 mol%)
was prepared in situ by stirring the mixture of [(PPh3)AuCl] (5 mol%) and
AgNTf2 (5 mol%) in dry DCM (2 mL) for 20 min. Then the nucleophile and
substrate (0.1 mmol) were added into the above catalyst system. The re-
action mixture was stirred at room temperature, and the products were
subsequently detected by TLC. The amount of N- and C-nucleophile, n-
butyric acid and acetic anhydride is 3 equiv of the substrate, while 0.2 mL
O-nucleophilic reagent such as alcohols or water was utilized in these
transformations. [b] Acetic anhydride (3 equiv of 2a) as a nucleophile.
In order to demonstrate the efficiency of this protocol, we
investigated different nucleophiles, including water, p-nitroani-
line, 1,3,5-trimethoxybenzene, and various substituted aryls-
1,5-enynols (Table 4). A closer inspection of the results shown
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Table 4. The scope of the allylic substitution of various aryl-substituted 1,5-enynols.[a]
[a] Standard procedure: Under a N2 atmosphere, [(PPh3)Au]NTf2 (5 mol%) was prepared in situ by stirring the mixture of [(PPh3)AuCl] (5 mol%) and AgNTf2
(5 mol%) in dry DCM (2 mL) for 20 min. After the addition of nucleophile and the substrate (0.1 mmol), the reaction was carried out under the given reac-
tion conditions and the products were subsequently detected by TLC. NuH=H2O, 0.2 mL; when NuH is the N- or C-nucleophile, the ratio of nucleophile to
enynol is 3:1.
in Table 4 revealed that the reaction worked well with several
typical substituted 1,5-enynols, affording good to high yields
of the desired products. In a general method, the H2O nucleo-
phile afforded the respective g-hydroxyketone (3aa–dd) in
good yields. Herein, the substrate with a 3-methylaryl group at
the terminal alkene resulted in the corresponding product 3bb
with 69% isolated yield in the presence of 5 mol% PtI2, whilst
suffering decomposition using Au catalyst. Notably, the alkyl
substituent (methyl) instead of a phenyl group on the terminal
of alkene was also competent (3dd). As far as p-nitroaniline
was concerned, only the 1,5-enynols with nonsubstituted or
electron-withdrawing-substituted arenes on the double bond
and electron-donating-substituted arenes on the triple bond
were efficient in this cascade reaction (4x–z of Table 3, 4ee,
3 ff–hh in Table 4), and the e-arylaminoketones were mainly
obtained for the enynol with an electron-withdrawing aryl on
the terminal of alkene (4ee). Additionally, when using 1,3,5-tri-
methoxy-benzene as the C-nucleophile, the reaction could pro-
ceed smoothly and give a mixture of g-substituted ketones
and e-substituted ketones in a short time, respectively (3ii–
mm and 4ii–mm). In short, all kinds of nucleophiles and aryl-
or alkyl-substituted 1,5-enynols were competent in this cas-
cade reaction.
entry 12 (Table 1) shows, the vinyl tetrahydrofuranyl ether 6a
was isolated with 89% yield. Moreover, TLC analysis and the
following NMR spectroscopic experiments disclosed that the
final product, g-methoxyketone 3a, was formed by this vinyl
tetrahydrofuranyl ether intermediate 6a in the presence of AuI,
AuIII, or PtII catalyst (Figure 1). The substrate 2a was almost
quantitatively converted into the intermediate 6a after 8 min.
Then the AuI salt as the Lewis acid promoted the allylic posi-
tion CÀO bond cleavage and the formation of the allyl cation;
MeOH as a nucleophile attacked the allyl cation by SN or SN’
allyl alkoxylation,[1c,1 g] thus rendering a mixture of compounds
g-methoxylketone 3a and e-isomer 3a’. Interestingly, the char-
acteristic peaks of e-methoxylketone 3a’ began to disappear
slowly as the reaction time was prolonged, and the signals of
3a were correspondingly strengthened. This demonstrated
that e-methoxylketone 3a’ was isomerized to 3a by a gold-
mediated allylic substitution of allylic ether moieties and pro-
vided the only thermodynamically stable g-methoxyl ketone.[15]
Simultaneously, high regioselective hydration of internal al-
kynes was achieved through this strategy, although the unsym-
metrical disubstituted internal alkyne remains a challenge for
the regioselective hydration.
Based on this, we proposed a possible mechanism for this
cascade reaction (Scheme 2). The initial 5-endo-dig cyclization
through the hydroxyl group OÀH insertion into the carbon–
Next, we investigated the possible mechanism for this cas-
cade formal allyl substitution and hydration of alkyne. As
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Figure 1. 1H NMR trace of the reaction between homopropargylic alcohol 2a and MeOH.
Scheme 2. Proposed possible mechanism for O-, N- and C-nucleophiles.
carbon triple bond activated by Au provided the dihydrofuran
metal intermediate TS-1, which can be tautomerized to TS-2,
followed by intermolecular hydroalkoxylation to give the five-
membered acetal product Int-6a.[10,14a,b] With the assistance of
Lewis acid AuI or AuIII salt, the CÀO bond at the allylic position
is cleaved, and simultaneously the ring-opening of Int-6a oc-
curred and gave the allyl cation intermediate TS-4. To the best
of our knowledge, this type of ring-opening of the vinyl tetra-
hydrofuran was unprecedented.[15,16] The external alcohol as
a nucleophile attacked the allyl cation to complete the SN1 al-
lylic alkoxylation and resulted in the only thermodynamically
stable g-methoxylketone. Herein, the gold catalyst acts as both
p-acid to accelerate the OÀH insertion into the triple bond and
Lewis acid to mediate allylic ether CÀO bond cleavage. For the
external N-, C-nucleophiles, the first step is similar with the
proposed path of O-nucleophiles, the pendent hydroxyl group
directed 5-endo-dig cyclization to give TS-1, which was isomer-
ized to TS-2. However, subsequent steps are different from O-
nucleophiles. No signal was observed of the corresponding N-
or C-nucleophilic addition to the cyclized vinyl metal inter-
mediate TS-3’ to form the possible vinyl tetrahydrofuran prod-
uct In-6a’.[14a,b] Instead, TS-3’ was activated to form the allylic
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cation TS-4’ in the presence of gold catalyst. At the end of the
catalytic cycle, the external N- or C-nucleophile attacks the al-
lylic cation to deliver the final g-substituted products and e-
functionalized isomer.[14a]
the nucleophilic substitution of allyl alcohol, our substrates
structural properties endow them self-selectivity and self-acti-
vation functions to achieve this cascade reaction. This corre-
sponding g-substituted ketone is a prevalent subunit in several
classes of biologically relevant molecules, and the reactivity of
the vinyl dihydrofuran functional group was explored. Future
plans include establishing the chiral g-substituted
To further ascertain the above mutual cooperation process,
we performed several additional control experiments
ketone that may be achieved by this method with
an additional chiral ligand, understanding the factors
governing the ring-opening of this vinyl dihydrofur-
an intermediate, and pursuing synthetic applications.
Acknowledgements
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (grants
21372120 and 21202084). We also thank support
from the Collaborative Innovation Center of Chemi-
cal Science and Engineering (Tianjin).
Scheme 3. Controlled experiments of various functional substrates.
Keywords: 1,5-enynols · cyclization · gold catalysis ·
hydration · nucleophilic substitution · ring-opening
reactions
(Scheme 3). In the case of simple homopropargyl alcohol 7
without a double bond, no g-methoxylketone was detected
even after stirring for 64 h with only furanylmethylether 8 gen-
[1] For reviews, see: a) Y. Tamaru, Eur. J. Org. Chem. 2005, 2647–2656; b) J.
Muzart, Tetrahedron 2005, 61, 4179–4212; c) M. Bandini, M. Tragni, Org.
Biomol. Chem. 2009, 7, 1501–1507; d) M. Bandini, Angew. Chem. Int. Ed.
2011, 50, 994–995; Angew. Chem. 2011, 123, 1026–1027; e) B. Sundar-
araju, M. Achard, C. Bruneau, Chem. Soc. Rev. 2012, 41, 4467–4483;
f) N. A. Butt, W. B. Zhang, Chem. Soc. Rev. 2015, 44, 7929–7967; g) B.
Biannic, A. Aponick, Eur. J. Org. Chem. 2011, 6605–6617.
[2] For representative publications of palladium-catalyzed allyl alcohol sub-
stitution, see: a) X. Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang,
Angew. Chem. Int. Ed. 2014, 53, 6776–6780; Angew. Chem. 2014, 126,
6894–6898; b) H. Zhou, H. Yang, M. Liu, C. Xia, G. Jiang, Org. Lett. 2014,
16, 5350–5353; c) B. M. Trost, J. Quancard, J. Am. Chem. Soc. 2006, 128,
6314–6315; for selected examples of iridium-catalyzed allyl alcohol
substitution, see: d) J. Deng, S. Zhou, W. Zhang, J. Li, R. Li, A. Li, J. Am.
Chem. Soc. 2014, 136, 8185–8188; e) M. Roggen, E. M. Carreira, J. Am.
Chem. Soc. 2013, 135, 19046–19046; f) Y. Yamashita, A. Gopalarathnam,
J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 7508–7509; for selected ex-
amples of gold-catalyzed allylic alcohol substitution, see: g) M. Bandini,
A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48, 9533–9537; Angew. Chem.
2009, 121, 9697–9701; h) M. Bandini, A. Bottoni, M. Chiarucci, G. Cera,
G. P. Miscione, J. Am. Chem. Soc. 2012, 134, 20690–20700; for bismuth-
catalyzed direct substitution of allylic alcohol, see: i) H. Qin, N. Yamagi-
wa, S. Matsunaga, M. Shibasaki, Angew. Chem. Int. Ed. 2007, 46, 409–
413; Angew. Chem. 2007, 119, 413–417.
[3] For reviews, see: a) B. M. Trost, D. L. Vanvranken, Chem. Rev. 1996, 96,
395–422; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–
2943; c) B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837; d) Z. Lu, S. M.
Ma, Angew. Chem. Int. Ed. 2008, 47, 258–297; Angew. Chem. 2008, 120,
264–303; e) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427–
440; f) B. M. Trost, Org. Process Res. Dev. 2012, 16, 185–194; g) B. M.
Trost, Tetrahedron 2015, 71, 5708–5733; h) J. T. Mohr, B. M. Stoltz,
Chem. Asian J. 2007, 2, 1476–1491.
[4] For recent Brønsted acid catalyzed allyilc alcohol substitution examples,
see: a) M. Rueping, U. Uria, M. Y. Lin, I. Atodiresei, J. Am. Chem. Soc.
2011, 133, 3732–3735; b) L. Xu, G. Gao, F. Gu, H. Sheng, L. Li, G. Lai, J.
Jiang, Adv. Synth. Catal. 2010, 352, 1441–1445; c) F. Z. Zhang, Y. Tian,
G. X. Li, J. Qu, J. Org. Chem. 2015, 80, 1107–1115.
1
erated in 75% H NMR spectroscopic yield. Compound 8 was
then transformed to g-hydroxyl ketone 8’ through alkaline
Al2O3 column chromatography (Scheme 3, Eq. (1)). When using
the terminal 1,5-enynol 9, a conjugated dienone 10 was gener-
ated in 39% isolated yield under the optimized conditions
(Scheme 3, Eq. (2)). For the protected 1,5-enynol 11, another
cycloisomerization product 12 was rendered by 5-endo and al-
koxycyclization of 1,5-enyne (Scheme 3, Eq. (3)). All these re-
sults demonstrated that the structures of the internal alkyne
and allyl alcohol were necessary for this novel cascade reac-
tion. The regioselective hydration of internal alkyne and formal
nucleophilic substitution of an allyl alcohol involve mutual co-
operation. In this sense, the existence of the vinyl group that
could stabilize the allyl cation formed is the driving force for
the subsequent possible ring-opening reaction and allyl-substi-
tution reaction.
In conclusion, a cooperated formal allyl alcohol nucleophilic
substitution reaction and hydration of alkyne was developed
in the presence of gold catalyst in one pot. This transformation
occurs under very mild conditions using readily available 1,5-
enynols (based on homopropargyl alcohols), and a series of g-
functionalized ketones can be obtained in high to excellent
yields. O-, N- and C-based nucleophiles are all competent in
this cascade reaction. Importantly, this reaction actually in-
volved an intramolecular OÀH insertion cyclization of alkyne to
form a vinyl dihydrofuran intermediate, which was followed by
nucleophilic addition ring-opening to give the highly regiose-
lective g-functionalized ketone. The ring-opening mode of
vinyl dihydrofuran involved was unprecedented. Despite of the
challenging regioselective hydration of the internal alkyne and
[5] W. Wu, W. Rao, Y. Q. Er, J. K. Loh, C. Y. Poh, P. W. H. Chan, Tetrahedron
Lett. 2008, 49, 2620–2624.
Chem. Eur. J. 2016, 22, 6458 – 6465
www.chemeurj.org
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Communication
[6] For a metal-catalyzed alkyne hydroxylation review, see: a) L. Hinter-
mann, A. Labonne, Synthesis 2007, 1121–1150; for selective publica-
tions of mercury-catalyzed alkynes hydration, see: b) M. Riediker, J.
Schwartz, J. Am. Chem. Soc. 1982, 104, 5842–5844; for selective publi-
cations of palladium-catalyzed alkynes hydration, see: c) X. B. Li, G. B.
Hu, P. Luo, G. Tang, Y. X. Gao, P. X. Xu, Y. F. Zhao, Adv. Synth. Catal. 2012,
354, 2427–2432; d) C. Xu, W. Du, Y. Zeng, B. Dai, H. Guo, Org. Lett.
2014, 16, 948–951; for selective publications on rhodium-catalyzed
alkyne hydration, see: e) J. H. H. Ho, S. W. S. Choy, S. A. Macgregor, B. A.
Messerle, Organometallics 2011, 30, 5978–5984; f) M. Kondo, T. Kochi, F.
Kakiuchi, J. Am. Chem. Soc. 2011, 133, 32–34; for selective publications
of ruthenium-catalyzed alkyne hydration, see: g) M. S. Zeng, L. Li, S. B.
Herzon, J. Am. Chem. Soc. 2014, 136, 7058–7067; h) B. M. Trost, Y. H.
Rhee, J. Am. Chem. Soc. 2002, 124, 2528–2533; for selective publica-
tions of platinum-catalyzed alkyne hydration, see: i) E. A. Baquero, G. F.
Silbestri, P. Gomez-Sal, J. C. Flores, E. de Jesus, Organometallics 2013, 32,
2814–2826; j) J. W. Hartman, W. C. Hiscox, P. W. Jennings, J. Org. Chem.
1993, 58, 7613–7614.
[7] For recent books on gold-catalyzed hydration or hydroalkoxylation of
alkynes, see: a) Modern Gold Catalyzed Synthesis (Eds.: A. S. K. Hashmi,
F. D. Toste), Wiley-VCH, Weinheim, 2012; b) Gold Catalysis: An Homoge-
neous Approach (Eds.: F. D. Toste, V. Michelet), Imperial College Press,
London, 2014; For selected reviews, see: c) A. Corma, A. Leyva-Perez,
M. J. Sabater, Chem. Rev. 2011, 111, 1657–1712; d) D. Pflästerer, A. S. K.
Hashmi, Chem. Soc. Rev. 2016; e) R. Dorel, A. M. Echavarren, Chem. Rev.
2015, 115, 9028–9072; f) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev.
2008, 37, 1766–1775; g) Y. Zhang, T. P. Luo, Z. Yang, Nat. Prod. Rep.
2014, 31, 489–503; for representive examples, see: h) J. Cordón, G. Ji-
menez-Oses, J. M. Lopez-de-Luzuriaga, M. Monge, M. E. Olmos, D. Pasc-
ual, Organometallics 2014, 33, 3823–3830; i) N. Ghosh, S. Nayak, A. K.
Sahoo, J. Org. Chem. 2011, 76, 500–511; j) E. Mizushima, K. Sato, T. Hay-
ashi, M. Tanaka, Angew. Chem. Int. Ed. 2002, 41, 4563–4565; Angew.
Chem. 2002, 114, 4745–4747.
[10] For recent reviews: a) H. Huang, Y. Zhou, H. Liu, Beilstein J. Org. Chem.
2011, 7, 897–936; for representive examples: b) S. Antoniotti, E. Genin,
V. Michelet, J. P. Genet, J. Am. Chem. Soc. 2005, 127, 9976–9977; c) J.
Barluenga, A. Dieguez, A. Fernandez, F. Rodriguez, F. J. Fananas, Angew.
Chem. Int. Ed. 2006, 45, 2091–2093; Angew. Chem. 2006, 118, 2145–
2147; d) A. S. Hashmi, M. Buhrle, M. Wolfle, M. Rudolph, M. Wieteck, F.
Rominger, W. Frey, Chem. Eur. J. 2010, 16, 9846–9854; irdium catalysis:
e) E. Genin, S. Antoniotti, V. Michelet, J. P. Genet, Angew. Chem. Int. Ed.
2005, 44, 4949–4953; Angew. Chem. 2005, 117, 5029–5033; f) V. Belting,
N. Krause, Org. Lett. 2006, 8, 4489–4492; g) P. Nun, R. S. Ramón, S. Gail-
lard, S. P. Nolan, J. Organomet. Chem. 2011, 696, 7–11.
[11] K. Huang, X. Ke, H. Wang, J. Wang, C. Zhou, X. Xu, L. Liu, J. Li, Org.
Biomol. Chem. 2015, 13, 4486–4493.
[12] A. K. Buzas, F. M. Istrate, F. Gagosz, Angew. Chem. Int. Ed. 2007, 46,
1141–1144; Angew. Chem. 2007, 119, 1159–1162.
[13] For representative publications on gold-catalyzed allyl alcohol etherifi-
cation, see: a) B. Biannic, T. Ghebreghiorgis, A. Aponick, Beilstein J. Org.
Chem. 2011, 7, 802–807; b) E. Coutant, P. C. Young, G. Barker, A. L. Lee,
Beilstein J. Org. Chem. 2013, 9, 1797–1806; c) P. C. Young, N. A. Schopf,
A.-L. Lee, Chem. Commun. 2013, 49, 4262–4264; d) M. Bandini, M.
Monari, A. Romaniello, M. Tragni, Chem. Eur. J. 2010, 16, 14272–14277;
e) G. Barker, D. G. Johnson, P. C. Young, S. A. Macgregor, A. L. Lee, Chem.
Eur. J. 2015, 21, 13748–13757; f) P. Mukherjee, R. A. Widenhoefer, Chem.
Eur. J. 2013, 19, 3437–3444.
[14] a) O. Debleds, E. Gayon, E. Vrancken, J. M. Campagne, Beilstein J. Org.
Chem. 2011, 7, 866–877; b) O. Debleds, C. Dal Zotto, E. Vrancken, J. M.
Campagne, P. Retailleau, Adv. Synth. Catal. 2009, 351, 1991–1998; c) Y.
Xie, P. E. Floreancig, Angew. Chem. Int. Ed. 2014, 53, 4926–4929; Angew.
Chem. 2014, 126, 5026–5029.
[15] Y. Sawama, K. Shibata, M. Takubo, Y. Monguchi, N. Krause, H. Sajiki, Org.
Lett. 2013, 15, 5282–5285.
[16] a) S. Enthaler, M. Weidauer, Catal. Lett. 2012, 142, 168–175; b) R. E.
Mulvey, V. L. Blair, W. Clegg, A. R. Kennedy, J. Klett, L. Russo, Nat. Chem.
2010, 2, 588–591; c) R. P. Smyj, J. M. Chong, Org. Lett. 2001, 3, 2903–
2906.
[8] For recent reviews: a) J. A. Goodwin, A. Aponick, Chem. Br. Chem.
Commun. (Camb) 2015, 51, 8730–8741; for representive examples:
b) B. D. Mokar, R. S. Liu, Chem. Commun. 2014, 50, 8966–8969; c) D.
Yang, J. Huang, B. Liu, Eur. J. Org. Chem. 2010, 2010, 4185–4188;
d) W. B. Wang, B. Xu, G. B. Hammond, J. Org. Chem. 2009, 74, 1640–
1643.
Received: January 19, 2016
[9] J. Jeong, D. Ray, C. H. Oh, Synlett 2012, 897–902.
Published online on March 22, 2016
Chem. Eur. J. 2016, 22, 6458 – 6465
www.chemeurj.org
6465
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim