Gold-Catalyzed Oxidative Cyclizations of { o-(Alkynyl)phenyl propargyl} Silyl Ether Derivatives Involving 1,2-Enynyl Migration: Synthesis of Functionalized 1 H-Isochromenes and 2 H-Pyrans

Article abstract of DOI:10.1021/acs.orglett.8b02380

A new and convenient strategy for the synthesis of functionalized 1H-isochromene and 2H-pyran derivatives based on gold-catalyzed oxidative cyclizations of o-(alkynyl)phenyl propargyl ether derivatives has been developed. The reaction proceeds via gold-catalyzed highly regioselective oxidation, followed by 1,2-migration of an enynyl group and nucleophlic addition. Isocoumarins were also constructed through oxidative cleavage of the exocyclic double bond of the obtained 1H-isochromenes.

Full text of DOI:10.1021/acs.orglett.8b02380

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Oxidative Cyclizations of {o‑(Alkynyl)phenyl
propargyl} Silyl Ether Derivatives Involving 1,2-Enynyl Migration:
Synthesis of Functionalized 1H‑Isochromenes and 2H‑Pyrans
Jidong Zhao, Wei Xu, Xin Xie, Ning Sun, Xiangdong Li, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
S
* Supporting Information
ABSTRACT: A new and convenient strategy for the synthesis
of functionalized 1H-isochromene and 2H-pyran derivatives
based on gold-catalyzed oxidative cyclizations of o-(alkynyl)-
phenyl propargyl ether derivatives has been developed. The
reaction proceeds via gold-catalyzed highly regioselective
oxidation, followed by 1,2-migration of an enynyl group and
nucleophlic addition. Isocoumarins were also constructed
through oxidative cleavage of the exocyclic double bond of the obtained 1H-isochromenes.
1H-Isochromene, isocoumarin, and 2H-pyran frameworks are
not only the core structures of many natural products and
pharmaceuticals, but also serve as the useful building blocks for
the construction of highly complex target molecules.1 They
also display a wide range of biological activities. For example,
mansonone F (a) exhibits antiproliferative effects and anti-
MRSA activities;2a,b compound b is a potential antitumor
agent against breast cancer,2c oosponol (c) exerts strong
antifungal activity;2d vermelhotin (d) exhibits moderate
antiplasmodial activity.2e (See Figure 1.) The great importance
Scheme 1. Metal-Catalyzed Cyclizations to 1H-
Isochromenes
Figure 1. Bioactive 1H-isochromene and its derivatives.
of these compounds initiated substantial efforts on the
development of efficient synthetic strategies for these hetero-
cycles. In this regard, transition-metal-catalyzed cycloisomeri-
zations of ortho-alkynylaryl aldehydes3 in the presence of C, N,
or O nucleophiles or ortho-alkynylbenzyl alcohols4 represent
one of the most convenient routes for the synthesis of 1H-
isochromenes (see Scheme 1, eqs 1 and 2). Despite the two
possible regioisomers (dihydroisobenzofurans vs 1H-isochro-
menes derived from 5-exo-dig and 6-endo-dig cyclization,
respectively) that might be principally formed in these
reactions, selective generation of 1H-isochromenes could be
usually achieved under the appropriate reaction conditions
using the former methods (Scheme 1, eq 1). However, the
latter one usually suffers from the low regioselectivity of the
cycloisomerization step. Recently, metal-catalyzed transforma-
tion of ortho-alkynylaryl aldehydes or ketones into 1H-
isochromenes through a reduction (including enantioselective
reduction) using Hantzsch ester as a hydride source5 or
asymmetric hydrogenation of the in situ-formed isochromeny-
lium ions6 have also been reported (Scheme 1, eq 3).
Received: July 27, 2018
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization of the Catalytic System
a
entry
catalyst
catalyst A (5 mol %)
N-oxide
solvent
temperature (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2b (2 equiv)
2c (2 equiv)
2d (2 equiv)
2e (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
2a (2 equiv)
THF
THF
THF
THF
THF
DCE
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
rt
10
6
24
16
3
5
4
5
24
18
18
18
24
18
12
19
10
14
24
24
61
78
64
83
89
9
69
75
46
PPh3AuNTf2 (5 mol %)
IPrAuCl/AgBF4 (5 mol %)
IPrAuCl/AgPF6 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
PicAuCl2 (5 mol %)
PicAuCl2 (5 mol %)/AgNTf2 (10 mol %)
IPrAuCl (5 mol %)
AgNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (5 mol %)
IPrAuNTf2 (2 mol %)
38
b
0 (83)
30
0 (90)
0 (90)
c
88
87
84
88
2a (2 equiv)
2a (1.5 equiv)
2a (1.0 equiv)
2a (1.5 equiv)
rt
rt
rt
a
b
c
1H NMR yields using as CH2Br2 as an internal standard. The yields of the recovered 1a are shown in parentheses. Complex mixture. 4 was
obtained in 45% yield.
However, it is still difficult to introduce a functional group at
the C-4 position of 1H-isochromenes using these methods.7
Recently, transformations involving electrophilic gold
carbenoids have attracted much attention, because such
intermediates can trigger a diversity of valuable reactions.8
Among these reactions, 1,2-migration of a C−C or C-X bond
to the adjacent gold carbenoids serves as an efficient protocol
for the construction of molecular complexity.9 Our previous
work revealed that the gold could catalyze a highly
regioselective and chemoselective oxidative ring expansion of
2-alkynyl-1,2-dihydropyridines to azepines using pyridine-N-
oxide as the oxidant, which proceeds via exclusive 1,2-
migration of a vinyl or an aryl group.9f The competitive 1,2-
hydride migration was not observed. Later, this system was
extended to the synthesis of tropone and various carbocycles
or heterocycles.9g−i During our further studies on gold-
catalyzed migration reactions, we found that new heterocycles
could be accessed by merging the gold-catalyzed 1,2-migration
of an enynyl group with a subsequent cyclization cascade
(Scheme 1, eq 4). It was noted that, in 2014, Hashmi et al.
reported an elegant synthesis of highly substituted 3-
formylfurans by a gold(I)-catalyzed oxidation/1,2-alkynyl
migration/cyclization cascade.9c Herein, we report a new and
convenient strategy for the synthesis of functionalized 1H-
isochromene and 2H-pyran derivatives via gold-catalyzed
oxidative cyclization of o-(alkynyl)phenyl propargyl ether
derivatives involving highly selective 1,2-enynyl group
migration, followed by nucleophilic addition. The exocyclic
CC bond in the obtained 1H-isochromenes could be
selectively reduced, or cleaved to provide isocoumarins, which
are also prevalent motifs in many bioactive molecules. It was
noted that 1,2-enynyl migration onto a gold-carbenoid species
has not yet been reported.
Our initial efforts focused on the gold-catalyzed oxidative
reaction of o-(alkynyl)phenyl propargyl ether 1a (Table 1).
After systematic and detailed investigation on the effects of
gold catalysts, ligands and N-oxides, we found that a 1H-
isochromene product 3a bearing a formyl group at the C-4
position was formed in 61% yield at 50 °C for 10 h upon
treatment of 1a with 5 mol % of Johnphos(MeCN)AuSbF6
(catalyst A) bearing a crowded biphenyl phosphine ligand and
2.0 equiv of 3,5-dichloropyridine N-oxide 2a in THF (Table 1,
entry 1). The results indicate that a selective 1,2-enynyl
migration might be involved during the reaction. The use of
PPh3-ligated gold catalyst PPh3AuNTf2 improved the yield of
3a to 78% (Table 1, entry 2). Gold(I)-carbene complex of
B
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IPrAuCl/AgBF4 (IPr = 2,6-bis(diisopropylphenyl)imidazol-2-
ylidene) was also effective for this reaction to afford 2a in 64%
yield (Table 1, entry 3). To our delight, further screening of
the catalysts revealed that changing the counterions on the
gold-carbene catalysts to PF6− or NTf2− gave high yields of 3a
Scheme 2. Substrate Scope of the Gold-Catalyzed Synthesis
of 1H-Isochromenes
a
−
(Table 1, entries 4 and 5, 83%−89%). Especially, NTf2 was
highly efficient for this transformation, leading to 3a in 89%
yield within 3 h. A complex reaction mixture was observed
when the reaction was carried out in DCE, whereas in toluene,
the desired product was produced in 69% yield (Table 1,
entries 6 and 7). Investigation of other N-oxides such as 2b−
2e indicated that N-oxide 2a gave the best results (Table 1,
entries 8−11 vs entry 5). In the presence of gold(III) complex
PicAuCl2 (dichloro(2-pyridinecarboxylato)gold), however, the
desired 3a was not obtained (Table 1, entry 12). The addition
of AgNTf2 as a chloride scavenger resulted in the formation of
3a in 30% yield (Table 1, entry 13). Control experiments with
IPrAuCl or AgNTf2 alone did not give the desired product
(Table 1, entries 14 and 15). Without N-oxides, naphthyl
ketone 4 was the major product (Table 1, entry 16). 4 might
be formed via first formation of an allenol intermediate,
followed by 6-endo-dig cyclization.10,11 When the reaction was
performed at room temperature, good results could also be
obtained with the use 2.0 or 1.5 equiv of N-oxide 2a (Table 1,
entries 17 and 18). Further decreasing the amounts of N-oxide
2a to 1.0 equiv resulted in a slightly decreased product yield
(84%) and a longer reaction time (Table 1, entry 19). High
yield of 3a was also observed in the presence of 2 mol % gold
catalyst (Table 1, entry 20).
a
Isolated yields. bReaction conditions: 1n (0.2 mmol), 8-methyl-
quinoline N-oxide (0.4 mmol) and catalyst A (5 mol %) in acetone at
50 °C.
We next examined the substrate scope of this novel
migration reaction under the conditions shown in Table 1,
entry 16. To our delight, the reaction proved to be quite
general, with respect to the substitution pattern on the
tethering benzene ring and the R1 and R2 groups on the alkyne
terminus; in most cases, the desired 1H-isochromene products
were obtained in good to high yields (Scheme 2). First, we
examined the effect of substituents R1 on the alkyne terminus.
In the cases of aryl-substituted alkynes, a variety of functional
groups on the aryl ring were tolerated well. For example, both
electron-rich (p-Me, p-OMe) and electron-deficient (p-F) aryl
alkynes underwent the reaction smoothly, providing the
corresponding products 3b−3d in high yields of 79%−83%.
Sterically encumbered 1-naphthyl group was also very
compatible (3e). The reactions of alkyl-substituted alkynes
such as n-butyl- or cyclopropyl-substituted ones were also
satisfactory, leading to 3f and 3g in 74% and 71% yields,
respectively. Next, we examined the substituent effects on the
bottom alkyne terminus (R2). As we expected, aryl, heteroaryl
(exemplified by 2-thienyl group) and alkyl groups were all
compatible for this reaction (3h−3j, 76%−87% yields). The
reaction was also well applicable to the substrates bearing
methoxyl or fluorine groups on the tethering aryl ring (3k−
3m). The reactivity of terminal alkynes on both side-arms were
also examined. However, the desired products were not
observed under the standard reaction conditions. After careful
screening, 30% yield of the target product 3n was isolated in
acetone catalyzed by JohnphosAu(MeCN)SbF6 in the
presence of 8-methylquinoline N-oxide as the oxidant using
1n bearing an upper terminal alkyne moiety as the substrate.
The method has also been successfully extended to enynyl
propargyl ethers 5 without the tethered aromatic ring, and 2H-
pyran derivatives 6 were synthesized accordingly (see Scheme
3). Note that these products generally have low stability;
Scheme 3. Substrate Scope of the Gold-Catalyzed Synthesis
of 2H-Pyrans
a
a
b
Isolated yields. 8-Methylquinoline N-oxide was used.
therefore, an appropriate separation procedure is very
important for getting pure products. After some trials, we
found that separation by column chromatography on silica gel
that was treated with petroleum ether: Et3N = 1:1 and then
petroleum ether before loading the sample afforded the desired
products (6) with high purity. The oxidative cyclization of
enynyl propargyl ethers 5 unsubstituted or with a phenyl
substituent at the central double bond transformed to
polyfunctionalized 3-formyl-2H-pyrans 6a−6d smoothly in
54%−77% yields. Note that, in the case of 6a, the use of 8-
methylquinoline N-oxide afforded higher yields of the pyran
C
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products. Substrate 5e bearing an alkyl group led to 6e in a low
yield, along with an unknown byproduct (ca. 27%). The
byproduct is likely derived through competitive 1,2-OTBS
migration. 2H-Pyrans 6f and 6g fused with a five- or six-
membered ring could also be synthesized in high yields via this
method. However, when a substrate with a fused seven-
membered ring was employed, although a major product could
be observed at the early stage of the reaction, it decomposed
gradually during the reaction process. Compared with the
results of 5a and 1a, the formation of pyran 6a occurs faster
than that of 3a. The results indicate that the migratory aptitude
of an alkynyl-linked vinyl group is more favorable than an
alkynyl-linked phenyl group.9g
results indicate that a 1,2-enynyl migration does indeed occur
in the reaction process.
Scheme 5. Isotopic Labeling Experiments
We next focused on the synthesis of the related 1H-
isochromene derivatives. Interestingly, cyclization of non-
protected propargyl alcohol 7 gave 4-acyl-isochromene 8 in
40% yield, along with 912 in 23% yield. 8 was formed via the
attack of a formyl group instead of a keto group to the triple
bond (Scheme 4, eq 1). However, the addition of NIS to the
Scheme 4. Synthesis of Related Compounds
In conclusion, we have developed a concise and
regioselective access to highly functionalized 1H-isochromene
and 2H-pyran derivatives. Mechanistic studies revealed that an
unprecedented 1,2-enynyl migration on an α-carbonyl gold
carbenoid intermediate was involved as the key step for this
transformation. The method offers several advantages, such as
easily accessible starting materials, high efficiency, and wide
functional group tolerance. Further extensions of this reaction
to the synthesis of other heterocycles are currently underway in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02380.
reaction mixture produced the iodinated 1H-isochromene 10
in high yield, in which phenyl group orients trans, with respect
to the O atom (Scheme 4, eq 2). Possibly, double bond
isomerization occurs under gold-catalyzed conditions.11 This
result also supports the formation of a vinyl gold intermediate
in a domino process. Reduction of 1H-isochromene 3a under
the classical conditions delivered 1H-isochromene 11 in 76%
yield, in which only the exocyclic double bond was reduced. 3a
could also be transformed to isocoumarin 12 by an oxidative
cleavage reaction of the exocyclic double bond (Scheme 4, eq
3). Isocoumarin moiety is found in many natural products and
biologically active molecules. Our method also provides a
practical procedure for the synthesis of functionalized
isocoumarins.
To validate the reaction mechanism, isotopic labeling
experiments were performed. Cyclization of 1a in the presence
of 5.0 equiv of D2O afforded 3a−3d in 79% yield with 81%
deuterium incorporation at the exocyclic double bond,
indicating a vinyl gold intermediate is involved. The proton
source in the reaction system probably comes from a trace
amount of water that existed in the reaction mixture. 18O- and
13C-labeled substrates were also prepared, which converted to
the corresponding 1H-isochromenes in high yields under the
standard conditions. Both the 18O- and 13C labels were found
at the formyl group in the products (see Scheme 5). The
Experimental details, spectroscopic characterization of
all new compounds, and X-ray crystallography of
compounds 3l, 6b, 8, and 10 (PDF)
Accession Codes
CCDC 1844822−1844825 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhliu@sioc.ac.cn.
ORCID
Yuanhong Liu: 0000-0003-1153-5695
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Key Research and Development
Program (No. 2016YFA0202900), the National Natural
■
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Widenhoefer, R. A. Chem. Soc. Rev. 2016, 45, 4533. (c) Qian, D.;
Zhang, J. Chem. Soc. Rev. 2015, 44, 677.
Science Foundation of China (No. 21572256), Science and
Technology Commission of Shanghai Municipality (No.
18XD1405000), the Strategic Priority Research Program of
the Chinese Academy of Sciences (No. XDB20000000), and
Shanghai Institute of Organic Chemistry (No. sioczz201807)
for financial support. We also thank Miss Qi Wang (Northwest
Normal University) and Yi Gan (Shanghai Institute of Organic
Chemistry) for their efforts regarding the preparation of the
starting materials.
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