Gold/Lewis acid catalyzed oxidative cyclization involving activation of nitriles

Article abstract of DOI:10.1039/d0cc06875f

A gold-catalyzed oxidative cyclization of alkyne-nitriles using water or alcohol as the external nucleophiles has been developed. The catalytic system, featured with gold and Lewis acid dual catalysis, allows a facile synthesis of functionalized isoquinolin-1(2H)-ones and 1-alkoxy-isoquinolines with a wide structural diversity. This journal is

Full text of DOI:10.1039/d0cc06875f

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S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC06875F
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Gold/Lewis Acid Catalyzed Oxidative Cyclization Involving
Activation of Nitriles
Received 00th January 20xx,
Accepted 00th January 20xx
Ali Wang, Xin Xie, Chunli Zhang and Yuanhong Liu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
functionalized products such as amides, esters, ketones,
amidines or heterocycles by reactions with various nucleophiles
under relatively mild conditions.5 Thus incorporation of nitriles
into cascade reactions is highly desirable for the creation of
novel C-C, C-N and C-O bonds. We envisioned that a reaction
shown in Scheme 1, eq 3 might be accessed initiated through
1,2-migration of a substituent tethered with a nitrile group (path
b). The highly electrophilic carbocation can be viewed as a
bifunctional building block and might be able to react with weak
nucleophiles such as water and alcohols via
A gold-catalyzed oxidative cyclization of alkyne-nitriles using
water or alcohol as the external nucleophiles has been devel-
oped. The catalytic system, featured with the gold and Lewis
acid dual catalysis, allows facile synthesis of functionalized
isoquinolin-1(2H)-ones and 1-alkoxy-isoquinolines with wide
structural diversity.
In recent years, gold-catalyzed oxidative reactions using
pyridine or quinoline N-oxides as the oxidants1 have been
shown to be a promising strategy for the construction of
diversely functionalized carbo- or heterocycles. Generally,
these reactions are initiated through nucleophilic attack of the
N-oxides to the gold-activated alkyne followed by elimination of
a neutral organic framework. The resulting highly electrophilic
-oxo gold-carbene intermediates can be utilized to induce a
variety of cascade reactions. Two main reaction pathways,
namely, nucleophilic attack (path a) and 1,2-C-X (X = C, N, O, S)
bond migration or 1,2-C-H insertion (path b) are usually
involved for further functionalizations (Scheme 1, eq 1).1
Although much progress has been achieved, the gold-catalyzed
oxidative reactions involving the nitrile group conversions are
quite limited, possibly due to the low reactivity of nitriles
deriving from high energy of the C≡N bond (854 kJ/mol; for
alkyne triple bond: 835kJ/mol).2 So far, nitriles have only been
used by trapping of -oxo gold carbene intermediates in gold-
catalyzed oxidative reactions via path a.3,4 For example, Zhang3e
et al. reported that -oxo gold carbene underwent [3+2]
cycloaddition with nitriles leading to oxa-zoles (Scheme 1, eq 2).
Liu3d et al. developed an oxoarylation of nitriles via
intramolecular trapping of -oxo gold carbene with nitriles. In
these reactions, nitriles are utilized as a nucleophile. It is known
that upon activation of the nitrile group by transition metals or
acids, nitriles can be transferred to a wide variety of
1) Generation and the reaction pattern of -oxo gold carbenes
R1
R1
O
Z
R2
O
R1
R2
O
Z
path b
R3
products
(1)
R2
LAu
R3
LAu+ R3
Nu
LAu+
Z
path a
-
+
-oxo gold carbene
O-Z = N-oxide
2) Known reports: trapping of the a-oxo gold carbene with nitrile (via path a)
O
R2
cat. Au+L
N-oxide
O
R1
R2
N
R2CN
Au+L
O
R1
R2
N+
AuL
R1
R1
(2)
(3)
+
N
3) Our strategy: reaction of the nitrile after 1,2-migration (via path b)
O
O
O
R2
R1
R2
R1
R1
R2
LAu
LAu
NuH
1,2-migration
or
LAu+
N
products
Nu
N
N
Nu
I
II
mode
mode
Scheme 1. Gold-catalyzed oxidative reactions involving nitriles
mode I or II. Herein we describe a dual gold/Lewis acid-
catalyzed oxidative cyclization of alkyne-nitriles in the presence
of external nucleophiles. The present transformation provides
an efficient route to isoquinolin-1(2H)-ones6 and 1-alkoxy-
isoquinolines, which are widely found in natural products,
bioactive compounds and medicines.7
To test our hypothesis, we initially investigated the gold-catalyzed
reactions of o-(cyano)phenyl propargyl ether 1a using water as the
nucleophile. After the extensive examination of the effects of the
gold catalysts, ligands, N-oxides etc. we found that most of the
starting materials remained or a complex reaction mixture was
formed. For example, when the reaction was catalyzed by
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 Road,
Shanghai 200032. E-mail: yhliu@sioc.ac.cn
Electronic Supplementary Information (ESI) available: CCDC-2006747, 2006748
and 2006749. For ESI and crystallographic data in CIF or other electronic format.
See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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PPh3AuNTf2, only complicated mixtures of products were observed butan-1-ol afforded the corresponding products 5b-5d in 56-66%
View Article Online
(Table 1, entry 1). We envisioned that the use of a Lewis acid as the yields. When allyl alcohol was used, theDpOroI:d10u.c10t359e/Dc0oCuCl0d68a7ls5oF
additive might be feasible to facilitate the desired process through be obtained. Secondary alcohols
nitrile activation. Gratifyingly, by addition of 0.5 equiv Zn(OTf)2, the
desired isoquinolin-1(2H)-one 3a8 was obtained in 32% yield in the
presence of 5 mol% Johnphos(MeCN)AuSbF6 (catalyst A), 2.0 equiv
Table 1. Optimization of the Reaction Conditions
2,6-dichloropyridine N-oxide and 2.0 equiv water in DCE at 100 oC for
5 mol% catalyst
2 h (entry 2). A screen of gold catalysts revealed that PPh3AuNTf2 was
O
Ph
2
2.0 equiv N-oxide ( )
OTBS
the most effective catalyst (entry 5). The results indicated that the
gold catalyst with a less bulky ligand afforded the better results,
possibly due to the reduced steric bulk created by the interaction of
the OTBS group with gold species. Interestingly, the commonly used
gold catalysts such as PPh3AuCl also showed good reactivity (entry
6). The high efficiency of PPh3AuCl might be attributed to the
formation of the cationic PPh3AuOTf through halide abstraction by
Zn(OTf)2.4d,9 To verify the hypothesis, the reaction with PPh3AuOTf as
the catalyst was performed, and good yield of 3a was also observed
(entry 7). The results supported that PPh3AuOTf might be the active
species in PPh3AuCl-catalyzed reaction. Other Lewis acids such as
Al(OTf)3 and Sc(OTf)3 were less effective (entries 9-10). The oxidant
of 3,5-dichloropyridine N-oxide worked also well (entry 11). No
desired product was observed without gold catalyst (entry 16). In this
case, 2-(3-oxo-3-phenylprop-1-yn-1-yl)benzonitrile was formed in ca.
34% yield (containing small amount of impurity), along with a minor
byproduct, the structure of which was not defined yet.
We next investigated the substrate scope under the conditions
shown in Table 1, entry 5 (Scheme 2). The reaction showed a broad
scope for alkyne-nitriles, since aryl, vinyl and alkyl groups at the
alkyne terminus were all suitable for this transformation. Electron-
deficient or electron-rich aryl alkynes underwent the reaction
smoothly to afford the corresponding 3b-3h in 60-84% yields. The
functional groups such as -Cl, -F, -CF3, -CN, -Me, tBu and -OMe groups
on the aryl rings tolerated well. However, reaction of the alkyne
bearing an ortho-substituent on the aryl ring afforded 3-amino-1H-
inden-1-one derivative 4 in 17% yield, indicating that the reaction is
sensitive to the steric hindrance. The product 4 might be formed
through 1,2-H migration of the α-oxo-gold carbene intermediate
followed by nucleophilic attack to the nitrile group.10 1-Naphthyl- or
cyclohexenyl-substituted alkynes were also suitable (3k-3l).
Aliphatic alkynes such as n-butyl, phenylethyl or cyclopropyl
substituted ones reacted efficiently (3m-3o). However, with a
phenoxy group on the alkyl chains, a lower product yield (3p,
34%) was observed, possibly due to the competitive
coordination of this group with the Lewis acid. Substitution of
the parent aryl ring with bromo or methoxy group was also
compatible (3q-3r). When a TMS-substituted alkyne was used,
desilylation occurred (3s). Alkynes with a chloro or an amino
group on the alkyl chain resulted in no formation of the desired
products, in these cases, decomposition of the starting
2.0 equiv H2O
0.5 equiv Lewis acid
solvent, 100 oC, 2 h
NH
Ph
CN
1a
O
3a
+SbF6
tBu
Au NCMe
tBu
Cl
Cl
Cl
P
R
Cl
N
O
N
O
N
N
R
R = H
O
O
R
A:
B:
2a
2b
2d
2c
i
R = Pr
N-oxide
yield (%)a
entry
1
catalyst
solvent
Lewis acid
b
2a
-
-
PPh3AuNTf2
DCE
DCE
DCE
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
A
B
2a
2a
2a
32
-(22)
2
3
4
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
IPrAuNTf2
57
PPh3AuNTf2
2a
2a
2a
2a
2a
2a
2b
2c
2d
5
88
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Al(OTf)3
Sc(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
6
PPh3AuCl
77
83
-
PPh3AuOTf
AuBr3
7
8
9
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
31
46
67
10
11
12
13
14
15
16
58
68
77c
PPh3AuNTf2
2a
2a
2a
DCE
DCE
DCE
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
-(24)
AgNTf2
-
d
-
aThe yields were determined by1H NMR using 1,3,5-trimethoxybenzene as an internal
1a
standard. The yields of the unreacted
are shown in parentheses. b6 h. c0.25 equiv
of Zn(OTf)2 was used. d12 h. 2-(3-Oxo-3-phenylprop-1-yn-1-yl)benzonitrile was
formed in ca. 34% yield.
such as isopropanol was examined. However, no apparent
formation of the desired product was observed. We envisioned
that dehydration of the secondary alcohol might occur under
the acidic conditions and a small amount of water contaminated
in the reaction mixture may also have an effect on the reaction
course. To our delight, the target product 5f could be obtained
in 44% yield by adding 3Å molecular sieves. Isoquinolines 5g and
5h could also be formed efficiently using cyclobutanol or
ethoxyethanol as the nucleophile, respectively. The above
results indicated that a wide range of alcohols were compatible
in this reaction, high-lighting the advantages of this
methodology.
materials were observed (3t-3u).
Inspired by the above results, we next applied this catalytic
system to the formation of 1-alkoxy-isoquinolines using
alcohols as the nucleophiles (Scheme 3). However, under the
standard conditions, only little product was resulted. After re
optimization of the reaction conditions, we were pleased to find
that the isoquinoline product 5a was formed in 70% yield using
We next investigated the reactivity of various type of alkyne-
nitriles. Treatment of alkyne 6 bearing an alkylnitrile moiety
under gold-catalyzed conditions at the room temperature led to
enol product 7. However, increasing the reaction temperature
o
gold catalyst with an electron-deficient phosphiteP(OAr)3 (Ar = to 80 C resulted in the formation of a complicated reaction
2,4-di-tert-butylphenyl) as the ligand in the presence of 10 mol%
AgNTf2, 0.5 equiv of Zn(OTf)2 and 20 equiv of MeOH. The yield
of 5a was decreased to 44% without a Lewis acid. A variety of
alcohols could be used as effective nucleophiles for this reaction.
For example, treatment of 1a with ethanol, propan-1-ol, or
mixture. Although the reaction of 6 failed to give the desired
product, the formation of 7 indicated that 1,2-migration of the
aryl ring11 in 6 indeed occur. When propargyl ether 8 bearing an
ortho-cyanophenyl group at the alkyne terminus was employed,
3-amino-indenone 9 was formed.10 The results indicated that
2 | J. Name., 2012, 00, 1-3
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presence of a gold catalyst without the use of Lewis acid
(Scheme 5, eq 1). In this reaction, most oDf O1aI: 1w0.a10s3c9o/Dn0suCmC0e6d8,75F
1,2-migration of the phenyl group at the propargylic position
should be involved (Scheme 4).12
View Article Online
5 mol% (ArO)3AuCl
5 mol% AgNTf2
2.0 equiv H2O
H
O
OTBS
H
O
O
R1
5 mol % PPh3AuNTf2
2.0 equiv H2O
0.5 equiv Zn(OTf)2
OTBS
CN
1.0 equiv Zn(OTf)2
R1
R1
+
Cl
N
O
Cl
DCE, rt, 4 h
O
O
+
R
R
Cl
2a
N
O
Cl
R1
DCE, 100 o
C
NH
Ar = 2, 4-di-tert-butylphenyl
CN
CN
O
, R1 = Ph, 66%
, R1 = 2-thienyl, 62%
6
2a
7a
(2.0 equiv)
(2.0 equiv)
1
3
7b
10 mol% PPh3AuCl
10 mol% AgSbF6
2.0 equiv H2O
OTBS
Ph
3b
3c
3d
3e
, X = Cl, 2 h, 73%
X
O
O
, X = F, 2 h, 83%
O
O
, X = CF3, 1.5 h, 66%
0.5 equiv Zn(OTf)2
+
Ph
NH2
b
, X = CN, 4 h, 67%
DCE, 100 oC, 3 h
N
O
NH
CN
NH
3f
, X = Me, 2 h, 84%
NH
t
O
3g
3h
, X = Bu, 3 h, 70%
, X = OMe, 2 h, 60%
O
8
2d
9
, 51%
(2.0 equiv)
O
3a
, 2 h, 80%
3i
, 2 h, 64%
Scheme 4. Transformation of various alkyne-nitriles
6 mmol scale, 2 h, 72%
O
O
O
O
O
and an unclean product was observed by TLC. Attempted to
isolate the product 10 through column chromatography was
failed due to its instability. Further transformation of 10 was
then performed. The reaction mixture was first quenched with
0.5 M NaOH aqueous solution followed by acidification, and the
resulting crude product reacted with phenylhydrazine to give
pyrazole 11 in 54% yield (containing small amount of impurity).
11 was formed via condensation of the ketoaldehydegenerated
via hydrolysis of silyl enol ether with phenylhydrazine.13 This
result supported the formation of 10. Next, to learn if 10 serves
as the intermediate, we carried out the following reaction by
generating the intermediate 10 in situ. When the reaction was
carried out first at the room temperature for 4 h, then water
and a Lewis acid were added, and stirring at 100 oC, the desired
3a could be formed in 69% yield (Scheme 5, eq 2). Without a
Lewis acid, no desired 3a was observed, indicating that a Lewis
acid plays a role in accelerating the cyclization process (Scheme
5, eq 3). Stepwise addition of gold catalyst and MeOH afforded
5a in 60% yield, indicating that a common intermediate was
formed in both reactions using water or alcohol as the
substrates (Scheme 5, eq 4). In addition, 18O-3a was formed in
79% yield in the presence of H218O under the gold-catalyzed
conditions (Scheme 5. eq 5). The 18O label locates at the amide
moiety, indicating that O atom of the amide group comes from
the water. However, the 18O content is not high (66%),
indicating that possibly, trace water contained in the reaction
mixture may also participate the reaction.
NH
O
NH
O
NH
NH2
O
3k
3l
3m
, 1 h, 62%
4
, 2 h, 43%
, 1.5 h, 60%
, 4 h, 17%
O
O
Ph
O
O
Ph
O
Br
NH
NH
NH
NH
O
O
O
O
3n
3o
3p
3q
, 2 h, 74%
, 2 h, 62%
, 1 h, 53%
, 2 h, 34%
Cl
3
O
O
N
Ph
O
H
O
NH
NH
O
NH
NH
MeO
O
O
O
3r
3s
3t
c3u
, 1.5 h, 0%
, 2 h, 40%
, 1 h, 23%
, 2 h, 0%
aIsolated yields. b It is hard to obtain the product with high purity through column chromatography,
was provided. c1.0 equiv Zn(OTf)2 was used.
3e
then NMR yield of
Scheme 2. Scope of alkyne-nitriles using water as the nucleophilea
10 mol% (ArO)3PAuCl
O
Ph
N
10 mol% AgNTf2
20.0 equiv ROH
0.5 equiv Zn(OTf)2
OTBS
CN
+
Cl
N
O
Cl
Ph
DCE, 100 o
C
OR
Ar = 2, 4-di-tert-butylphenyl
1a
2a
5
(2.0 equiv)
Based on the above experiments, a possible reaction
mechanism is given in Scheme 6. Initially, attack of pyridine N-
oxide onto the gold-coordinated alkyne enables the formation
of vinyl gold intermediate 12 with high regioselectivity, which is
governed by the inductive effect of the propynyl ethers. Frag-
mentation of 12 affords the α-oxo gold carbene 13, this is fol-
lowed by a 1,2-aryl migration onto the gold carbene11c to form
intermediate 14. Elimination of the gold complex affords 10,
which might form an equilibrium with 14, although the
equilibrium favors 10 rather than 14. Attack of water or an
alcohol to the nitrile group activated by a Lewis acid in 14
followed bynucleophilic attack to the oxonium moiety delivers
the inter mediate 15. Deauration of 15 gives the products 3 or
5 (path a). Alternatively, attack of water or an alcohol at the
oxonium ion moiety in 14 may occur at first, this is followed by
nucleophilic attack to the nitrile group and subsequent
rearrangement14(path b).
O
O
O
O
N
N
N
N
OnBu
OnPr
OMe
OEt
5a
5b, 2 h, 65%
5c
, 2 h, 70%
, 3 h, 56%
5d
, 3 h, 66%
O
O
O
O
N
O
N
O
N
O
N
O
iPr
OEt
b
b
b
5e
, 4 h, 45%
5f
, 3.5 h, 44%
5g
5h
, 2.5 h, 62%
, 3.5 h, 57%
aIsolated yields. b30 mg 3A MS was added.
Scheme 3. Scope of alcoholsa
To understand the reaction mechanism, various control
experiments were carried out. It was found that the oxidation
of alkyne 1a with 2a occurred at the room temperature in the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Ph
N
N
1
(a) L. Zhang, Acc. Chem. Res., 2014, 47, 877. (b) L.-W. Ye, X.-Q.
Ph
View Article Online
O
Ph
OTBS
OTBS
Zhu, R. L. Sahani, Y. Xu, P.-C. Qian and R.-S. Liu, Chem. Rev.,
5 mol %
PPh3AuNTf2
DOI: 10.1039/D0CC06875F
i) work-up
Doi: 10.1021/acs.chemrev.0c00348.
M. B. Smith and J. March, March’s Advanced Organic
Chemistry, 2007, 6th edn, p. 29.
(1)
+
Ph
ii) 3.0 equiv
PhNHNH2
DCE, rt, 6 h
Cl
N
O
Cl
DCE, rt, 4 h
CN
2
3
CN
10
possible product
CN
1a
2a
11
, 54%
(2 equiv)
(a) Q. Wang, M. Rudolph, F. Rominger and A. S. K. Hashmi, Adv.
Synth. Catal., 2020, 362, 755. (b) V. Ku-kushkin, D. Dar'in and
A. Dubovtsev, Adv. Synth. Catal., 2019, 361, 2926. (c) V. A.
Rassadin, V. P. Boyarskiy and V. Y. Kukushkin, Org. Lett., 2015,
17, 3502. (d) S. N. Karad and R. Liu, Angew. Chem. Int. Ed.,
2014, 53, 5444. (e) W. He, C. Li and L. Zhang, J. Am. Chem. Soc.,
2011, 133, 8482.
For gold-catalyzed reactions involving nitriles without the use
of an oxidant see: (a) R. Vanjari, S. Dutta, M. P. Gogoi, V.
Gandon and Sahoo, A, K. Org. Lett., 2018, 20, 8077. (b) S. N.
Karad and R. Liu, Angew. Chem. Int. Ed., 2014, 53, 9072. (c) Y.
Xiao and L. Zhang, Org. Lett., 2012, 14, 4662. (d) A. S. Demir,
M. Emrullahoglu and K. Buran, Chem. Commun., 2010, 46,
8032. (e) R. S. Ramón, N. Marion and S. P. Nolan. Chem. Eur.
J. 2009, 15, 8695.
2.0 equiv H2O
5 mol % PPh3AuNTf2
DCE, rt, 4 h
0.5 equiv Zn(OTf)2
(2)
(3)
1a
1a
+
2a
3a, 69%
100 oC, 2 h
2.0 equiv
2.0 equiv H2O
100 oC, 2 h
5 mol % PPh3AuNTf2
DCE, rt, 4 h
+
2a
3a
2.0 equiv
not observed
4
20 equiv MeOH
0.5 equiv Zn(OTf)2
10 mol % (ArO)3PAuCl
10 mol % AgNTf2
(4)
(5)
1a
1a
+
2a
5a
, 60%
100 oC, 2 h
DCE, rt, 4 h
2.0 equiv
O
Ph
5 mol % PPh3AuNTf2
2.0 equiv H218O (18O = 94%)
0.5 equiv Zn(OTf)2
+
2a
DCE, 100 oC, 2 h
NH
2.0 equiv
18O
79%, 18O = 66%
5
6
R. C. Larcok, Comprehensive Organic Transformations: A
Guide to Functional Group Preparations. 2nd ed. VCH: New
York, U.S.A, 1999.
18
3a,
O-
Scheme 5. Mechanistic studies
For the synthesis of isoquinolinones, see: (a) P. Jagtap, E.
Baloglu, G. Southan, W. Williams, A. Roy, A. Nivorozhkin, N.
Landrau, K. Desisto, A. Salzman and C. Szabó, Org. Lett., 2005,
7, 1753. (b) F. Wang, H. Liu, H. Fu, Y. Jiang and Y. Zhao, Org.
Lett., 2009, 11, 2469. (c) V. Tyagi, S. Khan, A. Giri, H. Gauniyal,
B. Sridhar and P. Chauhan, Org. Lett., 2012, 14, 3126. (d) N.
Webb, S. Marsden and S. Raw, Org. Lett., 2014, 16, 4718. (e)
B. Niu, R. Liu, Y. Wei and M. Shi, Org. Chem. Front., 2018, 5,
1466. (f) Y. Zhao, C. Shi, X. Sua and W. Xia, Chem. Commun.,
2020, 56, 5259. (g) There is only one report for the synthesis
of isoquinolinones bearing an aryl ketone moiety (one
example in the paper) through the reaction of ortho-
functionalized aryl ester with 1,3,5-triazine under strong basic
conditions: J. Hayashida and S. Yoshida, Tetrahedron Lett.,
2018, 59, 3876.
path a:
R1
R1
R1
-
+
LAu+
O-Z
LAu+
Z+
O
R1
O
R1
LAu
O
LAu+
O
LAu
OTBS
LA
OTBS
-LAu+
+LAu+
OTBS
OTBS
OTBS
N
N
N
N
N
LA
LA
12
13
14
10
-
+
O-Z = N-oxide
R1
O
R1
R1
O
R1
O
O
LAu
LAu
OTBS
OTBS
H+
or
NH
N
R
N
-LA
TBSOH
LAu+
N
ROH = H2O or alcohol
O
LA
O
OR
15
ROH
3
5
path b:
R1
O
O
R1
O
R1
O
R1
7
(a) J. Chen, H. Peng, J. He, X. Huan, Z. Miao and C. Yang, Bioorg.
Med. Chem. Lett., 2014, 24, 2669. (b) E. Kiselev, N. Empey, K.
Agama, Y. Pommier and M. Cushman, J. Org. Chem., 2012, 77,
5167. (c) J. H. Rigby, U. S. M. Maharoof and M. E. Mateo, J.
Am. Chem. Soc., 2000, 122, 6624.
O
LAu
LAu
LAu
LAu
OTBS
OTBS
OTBS
OTBS
H+
OR
N
NH
HOR
-LA
R
N
LA
O
R
LA
NH
R1
14
16
17
18
O
R1
O
8
9
CCDC-2006747 (3a), -2006748 (5a), and -2006749 (7b)
contain the supplementary crystallographic data for this
paper.
(a) A. Guérinot, W. Fang, M. Sircoglou, C. Bour, S. Bez-zenine-
Lafollée and V. Gandon, Angew. Chem. Int. Ed., 2013, 52, 5848.
(b) J. Han, N. Shimizu, Z. Lu, H. Amii, G. B. Hammond and B.
Xu, Org. Lett., 2014, 16, 3500.
LAu
OTBS
H+
3
5
or
NH
R
NH
R
H+
TBSOH
LAu+
O+
20
O+
19
Scheme 6. Possible reaction mechanism
In summary, we have developed a new reaction pattern of
gold-catalyzed oxidative cyclization of alkyne-nitriles. The
catalytic system, featured on the gold and Lewis acid dual
catalysis, allows facile synthesis of functionalized isoquinolin-
1(2H)-ones and isoquinolines which are privileged motifs in
many bioactive and pharmaceutical substances. Further
application of this new dual catalysis are currently underway in
our laboratory.
We thank the National Key Research and Development
Program (2016YFA0202900), the Science and Technology Com
mission of Shanghai Municipality (18XD1405000), and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000) for financial support.
10 For the proposed mechanism, see supporting information.
11 (a) J. Zhao, W. Xu, X. Xie, N. Sun, X. Li and Y. Liu, Org. Lett.,
2018, 20, 5461. (b) L. Wang, X. Xie and Y. Liu, Angew. Chem.,
Int. Ed., 2013, 52, 13302. (c) For DFT calculations involving
1,2-aryl migration, see: F. Zarkoob and A. Ariafard,
Organometallics, 2019, 38, 489.
12 When 6-phenylhex-5-ynenitrile was used as a substrate, (E)-
6-oxo-6-phenylhex-4-enenitrile was obtained derived from
1,2-H migration, see supporting information.
13 X. Yao, T. Wang, X. Zhang, P. Wang, B. Zhang, J. Wei and Z.
Zhang, Adv. Synth. Catal., 2016, 358, 1534.
14 For gold(I)-catalyzed intramolecular carboalkoxylation of
Alkynes initiated through attack of a -OMe group to the alkyne,
see: P. Dubeand and F. D. Toste, J. Am. Chem. Soc., 2006, 128,
12062.
Notes and references
4 | J. Name., 2012, 00, 1-3
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