Gold vs Rhodium Catalysis: Tuning Reactivity through Catalyst Control in the C-H Alkynylation of Isoquinolones

Article abstract of DOI:10.1021/acs.orglett.6b00175

A site-selective C-4/C-8 alkynylation of isoquinolones catalyzed by gold and rhodium complexes is reported. A broad range of synthetically useful functional groups (-F, -Cl, -Br, -CF₃, -OMe, alkyl, etc.) were tolerated, providing an efficient a

Full text of DOI:10.1021/acs.orglett.6b00175

Letter
pubs.acs.org/OrgLett
Gold vs Rhodium Catalysis: Tuning Reactivity through Catalyst
Control in the C−H Alkynylation of Isoquinolones
Aslam C. Shaikh, Dinesh R. Shinde, and Nitin T. Patil*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
S
* Supporting Information
ABSTRACT: A site-selective C-4/C-8 alkynylation of iso-
quinolones catalyzed by gold and rhodium complexes is
reported. A broad range of synthetically useful functional
groups (−F, −Cl, −Br, −CF3, −OMe, alkyl, etc.) were
tolerated, providing an efficient and robust protocol for the
synthesis either C-4- or C-8-alkynylated isoquinolones.
Scheme 1. Site-Selective C−H Functionalization of
Isoquinolones: Known and Present Work
soquinolone is a privileged structural motif widely found in
1
Inatural products and biologically valuable compounds.
Consequently, tremendous efforts have been devoted to the
effective synthesis and functionalization of isoquinolones. Over
the past few decades, transition-metal-catalyzed C−H function-
alization has emerged as an attractive, economical, and
environmentally benign alternative to the classical synthetic
methods, allowing the expeditious formation of diverse
isoquinolones.2 In particular, the direct C−H functionalization
of isoquinolones has witnessed great success for late-stage
modification of the preexistent quinolone scaffolds.
Hirano and Miura, for the first time, reported a copper-
mediated C6-selective heteroarylation of 2-pyridones in which
the observed site selectivity was directed by a pyridyl substituent
on the nitrogen atom of the isoquinolone ring.3 Recently, Hong
and co-workers reported an efficient catalytic system for the N-
pyrimidyl group directed C-2 selective C−H alkenylation of 4-
quinolones using a decarbonylative coupling strategy.4 Very
recently, pioneering work from Hong’s laboratory revealed an
interesting example of catalyst-controlled site selective C−H
arylation of isoquinolone using aryliodonium salts as the
coupling partners (Scheme 1, eq 1).5 Recently, the site-selective
direct alkynylation of quinolones was reported by them (Scheme
1, eq 2).6 The key for the success of this reaction was the use of
appropriate group placed at nitrogen atom of quinolones. We
were particularly interested in the introduction of an alkyne7 in
the isoquinolones, as alkynes are a key functional group for many
organic transformations. Herein, we describe a site-selective C-
4/C-8 alkynylation of isoquinolones enabled by gold and
rhodium complexes (Scheme 1, eq 2). Based on Hong’s report
(Scheme 1, eq 1)5 and our continued interest in the exploration
of molecular diversity through catalyst control,8 we speculated
that C-4 selectivity can be achieved with the use of electrophilc
metal catalysts while the C-8 selectivity is expected when metal
catalyst capable of coordinating the carbonyl group causing C8−
H activation is employed.
benziodoxol-3(1H)-one (TIPS-EBX) (2), which was first
reported by Waser in the alkynylation of indoles with gold or
palladium catalysis9 and further applied to Rh(III)- or Ir(III)-
catalyzed C−H alkynylation by Li,10 Loh,11 and Glorius.12 When
N-methylisoquinolone (1a) was treated with TIPS-EBX in the
presence of AuCl3/AuBr in DCE at 25 °C, the desired C4-
alkynylation product 3a was not obtained at all; starting material
was recovered in a quantitative amount (Table 1, entries 1 and
2). Pleasingly, 3a was obtained in 54% yield when AuCl was used
as catalyst (entry 3). The reaction worked with a broad range of
solvents (entries 3−6); however, more promising results were
obtained in the case of dry CH3CN. The product 3a was isolated
Our initial investigation focused on the reaction of N-
Received: January 19, 2016
methylisoquinolone (1a) and 1-[(triisopropylsilyl)ethynyl]-1,2-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00175
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization Studies
Table 2. Gold-Catalyzed C-4 Alkynylation
b
yield (%)
temp
entry
cat.
AuCl3
additives
solvent
(°C)
3a
4a
1
DCE
25
25
25
25
25
25
50
25
25
25
25
25
50
80
trace
2
AuBr
DCE
3
AuCl
DCE
54
64
74
81
92
4
AuCl
Et2O
5
AuCl
CHCl3
CH3CN
CH3CN
DCE
6
AuCl
7
AuCl
8
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
trace
trace
trace
13
9
Cu(OAc)2
Zn(OTf)2
AgOAc
DCE
10
11
12
13
14
DCE
DCE
AgSbF6
DCE
44
AgSbF6
DCE
62
c
AgSbF6
DCE
88
a
Reaction conditions: 0.15 mmol of 1a, 0.18 mmol of 2, 10 mol % of
a
b
Reaction conditions: (1) 0.15 mmol of 1a, 0.18 mmol of 2, 10 mol %
AuCl, dry CH3CN (2.0 mL), 50 °C, 24 h. No product formation,
starting material recovered. Isolated yields are given.
c
of catalyst, dry solvent (2.0 mL), 24 h (entries 1−7); (2) 0.15 mmol of
1a, 0.18 mmol of 2, 2.5 mol % of [RhCp*Cl2]2, 5 mol % of additives,
b
c
dry DCE (2.0 mL), 16 h (entries 8−14). Isolated yields. 10 mol % of
AgSbF6 was used.
3n−p were obtained in excellent yields (85−90%). In addition,
the C−H alkynylation reaction is readily found to proceed with
structurally related benzoisoquinolone substrate to give the
desired alkynylation product 3q in 76% yield.
We next examined the scope of the C-8-selective alkynylation
reaction. As shown in Table 3, isoquinolone bearing halogen as
well as electron-donating and -withdrawing groups in the phenyl
ring underwent smooth reaction with TIPS-EBX (2) to obtain
the corresponding C-8 alkynylation products in good yields. The
C-2-substituted isoquinolones were also found to be good
substrates affording the corresponding products in good yields
(4n−p, 85−90%). Similarly, when the benzoisoquinolone
substrate was submitted to the optimal reaction conditions, the
product 4q was isolated in 79% yield.
Next, we endeavored to achieve C-4/C-8 dialkynylation in a
stepwise as well as in a one-step fashion (Scheme 2). Thus, when
3a was treated with standard rhodium catalysis, product 5 was
obtained in 75% yield. Similarly, the treatment of 4a with
standard gold catalysis conditions afforded 5 in 48% yield.
Interestingly, dialkynylation product 5 could also be obtained in a
one-pot fashion under Au/Rh relay catalysis,14 albeit in 32%
yield.
On the basis of the Au-mediated alkynylation of indole, as
reported by Waser9d and proven theoretically by Ariafard,15 the
proposed mechanism for C-4 selective C−H alkynylation is given
in Scheme 3. At first, the coordination of AuCl to the triple bond
of TIPS-EBX 2 would take place to form gold−alkyne complex 6.
The gold−alkyne complex 6 would readily convert into vinyl−
gold complex 7 via isoquinolone metalation followed by α/β-
elimination followed by 1,2-shift depending on the regioselec-
tivity of the addition. Other mechanisms triggered by the
oxidative addition of Au(I) within the C−I bond cannot be ruled
out.9g Regarding C-8-selective C−H alkynylation, the catalytic
cycle could start from [RhCp*Cl2]2 (I). The first event would be
in 92% yield at 50 °C when reaction was run for 24 h.
Interestingly, in none of the cases was C8-alkynylation product
4a. In the search for a catalytic system suitable for obtaining 4a,
we screened various catalysts capable of affecting chelation-
assisted C−H activations. Although there exist a number of
reports on the C−H functionalization using heteroatom as
directing groups, very few reports exist where carbonyl (or amide
carbonyl) groups have been used as directing groups.13 Hence,
rhodium catalysts in combination with metal salts have been
examined at 25 °C (entries 8−10); however, the formation of 4a
was not observed. Interestingly, AgOAc, a popular additive for
[RhCp*Cl2]2 catalyzed C−H activation reactions, gave 4a, albeit
in 13% yield (entry 11). Switching the additive from AgOAc to
AgSbF6 increased the yield of 4a up to 44% (entry 12). With an
increase in the temperature up to 50 °C, 4a was obtained in 62%
yield (entry 13). A significant improvement in yield was noticed
when the amount of AgSbF6 was increased up to 10 mol % and
the temperature up to 80 °C (entry 14, 88%).
With the optimized reaction conditions in hand, the scope of
the reaction was examined with various isoquinolones. As shown
in Table 2, C-4 selective alkynylation of isoquinolones proceeded
well to give the desired products irrespective of substitution
patterns on the phenyl ring. Both electron-donating and
-withdrawing substituents, such as methyl (3f and 3g), methoxy
(3h and 3i), fluoro (3j), chloro (3k), bromo (3l), and
trifluoromethyl (3m), were compatible, providing alkynylisoqui-
nolones in moderate to good yields. It should be noted that N-
phenyl-substituted isoquinolones were unsuccessful in yielding
the desired coupling products under the present reaction
conditions (3e) probably because of the lower nucleophilicity.
Interestingly, introduction of a substitution at C-2 position of
isoquinolones did not hamper the outcome of the reaction, and
B
DOI: 10.1021/acs.orglett.6b00175
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Rhodium-Catalyzed C-8 Alkynylation
Scheme 3. Plausible Mechanism
a
Reaction conditions: 0.15 mmol of 1a, 0.18 mmol of 2, 2.5 mol %
[RhCp*Cl2]2, 10 mol % of AgSbF6, dry DCE (2.0 mL), 80 °C, 16 h.
Reaction shows complex mixture of products. Isolated yields are
b
c
given.
Scheme 2. Dialkynylation of Isoquinolones
Scheme 4. Utility of Products
the coordination of catalyst to 1a followed by C−H activation.
This process could be the rate-determining step and may follow a
concerted metalation/deprotonation pathway leading to inter-
mediate 8 as reported by Glorius and co-workers.12 Next, the
acetylene may coordinate to Rh(III) to yield intermediate 9.
From this point, insertion of acetylene in the Rh−C bond can
occur to give intermediate 10, which would finally lead to the
formation of 4a with the regeneration of Rh catalyst.11a
To demonstrate the synthetic utility of alkynylated products, a
few interesting organic transformations of 3a and 4a were carried
out (Scheme 4). The deprotection of the TIPS group in 3a and
4a was achieved with TBAF to obtain terminal alkynes 11a and
12a in 91 and 88% yield, respectively. The terminal alkynes 11a/
12a were then subjected to Sonogashira reactions and copper-
catalyzed azide−alkyne cycloadditions to afford 11b/12b and
11c/12c.
give terminal alkynes, a functional handle for many organic
transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00175.
Experimental procedures, analytical data, and 1H and 13
NMR spectra of all newly synthesized products (PDF)
X-ray data for 3n (CIF)
C
In summary, we developed site-selective (C-4 vs C-8) C−H
alkynylation of isoquinolones catalyzed by gold and rhodium
catalysts. The silyl-protecting groups could be easily removed to
X-ray data for 4l (CIF)
C
DOI: 10.1021/acs.orglett.6b00175
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: n.patil@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Department of Science and
Technology (DST), New Delhi (Grant No. SB/S1/OC-17/
2013) and the Council of Scientific and Industrial Research
(CSIR), New Delhi (Grant Nos. CSC0108 and CSC0130) is
gratefully acknowledged. A.C.S. thanks CSIR for the award of an
SPM Fellowship.
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