Synthesis of Isoquinolines through IrIII-Catalyzed C–H Activation/Annulation from Benzimidates with Hydroxylisopropylalkynes

Article abstract of DOI:10.1002/ejoc.201800410

An Ir^III-catalyzed cascade reaction consisting of C–H activation/annulation of benzimidates with hydroxylisopropylalkynes is reported. A broad range of isoquinolines has been prepared in one step with good functiona-group tolerance and high eff

Full text of DOI:10.1002/ejoc.201800410

A Journal of
Accepted Article
Title: Synthesis of Isoquinolines via Ir(III)-catalyzed C-H Activation/
Annulation from Benzimidates with Hydroxylisopropylalkynes
Authors: Jingjing Shi, Mingliang Liu, Wanchun Gong, Erli You, Haizhen
Zhang, Lei Shi, and Weiguo Cao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800410
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800410
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10.1002/ejoc.201800410
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Isoquinolines via Ir(III)-catalyzed C–H
Activation/Annulation from Benzimidates with
Hydroxylisopropylalkynes
Mingliang Liua,b, Wanchun Gongb, Erli Youb, Haizhen Zhangb, Lei Shib, Weiguo Caoa,c*, Jingjing Shib*
Dedication ((optional))
Abstract: Ir(III)-catalyzed cascade C–H activation/annulation of
benzimidates with hydroxylisopropylalkynes has been reported. A
broad range of isoquinolines have been prepared in one step with
good functional group tolerance, and high efficiency.
density of the N-atom was reported by Glorius in the Rh-
catalyzed oxidative cascade reaction of C−H amidation and N−N
bond formation, subsequently Ru or Co -catalyzed imidates
directing
oxidative
cascade
reaction
involving
C−H
activation/annulations was expanded.[6] Oxidative annulation of
the arene C–H bond with alkyne has been widely reported for
the construction of six-membered heteroarenes, and catalyzed
by Rh(III),[7] Ru(II),[8] Co(III),[9] Pd(II),[10] Fe(III).[11] Herein, we
describe an efficient way to prepare diverse isoquinoline
Introduction
Isoquinolines, like some other heterocyclic skeletonsare widely
existed in countless synthetic compounds that display various
derivatives
with
readily
available
benzimidates
and
hydroxylisopropylalkynes under oxidative conditions(Scheme
1b).
biological
activity,
includinganalgesic,
antitumor,
anti-
inflammatory, and antipsychotic.[1] As aresult, many efforts have
been made to achieve an efficient synthesis of these skeletons.
C–H activation/annulation is currently
a
topic attracting
significant interest. With the advent of transition metal-catalyzed
C–H activation reactions, several synthetic methodologies
toward isoquinolines based on straightforward oxidative C–H
annulations were elegantly developed. The majority of these
methods take the advantage of the kinds of transition metals,
such as rhodium, cobalt, manganese, iridium.[2] Although these
methods are effective, It is still necessary to develop new
catalytic system, directing groups and coupling partners
because of their interesting biological properties.
Cp*Ir(III) is powerful to catalyze aromatic C–H
functionalization to construct C–C bond using diazo compounds,
terminal alkynes, terminal alkenes, diaryliodonium salts,
construct C–N bond using organic azides, dioxazolones,
intramolecular amino group, and construct C–X ( X = Cl, Br, I)
bond
activation/annulations reactions were developed in the manners
of redox neutrality, however, oxidative C–H
using
N-halosuccinimides.[3]
Many
C–H
Scheme 1. Cp*Ir(III)-catalyzed oxidative annulation
functionalization/annulation reactions catalyzed by Cp*Ir(III)
have been reported rarely (Scheme 1a).[4] One of the reasons
may be the weaker oxidation capacity of Cp*Ir(III).[5] We
hypothesized that suitable directing groups and coupling
partners were necessary for the purpose of constructing
heterocycles. Imidates as a directing group with higher electron
Results and Discussion
We commenced our investigation using ethyl benzimidate 1a,
and hydroxylisopropylalkyne 2a as model substrates, in the
presence of [Cp*IrCl2]2 (10 mol%) and AgOAc (1.2 equiv) in
MeOH at room temperature for 12 h. Fortunately, the cascade
reaction proceeded smoothly to afford the desired product 3aa
(Table 1, entry 1) in 40% yield. The isolated yield of 3aa
dramatically increased to 68% yield when Ag2CO3 was used as
the additive (entry 2). Further screening revealed that DCE was
a desirable solvent to achieve this transformation in higher yield
(78%, entry 5). Interestingly, continuing to add PivOH further
improved the yield (87%, entry 7). The yield was nearly
unaffected when lower the catalyst loading to 5% (entry 8).
[a]
[b]
[c]
School of Environmental and Chemical Engineering, Shanghai
University
99 Shangda Road, Shanghai 200444, P. R. China
http://www.chem.shu.edu.cn/Default.aspx?tabid=12790
E-mail: wgcao@staff.shu.edu.cn
Shanghai Institute of Materia Medica, Chinese Academy of
Sciences
501 Haike Road, Shanghai 201203, P. R. China
http://www.simm.cas.cn
E-mail: shijingjing@simm.ac.cn
Department of Chemistry, Innovative Drug Research Center,
Shanghai University
Table 1.Optimization of the Reaction Conditions.a
99 Shangda Road, Shanghai 200444, P. R. China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800410
European Journal of Organic Chemistry
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regioisomers (2:1), which was confirmed by H1 NMR and LCMS
with a total yield of 65%.
Catalyst
(mol%)
Yield
(%)b
Entry
Additive
Solvent
1
2
3
4
5
[Cp*IrCl2]2 (10)
[Cp*IrCl2]2 (10)
[Cp*IrCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*IrCl2]2 (10)
AgOAc
Ag2CO3
Cu(OAc)2
Ag2CO3
Ag2CO3
MeOH
MeOH
MeOH
MeOH
DCE
40
68
50
36
78
6
7c
[Cp*IrCl2]2 (10)
[Cp*IrCl2]2 (10)
Ag2CO3
Ag2CO3
1,4-dioxane
DCE
51
87
8c
[Cp*IrCl2]2 (5)
Ag2CO3
DCE
86
9c
[Cp*IrCl2]2 (2.5)
Ag2CO3
DCE
67
Scheme 3. Substrate scope of propargyl alcohols. Reaction Condition: 1 (0.3
mmol), 2 (0.45 mmol), [Cp*IrCl2]2 (5% mol), Ag2CO3 (0.36 mmol), PivOH (0.3
mmol), DCE (2 mL), r.t. for 12 h. Yield of the isolated product.
a) Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst ( mol% ) and
additive (0.36 mmol.) in a solvent (2 mL) for 12 h. b) Isolated yield; c) PivOH (0.3
mmol) was added.
Scheme 2. Substrate scope of benzimidates. Reaction Condition: 1 (0.3
mmol), 2 (0.45 mmol), [Cp*IrCl2]2 (5% mol), Ag2CO3 (0.36 mmol), PivOH
(0.3mmol), DCE (2 mL), r.t. for 12 h. Yield of the isolated product.
Scheme 4. Mechanistic studies.
With the optimized conditions in hand (Table 1, entry 8), we
further explored the scope of substituted benzimidates (Scheme
2). The ethyl benzimidates substituted with electron-donating or
-withdrawing groups at the para-, meta-, or ortho- position
underwent C–H activation/cyclization cascade proceed smoothly
to afford corresponding substituted isoquinolines 3ba-na in
moderate to excellent yields (51-96%). Moreover, this reaction
showed good compatibility with a wide range of valuable
functional groups including fluoro (3da, 3ma), bromo (3ea), iodo
(3fa), ester (3ga), and acetyl (3ha, 3la) substituents which can
be used for further functional group manipulations. It is
Subsequently, we explored the scope of aryl ring of
hydroxylisopropylalkyne 2 (Scheme 3). Substrates of the aryl
ring all are tolerated in this reaction to give good to excellent
yields (69-90%). Substituted in para- (3ab-3ae), meta- (3af), or
ortho- (3ag) position were all well tolerated in the system. Also,
we turned our attention to probe the effects of different the
substitutions on the propargyl group, 3ah was given in 85% yield
under the standard conditions, while 3aj and 3ak were not
detected in the reaction.
To obtain insights into this reaction, preliminary mechanistic
studies have been performed. We isolated an Iridacyclic imidate
complex A from the stoichiometric C–H activation of 1a (Scheme
4a). The structure of A was confirmed by NMR and single-
noteworthy that m-fluorobenzimidate afforded
a
pair of
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10.1002/ejoc.201800410
European Journal of Organic Chemistry
COMMUNICATION
crystal X–ray diffraction analysis (CCDC 1590341). The reaction
of A, 2a, Ag2CO3 and PivOH was performed to rapidly afford 3aa
(75% yield, Scheme 4b). Scheme 4c showed that complex A
was an active catalyst for the coupling/annulation of 1a and 2a.
In addition, a competition experiment has been performed using
an equimolar mixture of 1b, 1g and 2a under the standard
conditions, from which 3ba and 3ga were obtained in 1.2:1 ratio
on the basis of 1H NMR analysis (Scheme 4d), indicating that an
electron-donating groups (EDG) tends to kinetically favor the
reaction.
On the basis of the known Ir-catalyzed C–H bond activation/
cyclization,[12] a plausible reaction mechanism is shown in
Scheme 5. Firstly, 1a and [Cp*IrCl2]2 form the Iridium
intermediate A, which is easily converted into the active Iridium
intermediate B. The coordination of alkyne 2a with complex B
gives intermediate C, and subsequently migratory insertion of
alkyne into the phenylimidate C (sp2)–Ir bond gives seven-
membered intermediate D. Subsequent,the Ir(III) species D may
be oxidized by Ag(I) to generate the Ir(V) species E. Finally,
reductive elimination gives product 3aa and regenerates the
active species B, closing the catalytic cycle.
The Author Gratefully Acknowledges the Support of SA-SIBS
Scholarship Program.
Keywords: isoqunoline; benzimidate; hydroxylisopropylalkynes;
C–H activation; Iridium
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Cl
NH
Cp*
NH
Ir
[Cp*IrCl2]2
OEt
1a
OEt
A
PivOH
OPiv
NH
OH
N
Cp* Ir
OEt
2a
B
Ag2CO3
OEt
reductive
elimination
3aa
2+
2X-
OH
HO
Cp*
Cp*
Ir
N
Ir
N
OEt
C
migration
insertion
OEt
E
HO
Cp*
Ir
2Ag
2Ag+
N
OEt
D
Scheme 5. Proposed Reaction Mechanism
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Conclusions
In summary, we have developed an efficient strategy for the
one-step synthesis of isoquinoline derivatives via a Ir(III)-
catalyzed cascade C–H activation/annulation. The reactions can
occur under mild conditions with broad functional group
tolerance. This protocol employed readily available aromatic
imidates and hydroxylisopropylalkynes as starting materials,
providing a straightforward and economic strategy to access
biologically important isoquinolines.
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Layout 2:
COMMUNICATION
Ir(III)-catalyzed，C–H Activation
M. Liu, W. Gong, E. You, H. Zhang, L.
Shi, W. Cao*, J. Shi*
Page No. – Page No.
Synthesis of Isoquinolines via Ir(III)-
catalyzed C–H Activation/Annulation
Ir(III)-catalyzed cascade C–H activation/annulation of benzimidates with
hydroxylisopropylalkynes has been reported. A broad range of isoquinolines have
been prepared in one step with good functional group tolerance, and high efficiency
from
Benzimidates
with
hydroxylisopropylalkynes
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