Cp Co(III)-Catalyzed C-H Functionalization Cascade of N-Methoxyamides with Alkynedione for the Synthesis of Indolizidines

Article abstract of DOI:10.1021/acs.orglett.7b00904

Cp Co(III)-catalyzed C-H functionalization cascade of N-methoxyamides with alkynedione has been reported for the synthesis of indolizidine scaffolds under redox-neutral conditions. The reaction displays broad functional group tolerance along with excellen

Full text of DOI:10.1021/acs.orglett.7b00904

Letter
pubs.acs.org/OrgLett
Cp*Co(III)-Catalyzed C−H Functionalization Cascade of
N‑Methoxyamides with Alkynedione for the Synthesis of
Indolizidines
Lahu N. Chavan,† Krishna Kumar Gollapelli, Rambabu Chegondi,* and Amit B. Pawar*,†
,‡
†
,†,‡
†
Division of Natural Product Chemistry, CSIR−Indian Institute of Chemical Technology, Hyderabad 500007, India
‡
Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
*
S Supporting Information
ABSTRACT: Cp*Co(III)-catalyzed C−H functionalization
cascade of N-methoxyamides with alkynedione has been
reported for the synthesis of indolizidine scaffolds under
redox-neutral conditions. The reaction displays broad func-
tional group tolerance along with excellent yield. The reaction
proceeds with kinetically relevant C−H bond activation
through carboxylate assistance with excellent diastereoselec-
tivity and complete opposite selectivity with respect to alkyne
insertion.
8
−10
ndolizidine represents one of the important structural motifs
functionalization reactions.
Until now, several directing
I
in bioactive natural products such as camptothecin, rosettacin,
α-lycorane, and tylophorine (Figure 1). Although various
groups such as pyridyl, pyrimidyl, anilides, imidates, and oximes
have been widely employed in Co(III)-catalyzed reactions.
However, the use of N-methoxyamides under redox-neutral
conditions, wherein the N−O bond acts as an internal oxidant, is
1
11
very rare.
Apart from C−H functionalization, Lewis acidity of Co(III)
catalyst has also been utilized via dual activation (Scheme 1). In
2
015, Glorius and co-workers reported an efficient Co(III)-
catalyzed C−H functionalization with diazo compounds to
access new class of conjugated polycyclic hydrocarbons, wherein
Co(III) is believed to play a dual role as a transition-metal
catalyst for C−H activation and Lewis acid to promote
Figure 1. Representative natural products containing indolizidine
scaffold.
12
nucleophilic addition. The same group has reported Co(III)-
catalyzed quinazoline synthesis from aryl imidates and
dioxazolones wherein cobalt is shown to perform a dual
synthetic methods have been reported to access the indolizidine
2
skeleton, the development of novel synthetic methods utilizing
inexpensive first-row transition-metal catalysts is highly desirable.
In 2010, Fagnou et al. reported first Rh(III)-catalyzed redox-
neutral C−H annulation of N-methoxy/pivaloyloxy benzamides
13a
role. A similar kind of transformation was also reported by
13b
Ackermann and co-workers.
Very recently, Zeng et al.
reported Co(III)-catalyzed [4 + 1] cyclative capture of 2-
arylpyridines with aldehydes in which cobalt catalysts play a dual
3
with alkynes to furnish isoquinolones. After these findings, N-
methoxyamide has been utilized as a versatile directing group in
number of valuable transformations and is considered as one of
14
role as a metal catalyst and Lewis acid. In continuation of our
15
4
interest in Cp*Co(III) catalysis, we postulated that the
the important oxidizing-directing group. However, there are a
treatment of N-methoxyamides with alkynedione in the presence
of Cp*Co(III) catalyst should furnish the isoquinolone via [4 +
few examples wherein an N−H group present in the product has
5
been engaged in the further cascade-type reaction. In recent
2
] annulation followed by nucleophilic addition of free N−H of
times, first-row transition-metal-catalyzed C−H bond function-
the amide onto the carbonyl wherein Co(III) can act as a Lewis
acid to furnish a tetracyclic indolizidine skeleton in a one-pot
manner (Scheme 1).
alization has gained tremendous importance in organic syn-
6
,7
thesis.
This is attributed to their low toxicity, high earth abundance,
and low cost as compared to precious metals such as Rh, Ru, and
Ir. Among the various first-row transition metals, Fe, Mn, Ni, and
Co are widely used in C−H activation. In particular, after
pioneering work from Kanai and Matsunaga Co(III) catalysis has
emerged as a powerful catalytic system for various C−H
In order to validate our hypothesis, a series of experiments
were conducted (see Table S1). Initially, N,4-dimethoxybenza-
Received: March 27, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Cp*Co(III)-Catalyzed C−H Functionalization
Cascade via Dual Activation
Scheme 2. Scope of Amides
mide was treated with alkyne dione 2a in the presence of 10 mol
%
of [Cp*Co(CO)I ] and NaOAc (1.0 equiv) in MeOH as a
2
solvent at 120 °C for 14 h. Unfortunately, no product was formed
under these conditions. The solvent screening revealed that 2,2-
trifluoroethanol (TFE) was the choice of the solvent furnishing
required tetracyclic indolizidine (±)-3ea in 72% yield. This may
be due to lower Lewis basicity of TFE as compared to the
16
conventional alcoholic solvents. The relative stereochemistry
of Me and OH groups in 3aa was assigned as cis based on NOE
experiments (see the Supporting Information). When the
amount of NaOAc was decreased up to 50 mol %, the yield of
the product was increased up to 85%. Various other additives
were tested, but none of them gave better results as compared to
NaOAc. The control experiments revealed that both [Cp*Co-
a
Reaction conditions: 1 (0.30 mmol), 2a (1.2 equiv), [Cp*Co(CO)I2]
10 mol %), and NaOAc (50 mol %) in TFE (2.4 mL) at 120 °C for
4 h under argon atmosphere. Isolated yields are provided.
(
1
(
CO)I ] and NaOAc are essential for the current C−H
2
functionalization cascade.
derivatives were also underwent C−H functionalization cascade
via vinylic C−H bond activation (3xa−za).
With the optimized conditions in hand, we next investigated
the scope and generality of the reaction using different N-
methoxyamides (Scheme 2). It was found that amides having
electron-donating groups furnished the products in good yields
We subsequently investigated the scope and reactivity pattern
of the alkynediones (Scheme 3). At first, electronic effects of the
aryl group were tested. The aryl groups having both electron-
donation and electron-withdrawing groups furnished the
corresponding products in good yields (3ab−ae), although the
reaction was slightly sluggish when an electron-withdrawing
group was present in the aryl ring. The replacement of a Me
group with Et at the C-2 position of cyclopentadienone did not
have much effect on the product formation (3af−jf). Satisfyingly,
six-membered alkynedione was also compatible with current
catalytic conditions (3ag−jg). However, our attempts to utilize a
terminal alkynedione devoid of an aryl group were unsuccessful.
Finally, we were interested in employing the present C−H
functionalization cascade protocol for late-stage functionaliza-
tion (Scheme 4). To our delight, N-methoxyamide derived from
the bioactive complex estrone also underwent a C−H
functionalization cascade to produce the corresponding products
(3aa−ga). However, in case of 3g, we isolated both of the
regioisomers. This is probably due to chelation of the oxygen
from the dioxy ring to the cobalt to direct the C−H activation at a
more hindered position. The wide range of N-methoxybenza-
mides containing important electrophilic and electron-with-
drawing functional groups, such as F, Cl, Br, I, NO , CF , CN,
2
3
CO Et, Ac, and cinnamate, were well tolerated, furnishing an
2
excellent yield of the corresponding indolizidine derivatives
(
3ha−qa). Moreover, meta-substituted amides and 2-naphthy-
lamide demonstrated excellent levels of positional selectivity to
furnish corresponding products as a single regioisomer (3ra−ta).
However, ortho-substituted amides were not a suitable substrate
(3ua−va). This can be attributed to the steric effects that hinder
the formation of cobaltacycle. Gratifyingly, this protocol was
further extended to amide-containing heteroarene such as
thiophene (3wa). It is important to mention that the protocol
was not limited to just arene C−H bonds. The acrylamide
17
having seven continuous rings.
Next, several experiments were conducted to elucidate the
mechanism of the present Co(III)-catalyzed C−H functionaliza-
B
DOI: 10.1021/acs.orglett.7b00904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Alkynediones
in product 3aa (see the Supporting Information for details).
These results clearly indicate that, under the present conditions,
18
the C−H activation step is irreversible. The intermolecular
competition experiment between electronically different N-
methoxybenzamides revealed that the more electron-deficient
arenes reacts preferentially. This observation suggests that an
electrophilic C−H activation is less likely to be operative but can
be rationalized in terms of a carboxylate-assisted deprotonative
19
C−H cobaltation. Furthermore, higher values of kinetic
isotope effect were observed in both parallel reactions and
competitive reactions, indicating that C−H bond cleavage is
20
involved in the rate-limiting step.
5c,11
Based on our mechanistic studies and precedent literature,
the plausible mechanism for the present study is depicted in
Scheme 6. We proposed that Cp*Co(III)-catalyzed C−H
Scheme 6. Plausible Mechanism
a
Reaction conditions: 1 (0.30 mmol), 2 (1.2 equiv), [Cp*Co(CO)I2]
10 mol %), and NaOAc (50 mol %) in TFE (2.4 mL) at 120 °C for
(
1
4 h under argon atmosphere. Isolated yields are provided.
Scheme 4. Late-Stage Functionalization of Estrone Derivative
tion cascade reaction (Scheme 5). At first, H/D exchange
experiments of N-methoxybenzamide 1a were carried out to
Scheme 5. Mechanistic Findings
functionalization cascade begins with the formation of catalyti-
cally active Co(III) species A from [Cp*Co(CO)I ] and
2
10n,11
NaOAc.
The catalytic active Co species A coordinates to
the nitrogen atom of N-methoxybenzamide 1a which is followed
by irreversible and rate-determining cobaltation to form five-
membered cobaltacycle B.
The weak coordination of carbonyl oxygen of alkynedione 2a
(
intermediate C) to the cobalt center followed by insertion into
the Co−C bond generates intermediate D. This weak
coordination is responsible for the opposite regioselectivity of
5c
alkyne insertion. The intermediate D then undergoes reductive
elimination and N−OMe bond cleavage to generate species E
which on proto-demetalation furnishes isoquinolone F with
concomitant release of the catalytic active cobalt species. Finally,
12−14
Co(III)-assisted
nucleophilic attack of amide N−H in
intermediate F on to the carbonyl leads to the formation of
desired indolizidine product 3aa.
In summary, we have developed a Cp*Co(III)-catalyzed C−H
functionalization cascade of N-methoxyamides and alkynedione
for the synthesis of indolizidine scaffolds with opposite
regioselectivity of alkyne insertion under redox-neutral con-
ditions. The reaction displayed excellent functional group
tolerance and is applicable for late-stage functionalization. The
further exploration of Cp*Co(III) catalysis in other cascade
reactions is currently underway in our laboratory.
investigate the reversibility of the C−H activation step. When 1a
was treated under catalytic conditions in the absence of
alkynedione with TFE/CD OD as solvent, 7% D incorporation
3
1
was observed at each ortho position as revealed by H NMR
analysis. When the same reaction was performed in the presence
of 2a; 10% D incorporation was detected in recovered starting
whereas; <5% D incorporation was detected at the ortho position
C
DOI: 10.1021/acs.orglett.7b00904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
011, 1047. (e) Miao, J.; Ge, H. Eur. J. Org. Chem. 2015, 2015, 7859.
ASSOCIATED CONTENT
Supporting Information
■
(f) Liu, W.; Ackermann, L. ACS Catal. 2016, 6, 3743. (g) Cera, G.;
*
S
Ackermann, L. Top. Curr. Chem. 2016, 374, 57.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00904.
(8) For reviews on Co-catalyzed C−H activation, see: (a) Gao, K.;
Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208. (b) Yoshikai, N. Bull. Chem.
Soc. Jpn. 2014, 87, 843. (c) Ackermann, L. J. Org. Chem. 2014, 79, 8948.
Experimental procedure and characterization of new
(d) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498.
(e) Wei, D.; Zhu, X.; Niu, L.; Song, M.-P. ChemCatChem 2016, 8, 1242.
(f) Wang, S.; Chen, S.-Y.; Yu, X.-Q. Chem. Commun. 2017, 53, 3165.
1
13
compounds ( H, C NMR spectra) (PDF)
(
9) For selected references, see: (a) Yoshino, T.; Ikemoto, H.;
Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed. 2013, 52, 2207.
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AUTHOR INFORMATION
Corresponding Authors
■
(
*
E-mail: rchegondi@iict.res.in.
*E-mail: amitorgchem@gmail.com, amitorgchem@iict.res.in.
ORCID
Amit B. Pawar: 0000-0002-6472-8119
Notes
(10) For selected references of Cp*Co(III) catalysis, see: (a) Li, J.;
The authors declare no competing financial interest.
Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 3635. (b) Li, J.;
Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 8551. (c) Mei, R.; Loup,
J.; Ackermann, L. ACS Catal. 2016, 6, 793. (d) Yu, D.-G.; Gensch, T.; de
Azambuja, T.; Vasquez-Cespedes, S.; Glorius, F. J. Am. Chem. Soc. 2014,
ACKNOWLEDGMENTS
■
A.B.P. thanks DST, New Delhi, for the INSPIRE Faculty Award
1
36, 17722. (e) Lerchen, A.; Vasquez-Cespedes, S.; Glorius, F. Angew.
(IFA 14, CH-157, GAP-0520). R.C. thanks DST, New Delhi, for
Chem., Int. Ed. 2016, 55, 3208. (f) Lu, Q.; Vasquez-Cespedes, S.;
Gensch, T.; Glorius, F. ACS Catal. 2016, 6, 2352. (g) Pawar, A. B.;
Chang, S. Org. Lett. 2015, 17, 660. (h) Patel, P.; Chang, S. ACS Catal.
the award of a Start-up Research Grant (young scientists). L.N.C.
thanks CSIR for a senior research fellowship. K.K.G. thanks DST,
New Delhi, for a research fellowship. We thank Mr. Kanakaraju
Marumudi for 2D NMR studies. We gratefully acknowledge to
Dr. S. Chandrasekhar (Director, CSIR-IICT) for his support and
encouragement.
2
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