Pd(II)-Catalyzed Intramolecular Tandem Olefin Amidation/C-H Activation Protocol for the Syntheses of the Protoberberine Class of Natural Products

Article abstract of DOI:10.1021/acs.orglett.6b01868

A Pd(II)-catalyzed intramolecular tandem olefin amidation/C-H activation protocol has been developed for the synthesis of an 8-oxoprotoberberine core. It was successfully applied for the syntheses of (±)-8-oxocanadine, (±)-8-oxotetrahydropalmitine, and (±

Full text of DOI:10.1021/acs.orglett.6b01868

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed Intramolecular Tandem Olefin Amidation/C−H
Activation Protocol for the Syntheses of the Protoberberine Class of
Natural Products
Dnyaneshwar N. Garad and Santosh B. Mhaske*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
S
* Supporting Information
ABSTRACT: A Pd(II)-catalyzed intramolecular tandem
olefin amidation/C−H activation protocol has been developed
for the synthesis of an 8-oxoprotoberberine core. It was
successfully applied for the syntheses of ( )-8-oxocanadine,
( )-8-oxotetrahydropalmitine, and ( )-8-oxostylopine, which
can be easily converted to the respective protoberberine
natural products. The short synthetic route demonstrated
would be useful for the synthesis of a large number of natural
products and their analogues featuring a protoberberine scaffold.
of natural products has acquired immense attention in the
scientific community for their synthesis by various approaches,
including transition-metal-catalyzed methods for their con-
struction.1−3 Pd-catalyzed direct aromatic carbonylation using
CO as the carbon source in the synthesis of 8-oxoberberines
was developed by Orito and co-workers.2e,f,i Other Pd-catalyzed
methods such as enolate arylation1 and intramolecular Heck-
type reaction2g were also utilized. Difunctionalization of olefins
is a powerful strategy in organic synthesis for the construction
of complex alkaloid natural products.4b
We envisioned that an intramolecular tandem C−N/C−C
bond formation (carboamidation) of internal olefins by C−H
activation could be an interesting method to construct an
isoquinoline core in the synthesis of protoberberine alkaloids.
In this context, the literature survey revealed that amino-
arylation reactions of olefins/alkynes are known, which requires
aryl halides as a coupling partner.4 Tandem Pd-catalyzed
intramolecular amidation of alkenes followed by intermolecular
C−H activation of arenes was reported by Michael et al. in
2009 (Figure 2, eq 1).5 Several examples of intermolecular
tandem C−C/C−N bond formation also have been
reported.4,6,7 Directing-group (N-OPiv amide)-specific, rho-
dium-catalyzed intramolecular amidoarylation of olefins was
reported by Rovis et al. (Figure 2, eq 2).8 The N-OPiv amide
also acts as a stoichiometric oxidant, which makes the catalytic
ring closure a redox-neutral process. There are few examples
known in the literature wherein difunctionalization of internal
alkynes was achieved by a tandem amidation/C−H activation
sequence (Figure 2, eq 3).9 However, to the best of our
knowledge, such difunctionalization of internal olefins to access
an isoquinolinone core of protoberberine alkaloids is not
known until now (Figure 2, eq 4). In this report, we describe a
rotoberberine alkaloids are a subdivision of natural
Pproducts containing an isoquinoline skeleton. They are
secondary metabolites having significant biological activities
because of their ability to bind or insert in DNA.1 Isolated from
a wide range of plants, all members of the protoberberine class
feature a 5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]-
isoquinoline moiety, typically functionalized with hydroxy,
methoxy, or methylenedioxy substituents (Figure 1).1,2 The
parent compound, berberine, is the most widely studied
alkaloid and exhibits antifungal, antibacterial, anti-inflammatory,
antimalarial, antidiabetic, and anticancer activities.3 This family
Figure 1. Selected natural products containing a protoberberine
core.1−3
Received: June 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
by reduction of its corresponding 8-oxoberberine derivative 2,
which can be obtained from vinyl amide 3 using the proposed
Pd-catalyzed tandem olefin amidation/C−H activation proto-
col. Vinyl amide 3 can be generated from the corresponding
aryl ethyl amine 6 and carboxylic acid 7 in three simple steps:
amide coupling, iodination, and Stille coupling.
The synthesis began with the coupling of the corresponding
aryl ethyl amines 6a/6b and carboxylic acids 7a/7b using EDC·
HCl10 to obtain amides 5a−c in good to moderate yields, and
amide 5d was synthesized by coupling amine 6a and benzoyl
chloride in moderate yield (Scheme 2). Amides 5a−d were
then treated with iodine and silver triflate11 in a dark
atmosphere to furnish iodoamides 4a−d in very good yields
and excellent regioselectivity. Iodoamides 4a−d were further
treated with tributyl(vinyl)stannane under Stille coupling
conditions10 catalyzed by Pd2(dba)3 and triphenylarsane as a
ligand to obtain vinylamides 3a−d in very good to excellent
yields.
Figure 2. Difunctionalization of olefins and alkynes.
Various catalysts, oxidants, and reaction conditions were
screened on vinylamide 3a for the expected tandem amidation/
C−H activation reaction to obtain an optimized protocol
(Table 1). The first reaction toward this goal used catalytic
Pd(OAc)2 and Cu(OAc)2 in the presence of base/additive
AgOAc at 110 °C in DMF, which gave the expected product,
though in low yield (entry 1). The base/additive AgOAc was
replaced with NaOAc, which enhanced the yield by 10% (entry
2). Variation in metal catalysts or solvents did not show
formation of expected product (entries 3−5). Interestingly, the
change in solvent from DMF to DMSO and performing the
reaction under oxygen atmosphere showed improvement in
yield to 35% along with 30% starting material recovery (entries
6 and 7). After variations in additives (entries 8−11), we found
an optimized reaction condition (entry 12), wherein the highest
unique intramolecular Pd-catalyzed tandem oxidative olefin
amidation/C−H activation protocol for the synthesis of a
protoberberine class of natural products.
Our retrosynthetic plan is shown in Scheme 1. The
protoberberine natural products 1a−c can be easily accessed
Scheme 1. Retrosynthetic Analysis of Protoberberines
Scheme 2. Synthetic Route for 8-Oxoberberines
B
DOI: 10.1021/acs.orglett.6b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Studies
a
entry
catalyst (mol %)
oxidant (equiv)
additive (equiv)
AgOAc (2)
solvent/temp
DMF/110 °C
DMF/110 °C
t-amyl alcohol/115 °C
CH3CN/110 °C
1,4-dioxane/100 °C
DMSO/100 °C
DMSO/100 °C
DMSO/100 °C
DMSO/100 °C
yield (%)
1
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
[RhCp*Cl2]2 (2.5)
[RuCl2(p-cy)]2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
[RhCp*Cl2]2 (2.5)
Pd(TFA)2 (10)
PdCl2 (10)
Cu(OAc)2 (0.2)
15
25
−
−
−
30
35
25
40
−
Cu(OAc)2 (0.2)
NaOAc (2)
3
Cu(OAc)2·H2O (2)
Cu(OAc)2 (0.2)
NaOAc (2)
4
AgOAc (1.5)
5
Cu(OAc)2·H2O (2)
Cu(OAc)2 (0.2)
AgSbF6 (0.2)
NaOAc (2)
6
7
Cu(OAc)2 (2), O2
Cu(OAc)2·H2O (2), O2
Cu(OAc)2·H2O (2), O2
O2
NaOAc (2)
8
KOAc (2)
9
NaOAc (2), PivOH (0.4)
NaOAc (2), PivOH (0.4)
NaOAc (2), PivOH (0.4)
NaOAc (3)
10
11
DMSO/100 °C
Cu(OAc)2·H2O (2), O2
Cu(OAc)2·H2O (1), O2
Cu(OAc)2·H2O (1), O2
Cu(OAc)2·H2O (1), O2
CuCl2·2H2O (1)
DMSO/H2O (9:1)/100 °C
DMSO/H2O (10:1)/100 °C
DMSO/H2O (10:1)/100 °C
DMSO/H2O (10:1)/100 °C
DMSO/H2O (10:1)/100 °C
DMAc/H2O (9:1)/100 °C
DMAc/DMSO (9:1)/100 °C
45
b
12
55 (75% brsm)
13
14
15
16
17
NaOAc (3)
−
NaOAc (3)
42
20
33
35
NaOAc (3)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Cu(OAc)2·H2O (1), O2
Cu(OAc)2·H2O (1), O2
NaOAc (3)
NaOAc (3)
a
b
All reactions were performed on 18 mg (0.05 mmol) scale of vinylamide 3a. DMSO/H2O (0.3:0.03 mL).
possible yield of product ( )-8-oxocanadine (2a, 55%, 75%
brsm) was obtained. However, further modifications (entries
13−17) or variation in catalyst loading did not show
improvement in the yield. Application of the developed
protocol on vinylamides 3b and 3c provided cyclized products
( )-8-oxotetrahydropalmitine (2b) and ( )-8-oxostylopine
(2c) in 45% (68% brsm) and 35% (55% brsm) yields,
respectively (Scheme 2). The analytical and spectral data of 8-
oxoberberines 2a−c are consistent with the reported data.2e
Their transformation to the corresponding natural products
( )-canadine (1a), ( )-tetrahydropalmitine (1b), and ( )-sty-
lopine (1c) is well-documented in the literature.2j,k,m,n
Unfortunately, vinylamide 3d, when subjected to our developed
protocol, showed formation of only a trace (ESI-HRMS)
amount of natural product gusanlung D (2d) and most of the
starting material remained unreacted. When the reaction
temperature was increased to 120−140 °C, decomposition of
vinylamide 3d was observed.
active catalyst might be formed by the coordination of DMSO
with Pd(II), which catalyzes further transformations.12 The
intrinsically unstable form of the catalyst “Pd(0)Ln” generated
in the reaction mixture is reoxidized (Figure 3i) by the oxidant
to complete the catalytic cycle; however, a competing reaction,
which deactivates Pd(0) to catalytically inactive palladium
black,13 might be the reason behind the incomplete conversion
(Figure 3ii).
In summary, a novel Pd(II)-catalyzed approach for the
synthesis of a protoberberine core was developed. The two new
bonds, C−N and C−C, have been formed in a single step by an
intramolecular tandem “amidation/C−H activation” sequence.
Short and efficient syntheses of ( )-8-oxocanadine, ( )-8-
oxotetrahydropalmitine, and ( )-8-oxostylopine were achieved
by implementing this novel protocol as a key step. Currently,
we are working on the total synthesis of other natural alkaloids
in this class using the developed protocol.
A proposed mechanism for the intramolecular carboamida-
tion protocol developed herein is depicted in Figure 3. The
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01868.
Experimental procedures, spectral and analytical data,
and copies of NMR spectra of all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in.
Notes
Figure 3. Proposed mechanism for the intramolecular carboamidation.
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
D.N.G. thanks UGC-New Delhi for the research fellowship.
S.B.M. gratefully acknowledges generous financial support from
DST and CSIR-ORIGIN, New Delhi.
REFERENCES
■
(1) Gatland, A. E.; Pilgrim, B. S.; Procopiou, P. A.; Donohoe, T. J.
Angew. Chem., Int. Ed. 2014, 53, 14555.
(2) (a) Ma, L.; Seidel, D. Chem. - Eur. J. 2015, 21, 12908.
(b) Gadhiya, S.; Ponnala, S.; Harding, W. W. Tetrahedron 2015, 71,
1227. (c) Meissner, Z.; Chrzanowska, M. Tetrahedron: Asymmetry
2015, 26, 225. (d) Gao, S.; Cheng, J.-J.; Ling, C.-Y.; Chu, W.-J.; Yang,
Y.-S. Tetrahedron Lett. 2014, 55, 4856. (e) Miyazawa, M.; Tokuhashi,
T.; Horibata, A.; Nakamura, T.; Onozaki, Y.; Kurono, N.; Senboku, H.;
Tokuda, M.; Ohkuma, T.; Orito, K. J. Heterocycl. Chem. 2013, 50, E48.
(f) Harada, R.; Nishida, N.; Uchiito, S.; Onozaki, Y.; Kurono, N.;
Senboku, H.; Masao, T.; Ohkuma, T.; Orito, K. Eur. J. Org. Chem.
2012, 2012, 366. (g) Wakchaure, P. B.; Easwar, S.; Argade, N. P.
Synthesis 2009, 2009, 1667. (h) Chang, J.-K.; Chang, N.-C.
Tetrahedron 2008, 64, 3483. (i) Orito, K.; Miyazawa, M.;
Kanbayashi, R.; Tokuda, M.; Suginome, H. J. Org. Chem. 1999, 64,
6583. (j) Matulenko, M. A.; Meyers, A. I. J. Org. Chem. 1996, 61, 573.
(k) Chrzanowska, M. J. Nat. Prod. 1995, 58, 401. (l) Yasuda, S.;
Hirasawa, T.; Hanaoka, M. Tetrahedron Lett. 1987, 28, 2399.
(m) Iwasa, K.; Gupta, Y. P.; Cushman, M. J. Org. Chem. 1981, 46,
4744. (n) Pandey, G. D.; Tiwari, K. P. Tetrahedron 1981, 37, 1213.
(3) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290.
(4) (a) Oh, K. R.; Kim, G. Bull. Korean Chem. Soc. 2012, 33, 3933.
(b) Schultz, D. M.; Wolfe, J. P. Synthesis 2012, 44, 351.
(5) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 9488.
(6) (a) Manna, M. K.; Hossian, A.; Jana, R. Org. Lett. 2015, 17, 672.
(b) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4684. (c) Zhu, C.;
Wang, R.; Falck, J. R. Chem. - Asian J. 2012, 7, 1502. (d) Scarborough,
C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251 and refs cited therein.
(7) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981.
(8) Davis, T. A.; Hyster, T. K.; Rovis, T. Angew. Chem., Int. Ed. 2013,
52, 14181.
(9) (a) Jayakumar, J.; Cheng, C.-H. Chem. - Eur. J. 2016, 22, 1800.
(b) Zhang, X.; Li, Y.; Shi, H.; Zhang, L.; Zhang, S.; Xu, X.; Liu, Q.
Chem. Commun. 2014, 50, 7306. (c) Quinones, N.; Seoane, A.; Garcia-
Fandino, R.; Mascarenas, J. L.; Gulias, M. Chem. Sci. 2013, 4, 2874.
(d) Xu, X.; Liu, Y.; Park, C.-M. Angew. Chem., Int. Ed. 2012, 51, 9372.
(10) Kim, G.; Lee, K. Y.; Yoo, C.-H. Synth. Commun. 2008, 38, 3251.
(11) Mulholland, G. K.; Zheng, Q.-H. Synth. Commun. 2001, 31,
3059.
(12) (a) Diao, T.; White, P.; Guzei, I.; Stahl, S. S. Inorg. Chem. 2012,
51, 11898. (b) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc.
2002, 124, 766.
(13) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348.
D
DOI: 10.1021/acs.orglett.6b01868
Org. Lett. XXXX, XXX, XXX−XXX