Development of Pd(OAc)2-catalyzed tandem oxidation of C[sbnd]N, C[sbnd]C, and C(sp3)–H bonds: Concise synthesis of 1-aroylisoquinoline, oxoaporphine, and 8-oxyprotoberberine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2020.152599

A catalytic tandem oxidation of C[sbnd]N, C[sbnd]C, and C(sp³)–H bonds is developed. This tandem oxidation is applied to two-step total syntheses of papaveraldine and pulcheotine A. Additionally, the total synthesis of liriodenine is achieved in six steps from homopiperonyl alcohol and 2-bromophenylacetonitrile by applying this catalytic tandem oxidation. Moreover, the direct conversion of xylopinine to 8-oxypseudopalmatine in a 76% yield demonstrates the versatility of this catalytic reaction.

Full text of DOI:10.1016/j.tetlet.2020.152599

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of Pd(OAc)2-catalyzed tandem oxidation of CAN, CAC,
and C(sp3)–H bonds: Concise synthesis of 1-aroylisoquinoline,
oxoaporphine, and 8-oxyprotoberberine alkaloids
⇑
Saeko Nishimoto, Hiromichi Nakahashi, Masahiro Toyota
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8231, Japan
a r t i c l e i n f o
a b s t r a c t
A catalytic tandem oxidation of CAN, CAC, and C(sp3)–H bonds is developed. This tandem oxidation is
applied to two-step total syntheses of papaveraldine and pulcheotine A. Additionally, the total synthesis
of liriodenine is achieved in six steps from homopiperonyl alcohol and 2-bromophenylacetonitrile by
applying this catalytic tandem oxidation. Moreover, the direct conversion of xylopinine to 8-oxypseu-
dopalmatine in a 76% yield demonstrates the versatility of this catalytic reaction.
Ó 2020 Elsevier Ltd. All rights reserved.
Article history:
Received 10 September 2020
Revised 19 October 2020
Accepted 22 October 2020
Available online xxxx
Keywords:
Catalytic tandem oxidation
Papaveraldine
Pulcheotine A
Liriodenine
8-Oxypseudopalmatine
Introduction
group has been reported. For instance, 2-benzylpyridines are
easily oxidized by Fe, Co, or halogens (Kornblum-type oxida-
Nitrogen containing heterocyclic compounds are potential
footholds in drug syntheses [1]. Therefore, new synthetic proto-
cols to assemble diverse heterocyclic compounds, including
nitrogen atoms, are being developed [2]. Among heterocyclic
compounds, bioactive molecules bearing a quinoline or an iso-
quinoline skeleton have attracted attention as drug candidates
[3]. There are roughly two ways to synthesize aromatic hetero-
cyclic compounds: a stepwise approach using multi-components
and an oxidation method of saturated multi-cyclic compounds.
Our research focuses on the latter methodology, and we
searched previous synthetic examples of quinoline and iso-
quinoline scaffolds for inspiration. Aerobic dehydrogenations of
nitrogen heterocycles with or without catalytic transition metals
have been studied for many years (Scheme 1, eqs. 1–3) [4].
1,2,3,4-Tetrahydroquinolines are catalytically transformed into
the corresponding quinolines using various transition metals
such as Mn, Cu, Fe, Co, or Ru in the presence of oxygen. On
the other hand, catalytic dehydrogenations of 1,2,3,4-tetrahy-
droisoquinolines produce isoquinolines by means of Cu, Co, or
Os, etc. Additionally, an oxidation reaction of a benzyl group
substituted on an aromatic heterocyclic compound to a benzoyl
tion), etc. to give aryl heteroaryl ketones. However, the tandem
catalytic oxidation of CAN, CAC, and C(sp3)–H bonds is not well
researched.
Consequently, we planned a catalytic one-pot conversion of 1-
benzyl-1,2,3,4-tetrahydroisoquinolines 1 into 1-aroylisoquinolines
2 (Scheme 1, eq. 4). Namely, we anticipated that 1-aroylisoquinolines
such as papaveraldine (3) and pulcheotine A (4) could be synthe-
sized from easily obtainable precursors such as 1 by a tandem oxi-
dation of the bonds in 1 indicated by the arrows, as shown in
Scheme 1 (eq. 4). Additionally, this protocol should assemble oxoa-
porphines such as liriodenine (5) from the corre-sponding perhy-
drodibenzoquinoline (structure with a dotted line in Scheme 1,
eq. 4) by (Fig. 1).
We recently reported
a catalytic one-pot preparation of
anthranilates from acyclic unsaturated b-enamino esters [5]. Dur-
ing our research, we found that methyl 2-(1H-pyrrol-1-yl)benzoate
(7) was directly generated from methyl (E)-3-(pyrrolidin-1-yl)
hepta-2,6-dienoate (6) in the presence of a catalytic amount of
Pd(OAc)2 (Scheme 2). In this transformation, cycloaromatization
was accompanied by sequential dehydrogenation of a pyrrolidine
ring in 6 to form pyrrolylbenzoate 7.
We conducted this study to confirm our hypothesis that the
tandem reaction (6 ? 7) would be applicable to the one-pot trans-
formation (1 ? 2).
⇑
Corresponding author.
https://doi.org/10.1016/j.tetlet.2020.152599
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Nishimoto, H. Nakahashi and M. Toyota, Development of Pd(OAc)2-catalyzed tandem oxidation of CAN, CAC, and C(sp3)–H bonds: Concise
synthesis of 1-aroylisoquinoline, oxoaporphine, and 8-oxyprotoberberine alkaloids, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152599

S. Nishimoto, H. Nakahashi and M. Toyota
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Catalytic tandem oxidation of CAN and CAC bonds in 8.2
Entry
Oxidant (equiv)
Conc
Solvent
Temp
Yield (%)
(mol/L)
(°C)
9
10
1
2
3
4
5
6
none
none
none
none
CuCl2 (2.0)
Cu(OAc)2ÁH2O (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
0.3
DMSO
DMSO
60
120
60
0
21
trace
26
trace
60
70
22
39
46
9
26
12
52
27a
15
9
45
0
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
120
120
120
120
120
180
120
120
7b,c
8
9
10
11
47
33
a
Starting material 8 was also isolated in a 67% yield.
When the reaction was conducted under N2 instead of O2, only N-acetyl-1,2,3,4-
b
tetrahydroisoquinoline was obtained in a 27% yield.
c
When the reaction was conducted only using 10 mol % Cu(OAc)2, 10 was iso-
lated in a 66% yield together with 9 (3%).
Scheme 1. Various aerobic oxidation of N-heterocycles.
(Table 1, entry 4). Then we evaluated the efficient conversion of
10 into 9 using different oxidants. Employing 2 equivalents of
DDQ as an oxidizing agent did not form 9 or 10. Similarly, the addi-
tion of CuCl2 did not improve the yield (Table 1, entry 5). On the
other hand, the presence of Cu(OAc)2ÁH2O drastically enhanced
the yield (Table 1, entry 6) [6]. The best isolated yield (70%) was
obtained when the reaction was performed at 120 °C in toluene
in the presence of 10 mol% Pd(OAc)2 using 20 mol% Cu(OAc)2 as
an oxidant (Table 1, entry 7). Conducting the reaction in an atmo-
sphere of nitrogen instead of oxygen gave only N-acetyl-1,2,3,4-
tetrahydroisoquinoline in a 27% yield. In addition, using 10 mol%
Cu(OAc)2 provided mostly 10. Increasing Cu(OAc)2 to 1 equivalent
decreased the production ratio of 9 (Table 1, entry 8). Raising the
reaction temperature to 180 °C produced only 9, but the isolated
yield was 39% (Table 1, entry 9). The yield of product 9 was not
affected by the concentration of substrate 8 (Table 1, entries 10
and 11).
Fig. 1. Structures of papaveraldine (3), pulcheotine A (4), and liriodenine (5).
The reaction conditions shown in Table 1, entry 7 were applied
to the oxidative conversion of 1,2,3,4-tetrahydronaphthalene (11)
to naphthalene (12). The reaction did not proceed at all, and 11
was recovered intact. Hence, this oxidation reaction cannot be used
for dehydrogenation of hydrocarbon compounds (Scheme 3).
To investigate the versatility of the catalytic tandem oxidation,
a CAC bond oxidation and a tandem CAN and CAC bonds oxidation
in N-containing heterocycles were examined (Scheme 4). Indoline
(13a) was converted to indole (14a) in a 68% yield, and 1-
phenylpyrrolidine (13b) was successively oxidized to afford 1-phe-
nyl-1H-pyrrole (14b) in a 76% yield. To complete oxidation reac-
tions of 13c and 13d in 24 h, 99.98% pure Pd(OAc)2 was used in
both oxidations to give 14c and 14d in isolated yields of 70% and
74%, respectively. The tandem oxidation reaction of CAN and
CAC bonds in the same molecule does not depend on the sub-
strates and tends to proceed smoothly. For example, 1,2,3,4-
tetrahydroquinoline (13e) was transformed into quinoline (14e)
in a 76% yield. 1-Phenylperhydroisoquinoline 13f was also oxi-
dized to furnish 1-phenylquinoline (14f) in a 62% yield. In the case
of 13f, the reaction was completed by changing the solvent to DMF
and increasing the reaction temperature to 150 °C. We applied the
above-mentioned catalytic oxidation to a tandem oxidation of
CAN, CAC, and C(sp3)-H bonds built-in the same molecule. When
Scheme 2. Pd(OAc)2-catalyzed tandem cycloaromatization-dehydrogenation.
Results and discussion
As the first step, we examined the tandem oxidation of CAN and
CAC bonds using 1,2,3,4-tetrahydroisoquinoline (8) as a model
compound. Applying the reaction conditions in Scheme 2 to the
tandem oxidation of 8 gave 3,4-dihydroisoquinoline (10) in 9%
yield (Table 1, entry 1). Extending the reaction time to 36 h did
not improve the chemical yield of 10. However, increasing the
reaction temperature to 120 °C provided desired 9 in 21% yield
together with 10 (26%) (Table 1, entry 2). This result suggested that
imine 10 is a precursor of isoquinoline (9). Next we investigated
the solvent effect. The reaction did not proceed when THF, MeCN,
or dichloromethane (DCM) was used as a solvent. However, in the
case of toluene, a small amount of 9 was obtained even at 60 °C
(Table 1, entry 3). It should be noted that compared to using DMSO
as the solvent, the reaction in toluene was clearer, and the crude 1H
NMR spectrum did not show any byproducts. Increasing the reac-
tion temperature to 120 °C improved the total yield of 9 and 10
2

S. Nishimoto, H. Nakahashi and M. Toyota
Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Transformational examination of 11.
Scheme 5. Two-step total synthesis of natural alkaloids 3 and 4.
Scheme 6. Plausible reaction mechanism.
Scheme 7. Total synthesis of liriodenine (5).
Scheme 8. Total synthesis of two 8-oxoprotoberberine alkaloids.
Scheme 4. Catalytic CAN, CAC, and C(sp3)–H bonds oxidation of 13a–h.
42% yield. Changing the reaction substrate to 1-benzyl-6,7-
dimethoxy-3,4-dihydroisoquinoline (13h) increased the chemical
yield of the tandem oxidation to 78%. Although there is not exper-
imental evidence that the relatively bulky benzyl group in the case
1-benzylperhydroisoquinoline 13g was subjected to the tandem
oxidation, desired 1-benzoylisoquinoline 14g was obtained in a
3

S. Nishimoto, H. Nakahashi and M. Toyota
Tetrahedron Letters xxx (xxxx) xxx
8-oxypseudopalmatine (22), was synthesized (Scheme 8). Specifi-
cally, hydride reduction of imine 15 followed by a Mannich reac-
tion provided xylopinine (21) [11] with a total yield of 64%. The
key catalytic tandem oxidation was performed using 21 under
the reaction conditions described in Table 1, entry 7 to afford 8-
oxypseudopalmatine (22) in a 75% yield. It is noteworthy that
the reaction was clean and byproducts were not detected in the
crude 1H NMR spectrum. The 1H and 13C NMR spectra of synthetic
22 were identical to those previously reported [12].
Although we did not attempt to experimentally verify the reac-
tion mechanism of this oxidative transformation of 21 into 22,
Scheme 9 depicts a plausible reaction pathway. Namely, the cat-
alytic oxidation of 21 gave enamine II through ammonium ion I.
Under thermal conditions, a 1,5-hydrogen shift of II produced
intermediate III, which reacted with oxygen to give hydroperoxide
IV. Recovery of the aromaticity of IV followed by dehydration pro-
duced 22.
Scheme 9. Plausible reaction mechanism.
Declaration of Competing Interest
of 13g prevented the initial bond formation between the nitrogen
atom in the substrate and Pd(OAc)2, the isolated yield of 14g
dropped to 42%. Since imines such as 13h can be synthesized in
a single step using a Bischler-Napieralski type reaction, the total
synthesis of various of 1-aroylisoquinolines should be assembled
in two steps according to the present protocol.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Appendix A. Supplementary data
Next we employed the present catalytic tandem oxidation to
realize the two-step syntheses of papaveraldine (3) and pul-
cheotine A (4). For the key reaction, requisite imine 15 was pre-
pared from 2-(3,4-dimethoxyphenyl)ethanol and 2-(3,4-
dimethoxyphenyl)acetonitrile using Hu’s protocol [7]. Crude imine
15 was subjected to the catalytic tandem oxidation to give papa-
veraldine (3) in a 61% overall yield. Pulcheotine A (4) was similarly
synthesized from 2-(3,4-dimethoxyphenyl)ethanol and 2-(4-meth-
oxyphenyl)acetonitrile via imine 16 with a total yield of 83%
(Scheme 5). The spectral data of synthetic papaveraldine (3) [8]
and pulcheotine A (4) [8] were identical with those reported.
Although we did not attempt to experimentally verify the reac-
tion mechanism, Scheme 6 depicts a plausible reaction pathway.
Under thermal conditions, imine A was isomerized to B via sequen-
tial 1,5-hydrogen shift (tautomerization). Amine B was oxidized to
afford 1-benzylisoquinoline D by Pd(OAc)2 through intermediate C.
After isomerization of D to enamine E, oxygen was caught to pro-
duce peroxide F. Finally, dehydration from peroxide F produced 1-
aroylisoquinoline G. The Pd(0) species could be oxidized to Pd
(OAc)2 by oxygen in the presence of Cu(OAc)2 (Scheme 6) [9].
Then we aimed for the total synthesis of liriodenine (5) utilizing
this catalytic tandem oxidation. Imine 17 was prepared from
homopiperonyl alcohol and 2-bromophenylacetonitrile as previ-
ously reported. At this point, an intramolecular coupling reaction
between the 8-position carbon and a bromobenzene on the side
chain was conducted. However, the desired product was not
obtained. Therefore, we decided to carry out an intramolecular
coupling reaction after protecting the nitrogen atom. Hydride
reduction of 17 and subsequent protection with di-tert-butyl dicar-
bonate (Boc2O) furnished 18 (total yield of 49% in 3 steps), which
was converted to pentacyclic compound 19 by means of an
intramolecular coupling reaction. After deprotection of 19 with
hydrogen chloride, resulting amine 20 was isolated in two steps
with 74% yield. The key catalytic tandem oxidation was performed
using anonaine (20) to give rise to liriodenine (5) in a 68% yield
(Scheme 7). The spectral properties of synthetic 5 were identical
with those previously reported [10].
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152599.
References
[1] (a) N. Kerru, L. Gummidi, S. Maddila, K.K. Gangu, S.B. Jonnalagadda, Molecules
25 (2020) 1909;
(b) E. Vitaku, D.T. Smith, J.T. Njardarson, J. Med. Chem. 57 (2014) 10257–
10274;
(c) R.D. Taylor, M. MacCoss, A.D.G. Lawson, J. Med. Chem. 57 (2014) 5845–
5859.
[2] (a) R.A. Mekheimer, M.A. Al-Sheikh, H.Y. Medrasi, K.U. Sadek, RSC Adv. 10
(2020) 19867–19935;
(b) J.F. Campos, S. Berteina-Raboin, Catalysts 10 (2020) 429;
(c) A.P. Taylor, R.P. Robinson, Y.M. Fobian, D.C. Blakemore, L.H. Jones, O.
Fadeyi, Org. Biomol. Chem. 14 (2016) 6611–6637;
(d) M. Baumann, I. Baxendale, Beilstein J. Org. Chem. 9 (2013) 2265–2319.
[3] (a) A.S. Nugraha, Y.D. Damayanti, P. Wangchuk, P.A. Keller, Molecules 24
(2019) 4419;
(b) D. Liu, X. Meng, D. Wu, Z. Qiu, H. Luo, Front. Pharmacol. 10 (2019) Article 9;
(c) S. Jian, V. Chandra, P.K. Jian, K. Pathak, D. Pathak, A. Vaidya, Arab. J. Chem.
12 (2019) 4920–4946;
(d) X.-F. Shang, S.L. Morris-Natschke, Y.-Q. Liu, X. Guo, X.-S. Xu, M. Goto, J.-C.
Li, G.-Z. Yang, K.-H. Lee, Med. Res. Rev. 38 (2018) 775–828;
(e) S. Srivastava, M. Srivastava, A. Misra, G. Pandey, A.K.S. Rawat, EXCLI J. 14
(2015) 247–267;
(f) M. Iranshahy, R.J. Quinn, M. Iranshahi, RSC Adv. 4 (2014) 15900–15913;
(g) A. Marella, O.P. Tanwar, R. Saha, M.R. Ali, S. Srivastava, M. Akhter, M.
Shaquiquzzaman, M.M. Alam, Saudi Pahrm. J. 21 (2013) 1–12;
(h) E.G. Pérez, B.K. Cassels, The alkaloids, Academic Press 68 (2010) 83–156;
(i) J.P. Michael, Nat. Prod. Rep. 25 (2008) 166–187;
(j) K.W. Bentley, Nat. Prod. Rep. 23 (2006) 444–463.
[4] Selected recent papers, quinoline syntheses (Scheme 2, eq 1): (a) B. A. Dalvi, P.
D. Lokhande, Tetrahedron Lett. 59 (2018), 2145-2149; (b) W. Zhou, D. Chen, F.
Sun, J. Qian, M. Mingyang, Q. Chen, Tetrahedron Lett. 59 (2018) 949-953; (c) M.
´
´
A. Esteruelas, V. Lezaun, A. Martínez, M. Oliván, E. Onate, Organometallics 37
(2018) 2996-3004; (d) Q. Wang, H. Chai, Z. Yu, Organometallics 37 (2018) 584-
591; (e) K. Mullick, S. Biswas, A. M. Angeles-Boza, S. L. Suib, Chem. Commun. 53
(2017) 2256-2259; (f) Y. Wang, C. Li, J. Huang, Asian J. Org. Chem. 6 (2017) 44-
46; (g) X. Cui, Y. Li, S. Bachmann, M. Scalone, A.-E. Surkus, K. Junge, C. Topf, M.
Beller, J. Am. Chem. Soc. 137 (2015) 10652-10658; (h) A. V. Iosub, S. S. Stahl,
Org. Lett. 17 (2015) 4404-4407. Isoquinoline syntheses (Scheme 2, eq 2): (i) B.
Zheng, T. H. Trieu, F.-L. Li, X.-L. Zhu, Y.-G. He, Q.-Q. Fan, ACS Omega, 3 (2018)
8243-8252; (j) 3(a); (k) 3(f). Benzylic oxidations (Scheme 2, eq 3): (l) H. Yu, Q.
Zhao, Z. Wei, Z. Wu, Q. Li, S. Han, Y. Wei, Chem. Commun. 55 (2019) 7840-
7843; (m) R. Ye, Y. Cao, X. Xi, L. Liu, T. Chen, Org. Biomol. Chem. 17 (2019)
4220-4224; (n) S. Guha, G. Sekar, Chem. Eur. J. 24 (2018) 14171-14182; (o) D.
P. Hruszkewycz, K. C. Miles, O. R. Thiel, S. S. Stahl, Chem. Sci. 8 (2017) 1282-
1287; (p) L. Ren, L. Wang, Y. Lv, G. Li, S. Gao, Org. Lett. 17 (2015) 2078-2081.
To expand the versatility of the catalytic tandem oxidation, the
conversion of protoberberines to 8-oxoprotoberberines [11] was
attempted. Xylopinine (21), which is a biological precursor for
4

S. Nishimoto, H. Nakahashi and M. Toyota
Tetrahedron Letters xxx (xxxx) xxx
[5] S. Mikami, S. Okada, R. Kishimoto, T. Takabatake, M. Toyota, Tetrahedron Lett.
(c) T. Takabatake, K. Fujiwara, S. Okada, R. Kishimoto, N. Kagawa, M. Toyota,
Tetrahedron Lett. 61 (2020) 152275.
61 (2020) 151659.
[6] K. Sreenath, Z. Yuan, M. Macias-Contreras, V. Ramachandran, R.J. Clark, L. Zhu,
[10] B. Zheng, H.-Y. Qu, T.-Z. Meng, X. Lu, J. Zheng, Y.-G. He, Q.-Q. Fan, X.-X. Shi, RSC
Adv. 8 (2018) 28997–29007.
Eur. J. Inorg. Chem. (2016) 3728–3743.
[7] L. Min, W. Yang, Y. Weng, W. Zheng, X. Wang, Y. Hu, Org. Lett. 21 (2019) 2574–
[11] (a) T. Nishiyama, M. Hironaka, M. Takemori, E. Taguchi, R. Kotouge, Y.
Shigemori, N. Hatae, M. Ishikura, T. Choshi, Eur. J. Org. Chem. (2018) 673–678;
(b) A. Lerchen, T. Knecht, M. Koy, C.G. Daniliuc, F. Glorius, Chem. Eur. J. 23
(2017) 12149–12152;
2577.
[8] K. Matcha, A.P. Antonchick, Angew. Chem. Int. Ed. 52 (2013) 2082–
2086.
[9] (a) M. Toyota, T. Wada, K. Fukumoto, M. Ihara, J. Am. Chem. Soc. 120 (1998)
4916–4925;
(c) K. Li, J. Ou, S. Gao, Angew. Chem. Int. Ed. 55 (2016) 14778–14783;
(d) D.N. Garad, S.B. Mhaske, Org. Lett. 18 (2016) 3862–3865;
(e) S. Gadhiya, S. Ponnala, W.W. Harding, Tetrahedron 71 (2015) 1227–1231.
[12] S. Zhou, R. Tong, Chem. Eur. J. 22 (2016) 7084–7089.
(b) R.C. Larock, T.R. Hightower, G.A. Kraus, P. Hahn, D. Zheng, Tetrahedron Lett.
36 (1995) 2423–2426;
5