Palladium-catalyzed arylation of 1,4-naphthoquinones with aryl iodides and its synthetic application to the benzo[b]phenanthridine skeleton

Article abstract of DOI:10.1016/j.tetlet.2020.152446

We report a Pd-catalyzed arylation of 1,4-naphthoquinones with aryl iodides. This reaction shows excellent functional group tolerance and high regioselectivity when using nonsymmetric 1,4-naphthoquinone. Furthermore, the resulting 2-aryl-1,4-naphthoquinon

Full text of DOI:10.1016/j.tetlet.2020.152446

Tetrahedron Letters 61 (2020) 152446
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed arylation of 1,4-naphthoquinones with aryl iodides
and its synthetic application to the benzo[b]phenanthridine skeleton
⇑
Yusuke Akagi , Toshiya Komatsu
Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a Pd-catalyzed arylation of 1,4-naphthoquinones with aryl iodides. This reaction shows excel-
lent functional group tolerance and high regioselectivity when using nonsymmetric 1,4-naphthoquinone.
Furthermore, the resulting 2-aryl-1,4-naphthoquinone could be successfully converted into benzo[b]
phenanthridine-7,12-dione through treatment with aqueous ammonia, followed by oxidative cyclization
using MnO2.
Received 10 August 2020
Revised 2 September 2020
Accepted 7 September 2020
Available online 10 September 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
1,4-naphthoquinone
Palladium-catalyzed arylation
Aryl iodide
Benzo[b]phenanthridine
Introduction
O
O
O
O
Aryl-1,4-naphthoquinones (1–3) are known as b-secretase
(BACE1) inhibitors (Fig. 1) [1,2]. In addition, aryl-1,4-naphtho-
quinone cores are included in the structures of bioactive natural
products such as phenanthroviridin aglycon (4) [3–6] and jadomy-
cin A (5) [7–15]. Therefore, aryl-1,4-naphthoquinones are attrac-
tive targets for many organic synthetic chemists, and the direct
arylation of 1,4-naphthoquinones has been studied as an efficient
synthetic method for their construction [16–30]. In 1985, Itahara
reported pioneering work in the Pd-catalyzed direct arylation of
1,4-naphthoquinone with arenes (Fig. 2A) [16]. In 2009, Molina’s
group reported the direct arylation of benzo-fused 1,4-quinones
by the dicationic Pd(II)-catalyzed addition of boronic acids (Fig. 2B)
[18]. They studied using not only 1,4-naphthoquinone but also
nonsymmetric quinones such as juglone (5-hydroxy-1,4-naphtho-
quinone). The reaction showed high regioselectivity when using
nonsymmetric quinones. In 2011, Baran’s group reported the Ag-
catalyzed direct arylation of 1,4-naphthoquinones with boronic
acids (Fig. 2C), which is presumed to proceed through a radical
mechanism [20]. The regioselectivity of this reaction with juglone
as the starting material was not very high. In 2014, Wang’s group
reported the Pd-catalyzed direct arylation of 1,4-naphthoquinone
with aryl iodides having only electron-donating groups (Fig. 2D)
[27]. In addition to metal-mediated arylation of 1,4-naphtho-
quinones with aryl sources [16–23,26–29], metal-free arylation
R
OH
1: R = H
2: R = OH
3
HO
Me
HO
Me
O
O
H
O
N
N
OH
O
OH
O
O
Me
Me
phenanthroviridin aglycon (4)
jadomycin A (5)
Fig. 1. Structures of aryl-1,4-naphthoquinones (1–3), phenanthroviridin aglycon
(4) and jadomycin A (5).
using diaryliodonium salts [25] and aryl hydrazines [24,30] has
also been developed.
Inspired by these previous works [16–30] and our recent dis-
covery of the Pd-catalyzed arylation of a,b -unsaturated O-methyl
oximes with aryl iodides [31], we began to consider the direct
arylation of 1,4-naphthoquinones. In this paper, we describe the
Pd-catalyzed direct arylation of 1,4-naphthoquinones with aryl
⇑
Corresponding author.
E-mail address: y.akagi@thu.ac.jp (Y. Akagi).
https://doi.org/10.1016/j.tetlet.2020.152446
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

Y. Akagi, T. Komatsu
Tetrahedron Letters 61 (2020) 152446
Table 2
A. Itahara's approach
B. Molina's approach
Substrate scope of aryl iodides.a
1
84%
6
51%
7
47%
8
59%
C. Baran's approach
D. Wang's approach
electron-rich Ar
9
10
11
12
52%
67%
62%
89%
E. Our approach this work
electron-rich Ar
and
electron-deficient Ar
13
14
15
16
82%
99%
89%
95%
Fig. 2. Arylation of 1,4-naphthoquinones.
iodides having both electron-donating and electron-withdrawing
groups (Fig. 2E) and synthesis of the benzo[b]phenanthridine
skeleton (benzo[b]phenanthridine-7,12-dione) from the resulting
2-aryl-1,4-naphthoquinone.
17
0%
18
42%
a
All the reactions were run with 1,4-naphthoquinone (0.2 mmol) and aryl iodine
(0.2 mmol) in 1.0 mL solvent for 19 h.
addition of acidic HFIP proved to be less effective in this reaction.
Moreover, only H2O or ethanol without 1,4-dioxane resulted in
decreased yields (entries 6 and 7). 1,4-dioxane was most suitable
for this reaction, because solvents such as toluene and p-xylene
reacted with 1,4-naphthoquinone [31,32]. Finally, additives were
investigated. Cs2CO3 was less effective (entry 8).
With the optimized conditions in hand, the substrate scope of
the aryl iodides was investigated (Table 2). Substitutions on the
aryl group at the ortho, meta, and para positions were all tolerated
(6–12). Aryl iodides with both electron-donating and electron-
withdrawing groups participated to give the corresponding
2-aryl-1,4-naphthoquinones (6–16). Under these reaction condi-
tions, a variety of functional groups were tolerated, including aryl
ethers (6–8), nitriles (13), esters (14), trifluoromethyl groups (15),
Results and discussion
The Pd-catalyzed direct arylation of 1,4-naphthoquinone with
iodobenzene was initially studied (Table 1). The reaction did not
proceed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)/1,4-dioxane
(1:1) with AgTFA (2 equiv) as the additive in the presence of Pd
(TFA)2 (10 mol%) and PCy3 (20 mol%) (entry 1). Based on our recent
work [31], Pd(TFA)2, PCy3 and AgTFA were changed to Pd(PPh3)2Cl2
(10 mol%) and AgOAc (2 equiv) in the absence of a ligand (entry 2).
As a result, the desired 2-phenyl-1,4-naphthoquinone (1) was
obtained in 41% yield. Replacing Pd(PPh3)2Cl2 with Pd(dppf)Cl2
resulted in decreased yield (entry 3). Solvent effects were also
surveyed. Excluding HFIP improved the yield to 84% yield (entry
4). H2O/1,4-dioxane (1:1) was also efficient (entry 5). Thus,
Table 1
Optimization of reaction conditions.a
1
Entry
Pd catalyst
Ligand
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Pd(TFA)2
PCy3
none
none
none
none
none
none
none
AgTFA
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cs2CO3
HFIP/1,4-dioxane
HFIP/1,4-dioxane
HFIP/1,4-dioxane
1,4-dioxane
H2O/1,4-dioxane
H2O
0
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
41
26
84
84
39
48
22
EtOH
1,4-dioxane
All the reactions were run with 1,4-naphthoquinone (0.2 mmol) and iodobenzene (0.2 mmol) in 1.0 mL solvent for 19 h.
2

Y. Akagi, T. Komatsu
Tetrahedron Letters 61 (2020) 152446
reaction shows extensive functional group tolerance and high
regioselectivity when using the nonsymmetric 1,4-naphtho-
quinone, juglone, as a starting material. We also successfully devel-
oped a synthetic pathway for the benzo[b]phenanthridine skeleton
(benzo[b]phenanthridine-7,12-dione) from the resulting 2-aryl-
1,4-naphthoquinone. Efforts on the total synthesis of phenan-
throviridin aglycon and jadomycins are ongoing.
O
Ph-I
O
O
O
O
Pd(PPh3)2Cl2
AgOAc
2
+
1,4-dioxane
80 °C, 19 h
3
OH
O
OH
OH
2: 61%
3: 15%
Scheme 1. Arylation of juglone (5-hydroxy-1,4-naphthoquinone) with
iodobenzene.
Declaration of Competing Interest
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.
O
O
O
28% NH3 aq.
MeOH
60 °C, 2 h
61%
OAc
NH2 OH
Appendix A. Supplementary data
O
O
18
20
19
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152446.
MnO2
References
CH2Cl2
rt, 17 h
81%
N
[1] P. Bermejo-Bescós, S. Martín-Aragón, K.L. Jiménez-Aliaga, A. Ortega, M.T.
Molina, E. Buxaderas, G. Orellana, A.G. Csákÿ, Biochem. Biophys. Res. Commun.
400 (2010) 169–174.
O
[2] A. Ortega, Á. Rincón, K.L. Jiménez-Aliaga, P. Bermejo-Bescós, S. Martín-Aragón,
M.T. Molina, A.G. Csákÿ, Bioorg. Med. Chem. Lett. 21 (2011) 2183–2187.
[3] M.P. Gore, S.J. Gould, D.D. Weller, J. Org. Chem. 56 (1991) 2289–2291.
[4] M.P. Gore, S.J. Gould, D.D. Weller, J. Org. Chem. 57 (1992) 2774–2783.
[5] S. Mohri, M. Stefinovic, V. Snieckus, J. Org. Chem. 62 (1997) 7072–7073.
[6] Ó. Frutos, C. Atienza, A.M. Echavarren, Eur. J. Org. Chem. (2001) 163–171.
[7] S.W. Ayer, A.G. Mclnnes, P. Thibault, J.A. Walter, J.L. Doull, T. Parnell, L.C.
Vining, Tetrahedron Lett. 32 (1991) 6301–6304.
[8] J.L. Doull, S.W. Ayer, A.K. Singh, P. Thibault, J. Antibiotics 46 (1993) 869–871.
[9] J.L. Doull, A.K. Singh, M. Hoare, S.W. Ayer, J. Ind. Microbiol. 13 (1994) 120–125.
[10] R.T. Syvitski, C.N. Borissow, C.L. Graham, D.L. Jakeman, Org. Lett. 8 (2006) 697–700.
[11] Y. Akagi, S. Yamada, N. Etomi, T. Kumamoto, W. Nakanishi, T. Ishikawa,
Tetrahedron Lett. 51 (2010) 1338–1340.
Scheme 2. Synthesis of benzo[b]phenanthridine-7,12-dione (20).
and nitro groups (16). Unfortunately, when using 2-iodobenzyl
alcohol, the desired 2-aryl-1,4-naphthoquinone (17) was not
obtained. However, by acetyl protection of the hydroxyl group
[32], the reaction proceeded to give the corresponding product
(18) in a moderate yield. At the moment, it is unclear how the sub-
stitutions on the aryl group affect the reaction yields.
A nonsymmetric 1,4-naphthoquinone, juglone (5-hydroxy-1,4-
naphthoquinone), was also examined (Scheme 1). As reported by
Molina’s group [18], the C-2 isomer (2) was obtained preferentially
over the C-3 isomer (3). It is considered that activation of C-4 by
internal chelation of the hydroxyl group made C-2 more elec-
tron-deficient. As a result, arylation at C-2 took precedence over
that at C-3. The ratio of 2:3 was 4:1, comparable to that by the
group of Molina (up to approx. 5.7:1) [18]. With a view to applying
this reaction to the total synthesis of natural products such as
phenanthroviridin aglycon (4) and jadomycin A (5), we examined
solvents and additives to further improve the regioselectivity.
However, good results have not been obtained [32].
Further synthetic application of 2-aryl-1,4-naphthoquinone
was explored, as described in Scheme 2. By treating 2-aryl-1,4-
naphthoquinone (18) with aqueous ammonia [5], introduction of
the amino group and removal of the acetyl group occurred to afford
enamine (19) in a moderate yield. Oxidative cyclization of the
resulting benzyl alcohol (19) with MnO2 successfully yielded
benzo[b]phenanthridine-7,12-dione (20) [5,33].
[12] M. Shan, E.U. Sharif, G.A. O’Doherty, Angew. Chem. Int. Ed. 49 (2010) 9492–9495.
[13] T. Tajima, Y. Akagi, T. Kumamoto, N. Suzuki, T. Ishikawa, Tetrahedron Lett. 53
(2012) 383–387.
[14] E.U. Sharif, G.A. O’Doherty, Eur. J. Org. Chem. (2012) 2095–2108.
[15] X. Yang, B. Yu, Chem. Eur. J. 19 (2013) 8431–8434.
[16] T. Itahara, J. Org. Chem. 50 (1985) 5546–5550.
[17] P.K. Singh, B.K. Rohtagi, R.N. Khanna, Synth. Commun. 22 (1992) 987–993.
[18] M.T. Molina, C. Navarro, A. Moreno, A.G. Csákÿ, Org. Lett. 11 (2009) 4938–
4941.
[19] O.M. Demchuk, K.M. Pietrusiewicz, Synlett 7 (2009) 1149–1153.
[20] Y. Fujiwara, V. Domingo, I.B. Seiple, R. Gianatassio, M.D. Bel, P.S. Baran, J. Am.
Chem. Soc. 133 (2011) 3292–3295.
[21] J. Wang, S. Wang, G. Wang, J. Zhang, X.-Q. Yu, Chem. Commun. 48 (2012)
11769–11771.
[22] A. Honraedt, F.L. Callonnec, E.L. Grognec, V. Fernandez, F.-X. Felpin, J. Org.
Chem. 78 (2013) 4604–4609.
[23] A. Deb, S. Manna, A. Maji, U. Dutta, D. Maiti, Eur. J. Org. Chem. (2013) 5251–
5256.
[24] P. Patil, A. Nimonkar, K.G. Akamanchi, J. Org. Chem. 79 (2014) 2331–2336.
[25] D. Wang, B. Ge, L. Li, J. Shan, Y. Ding, J. Org. Chem. 79 (2014) 8607–8613.
[26] D. Wang, B. Ge, L. Du, H. Miao, Y. Ding, Synlett 25 (2014) 2895–2898.
[27] D. Wang, B. Ge, S. Yang, H. Maio, Y. Ding, Russ. J. Gen. Chem. 84 (2014) 1615–
1621.
[28] Y. Moon, Y. Jeong, D. Kook, S. Hong, Org. Biomol. Chem. 13 (2015) 3918–3923.
[29] T.P.A. Krishna, S. Pandaram, A. Ilangovan, Org. Chem. Front. 6 (2019) 3244–
3251.
[30] S. Sar, J. Chauhan, S. Sen, ACS Omega 5 (2020) 4213–4222.
[31] Y. Akagi, S. Fukuyama, T. Komatsu, Chem. Pharm. Bull. 68 (2020) 288–291.
[32] See Supplementary Material in details.
[33] P. Pradeep, K.J. Ngwira, C. Reynolds, A.L. Rousseau, A. Lemmerer, M.A.
Fernandes, M.M. Johnson, C.B. de Koning, Tetrahedron 72 (2016) 8417–8427.
Conclusion
In summary, we have developed a novel method for the Pd-cat-
alyzed arylation of 1,4-naphthoquinones with aryl iodides. This
3