A one-pot synthesis of phaitanthrin e through intermolecular condensation/intramolecular aryl C-H amination cascade

Article abstract of DOI:10.3987/COM-16-13465

A one-pot synthesis of phaitanthrin E starting from methyl indole-3-carboxylate and isatoic anhydride through intermolecular condensation/intramolecular aryl C-H amination cascade was developed.

Full text of DOI:10.3987/COM-16-13465

HETEROCYCLES, Vol. 92, No. 6, 2016, pp. 1132 - 1136. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 16th March, 2016, Accepted, 12th April, 2016, Published online, 27th April, 2016
DOI: 10.3987/COM-16-13465
A
ONE-POT SYNTHESIS OF PHAITANTHRIN
E
THROUGH
INTERMOLECULAR CONDENSATION/INTRAMOLECULAR ARYL
C-H AMINATION CASCADE
Tomoki Itoh,a Takumi Abe,a Tominari Choshi,b Takashi Nishiyama,b and
Minoru Ishikuraa*
aSchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail: ishikura@hoku-iryo-u.ac.jp
bFaculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
Abstract – A one-pot synthesis of phaitanthrin E starting from methyl
indole-3-carboxylate
and
isatoic
anhydride
through
intermolecular
condensation/intramolecular aryl C-H amination cascade was developed.
Alkaloids with an indolo[2,1-b]quinazoline core, represented by tryptanthrin (1), have attracted
considerable biological and synthetic interest because of their intriguing structural features and wide
range of promising biological activities.1 Many structural analogues of these alkaloids have been
synthesized and some compounds have shown notable activity.2 In 2008, five new alkaloids, phaitanthrins
A (2), B (3), C (4), D (5), and E (6), were isolated from Phaius mishmensis (Orchidaceae), and compound
2 showed moderate cytotoxicity against three human cancer cell lines.3 Total syntheses of 2, 3, and 4
were reported separately by two groups in 2013.4,5 In 2015, the first total synthesis of 5 and 6 was
accomplished through a biogenetic pathway starting from anthranilic acid, o-aminophenylacetic acid, and
glycolic acid, involving a one-pot transformation of a diamide intermediate through intramolecular
dehydrative cyclization.6 We previously reported a one-pot synthesis of tryptanthrin (1) and candidine (7)
by oxidative dimerization of indole-3-carboxaldehyde involving further conversion of 1 to 2 and 3, and
we found that oxidative coupling of indole-3-carboxaldehyde with isatoic anhydride also produced 1 and
4.7 Moreover, 1 was synthesized through oxidative dimerization of skatole in a one-pot reaction.8 In
continuing our studies, we envisioned that methyl indole-3-carboxylate (8) bearing the CO2Me group
could serve as a useful building block for 6. In this paper, we describe one-pot access to 6 starting from
methyl indole-3-carboxylate (8) and isatoic anhydride (9) through an intermolecular
condensation/intramolecular aryl C-H amination cascade.

O
O
OH
MeO
O
O
OH
N
OH
N
N
N
N
N
N
N
O
O
O
O
(-)-phaitanthrin A (2)
(-)-phaitanthrin B (3)
(-)-phaitanthrin C (4)
tryptanthrin (1)
O
O
O
CO2Me
NH
NH
NH
N
N
O
N
N
O
O
candidine (7)
(-)-phaitanthrin D (5)
phaitanthrin E (6)
Figure 1. Indoloquinazoline alkaloids
Initially, according to a previously reported protocol,7 the oxidative coupling reaction of 8 with 9 (1.5
equiv) using urea-hydrogen peroxide (UHP) (5 equiv) in toluene at 75 °C in air for 12 h was performed.
This resulted in recovery of 8 (80%) along with trace amounts of amide 10 (8%). Ester 8 withstood the
oxidative conditions for long reaction time, in contrast to the formation of 1 by the reaction of
indole-3-carboxaldehyde with 9. Amide 10 was obtained in 72% yield by heating 8 with 9 in the presence
of Et3N (2 equiv) in DMF at 130 °C for 16 h (Scheme 1).
CO2Me
H
CO2Me
N
Et3N (2 equiv)
O
NH2
N
+
O
DMF, 130 °C, 16 h
72%
N
H
8
9
O
O
10
CO2Me
NH
O
CO2Me
CuI, Et3N
UHP
toluene
N
NH2
N
N
N
DMF
75 °C , 2 h
130 °C, 16 h
O
6
O
O
10
40%
1
65%
Scheme 1

Table 1. Cu-Mediated coupling reaction of methyl indole-3-carboxylate (7) with isatoic anhydride (8)a
CO2Me
NH
CO2Me
NH2
O
H
N
CO2Me
O
9
conditions
+
N
N
+
N
N
+
O
N
O
O
O
8
H
O
10
6
1
Yield (%)b
Entry
CuX
Amine
Solv.
Temp.
Time
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
6
10
12
10
---
28
16
5
1
1
2
3
4
5
6
7
8
9
CuI (1.5 equiv)
CuI (1.5 equiv)
-----
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
DMF 130 °C
---
62
10
47
23
60
---
51
20
35
---
---
---
---
---
---
---
33
Et3N (2 equiv)
Et3N (2 equiv)
Et3N (2 equiv)
Et3N (2 equiv)
Et3N (2 equiv)
pyridine (2 equiv)
i-Pr2NEt (2 equiv)
DABCO (2 equiv)
CuBr (1.5 equiv)
CuI (1.0 equiv),
CuI (0.5 equiv),
CuI (3 equiv)
CuI (1.5 equiv)
CuI (1.5 equiv)
CuI (1.5 equiv)
---
---
---
a 8 and 9 (1.5 equiv) were heated in air. b Isolated yield.
We expected that intramolecular C-H amination of 10 would produce the indoloquinazoline core. Initially,
10 was oxidized with UHP (5 equiv) in toluene at 75 °C for 2 h, producing 1 in 65% yield. Considerable
efforts have been made to develop metal-mediated C-H amination;9 therefore, we investigated whether a
copper-mediated intramolecular aryl C-H amination in 10 would lead to 6. Heating 10 with CuI (1.5
equiv) in DMF at 130 °C for 16 h provided no products. However, to our surprise, we found that the
addition of Et3N (2 equiv) promoted the reaction to produce 6 in 40% yield.
Therefore, we envisioned that coupling 8 with 9 in the presence of a copper complex could allow the
one-pot formation of 6 involving the formation of amide 10 and intramolecular amination steps (Table 1).
Although heating 8 and 9 with CuI (1.5 equiv) in DMF at 130 °C provided 10 (12%) and 1 (35%) without
6, performing the reaction in the presence of Et3N (2 equiv) produced 6 in 62% yield along with trace
amounts of 10 (10%) (entries 1 and 2). The NMR data for 6 agreed well with the literature data.6 Hence,
in a search for optimized conditions, other copper complexes were screened initially. However, the
reaction did not occur with CuOAc, Cu(OAc)2, CuCl, CuCl2, and CuBr2, and only trace amounts of 6 was
obtained with CuBr (entry 3). Reducing the amount of CuI resulted in a considerable decrease in the yield
of 6 (entries 4 and 5), and increasing the amount to 3 equiv did not improve the yield (entry 6). Pyridine,
i-Pr2NEt, and DABCO were less effective than Et3N (entries 7–9).

In summary, we have developed a one-pot synthesis of phaitanthrin E (6) using methyl
indole-3-carboxylate (8) and isatoic anhydride (9) in the presence of CuI. The one-pot reaction proceeded
through in situ generation of amide 10, followed by Cu-mediated intramolecular aryl C-H amination.
EXPERIMENTAL
Melting points were recorded with a Yamato MP21 and were uncorrected. High-resolution MS spectra
were recorded with a JEOL JMS-T100LP mass spectrometer. IR spectra were measured with a Shimadzu
IRAffinity-1 spectrometer. The NMR experiments were performed with a JEOL JNM-ECA500 (500
MHz) spectrometer, and chemical shifts are expressed in ppm ().
Methyl 1-[(2-aminophenyl)carbonyl]-1H-indole-3-carboxylate (10): Et3N (4 mmol) was added to a
solution of 8 (355 mg, 2 mmol) and 9 (490 mg, 3 mmol) in DMF (20 mL), and the mixture was stirred at
130 °C for 16 h. After cooling to room temperature, the mixture was added to 10% aq. HCl, extracted
with AcOEt (100 mL), washed with brine, and dried over MgSO4. The solvent was removed, and the
residue was purified by silica gel column chromatography with CH2Cl2/AcOEt (50:1) to give 10 (431 mg,
73%) as a colorless solid. Mp 158–159 °C (CH2Cl2/hexane). IR (CHCl3): 3343, 1694, 1660 cm-1.
1H-NMR (CDCl3) : 3.91 (s, 3H), 5.27 (br s, 2H), 6.74 (td, J = 1.2, 6.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H),
7.33–7.37 (m, 2H), 7.38–7.42 (m, 2H), 8.05 (s, 1H), 8.19–8.21 (m, 2H). 13C-NMR (CDCl3) 51.6, 112.5,
114.2, 115.8, 116.9, 117.3, 121.7, 124.7, 125.3, 127.7, 131.7, 134.0, 134.4, 136.5, 150.1, 164.7, 169.3.
HR-MS (ESI) m/z: Calcd for C17H14N2NaO3 [(M + Na) +]: 317.0902. Found 317.0877.
Dakin oxidation of 10 using UHP: UHP (941 mg, 10 mmol) was added to a solution of 10 (588 mg, 2
mmol) in toluene (30 mL) at room temperature, and the mixture was heated at 75 °C. After 16 h, the
mixture was gradually cooled to room temperature, 10% NaOH solution (4 mL) was added to the mixture,
and stirred for 0.5 h. The mixture was diluted with AcOEt (100 mL) and washed with brine, and dried
over MgSO4. The solvent was removed, and the residue was separated by silica gel column
chromatography with CH2Cl2/AcOEt (50:1) to give 17 (322 mg, 65%).
Phaitanthrin E (6): After a mixture of CuI (1.05 g, 6 mmol) and Et3N (1.3 g, 8 mmol) in DMF (50 mL)
was stirred at room temperature for 0.5 h, methyl indole-3-carboxylate (8) (701 mg, 4 mmol) and isatoic
anhydride (9) (979 mg, 6 mmol) were added to the mixture and the mixture was stirred at 130 °C for 16 h.
After cooling, 10% aq. HCl solution was added to the mixture, and the mixture was extracted with AcOEt
(100 mL). The organic layer was washed with brine and dried over MgSO4. The solvent was removed,
and the residue was separated by silica gel column chromatography with CH2Cl2 to give 6 (725 mg, 62%)
1
as amorphous powder and 10 (10%). IR (CHCl3): 3329, 3020, 1697, 1665, 1626, 1579 cm-1. H-NMR
(CDCl3) : 4.01 (s, 3H), 7.28 (d, J = 8.6 Hz, 1H), 7.30–7.34 (m, 2H), 7.43 (td, J = 1.2, 8.0 Hz, 1H), 7.71
(td, J = 1.7, 7.7 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.70 (d, J = 8.0 Hz, 1H),

13
10.29 (br s 1H). C-NMR (CDCl3) : 51.4, 86.7, 114.4, 115.7, 116.3, 119.4, 122.4, 123.2, 125.7, 126.3,
128.7, 130.4, 135.3, 138.2, 144.1, 158.5, 167.3. HR-MS (ESI) m/z: Calcd for C17H13N2O3 [(M + H)+]
293.0926. Found 293.0926.
ACKNOWLEDGEMENTS
This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology
of Japan through a Grant-in Aid for Scientific Research (No. 26460012), and the Akiyama Foundation.
REFERENCES
1. A. M. Tucker and P. Grundt, ARKIVOC, 2012, i, 546; Y. Jahng, Arch. Pharm. Res., 2013, 36, 517; U.
A. Kshirsagar, Org. Biomol. Chem., 2015, 13, 9336.
2. B. Krivogorsky, A. C. Nelson, K. A. Douglas, and P. Grundt, Bioorg. Med. Chem. Lett., 2013, 23,
1032; J. M. Hwang, T. Oh, T. Kaneko, A. M. Upton, S. G. Franzblau, Z. Ma, S. N. Cho, and P. Kim,
J. Nat. Prod., 2013, 76, 354; K. Seya, A. Yamaya, S. Kamachi, M. Murakami, H. Kitahara, J.
Kawakami, K. Okumura, M. Murakami, S. Motoura, and K.-I. Furukawa, J. Nat. Prod., 2014, 77,
1413.
3. C.-W. Jao, W.-C. Lin, Y.-T. Wu, and P.-L. Wu, J. Nat. Prod., 2008, 71, 1275.
4. S. D. Vaidya and N. P. Argade, Org. Lett., 2013, 15, 4006.
5. G. Kang, Z. Luo, C. Liu, H. Gao, Q. Wu, H. Wu, and J. Jiang, Org. Lett., 2013, 15, 4738.
6. S. D. Vaidya and N. P. Argade, Org. Lett., 2015, 17, 6218.
7. T. Abe, T. Itoh, T. Choshi, S. Hibino, and M. Ishikura, Tetrahedron Lett., 2014, 55, 5268.
8. T. Itoh, T. Abe, S. Nakamura, and M. Ishikura, Heterocycles, 2015, 91, 1423.
9. For recent reviews for aryl C-H amination, see K. Okano, H. Tokuyama, and T. Fukuyama, Chem.
Commun., 2014, 50, 13650; M. Moselage, J. Li, and L. Ackermann, ACS Catal., 2016, 6, 498; J. Jiao,
K. Murakami, and K. Itami, ACS Catal., 2016, 6, 610.