Palladium-catalyzed total synthesis of euchrestifoline using a one-pot Wacker oxidation and double aromatic C-H bond activation

Article abstract of DOI:10.1039/b813670j

We describe the total synthesis of euchrestifoline featuring an unprecedented one-pot Wacker oxidation and double aromatic C-H bond activation. The 2008 Royal Society of Chemistry.

Full text of DOI:10.1039/b813670j

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Palladium-catalyzed total synthesis of euchrestifoline using a one-pot Wacker
oxidation and double aromatic C–H bond activation†
Konstanze K. Gruner and Hans-Joachim Kno¨lker*
Received 6th August 2008, Accepted 1st September 2008
First published as an Advance Article on the web 29th September 2008
DOI: 10.1039/b813670j
We describe the total synthesis of euchrestifoline featuring
an unprecedented one-pot Wacker oxidation and double
aromatic C–H bond activation.
We have developed a convergent synthesis of euchrestifoline
(1) following our retrosynthetic analysis (Scheme 1). The tetra-
cyclic ring system is assembled from bromobenzene (3) and the
aminochromene 4 via a sequence of palladium(0)-catalyzed ami-
nation and oxidative biaryl cyclization by palladium(II)-catalyzed
double C–H bond activation. Transformation of the chromene to
the chroman-4-one can be achieved by a Wacker oxidation using
the same reaction conditions as required for oxidative cyclization.
The useful biological activities of carbozole alkaloids have
induced an increasing interest in their synthesis.1–3 We
have developed a highly convergent route to carbazoles via
palladium(0)-catalyzed Buchwald–Hartwig amination followed
by palladium(II)-catalyzed oxidative cyclization.2 The oxidative
cyclization of the intermediate N,N-diarylamine is based on an
˚
earlier report by Akermark et al. using stoichiometric amounts
of palladium(II).4 By application of conditions known for the
classical Wacker process (reoxidation of Pd(0) to Pd(II) with Cu(II)
salts),5 we have shown first that the biaryl cyclization can be
induced using catalytic amounts of palladium.6,7 Subsequently, the
palladium(II)-catalyzed oxidative cyclization by double aromatic
C–H bond activation has found various applications in carbazole
synthesis.1,8,9 The present example describes for the first time a
palladium(II)-catalyzed Wacker oxidation5 of a vinylarene to an
arylketone followed by cyclization of a diarylamine to a carbazole.
Execution of both transformations as a one-pot reaction leads
to sequential activation of three C–H bonds in a palladium(II)-
catalyzed process.
Euchrestifoline (1), our target molecule, was isolated in 1996
by Wu and coworkers from the leaves of the Chinese medicinal
plant Murraya euchrestifolia (Fig. 1).10 No total synthesis has been
reported so far for this natural product. However, compound 1 was
used as an intermediate for a synthesis of the structurally related
girinimbine (2) described in 1971 by Chakraborty and Islam.11
Girinimbine (2), the first pyrano[3,2-a]carbazole alkaloid from
natural sources, was isolated by Chakraborty and his group from
the stem bark of Murraya koenigii and by Joshi et al. from the
root bark of Clausena heptaphylla. The structural assignment of
girinimbine (2) was based on spectroscopic studies and chemical
transformations.12,13
Scheme 1 Retrosynthetic analysis of euchrestifoline (1)
Preparation of the precursor starts with conversion of 2-
methyl-3-butyn-2-ol (5) to the trifluoroacetate 6 (Scheme 2).14
The resulting crude product was used for alkylation of 2-
methyl-5-nitrophenol (7) to the corresponding aryl propargyl
ether 8.14,15 Thermally induced [3,3]-sigmatropic rearrangement
followed in situ by rearomatization and cyclization afforded the
nitrochromene 9. Reduction using iron in glacial acetic acid led
quantitatively to the aminochromene 4. Using this improved
sequence, the aminochromene 4 is available in 3 steps and 70%
overall yield based on the nitrophenol 7 (previous synthesis:
3 steps, 60% overall yield).15 Buchwald–Hartwig amination of
bromobenzene (3) with the aminochromene 4 provided the
diarylamine 10. ‡
Heating of the diarylamine 10 with catalytic amounts of
palladium(II) acetate in a mixture of acetic acid and water (10 : 1)
in the presence of 2.5 equivalents cupric acetate at 90 ◦C for
5 h led to Wacker oxidation and afforded the chromanone 11
(Scheme 3).§ Extension of the reaction time to 24 h resulted in
cyclization via double aromatic C–H bond activation and afforded
euchrestifoline (1) (26% yield) along with the chromanone 11 (23%
yield). Optimized conditions (heating of the diarylamine 10 for
2 days using catalytic amounts of palladium(II) acetate and cupric
acetate) resulted in direct conversion to euchrestifoline (1).¶ The
spectroscopic data of our synthetic euchrestifoline (1) were in
good agreement with those reported for the natural product.10
Compound 1 exhibits an intense fluorescence with an emission at
501 nm and a large Stokes shift.
Fig. 1 Pyrano[3,2-a]carbazole alkaloids euchrestifoline and girinimbine.
It was obvious that activation of the vinylic C–H bond, which
leads to Wacker oxidation, takes place first. The subsequent
activation of the aromatic C–H bonds leads to cyclization of the
initially formed chromanone 11 to euchrestifoline (1). In order
Department Chemie, Technische Universita¨t Dresden, Bergstrasse 66,
01069 Dresden, Germany. E-mail: hans-joachim.knoelker@tu-dresden.de;
Fax: +49 351-463-37030
† Part 88 of ‘Transition Metals in Organic Synthesis’; for Part 87, see: ref. 1.
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reported by Chakraborty and Islam.11 Structural assignment for
girinimbine (2) was based on comparison of the spectroscopic data
with those reported for the natural product12,13 and the synthetic
product obtained earlier by a molybdenum-mediated approach.15
In conclusion, we have developed a highly efficient route to
the aminochromene 4 (3 steps and 70% yield based on 7), a
useful building block for the synthesis of pyrano[3,2-a]carbazole
alkaloids. Three consecutive palladium-catalyzed reactions con-
vert compound 4 into euchrestifoline (1): Buchwald–Hartwig
amination, Wacker oxidation, and subsequent oxidative biaryl
cyclization by double aromatic C–H bond activation. As both
latter transformations are palladium(II)-catalyzed, they are most
efficiently accomplished as one-pot process to provide euchrestifo-
line (1) in two steps and 37% overall yield based on bromobenzene
(3). The pyrano[3,2-a]carbazoles are of interest because of their
potential anti-TB activity.16
Notes and references
‡ Spectroscopic data for the diarylamine (10): Yellow solid, mp 105–107 ◦C;
IR (ATR): n = 3389, 3046, 2977, 2925, 2851, 1637, 1594, 1578, 1506, 1477,
1408, 1378, 1315, 1257, 1204, 1172, 1123, 1057, 1025, 941, 898, 875, 787,
745, 720, 689 cm-1; 1H NMR (500 MHz, CDCl3): d = 1.44 (s, 6 H), 2.17
(s, 3 H), 5.40 (br s, 1 H), 5.59 (d, J = 9.9 Hz, 1 H), 6.46 (d, J = 9.9 Hz,
1 H), 6.67 (d, J = 8.1 Hz, 1 H), 6.82 (m, 3 H), 6.93 (d, J = 8.1 Hz, 1 H),
7.20 (m, 2 H); 13C NMR and DEPT (125 MHz, CDCl3): d = 15.29 (CH3),
27.62 (2 CH3), 75.06 (C), 114.11 (CH), 115.18 (C), 115.70 (2 CH), 118.43
(CH), 119.39 (CH), 121.07 (C), 129.19 (2 CH), 129.93 (CH), 130.32 (CH),
135.82 (C), 145.54 (C), 151.62 (C); MS (EI): m/z (%) = 265 (M+, 39), 250
(100); HRMS: m/z calc. for C18H19NO (M+): 265.1467, found: 265.1450;
anal. calc. for C18H19NO: C 81.47, H 7.22, N 5.28, found: C 81.22, H 7.49,
N 5.06.
Scheme 2 Synthesis of the diarylamine 10. Reagents and conditions:
(a) 1.0 equiv. (CF3CO)2O, 1.3 equiv. DBU, MeCN, -5 ◦C, 70 min;
(b) 1.15 equiv. 6, 1 mol% CuCl2·2 H2O, 1.3 equiv. DBU, MeCN, 0 ◦C,
7 h, 71% (over 2 steps); (c) o-xylene, 140 ◦C, 18 h, 98%; (d) 10 equiv. Fe,
HOAc, rt, 2 h, 100%; (e) 1.0 equiv. 3, 1.2 equiv. 4, 1.4 equiv. Cs2CO3,
6 mol% Pd(OAc)2, 6 mol% BINAP, toluene, 110 ◦C, 36 h, 93%.
§ Spectroscopic data for the chromanone (11): Yellow oil; IR (ATR): n =
3260, 3028, 2975, 2928, 1640, 1591, 1518, 1456, 1431, 1386, 1370, 1235,
1217, 1176, 1093, 1042, 912, 889, 803, 737, 692 cm-1; 1H NMR (500 MHz,
CDCl3): d = 1.47 (s, 6 H), 2.08 (s, 3 H), 2.73 (s, 2 H), 6.67 (d, J = 8.5 Hz, 1
H), 7.08 (d, J = 8.5 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.25 (m, 2 H), 7.33
(m, 2 H), 10.45 (br s, 1 H); 13C NMR and DEPT (125 MHz, CDCl3): d =
15.15 (CH3), 26.75 (2 CH3), 49.39 (CH2), 77.58 (C), 104.00 (CH), 105.98
(C), 113.99 (C), 122.89 (2 CH), 123.52 (CH), 129.20 (2 CH), 138.17 (CH),
=
140.56 (C), 146.44 (C), 158.43 (C), 195.41 (C O); MS (EI): m/z (%) = 281
(M+, 100), 266 (68), 226 (26), 225 (17), 224 (32), 196 (12); HRMS: m/z
calc. for C18H19NO2 (M+): 281.1416, found: 281.1403.
¶ Synthesis of euchrestifoline (1): A mixture of the diarylamine 10 (56.5 mg,
0.21 mmol), palladium acetate (4.8 mg, 0.02 mmol) and cupric acetate
(3.8 mg, 0.02 mmol) in glacial acetic acid (5 mL) and water (0.5 mL) was
heated at 90 ◦C in air for 48 h. After cooling to rt, a small amount of silica
gel was added to the reaction mixture and the solvent was removed under
vacuum. Flash chromatography of the residue on Celite and silica gel (light
petroleum ether–EtOAc, 9 : 1) provided euchrestifoline (1), yield: 23.7 mg
(40%). Yellow crystals, mp 181 ◦C (ref. 10: 187–189 ◦C); UV (MeOH): l =
230, 256, 285, 291, 334, 386 nm; fluorescence (MeOH): lem = 501 (lex
=
386) nm; IR (ATR): n = 3381, 2969, 2919, 2849, 1710, 1649, 1608, 1590,
1492, 1450, 1384, 1369, 1311, 1213, 1193, 1171, 1136, 1039, 1003, 930, 887,
Scheme 3 Pd(II)-catalyzed synthesis of euchrestifoline (1) and conversion
into girinimbine (2). Reagents and conditions: (a) 10 mol% Pd(OAc)2, 2.5
equiv. Cu(OAc)2, HOAc–H2O (10 : 1), 90 ◦C, 5 h, 57%; (b) 10 mol%
Pd(OAc)2, 10 mol% Cu(OAc)2, HOAc, 90 ◦C, 24 h, 44%; (c) 10 mol%
Pd(OAc)2, 10 mol% Cu(OAc)2, HOAc–H2O (10 : 1), 90 ◦C, 48 h, 40%;
(d) 1. 4 equiv. LiAlH4, THF, 0 ◦C to rt, 17 h; 2. 5% HCl, 60 ◦C, 1 h, 70%.
1
773, 744, 690, 651, 607 cm-1; H NMR (500 MHz, CDCl3): d = 1.53 (s,
6 H), 2.34 (s, 3 H), 2.82 (s, 2 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.35 (t, J =
7.5 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.93 (d, J = 7.5 Hz, 1 H), 8.00 (s, 1
H), 10.14 (br s, 1 H); 13C NMR and DEPT (125 MHz, CDCl3): d = 16.08
(CH3), 26.82 (2 CH3), 48.54 (CH2), 79.49 (C), 104.67 (C), 111.08 (CH),
116.23 (C), 117.76 (C), 119.21 (CH), 119.98 (CH), 122.27 (C), 124.62 (CH),
=
129.26 (CH), 137.00 (C), 139.40 (C), 157.65 (C), 194.33 (C O); MS (EI):
m/z (%) = 279 (M+, 100), 264 (82), 224 (35), 223 (62), 195 (15), 167 (30),
132 (15); HRMS: m/z calc. for C18H17NO2 (M+): 279.1259; found: 279.
1261; anal. calc. for C18H17NO2: C 77.40, H 6.13, N 5.01, found: C 77.43,
H 6.28, N 4.71.
to confirm this assumption, it was shown that transformation of
the chromanone 11 to euchrestifoline (1) is achieved in one day
using the same reaction conditions. Previously, 1 was prepared
via Fries rearrangement.11 Finally, reduction of euchrestifoline
(1) followed by acidic work-up led via elimination of water
to girinimbine (2).ꢀ This conversion of euchrestifoline (1) into
girinimbine (2) is superior to the 3-step-sequence previously
ꢀ Spectroscopic data for girinimbine (2): Colorless crystals, mp 173 ◦C (ref.
12a: 176 ◦C); 1H NMR (500 MHz, acetone-d6): d = 1.50 (s, 6 H), 2.33 (s, 3
H), 5.81 (d, J = 9.8 Hz, 1 H), 6.95 (d, J = 9.8 Hz, 1 H), 7.14 (t, J = 7.5 Hz,
1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 7.97
(d, J = 7.5 Hz, 1 H), 10.33 (br s, 1 H); 13C NMR and DEPT (125 MHz,
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acetone-d6): d = 16.19 (CH3), 27.83 (2 CH3), 76.48 (C), 105.36 (C), 111.29
(CH), 117.46 (C), 118.30 (C), 118.58 (CH), 119.64 (CH), 119.85 (CH),
121.70 (CH), 124.36 (C), 124.88 (CH), 129.80 (CH), 136.16 (C), 140.85
(C), 150.44 (C).
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