Convergent total syntheses of the amaryllidaceae alkaloids lycoranine A, lycoranine B, and 2-methoxypratosine

Article abstract of DOI:10.1021/jo4006987

The title alkaloids, 1, 2, and 3 respectively, have been prepared in a convergent manner by two related routes. The superior one involves C-H functionalization of the relevant 5-methoxyindole at C-7 using Hartwig's protocol and thus forming the correspond

Full text of DOI:10.1021/jo4006987

Note
pubs.acs.org/joc
Convergent Total Syntheses of the Amaryllidaceae Alkaloids
Lycoranine A, Lycoranine B, and 2‑Methoxypratosine
Hye Sun Kim, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
S
* Supporting Information
ABSTRACT: The title alkaloids, 1, 2, and 3 respectively, have
been prepared in a convergent manner by two related routes.
The superior one involves C−H functionalization of the relevant
5-methoxyindole at C-7 using Hartwig’s protocol and thus
forming the corresponding borolated indole that could be
coupled with the requisite 2-bromobenzoate to deliver the title
natural products. Single crystal X-ray analyses of the synthetically
derived samples of compounds 1 and 2 are reported.
ycoranine A (1) and lycoranine B (2) were isolated from
Lthe bulbs of Lycoris radiata, an Amaryllidaceae species
collected in the Zhejiang Province of China and the crude
extracts of which have been used as folk remedies for laryngeal
problems as well as for the treatment of boils and carbuncles.1
The structures of compounds 1 and 2 were proposed on the
basis of extensive spectroscopic analyses, most particularly
various 2D NMR studies. They represent the first examples of
the pyrrolophenanthridinone class of natural product incorpo-
rating oxygenation (in this case in the form of a methoxy
group) in the A-ring. The presence of the C4 methyl group in
compound 2 is of biosynthetic interest because it suggests that
the decarboxylation step that takes place during the in vivo
production of all previously reported alkaloids of this type is
not an obligatory event. The related 2-methoxypratosine (3, aka
2-MPT) was isolated from whole plants of Narcissus serotinus L.,
an autumn flowering species collected in the Spanish region of
Valencia, and its structure was established using the usual range
of spectroscopic techniques.2 Alkaloids of the genus Narcissus
have been shown to possess, inter alia, cytotoxic, antiparasitic,
and antifungal properties.3
Given the continued interest in the biological properties of
the pyrrolophenanthridinone alkaloids generally,4 the limited
quantities of the title natural products available from their
natural sources, and the lack of biological data on them, we
sought to establish concise syntheses of these novel
compounds. Details of the outcome of our studies in this
area, which have culminated in total syntheses of the title
alkaloids (1, 2, and 3, respectively),5 are presented herein.
Our initial approach to compounds 1, 2, and 3 involved
coupling the readily derived 2,6-dibromo-derivative, 5,6 of p-
anisidine (4) (Scheme 1) with the known7 acid chloride 6,
thereby generating the amide 7 in 55% yield. However,
compound 7 failed to participate in the desired intramolecular
Ullmann cross-coupling reaction8 to deliver phenanthridinone
8. Rather, upon exposure to copper powder in DMSO,
acetanilide 7 afforded, probably via dimerization of intermediate
benzoxazole 9, the novel polycyclic compound 10 (7%). While
all of the spectroscopic data obtained on this last compound
were in accord with the assigned structure, final confirmation of
this followed from a single-crystal X-ray analysis.9 The
conversion 7 → 9 is not without precedent. Thus, for example,
Glorius, Batey, and Sekar10 have each shown that various
amides derived from o-bromoanilines are converted, via C−O
bonding forming processes, into the corresponding benzox-
azoles upon treatment of the former compounds with certain
copper species.
The lack of success associated with the above-mentioned
approach to the title alkaloids prompted consideration of one of
a number introduced by Tønder et al.5r and wherein Suzuki−
Miyaura cross-coupling of a C-7 halogenated indole with an
o‑borolated benzoate is followed by an in situ lactamization
reaction that delivers the pyrrolophenanthridinone framework.
A related approach has been delineated by Snieckus5l wherein a
Received: April 5, 2013
Published: April 22, 2013
© 2013 American Chemical Society
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Scheme 1
Scheme 2
C-7 borolated indole is cross-coupled with an o-halogenated
benzoic acid ester. Pursuit of either one of these variants
requires construction of the relevant C-7 substituted indole, a
nontrivial task. While the Bartoli reaction11 failed12 to provide a
means for converting 2-bromo-4-methoxynitrobenzene into
7‑bromo-5-methoxyindole and its C-2 methylated derivative (as
required for the assembly of targets 1−3 via Tønder’s
approach), these heterocycles could be prepared using
modifications to an underutilized protocol reported some
time ago by Sugasawa et al.13 In particular, and as shown in
Scheme 2, reaction of p-anisidine (4) with benzyltrimethyl-
ammonium tribromide (BTMABr3)14 afforded the
monobromo-derivative 116,15 (40%) that upon reaction with
either α-chloroacetonitrile or α-chloropropionitrile in the
presence of boron trichloride and titanium tetrachloride gave
the 2-amino-α-chloroacetophenone 12 or the corresponding
propiophenone 13 in 45% and 51% yields, respectively.
Independent treatment of these aryl ketones with sodium
borohydride resulted in sequential reductive cyclization and
elimination reactions to afford the required indole 1416 (81%)
or 15 (93%). In the final step, compound 14 was engaged in a
Suzuki−Miyaura cross-coupling reaction with the readily
available arylboronate ester 1617 or its dimethoxy-analogue
1718 to afford, presumably via either intermediate 18 or 20,
target compounds 11 (81%) and 32 (89%), respectively. In an
analogous manner, indole 15 was coupled with arylboronate
ester 16 and thereby affording, via intermediate 19, lycoranine
B (2)1 in 65% yield. The NMR spectroscopic properties of the
synthetically derived samples of compounds 1−3 were in
complete accord with the assigned structures and matched
those reported for the natural products (see Tables 1 and 2).
Final confirmation of the structures of targets 1 and 2 followed
from single-crystal X-ray analyses.9 The derived ORTEPs are
shown in the Supporting Information.
As noted above, the reversal of the polarity of the cross-
coupling process used by Tønder5r in his approach to
pyrrolophenanthridinones has been introduced by Snieckus
and co-workers.5l The C-7 borolated indoles required in
applying such an approach can be prepared in various ways
including via directed-metalation techniques. In a recent
refinement of these, Hartwig et al.5t have established an
iridium-catalyzed method for the direct borolation of indoles at
C-7 and exploited this in a one-pot synthesis of the natural
product hippadine (the demethoxy-analogue of lycoranine A).
Accordingly, we sought to explore the utility of such
methodology in allowing access to the title natural products.
To such ends, each of the commercially available indoles 21
and 22 was subjected, in a one-pot operation, to treatment with
[Ru(p-cymene)Cl2]2 and diethylsilane (so as to form the
corresponding N-hydrosilylindole) and then/or [Ir(OMe)-
COD]2 in the presence of 4,4′-di-tert-butyl-2,2′-bipyridine
(di-t-bpy), bis(pinacolato)diboron (B2Pin2), and pinacolborane
(HBPin) followed by a “workup” using aqueous sodium acetate
(Scheme 3). By such means the requisite C-7 borolated indole,
235t,19 (36%) and 2420 (66%) respectively, was obtained.
Pleasingly, Suzuki−Miyaura cross-coupling of compound 23
with the readily available 2-bromobenzoate 2517 afforded
lycoranine A (1) in 88% yield while analogous coupling of
the same indole with bromobenzoate 2619 yielded 2-MPT (3)
in near-quantitative yield. Similarly, coupling of compounds 24
and 25 led directly to lycoranine B (2) which was obtained in
66% yield. The spectral data recorded on each of compounds
1−3 obtained via the Snieckus/Hartwig route matched those
derived from the materials secured using Tønder’s approach.
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Table 1. Comparison of the 13C NMR Data (δC) Recorded for the Synthetically Derived Samples of Compounds 1−3 with
Those Reported for Lycoranines A and B and 2-MPT
a
b
a
b
a
c
compd 1
lycoranine A
compd 2
lycoranine B
compd 3
2-MPT
157.9
157.6
152.5
148.7
131.3
128.9
126.3
124.1
122.8
116.9
110.7
108.2
107.3
106.0
102.3
101.8
56.3
157.9
157.6
152.5
148.7
131.3
128.9
126.3
124.1
122.9
116.9
110.7
108.2
107.4
106.0
102.3
101.8
56.4
159.6
157.4
152.4
148.5
140.1
131.3
128.2
127.0
123.5
116.5
109.1
108.0
106.1
103.9
102.2
101.5
56.3
159.6
157.4
152.4
148.5
140.1
131.3
128.2
126.9
123.5
116.5
109.1
108.0
106.1
103.9
102.2
101.5
56.3
158.1
157.6
153.6
149.8
129.1
128.9
126.4
124.0
121.0
116.9
110.5
110.3
106.7
106.0
103.9
56.4
158.3
157.7
153.7
149.9
129.3
129.1
126.6
124.2
121.2
117.1
110.7
110.4
106.9
106.2
104.1
56.5
56.3
56.4
−
−
16.0
15.9
56.2
56.4
c
a
b
Recorded in CDCl3 at 200 MHz on a sample obtained by route described above. Obtained from ref 1; recorded in CDCl3 at 100 MHz. Obtained
from ref 2; recorded in CDCl3 at 125 MHz.
1
Table 2. Comparison of the H NMR Data (δH) Recorded for the Synthetically Derived Samples of Compounds 1−3 with
Those Reported for Lycoranines A and B and 2-MPT
a
b
a
b
a
c
compd 1
lycoranine A
compd 2
lycoranine B
7.96 (1H, s)
7.56 (1H, s)
7.39 (1H, d, J = 1.9 Hz) 7.38 (1H, d, J = 1.9 Hz) 7.55 (1H, s)
compd 3
2-MPT
8.01 (1H, d, J = 3.2 Hz) 8.01 (1H, d, J = 3.6 Hz) 7.97 (1H, s)
8.01 (1H, d, J = 3.6 Hz) 8.03 (1H, d, J = 3.5 Hz)
7.98 (1H, s)
7.59 (1H, s)
7.98 (1H, s)
7.59 (1H, s)
7.57 (1H, s)
7.98 (1H, s)
8.01 (1H, s)
7.59 (1H, s)
7.50 (1H, d, J = 1.6 Hz) 7.49 (1H, d, J = 1.9 Hz) 7.18 (1H, d, J = 1.9 Hz) 7.17 (1H, d, J = 1.9 Hz) 7.51 (1H, d, J = 1.6 Hz) 7.55 (1H, d, J = 2.0 Hz)
7.30 (1H, d, J = 1.6 Hz) 7.30 (1H, d, J = 1.9 Hz) 6.48 (1H, q, J = 1.2 Hz) 6.47 (1H, s)
7.28 (1H, d, J = 1.6 Hz) 7.30 (1H, d, J = 2.0 Hz)
6.82 (1H, d, J = 3.6 Hz) 6.84 (1H, d, J = 3.5 Hz)
6.83 (1H, d, J = 3.2 Hz) 6.82 (1H, d, J = 3.6 Hz) 6.16 (2H, s)
6.16 (2H, s)
3.95 (3H, s)
6.17 (2H, s)
3.97 (3H, s)
−
6.17 (2H, s)
3.96 (3H, s)
−
3.95 (3H, s)
4.11 (3H, s)
4.06 (3H, s)
3.97 (3H, s)
4.12 (3H, s)
4.07 (3H, s)
3.98 (3H, s)
2.88 (3H, d, J = 1.2 Hz) 2.87 (3H, s)
−
−
a
b
c
Recorded in CDCl3 at 800 MHz on sample obtained by route described above. Obtained from ref 1; recorded in CDCl3 at 400 MHz. Obtained
from ref 2; recorded in CDCl3 at 500 MHz.
borolated indoles using Hartwig chemistry5t and the removal of
Scheme 3
any need, therefore, to convert 2-bromobenzoates into the
corresponding 2-borolated congeners. The present studies not
only serve to confirm the structures assigned to the title natural
products but also provide a means by which sufficient quantities
can be generated so as to undertake appropriate biological
evaluations, a worthwhile endeavor given the generally
significant cytotoxic, antifungal, and/or other biological proper-
ties of many pyrrolophenanthridinones.
EXPERIMENTAL SECTION
■
General Experimental Procedures. These have been detailed
elsewhere.21 Certain NMR spectra were recorded on an 800 MHz
instrument.
Compound 5. A magnetically stirred solution of compound 4
(1.00 g, 8.12 mmol) in dichloromethane/methanol (100 mL of a 3:1
v/v mixture) was treated with calcium carbonate (3.02 g, 30.2 mmol)
and benzyltrimethylammonium tribromide (6.49 g, 16.6 mmol). The
ensuing mixture was stirred at 18 °C for 2 h and then filtered through
The two approaches to the title natural products reported
a pad of diatomaceous earth. The filtrate was concentrated under
herein only differ in the nature of the polarity of the pivotal
Suzuki−Miyaura cross-coupling reactions. The second ap-
proach is superior because of the ready ease of access to C-7
reduced pressure and then treated with HCl (80 mL of a 1 M aqueous
solution) before being extracted with dichloromethane (3 × 80 mL).
The combined organic extracts were washed with brine (1 × 100 mL),
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then dried (Na2SO4), filtered, and concentrated under reduced
pressure to afford a dark-purple oil. Subjection of this material to
flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.35) then gave the
title compound 56 (1.69 g, 74%) as a white, crystalline solid, mp 81−
82 °C (lit.6 mp 79−80 °C) (Found: M+•, 278.8896. Calcd for
C7H779Br2NO: M+•, 278.8894). 1H NMR (CDCl3, 400 MHz) 7.01 (s,
2H), 4.19 (broad s, 2H), 3.72 (s, 3H); 13C NMR (CDCl3, 100 MHz)
152.0, 136.2, 118.0, 109.1, 56.1; IR νmax (KBr) 3401, 3281, 2950, 2928,
2829, 1591, 1551, 1480, 1435, 1313, 1234, 1207, 1045, 836 cm−1;
Mass spectrum (EI) m/z 283, 281, and 279 (M+•, 43, 75, and 45%),
268, 266, and 264 (58, 100, and 61), 240, 238, and 236 (16, 27, and
16), 78 (35).
Compound 7. A magnetically stirred suspension of the carboxylic
acid precursor to compound 6 (261 mg, 1.07 mmol) in dichloro-
methane (10 mL) maintained at 0 °C was treated with oxalyl chloride
(0.12 mL, 1.40 mmol) and DMF (3 drops). The ensuing mixture was
stirred at 0 °C for 0.08 h, then allowed to warm to 18 °C, and stirred
at this temperature for 0.5 h before being cooled back to 0 °C and
then treated, dropwise, with a solution of compound 5 (360 mg, 1.28
mmol) and triethylamine (0.37 mL, 2.65 mmol) in dichloromethane
(5 mL). The resulting solution was stirred at 0 °C for 0.5 h, then
allowed to warm to 18 °C, and stirred at this temperature for 3.5 h
before being poured into ice-cold NaHCO3 (20 mL of a saturated
aqueous solution) and extracted with dichloromethane (3 × 20 mL).
The combined organic extracts were washed with HCl (1 × 30 mL of
a 1 M aqueous solution) and brine (1 × 30 mL), then dried (Na2SO4),
filtered, and concentrated under reduced pressure to give a yellow oil.
Trituration of this material with ice-cold dichloromethane then gave
the title compound 7 (295 mg, 55%) as a white, crystalline solid, mp
material to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane
elution) and concentration of the appropriate fractions (Rf = 0.15)
gave the title compound 116,15 (1.31 g, 40%) as a light-brown oil
1
(Found: M+•, 200.9790. Calcd for C7H879BrNO: M+•, 200.9789). H
NMR (CDCl3, 400 MHz) 7.01 (d, J = 2.4 Hz, 1H), 6.71 (m, 2H), 3.83
(broad s, 2H), 3.71 (s, 3H); 13C NMR (CDCl3, 100 MHz) 152.5,
137.8, 117.4, 116.5, 114.9, 109.4, 55.8; IR νmax (KBr) 3442, 3359,
3203, 2999, 2947, 2832, 1623, 1600, 1574, 1499, 1440, 1274, 1230,
1212, 1037, 865, 808 cm−1; MS (EI) m/z 203 and 201 (M+•, 74 and
75%), 188 and 186 (99 and 100), 160 and 158 (17 and 18), 86 (29),
84 (45).
Compound 12. A magnetically stirred solution of compound 11
(336 mg, 1.66 mmol) in dichloromethane (15 mL) maintained at 0 °C
was treated, dropwise, with boron trichloride (2.5 mL of a 1 M
solution in dichloromethane, 2.50 mmol), α-chloroacetonitrile (0.2
mL, 3.16 mmol), and then titanium tetrachloride (2.5 mL of a 1 M
solution in dichloromethane, 2.50 mmol). The ensuing mixture was
heated at reflux for 72 h before being cooled to 18 °C and poured into
a mixture of ice and HCl (10 mL of a 20% aqueous solution). The
volatile organic component of the resulting biphasic system was
removed by distillation, and the aqueous residue was heated at reflux
for 0.5 h. The cooled reaction mixture was then treated, dropwise at 0
°C, with NaOH (40 mL of a saturated aqueous solution) until pH 4
was attained, and then it was extracted with diethyl ether (3 × 100
mL). The combined organic extracts were washed with brine (1 × 100
mL) before being dried (Na2SO4), filtered, and concentrated under
reduced pressure to give a brown solid. Subjection of this material to
flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.25) gave the title
compound 12 (209 mg, 45%) as a yellow, crystalline solid, mp 80−81
°C (Found: M+•, 276.9506. Calcd for C9H979Br35ClNO2: M+•,
233−235 °C [Found: (M
+
H)+, 505.8238. Calcd for
C15H1079Br3NO4: (M + H)+, 505.8238]. H NMR (DMSO-d6, 400
MHz) 10.13 (s, 1H), 7.35 (s, 2H), 7.32 (s, 1H), 7.14 (s, 1H), 6.16 (s,
2H), 3.82 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) 165.3, 159.0,
149.2, 146.7, 131.1, 127.8, 124.7, 117.7, 113.1, 110.6, 108.7, 102.5,
56.2; IR νmax (KBr) 3216, 3182, 3008, 2960, 2896, 1671, 1594, 1514,
1496, 1475, 1258, 1227, 1038, 935 cm−1; MS (ESI) m/z 532 and 530
[(M + Na)+, 96 and 100%], 510 and 508 [(M + H)+, both 34], 350
and 348 (27 and 30), 339, 337, and 335 (18, 35, and 18), 229 and 227
(36 and 35).
276.9505). H NMR (CDCl3, 400 MHz) 7.36 (d, J = 3.2 Hz, 1H),
1
1
7.15 (d, J = 3.2 Hz, 1H), 4.66 (s, 2H), 3.78 (s, 3H) (signals due to
NH2 group protons obscured/not observed); 13C NMR (CDCl3, 100
MHz) 191.7, 149.3, 143.1, 126.7, 115.3, 113.9, 112.0, 56.3, 46.5; IR
νmax (KBr) 3478, 3342, 2988, 2938, 1664, 1568, 1535, 1455, 1231,
1048, 834 cm−1; MS (EI) m/z 281, 279, and 277 (M+•, 24, 93, and
73%), 230 and 228 (94 and 100), 202 and 200 (30 and 32), 86 (30),
84 (45), 78 (29).
Compound 13. A magnetically stirred solution of compound 11
(570 mg, 2.82 mmol) in 1,2-dichloroethane (13 mL) maintained at 0
°C was treated, dropwise, with boron trichloride (3.4 mL of a 1 M
solution in dichloromethane, 3.40 mmol), α-chloropropionitrile (0.37
mL, 4.18 mmol), and titanium tetrachloride (3.4 mL of a 1 M solution
in dichloromethane, 3.40 mmol). The ensuing mixture was heated at
reflux for 24 h before being cooled to 18 °C and then poured into a
mixture of ice and HCl (10 mL of a 20% aqueous solution). The
volatile organic component of the resulting biphasic system was
removed by distillation, and the aqueous residue was heated at reflux
for 0.5 h. The cooled reaction mixture was treated, dropwise at 0 °C,
with NaOH (40 mL of a saturated aqueous solution) until pH 4 was
attained and then extracted with diethyl ether (3 × 100 mL). The
combined organic extracts were washed with brine (1 × 100 mL)
before being dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a brown solid. Subjection of this material to flash
chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.30) then gave the
title compound 13 (420 mg, 51%) as a yellow, crystalline solid, mp
107−108 °C (Found: M+•, 292.9646. Calcd for C10H1181Br35ClNO2:
Compound 10. A magnetically stirred solution of compound 7
(200 mg, 0.394 mmol) in DMSO (5 mL) was treated with Cu powder
(125 mg, 1.97 mmol), and the ensuing mixture was stirred at 100 °C
for 48 h. The cooled reaction mixture was diluted with dichloro-
methane (20 mL), and the resulting solution was washed with
NH4OH (2 × 10 mL of a 4% aqueous solution) and then water (1 ×
10 mL) before being dried (Na2SO4), filtered, and concentrated under
reduced pressure to yield a brown oil. Subjection of this material to
flash chromatography (silica, 1:4 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.15) then gave the
title compound 10 (18 mg, 7%) as a white, crystalline solid, mp 266−
270 °C [Found: (M + Na)+, 714.9328. Calcd for C30H1879Br2N2O8:
1
(M + Na)+, 714.9328]. H NMR (CDCl3, 400 MHz) 7.72 (s, 2H),
7.03 (d, J = 2.0 Hz, 2H), 6.77 (s, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.10
(broad s, 4H), 3.78 (s, 6H); 13C NMR (CDCl3, 200 MHz) 162.3,
158.1, 151.1, 149.7, 147.4, 136.2, 135.1, 120.1, 115.6, 112.2, 111.2,
109.5, 102.0, 94.9, 56.2; IR νmax (KBr) 3105, 2965, 2909, 2838, 1615,
1598, 1475, 1441, 1307, 1260, 1236, 1202, 1119, 1030, 974, 826 cm−1;
MS (ESI) m/z 719, 717, and 715 [(M + Na)+, 47, 85, and 40%], 697,
695, and 693 [(M + H)+, 48, 78, and 43], 617 and 615 (41 and 40),
169 (100).
Compound 11. A magnetically stirred solution of compound 4
(1.98 g, 16.08 mmol) in dichloromethane/methanol (150 mL of a 2:1
v/v mixture) was treated with benzyltrimethylammonium tribromide
(6.58 g, 16.87 mmol). The ensuing mixture was stirred at 20 °C for 2 h
and then treated with Na2SO3 (100 mL of a saturated aqueous
solution) before being extracted with diethyl ether (1 × 150 mL). The
separated organic extract was washed with water (1 × 100 mL) and
brine (1 × 100 mL), then dried (Na2SO4), filtered, and concentrated
under reduced pressure to afford a dark-red oil. Subjection of this
1
M+•, 292.9641). H NMR (CDCl3, 400 MHz) 7.35 (d, J = 3.2 Hz,
1H), 7.30 (d, J = 3.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1 H), 3.78 (s, 3H),
1.73 (d, J = 6.8 Hz, 3H) (signal due to NH2 protons obscured/not
observed); 13C NMR (CDCl3, 100 MHz) 194.4, 149.3, 143.5, 126.7,
115.1, 114.2, 111.9, 56.3, 53.0, 20.3; IR νmax (KBr) 3427, 3314, 2960,
1647, 1568, 1533, 1454, 1363, 1249, 1219, 1049, 896, 844, 784 cm−1;
MS (EI) m/z 295, 293, and 291 (M+•, 15, 58, and 46%), 230 and 228
(98 and 100), 202 and 200 (30 and 31), 78 (28).
Compound 14. A magnetically stirred solution of compound 12
(209 mg, 0.750 mmol) in 1,4-dioxane/water (10 mL of a 9:1 v/v
mixture) was treated with sodium borohydride (29 mg, 0.767 mmol).
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The ensuing mixture was heated at reflux for 17 h, then cooled, poured
into HCl (10 mL of a 0.1 M aqueous solution), and extracted with
dichloromethane (3 × 20 mL). The combined organic extracts were
washed with brine (1 × 30 mL) before being dried (Na2SO4), filtered,
and concentrated under reduced pressure to give a brown oil.
Subjection of this material to flash chromatography (silica, 1:9 v/v
ethyl acetate/hexane elution) and concentration of the appropriate
fractions (Rf = 0.25) then gave the title compound 1416 (137 mg,
81%) as a pale-yellow, crystalline solid, mp 66−68 °C. 1H NMR
(CDCl3, 400 MHz) 8.18 (broad s, 1H), 7.24 (t, J = 2.6 Hz, 1H), 7.06
(s, 2H), 6.55 (dd, J = 2.8 and 2.4 Hz, 1H), 3.84 (s, 3H); 13C NMR
(CDCl3, 100 MHz) 154.6, 130.1, 128.8, 125.4, 114.6, 104.5, 103.6,
102.2, 56.2; IR νmax (KBr) 3423, 3123, 2998, 2934, 2830, 1620, 1563,
1479, 1313, 1295, 1222, 1133, 1033, 965 cm−1.
second test tube was dissolved in degassed hexane (1 mL) and the
resulting solution was added to the mixture of [Ir(OMe)COD]2 and
pinacolborane; after 0.02 h this was transferred to the Schlenk flask
containing compound 22. Additional hexane (2 × 1 mL) was used to
wash the test tubes, and the washings were transferred to the Schlenk
flask that was then removed from the drybox and attached to a Schlenk
line. The reaction mixture was heated, under N2, at 60 °C for 4 h
before being cooled and concentrated under reduced pressure to
afford a brown oil. This oil was dissolved in dichloromethane, and the
mixture thus obtained was filtered through a pad of TLC-grade silica
gel and diatomaceous earth. The filtrate was concentrated under
reduced pressure to afford a clear, colorless oil. Trituration of this
material (hexane) at −10 °C then gave the title compound 2420 (190
mg, 66%) as a white, crystalline solid, mp 73−74 °C (lit.20 mp 72−74
°C) (Found: M+•, 287.1694. C16H2211BNO3 requires M+•, 287.1693).
1H NMR (CDCl3, 400 MHz) 8.72 (broad s, 1H), 7.22 (d, J = 2.4 Hz,
1H), 7.16 (d, J = 2.4 Hz, 1H), 6.14 (broad s, 1H), 3.86 (s, 3H), 2.48
(s, 3H), 1.41 (s, 12H); 13C NMR (CDCl3, 100 MHz) 153.6, 136.8,
136.0, 128.9, 115.8, 107.2, 99.5, 83.8 (2C), 56.2, 24.9 (4C), 13.9
(signal due to one carbon obscured or overlapping); IR νmax (KBr)
3454, 2978, 1482, 1372, 1335, 1283, 1215, 1142, 1126, 1041, 851, 751
cm−1; MS (EI) m/z 288 [(M + H)+, 31%], 287 and 286 (M+•, 100 and
41), 272 (11), 230 (13), 214 (11), 205 (14), 187 and 186 (63 and 28),
172 and 171 (31 and 10), 144 and 143 (16 and 10).
Compound 1. Method A. A magnetically stirred solution of
compound 14 (25 mg, 0.11 mmol), boronate ester 16 (48 mg, 0.164
mmol), PdCl2(dppf)·CH2Cl2 (9 mg, 0.01 mmol), and triethylamine
(0.15 mL, 1.08 mmol) in THF/water (6 mL of a 9:1 v/v mixture) was
purged with nitrogen for 0.25 h and then heated at reflux for 72 h
before being cooled and then diluted with ethyl acetate (10 mL) and
water (10 mL). The separated aqueous layer was extracted with ethyl
acetate (2 × 10 mL), and the combined organic extracts were passed
through a pad of TLC-grade silica gel. The resulting filtrate was
concentrated under reduced pressure to give a brown solid.
Recrystallization (9:1 v/v mixture of chloroform/methanol) of this
material then gave the title compound 11 (26 mg, 81%) as a white,
crystalline solid, mp 260−261 °C (lit.1 mp 230−232 °C) (Found:
M+•, 293.0688. C17H11NO4 requires M+•, 293.0688). 1H NMR
(CDCl3, 800 MHz) see Table 2; 13C NMR (CDCl3, 200 MHz) see
Table 1; IR νmax (KBr) 2949, 2929, 1682, 1624, 1494, 1369, 1343,
1307, 1252, 1133, 1026, 921 cm−1; MS (EI) m/z 294 [(M + H)+,
20%], 293 (M+•, 100), 278 (36), 250 (43), 164 (14).
Method B. A magnetically stirred solution of compound 25 (15 mg,
0.058 mmol), borylindole 23 (24 mg, 0.088 mmol),
PdCl2(dppf)·CH2Cl2 (5 mg, 0.006 mmol), and triethylamine (0.08
mL, 0.577 mmol) in THF/water (5 mL of a 9:1 v/v mixture) was
purged with nitrogen for 0.25 h and then heated at reflux for 72 h
before being cooled and then diluted with ethyl acetate (10 mL) and
water (10 mL). The separated aqueous layer was extracted with ethyl
acetate (2 × 10 mL), and the combined organic extracts were passed
through a pad of TLC-grade silica gel and diatomaceous earth; the
resulting filtrate was concentrated under reduced pressure to give a
brown solid. Recrystallization of this material (9:1 v/v chloroform/
methanol) afforded compound 1 (15 mg, 88%) as a white, crystalline
solid. This material was identical, in all respects, with that obtained by
Method A.
Compound 2. Method A. A magnetically stirred solution of
compound 15 (41 mg, 0.17 mmol), boronate ester 16 (74 mg, 0.254
mmol), PdCl2(dppf)·CH2Cl2 (14 mg, 0.02 mmol), and triethylamine
(0.23 mL, 1.67 mmol) in THF/water (9.2 mL of a 9:1 v/v mixture)
was purged with nitrogen for 0.25 h and then heated at reflux for 120 h
before being cooled and then diluted with ethyl acetate (15 mL) and
water (15 mL). The aqueous layer was extracted with ethyl acetate (2
× 10 mL), and the combined organic extracts were passed through a
pad of TLC-grade silica gel. The resulting filtrate was concentrated
under reduced pressure to give a brown solid. Recrystallization (9:1
v/v mixture of chloroform/methanol) of this material gave the title
compound 21 (34 mg, 65%) as a white, crystalline solid, mp 257 °C
(lit.1 mp 220−222 °C) (Found: M+•, 307.0847. C18H13NO4 requires
M+•, 307.0845). 1H NMR (CDCl3, 800 MHz) see Table 2; 13C NMR
Compound 15. Compound 13 (213 mg, 0.728 mmol) was
subjected to the same procedure as employed for the conversion 12 →
14, and a brown oil was thereby obtained. Subjection of this material
to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution)
and concentration of the appropriate fractions (Rf = 0.3) then gave the
title compound 15 (163 mg, 93%) as a white, crystalline solid, mp 68−
69 °C (Found: M+•, 240.9928. C10H1081BrNO requires M+•,
1
240.9925). H NMR (CDCl3, 400 MHz) 7.88 (broad s, 1H), 6.95
(t, J = 2.4 Hz, 2H), 6.21 (m, 1H), 3.82 (s, 3H), 2.45 (s, 3H); 13C
NMR (CDCl3, 100 MHz) 154.4, 136.7, 130.1, 130.0, 112.8, 103.6,
101.7, 101.5, 56.2, 13.8; IR νmax (KBr) 3425, 2937, 1578, 1486, 1396,
1223, 1204, 1125, 1037, 834 cm−1; MS (EI) m/z 241 and 239 (M+•,
98 and 100%), 226 and 224 (45 and 46), 198 and 196 (41 and 42),
117 (30).
Compound 23. While being maintained in a drybox, a dry
borosilicate glass tube containing a stirring bar and capable of being
fitted with a PTFE-lined screwcap was charged with indole 21 (148
mg, 1.01 mmol), [Ru(p-cymene)Cl2]2 (6 mg, 0.01 mmol, 1 mol %),
diethylsilane (0.194 mL, 1.50 mmol), and degassed toluene (0.5 mL).
The ensuing mixture was sealed in the tube and stirred at 20 °C for 18
h before being concentrated under reduced pressure to afford a brown
oil. [Ir(OMe)COD]2 (10 mg, 0.015 mmol, 3 mol %), di-tert-
butylbipyridine (8 mg, 0.03 mmol, 3 mol %), bis(pinacolato)diboron
(383 mg, 1.51 mmol), pinacolborane (0.02 mL, 0.138 mmol), and
degassed THF (1 mL) were then added to this oil, and the ensuing
mixture was stirred at 80 °C for 22 h. After the mixture had cooled to
20 °C, the volatile components of the reaction mixture were removed
under high vacuum at 40 °C. The resulting brown oil was dissolved in
THF (2 mL), and the solution thus obtained treated with sodium
acetate (0.5 mL of 3 M aqueous solution). The ensuing mixture was
stirred at 20 °C for 4 h before being diluted with diethyl ether (20 mL)
and water (20 mL). The separated aqueous layer was extracted with
diethyl ether (2 × 20 mL), and the combined organic extracts were
washed with brine (1 × 20 mL), then dried (Na2SO4), filtered, and
concentrated under reduced pressure to afford a brown oil. Subjection
of this material to flash chromatography (silica, 1:9 v/v ethyl acetate/
hexane elution) and concentration of the appropriate fractions (Rf =
0.25) then gave the title compound 235t,19 (97 mg, 36%) as a white,
crystalline solid, mp 106−109 °C (Found: M+•, 273.1537.
C15H2011BNO3 requires M+•, 273.1536). 1H NMR (CDCl3, 400
MHz) 9.08 (broad s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz,
1H), 7.23 (broad t, J = 2.8 Hz, 1H), 6.46 (dd, J = 2.8 and 2.0 Hz, 1H),
3.86 (s, 3H), 1.38 (s, 12H); 13C NMR (CDCl3, 100 MHz) 153.8,
136.4, 127.6, 124.8, 117.8, 107.6, 101.5, 83.9 (2C), 56.2, 25.0 (4C)
(signal due to one carbon obscured or overlapping); IR νmax (KBr)
3454, 2978, 2935, 1598, 1477, 1426, 1371, 1315, 1218, 1137, 1039,
985 cm−1; MS (EI) m/z 274 [(M+H)+, 30%], 273 and 272 (M+•, 100
and 40), 258 and 257 (13 and 4), 216 and 215 (34 and 11), 191 (16),
173 (61), 158 (31), 130 (17).
Compound 24. While being maintained in a drybox, a Schlenk
flask containing a magnetic stirring bar was charged with indole 22
(161 mg, 1.00 mmol). Two separate test tubes within the same drybox
were charged with [Ir(OMe)COD]2 (10 mg, 0.015 mmol, 3 mol %)
and di-tert-butylbipyridine (8 mg, 0.03 mmol, 3 mol %), respectively.
Pinacolborane (0.22 mL, 1.52 mmol) was added to the [Ir(OMe)-
COD]2-containing test tube, and the di-tert-butylbipyridine in the
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The Journal of Organic Chemistry
Note
(CDCl3, 200 MHz) see Table 1; IR νmax (KBr) 2962, 2918, 1677,
1621, 1483, 1365, 1329, 1299, 1252, 1193, 1104, 1039, 931 cm−1; MS
(EI) m/z 308 [(M + H)+, 20%], 307 (M+•, 100), 292 (17), 264 (27),
160 (22).
grateful recipient of IPRS and Alan Sargeson Merit Scholar-
ships.
REFERENCES
■
Method B. A magnetically stirred solution of compound 25 (18 mg,
0.069 mmol), borylindole 24 (30 mg, 0.104 mmol),
PdCl2(dppf)·CH2Cl2 (6 mg, 0.007 mmol), and triethylamine (0.096
mL, 0.693 mmol) in THF/water (6 mL of a 9:1 v/v mixture) was
purged with nitrogen for 0.25 h and then heated at reflux for 120 h
before being cooled and diluted with ethyl acetate (10 mL) and water
(10 mL). The aqueous layer was extracted with ethyl acetate (2 × 10
mL), and the combined organic extracts were passed through a pad of
TLC-grade silica gel and diatomaceous earth. The resulting filtrate was
concentrated under reduced pressure to give a brown solid.
Recrystallization of this material (9:1 v/v chloroform/methanol)
gave compound 2 (14 mg, 66%) as a white, crystalline solid. This
material was identical, in all respects, with that obtained by Method A.
Compound 3. Method A. A magnetically stirred solution of
compound 14 (36 mg, 0.159 mmol), boronate ester 17 (77 mg, 0.239
mmol), PdCl2(dppf)·CH2Cl2 (13 mg, 0.016 mmol), and triethylamine
(0.22 mL, 1.59 mmol) in THF/water (6 mL of a 9:1 v/v mixture) was
purged with nitrogen for 0.25 h, heated at reflux for 48 h, and then
cooled before being diluted with ethyl acetate (10 mL) and water (10
mL). The separated aqueous layer was extracted with ethyl acetate (2
× 10 mL), and the combined organic extracts were passed through a
pad of TLC-grade silica gel; the filtrate thus obtained was concentrated
under reduced pressure to give a brown solid. Recrystallization (4:1
v/v dichloromethane/methanol) gave the title compound 32 (44 mg,
89%) as a white, crystalline solid, mp 218−220 °C (Found: M+•,
309.1000. C18H15NO4 requires M+•, 309.1001). 1H NMR (CDCl3,
800 MHz) see Table 2; 13C NMR (CDCl3, 200 MHz) see Table 1; IR
νmax (KBr) 2939, 2833, 1668, 1603, 1507, 1467, 1365, 1310, 1267,
1143, 1100 cm−1; MS (EI) m/z 310 [(M + H)+, 21%], 309 (M+•,
100), 294 (17), 266 (21).
Method B. A magnetically stirred solution of compound 26 (9 mg,
0.033 mmol), borylindole 23 (14 mg, 0.051 mmol),
PdCl2(dppf)·CH2Cl2 (3 mg, 0.004 mmol), and triethylamine (0.05
mL, 0.361 mmol) in THF/water (3 mL of a 9:1 v/v mixture) was
purged with nitrogen for 0.25 h, heated at reflux for 48 h, then cooled,
and diluted with ethyl acetate (5 mL) and water (5 mL). The
separated aqueous layer was extracted with ethyl acetate (2 × 5 mL),
and the combined organic extracts were passed through a short pad of
TLC-grade silica gel and diatomaceous earth; the filtrate thus obtained
was concentrated under reduced pressure to give a brown solid.
Recrystallization (4:1 v/v chloroform/methanol) of this material gave
compound 3 (10 mg, quantitative) as a white, crystalline solid. This
material was identical, in all respects, with that obtained by Method A.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data (CIFs), anisotropic displacement ellip-
soid plots, and unit cell packing diagrams derived from the
(6) Cossy, J.; Poitevin, C.; Gomez Pardo, D.; Peglion, J. L. Synth.
Commun. 1997, 27, 3525.
1
single-crystal analyses of compounds 1, 2, and 10; H and 13C
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(9) See Supporting Information for details. CCDC 929921−929923
contain the supplementary crystallographic data for compounds 1, 2,
and 10. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
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NMR spectra for compounds 1−3, 7, 10, 12−15, 23, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mgb@rsc.anu.edu.au.
Notes
(11) (a) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163.
(b) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
The authors declare no competing financial interest.
(12) Presumably the electron-donating effects of the methoxy group
in the substrate prevent ready addition of the Grignard reagent to the
nitro-group oxygen, and so the Bartoli reaction fails in this instance.
(13) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org.
Chem. 1979, 44, 578.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support. H.S.K. is the
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The Journal of Organic Chemistry
Note
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