Synthetic studies of cephalandole alkaloids and the revised structure of cephalandole A

Article abstract of DOI:10.1021/np800334j

A synthesis of the originally proposed 2-(1H-indol-3-yl)-4H-3,1-benzoxazin- 4-one structure of the alkaloid cephalandole A (1) led to a structural revision, and the isolated natural product has now been identified as the previously known compound 3-(1H-in

Full text of DOI:10.1021/np800334j

J. Nat. Prod. 2008, 71, 1447–1450
1447
Synthetic Studies of Cephalandole Alkaloids and the Revised Structure of Cephalandole A
Jeffrey J. Mason, Jan Bergman,* and Tomasz Janosik*
Unit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, NoVum Research Park,
SE-141 57 Huddinge, Sweden
ReceiVed June 5, 2008
A synthesis of the originally proposed 2-(1H-indol-3-yl)-4H-3,1-benzoxazin-4-one structure of the alkaloid cephalandole
A (1) led to a structural revision, and the isolated natural product has now been identified as the previously known
compound 3-(1H-indol-3-yl)-2H-1,4-benzoxazin-2-one (7). The structural assignment was corroborated by detailed NMR
studies. A short synthesis of the related natural compound cephalandole B (2) has also been performed, confirming its
structure. In addition some chemical transformations, involving, for example, the related synthetic molecule 2-(1H-
indol-3-yl)-3H-quinazolin-4-one (9), are presented.
Investigations of the constituents of the cytotoxic methanol
extract of the Taiwanese orchid Cephalanceropsis gracilis (Orchi-
daceae) resulted in the isolation of several indole alkaloids,
including cephalandoles A and B, and the indolotryptanthrins
cephathrindoles A and B.1 Cephalandoles A and B were assigned
the respective structures of 1 and 2 (Figure 1), on the basis of the
interpretation of the spectroscopic data.1a 2-(1H-Indol-3-yl)-4H-
3,1-benzoxazin-4-one (1) attracted our interest, as it constitutes a
useful substrate in the construction of quinazolinones bearing an
indole unit at C-2 by treatment with appropriate primary amines.
To the best of our knowledge, there is only one other compound
described with a 2-(1H-indol-3-yl)-3H-quinazolin-4-one structural
motif, belonging to an extensive library of quinazolinones with
cytotoxic effects.2 This material was prepared in a one-pot procedure
from anthranilic acid and indole-3-carboxylic acid in the presence
of triphenyl phosphite and pyridine, followed by treatment with a
primary amine under microwave irradiation, most likely involving
the benzoxazinone (1) as the intermediate. Interestingly, the
synthesis of an isomeric structure, 2-(1H-indol-2-yl-carbonyl)-4H-
3,1-benzoxazin-4-one (3), has been known since 1982,3 whereas 1
has never been synthesized.
Figure 1. Proposed structures of cephalandoles A (1) and B (2)
from ref 1a, and the structure of 2-(indol-2-yl)-4H-3,1-benzoxazin-
4-one (3).
Results and Discussion
Our synthetic approach to 1 started with the readily available
acid chloride 4,4 which was treated with methyl anthranilate, giving
2-[(1-phenylsulfonyl-1H-indol-3-yl-carbonyl)amino]methyl ben-
zoate (5) (Scheme 1). This material was subjected to hydrolysis
using aqueous sodium hydroxide in methanol and subsequent
acidification, to afford the deprotected carboxylic acid 6,5 resulting
from simultaneous cleavage of the sulfonamide and the methyl ester.
Finally, the target compound 1 was obtained by cyclization of 6 in
neat thionyl chloride.
Figure 2. Structure of 3-(1H-indol-3-yl)-2H-1,4-benzoxazin-2-one
(7).
medium between the measurements. Furthermore, the natural
material was isolated as a yellow, amorphous powder,1a whereas
our synthetic molecule 1 was obtained as an off-white, crystalline
solid. Hence, it was clear that cephalandole A had an alternative,
but rather closely related structure with the same elemental
composition as 1. Consequently, structure 7 (Figure 2) was selected
as the most likely candidate, as it possesses the same elemental
composition, but incorporates a 2H-1,4-benzoxazin-2-one core
instead of the 4H-3,1-benzoxazin-4-one unit suggested in 1.
Compound 7 has previously been described as a yellow solid
resulting from heating of 2-aminophenol with methyl indole-3-
glyoxylate in 33% yield.6 This unambiguous approach was repeated
as described, providing a similar yield of the yellow substance 7
(40%), which displayed spectroscopic data fully consistent with
1
After inspection of the H and 13C NMR data of 1 recorded in
acetone-d6, it was apparent that the structure originally assigned as
the natural product cephalandole A must be incorrect, as our
synthetic compound displayed significantly different data from those
given in the literature.1a For example, the most downfield signal
(carbonyl) of 1 in the 13C NMR spectrum resonated at δ 160.2,
whereas the most downfield value reported in the original paper
appeared at δ 153.0.1a We therefore chose to conduct several 2D
NMR experiments (COSY, HMQC, and HMBC) to fully character-
ize 1. Comparison of the reported IR absorptions (KBr, νmax 3298,
2921, 1719, 1605, 1533 cm-1) with the experimental values of 1
(neat, νmax 3415, 1740, 1623, 1594, 1465 cm-1) displayed significant
discrepancies that could not be associated with the change of
1
its structure. As seen in Table 1, the H and 13C NMR data for 7
recorded in acetone-d6 matched the data previously reported for
cephalandole A,1a revealing its true identity. Thus, the revised
structure of cephalandole A is 7. We have further confirmed the
identity of 7 by examination of COSY, HMQC, and HMBC spectra
recorded in acetone-d6. The complete assignments based on those
* Corresponding authors. Fax: +46 8 6081501. E-mail: jan.bergman@ki.se;
tomasz.janosik@ki.se.
10.1021/np800334j CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/24/2008

1448 Journal of Natural Products, 2008, Vol. 71, No. 8
Mason et al.
Scheme 1a
benzoxazin-4-ones have been previously accomplished from sec-
ondary and tertiary amides.11
In conclusion we have shown unequivocally that the originally
proposed structure of cephalandole A (1) was incorrectly assigned,
and the revised structure 7 should be given this appropriate name.
It would be well advised to state that a reinvestigation of C. gracilis
should be performed in order to establish the true structure and
origin of cephalandole B, whether structure 1 is a true natural
product and whether 2 is or is not an artifact.
Experimental Section
General Experimental Procedures. NMR spectra were recorded
1
on a Bruker DPX 300 instrument operating at 300.1 MHz for H and
75.5 MHz for 13C, or a JEOL Eclipse 500 spectrometer operating at
500.2 MHz for 1H and 125.7 MHz for 13C (where indicated), using the
residual solvent signal as reference. Assignments are based on standard
1H, APT, COSY, HMQC, and HMBC experiments. IR spectra were
acquired on a Thermo Nicolet Avatar 330 FT-IR instrument. Elemental
analyses were performed by H. Kolbe Mikroanalytisches Laboratorium,
Mu¨lheim an der Ruhr, Germany. Melting points were determined in
open capillary tubes on a Bu¨chi B-545 melting point apparatus. The
microwave reaction was performed using an Emrys Optimizer (Personal
Chemistry) (max. 300 W). LCMS (ESI) analyses were performed with
a Shimadzu SCL-10Avp UV/vis detector at 254 nm, a HPLC System,
a SunFire 5 µm SB-C8, 2.1 × 50 mm column, and a Perkin-Elmer
SCIEX API 1500EX mass spectrometer. Chemicals and solvents were
obtained from commercial sources and used as received, with the
exception of THF, which was distilled from sodium and benzophenone,
and DMF, which was stored over activated 4 Å molecular sieves. All
reactions were performed under a nitrogen atmosphere. Chromatography
was performed using silica gel (40-63 µm).
2-[(1-Phenylsulfonyl-1H-indol-3-ylcarbonyl)amino]methyl Ben-
zoate (5). Methyl anthranilate (18.9 g, 125.0 mmol) was added to a
solution of freshly prepared 1-phenylsulfonylindol-3-ylcarboxylic acid
chloride (4)4 (16.00 g, 50.0 mmol), in CH2Cl2 (300 mL), and the
resulting mixture was stirred at room temperature overnight. The
reaction mixture was diluted with CH2Cl2 (100 mL) and washed with
aqueous HCl (2 M, 2 × 100 mL), water (100 mL), and brine (100
mL), and the combined organic portions were dried over MgSO4.
Evaporation of the solvent gave the crude product, which was triturated
with diethyl ether. The solid was collected by filtration and washed
with EtOAc/heptane (1:5). Recrystallization from absolute ethanol gave
5 (14.97 g, 69%), in three crops, as a white, amorphous solid, mp
175-176 °C; IR (neat) 1697, 1679, 1607, 1590, 1533 cm-1; 1H NMR
(DMSO-d6) δ 11.11 (1H, br s), 8.63 (1H, s), 8.27 (1H, dd, J ) 8.2, 0.8
Hz), 8.19-8.16 (1H, m), 8.13-8.10 (2H, m), 8.00-7.95 (2H, m),
7.78-7.72 (1H, m), 7.69-7.62 (3H, m), 7.48-7.36 (2H, m), 7.29-7.23
(1H, m), 3.87 (3H, s); 13C NMR (DMSO-d6) δ 164.6 (C), 161.0 (C),
139.0 (C), 136.4 (C), 135.2 (CH), 134.1 (C), 133.8 (CH), 130.6 (CH),
130.1 (CH), 130.1 (CH), 128.7 (CH), 127.8 (C), 127.1 (CH), 127.1
(CH), 125.8 (CH), 124.5 (CH), 123.7 (CH), 122.1 (CH), 121.9 (CH),
119.1 (C), 117.0 (C), 113.1 (CH), 52.5 (CH3); MS (ESI+) m/z 435 [M
+ H]+; HRMS (FAB+) m/z calcd for C23H18N2O5S + H 435.1015,
found 435.1012 [M + H]+.
a Reagents and conditions: (i) methyl anthranilate, CH2Cl2, rt, 18 h, 69%;
(ii) NaOH, CH2Cl2, MeOH, H2O, 50 °C, 2 h, 100%; (iii) SOCl2, reflux, 2 h,
70%.
experiments (all performed in acetone-d6) are included in Table 1,
along with those obtained for the synthetic compound 1 and the
data from the work of Wu et al.1a At this point we would like to
point out the difference in the numbering of the benzoxazinone
portions of structures of 1 and 7, as well as the numbering from
the paper by Wu et al.1a The numbering systems in our work were
chosen since they follow the IUPAC rules for nomenclature of
organic compounds. The indole portion of both structures is
indicated as the secondary system with the use of the “prime”
annotation.
The metabolite 2-aminophenol has previously been suggested
in another natural system, as an intermediate formed by decar-
boxylation of 3-hydroxyanthranilic acid, during biosynthesis of the
antibiotic LL-C10037R produced by a strain of Streptomyces.7 Since
several of the alkaloids derived from Cephalanceropsis gracilis
incorporate an anthranilic acid subunit, the identification of the 2H-
1,4-benzoxazin-2-one unit within the structure of cephalandole A
(7) is therefore not implausible, as it could possibly be biosynthe-
sized from 2-aminophenol and a suitable indolic precursor related
to indole-3-acetic acid. To the best of our knowledge, the true
cephalandole A (7) represents the first example of a natural product
featuring a 3-substituted 2H-1,4-benzoxazin-2-one core, although
there are many examples of other naturally occurring benzoxazi-
noids.8
Next, a synthesis of cephalandole B (2) was devised, in order to
unambiguously confirm its structure. The commercially available
compound indole-3-carboxylic acid (8) was converted to its acid
chloride by reaction with an excess of oxalyl chloride in CH2Cl2
in the presence of a catalytic amount of DMF (Scheme 2).9 The
resulting intermediate was in turn treated with methyl anthranilate
in THF to afford the desired product 2. The 1H and 13C NMR data
for cephalandole B (2) in CDCl3 were in excellent agreement with
those reported for the natural product.1a Cephalandole B (2) was
also formed directly upon heating 1 in methanol. The outcome of
this reaction suggests that the methanol extraction conditions
described by Wu et al.1a could have converted the proposed
structure 1 into 2, provided that it ever existed. In such a case,
cephalandole B would not be a natural product but an artifact
produced by ring opening of the proposed natural product 1.
Furthermore, the quinazolinone compound 9 was synthesized by
heating 1 with formamide under microwave irradiation,10 displaying
the utility of the 4H-3,1-benzoxazin-4-one core in the preparation
of 3H-1,3-quinazolin-4-ones (Scheme 3). Finally, the ring-opened
amide (10) was prepared by reacting 1 with ammonium acetate in
DMF at 70 °C. When compound 10 was heated in xylenes with a
catalytic amount of p-toluenesulfonic acid monohydrate, cyclization
was achieved, exclusively giving 1 and not the expected quinazoli-
none 9. Similar acid-catalyzed cyclizations leading to 4H-3,1-
2-[(1H-Indol-3-ylcarbonyl)amino]benzoic Acid (6). Compound 5
(2.173 g, 5.0 mmol) was hydrolyzed in a 1:1 mixture of MeOH and
CH2Cl2 (80 mL) and aqueous NaOH (6 M, 10 mL), at reflux for 1 h.
The solvents were then evaporated and the residue was redissolved in
water (200 mL). Acidification to pH 2 with 3 M HCl gave a precipitate,
which was collected by filtration and coevaporated three times with
toluene, giving 6 as an amorphous, white powder (1.40 g, 100%), mp
229-230 °C (lit.4 248 °C); IR (neat) 3302, 1658, 1581, 1522 cm-1
;
1H NMR (DMSO-d6) δ 13.68 (1H, br s), 11.90 (1H, br s), 11.83 (1H,
s), 8.78 (1H, d, J ) 8.5 Hz), 8.23 (1H, dd, J ) 6.6, 1.5 Hz), 8.07-8.03
(2H, m), 7.66-7.60 (1H, m), 7.54-7.51 (1H, m), 7.26-7.11 (3H,m);
13C NMR (DMSO-d6) δ 170.1 (C), 162.9 (C), 142.1 (C), 136.6 (C),
134.2 (CH), 131.3 (CH), 128.8 (CH), 125.4 (C), 122.5 (CH), 121.8
(CH), 121.0 (CH), 120.5 (CH), 119.7 (CH), 115.4 (C),112.3 (CH), 111.2
(C); MS (ESI+) m/z 281 [M + H]+.
2-(1H-Indol-3-yl)-4H-3,1-benzoxazin-4-one (1). Compound 6 (1.44
g, 5.13 mmol) was heated at reflux in thionyl chloride (20 mL) for
2 h. Evaporation to dryness and crystallization of the residue from
acetonitrile gave the crude product, which was recrystallized once more

Synthetic Studies of Cephalandole Alkaloids
Journal of Natural Products, 2008, Vol. 71, No. 8 1449
1a
1
Table 1. Comparison of H and 13C NMR Data of the Two Synthetically Generated Compounds 1 and 7 and the Literature Values of
the Isolated Compound in Acetone-d6
compound 1a
δH (J/Hz)
compound 7a
δH (J/Hz)
natural cephalandole Ab
c
c
position
δC
position
δC
positiond
δH (J/Hz)
δC
1′
2′
3′
4′
5′
6′
7′
7a′
3a′
2
8a
4a
5
6
7
11.18 br s
8.29 m
1′
2′
3′
4′
5′
6′
7′
7a′
3a′
3
8a
4a
5
6
7
11.09 br s
8.83 d (2.9)
1
2
3
4
5
6
7
8
9
11.11 br s
8.81 d (3.0)
131.8 (CH)
108.5 (C)
134.6 (CH)
112.4 (C)
134.6
112.3
124.1
122.5
124.1
112.8
137.9
127.3
149.0
146.2
133.2
128.9
126.1
129.6
116.7
153.0
8.59-8.56 m
7.32-7.29 m
7.32-7.29 m
7.61-7.57 m
122.7 (CH)
122.5 (CH)
124.0 (CH)
113.1 (CH)
138.2 (C)
126.3 (C)
157.0 (C)
149.0 (C)
117.6 (C)
128.9 (CH)
127.6 (CH)
137.3 (CH)
127.3 (CH)
160.2 (C)
8.92-8.88 m
7.32-7.27 m
7.32-7.27 m
7.60-7.56 m
124.1 (CH)
122.5 (CH)
124.2 (CH)
112.8 (CH)
137.9 (C)
127.4 (C)
149.0 (C)
146.2 (C)
133.2 (C)
128.9 (CH)
126.1 (CH)
129.6 (CH)
116.7 (CH)
153.0 (C)
8.88 d (8.1)
7.27 m
7.27 m
7.56 d (8.1)
10
1′
2′
3′
4′
5′
6′
7′
8.16 dd (7.8, 1.5)
7.54-7.50 m
7.92-7.88 m
7.71 d (8.0)
7.90 dd (7.8, 1.6)
7.46-7.42 m
7.51-7.48 m
7.36 dd (8.0, 1.4)
7.89 d (7.8)
7.43 t (7.8)
7.49 t (7.8)
7.35 d (7.8)
8
4
8
2
a Recorded at 500.2 MHz (1H) or 125.7 MHz (13C) in acetone-d6. b Data from ref 1a. c Multiplicity from APT experiment. d Originally proposed
numbering, from ref 1a.
Scheme 2a
16), 112.5 (C-7), 106.4 (C-3); for NMR data recorded in acetone-d6,
see Table 1; MS (ESI+) m/z 263 [M + H]+; anal. calcd for C16H10N2O2
C, 73.27; H, 3.84; N, 10.68; found C, 73.38; H, 3.93; N, 10.76.
3-(1H-Indol-3-yl)-2H-1,4-benzoxazin-2-one (7). Ethyl indole-3-
glyoxalate (2.175 g, 10.0 mmol) and 2-aminophenol were heated at
reflux in anhydrous DMF (7 mL) for 6 h. The solvent was removed in
Vacuo, and the crude product was crystallized twice from ethanol, giving
compound 7 as bright yellow crystals (1.07 g, 40%); mp 236-237 °C
(lit.6b 233-247 °C); IR (neat) 3284, 1714, 1603, 1529, 1428 cm-1; 1H
NMR (DMSO-d6, 500.2 MHz) δ 11.98 (1H, br s), 8.77-8.75 (1H, m),
8.70 (1H, s), 7.86-7.85 (1H, m), 7.55-7.53 (1H, m), 7.49-7.46 (1H,
m), 7.43-7.40 (2H, m), 7.29-7.25 (2H, m); 13C NMR (DMSO-d6,
125.6 MHz) δ 152.0 (C), 147.9 (C), 144.8 (C), 136.5 (C), 133.7 (CH),
131.9 (C), 128.6 (CH), 127.7 (CH), 125.9 (C), 125.3 (CH), 123.0 (CH),
122.8 (CH), 121.5 (CH), 115.9 (CH), 112.2 (CH), 110.5 (C); for NMR
data recorded in acetone-d6, see Table 1; MS (ESI+) m/z 263 [M +
H]+.
Cephalandole B (2). To a suspension of indole-3-carboxylic acid
a Reagents and conditions: (i) (COCl)2, DMF (cat.), CH2Cl2, rt, 2 h; (ii) methyl
anthranilate, THF, rt, 18 h, 58% over two steps; (iii) MeOH, reflux, 4 h, 99%.
(1.612 g, 10.0 mmol) in CH2Cl2 (100 mL) was added an excess of
oxalyl chloride (4.4 mL, 50 mmol), followed by one drop of DMF.
The resulting mixture was stirred at room temperature for 2 h. The
clear solution was evaporated in Vacuo and coevaporated three times
with benzene (3 × 20 mL), giving the acid chloride as a colorless solid
(1.80 g, 100%). This was added dropwise over 15 min as a solution in
anhydrous THF (30 mL), to a solution of methyl anthranilate (3.9 mL,
30.2 mmol) in anhydrous THF (30 mL), and the resulting mixture was
allowed to stir for 18 h. Removal of the solvent gave a viscous, oily
residue, which was dissolved in EtOAc (150 mL) and washed with
water (2 × 50 mL), followed by brine (2 × 50 mL). The aqueous
phases were back-extracted with EtOAc (2 × 50 mL), and the organic
portions were combined and dried over MgSO4. Removal of the solvents
produced a residue, which was subjected to column chromatography
(gradient system heptane/ethyl acetate, 7:3 to 1:1), giving an off-white
substance, which was triturated with diethyl ether, giving cephalandole
B (2) (1.71 g, 58%), mp 179.5-180 °C; IR (neat) 3260, 1681, 1644,
1586, 1529 cm-1; 1H NMR (CDCl3) δ 11.73 (1H, br s), 8.94 (1H, dd,
J ) 8.5, 0.9 Hz), 8.42 (1H, dd, J ) 8.1, 1.8 Hz), 8.07 (2H, dd, J )
8.4, 1.6 Hz), 7.93 (1H, d, J ) 2.9 Hz), 7.58 (1H, ddd, J ) 8.7, 7.1, 1.3
Hz), 7.43-7.40 (1H, m), 7.34-7.24 (2H, m), 7.08 (1H, ddd, J ) 8.2,
7.1, 0.8 Hz), 3.95 (3H, s); 13C NMR (CDCl3) δ 169.2 (C), 164.0 (C),
142.6 (C), 136.6 (C), 134.9 (CH), 131.1 (CH), 127.7 (CH), 125.8 (C),
123.4 (CH), 122.1 (CH), 122.0 (CH), 121.5 (CH), 120.7 (CH), 114.8
(C), 113.3 (C), 111.7 (CH), 52.5 (CH3); MS (ESI+) m/z 295 [M +
H]+; anal. calcd for C17H14N2O3 C, 69.38; H, 4.79; N, 9.52: found C,
69.50; H, 4.87; N, 9.47.
Scheme 3a
a Reagents and conditions: (i) formamide (neat), 200 °C, 10 min, MW; (ii)
NH4OAc, DMF, 70 °C, 2 h; (iii) xylenes, p-TsOH (cat.), reflux, (Dean-Stark
trap), 24 h.
from acetonitrile to give the desired product 1 (0.94 g, 70%) as an
off-white powder, mp 235-236 °C; IR (neat) 3414, 1740, 1594 cm-1
;
1H NMR (DMSO-d6) δ 12.13 (1H, br s, H-1), 8.45-8.43 (1H, m, H-4),
8.29 (1H, d, J ) 2.8 Hz, H-2), 8.10 (1H, d, J ) 7.4 Hz, H-15),
7.87-7.84 (1H, m, H-13), 7.64 (1H, d, J ) 8.3 Hz, H-12), 7.54-7.52
(1H, m, H-7), 7.48-7.45 (1H, m, H-14), 7.28-7.26 (2H, m, H-5, H-6);
13C NMR (DMSO-d6) δ 159.2 (C-17), 155.6 (C-10), 147.6 (C-11), 137.0
(C-8), 136.6 (C-13), 131.5 (C-2), 127.9 (C-15), 126.8 (C-14), 126.1
(C-12), 124.9 (C-9), 122.8 (C-6), 121.4 (C-5), 121.3 (C-4), 116.2 (C-
Preparation of Cephalandole B (2) from 1. Compound 1 (0.135
g, 0.5 mmol) was heated at reflux in methanol (20 mL) for 4 h. Removal
of the solvent gave the off-white compound 2 (0.151 g, 99%). All
spectroscopic data matched those of compound 2 prepared as above.

1450 Journal of Natural Products, 2008, Vol. 71, No. 8
Mason et al.
2-[(1H-Indol-3-ylcarbonyl)amino]-3H-1,3-quinazolin-4-one (9).
Compound 1 (0.132 g, 0.5 mmol) was suspended in formamide (1.0
mL) and heated to 200 °C in a microwave reactor (300 W) for 10 min
in a sealed tube. Removal of the solvent gave the crude product 9 (0.093
g, 71%), which was recrystallized from acetonitrile: mp 286-288 °C;
IR (neat) 3391, 3114, 1671, 1592, 1429 cm-1; 1H NMR (DMSO-d6) δ
12.15 (1H, br s), 11.86 (1H, br s), 8.73-8.70 (1H, m), 8.55 (1H, d, J
) 2.8 Hz), 8.11 (1H, d, J ) 7.7 Hz), 7.81-7.72 (2H, m), 7.52-7.49
(1H, m), 7.44-7.39 (1H, m), 7.26-7.20 (2H, m); 13C NMR (DMSO-
d6) δ 162.1 (C), 150.3 (C), 149.7 (C), 136.8 (C), 134.3 (CH), 129.1
(CH), 126.6 (CH), 125.8 (CH), 125.5 (C), 125.1 (CH), 122.6 (CH),
122.4 (CH), 120.9 (CH), 120.4 (C), 112.0 (CH), 108.6 (C); MS (ESI+)
m/z 262 [M + H]+; HRMS (FAB+) m/z calcd for C16H11N3O + H
262.0980, found 262.0979 [M + H]+.
2-[(1H-Indol-3-ylcarbonyl)amino]benzamide (10). Compound 1
(0.263 g, 1.0 mmol) was dissolved in DMF (2.0 mL), ammonium
acetate (0.250 g) was added, and the resulting mixture was stirred at
70 °C for 2 h. The solution was poured over crushed ice, and the
precipitate was collected by filtration and dried, giving the white solid
10 (0.247 g, 88%): mp 233-234 °C; IR (neat) 3229, 1653, 1613, 1571,
1509, 1444 cm-1; 1H NMR (DMSO-d6) δ 12.45 (1H, br s), 11.86 (1H,
br s), (1H, m), 8.55 (1H, d, J 2.8 Hz), 8.11 (1H, d, J 7.7 Hz), 7.81-7.72
(2H, m), 7.52-7.49 (1H, m), 7.44-7.39 (1H, m), 7.26-7.20 (2H, m);
13C NMR (DMSO-d6) δ 171.4 (C), 162.9 (C), 140.9 (C), 136.6 (C),
132.4 (CH), 128.7 (CH), 128.6 (CH), 125.4 (C), 122.4 (CH), 121.6
(CH), 121.0 (CH), 120.6 (CH), 120.1 (CH), 118.7 (C), 112.3 (CH),
111.4 (C); MS (ESI+) m/z 280 [M + H]+; HRMS (FAB+) m/z calcd
for C16H11N3O + H+ 280.1086, found 280.1082 [M + H]+.
Supporting Information Available: NMR and IR spectra for all
new compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References and Notes
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Cyclization of Compound 10 to Compound 1. Compound 10
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filtration as an off-white solid (0.232 g, 88%). All spectroscopic data
matched those of compound 1 prepared as above.
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Acknowledgment. We thank Dr. I. Romero for assistance with
acquisition of the NMR data, and Mr. P. Rho¨nnstad for the LCMS
analyses.
NP800334J