Rapid synthesis of indole cis-enamides via hydroamidation of indolic alkynes

Article abstract of DOI:10.1016/j.tetlet.2013.07.081

The synthesis of indolic cis-enamides using a ruthenium-mediated hydroamidation of indole alkynes with primary oxalamides or α-keto amides is reported. Using this method the total synthesis of igzamide and Z-coscinamides A and B has been achieved.

Full text of DOI:10.1016/j.tetlet.2013.07.081

Tetrahedron Letters 54 (2013) 5239–5242
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Tetrahedron Letters
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Rapid synthesis of indole cis-enamides via hydroamidation of indolic
alkynes
⇑
Emma Dickson, Brent R. Copp, David Barker
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of indolic cis-enamides using a ruthenium-mediated hydroamidation of indole alkynes
Received 6 June 2013
Revised 1 July 2013
Accepted 12 July 2013
Available online 20 July 2013
with primary oxalamides or
and Z-coscinamides A and B has been achieved.
a-keto amides is reported. Using this method the total synthesis of igzamide
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Indole enamide
cis-Enamide
Hydroamidation
Total synthesis
A number of natural products have been reported which con-
tain an indole with substitution linked through the 3-position to
an enamide moiety.1 Examples of both trans-enamide, for example,
chondriamide A (1)1k and cis-enamides, for example, kottamide
A (2)1c occur naturally, with the majority being cis-enamides. Several
of these natural products have enamides where the carbon alpha to
the amide is in the carbonyl oxidation state. For example, igzamide
(3)1b contains an oxalamide-linked enamide whilst coscinamides
NH
O
Br
Br
H
N
N
O
NH
HN
O
N
H
N
H
chondriamide A, 1
kottamide A, 2
A (4) and B (5)1a have an
a-keto-indole group (Fig. 1). These natural
O
H
O
products have interesting biological activities including cytotoxic-
ity, anti-inflammatory activity and anti-viral activity. Previous syn-
theses of indolic enamides have relied on dehydration2 or
elimination3 methods to introduce the enamide functionality, with
both methods favouring the formation of the trans-enamide prod-
uct. Alternatively, others have used the light-induced isomerisa-
tion of indole trans-enecarbamates to give the cis-isomer, but
these methods have low reported yields.4 We herein report the
synthesis of indole-enamide natural products using a ruthenium
complex/ytterbium triflate catalysed coupling to give exclusively
the indole cis-enamide isomers.
Gooßen and co-workers have reported the hydroamidation of
terminal alkynes and primary amides in the presence of a ruthe-
nium complex and ytterbium triflate to form predominately cis-
enamides.5 Additionally it was shown that heating the cis-enamide
with base caused almost complete isomerisation to the trans-
enamide (Scheme 1). Whilst the method was not explored with
indolic alkynes, we envisaged that the coupling of appropriately
N
O
R
NH2
HN
Br
NH
N
H
O
N
H
coscinamide A, R=Br, 4
coscinamide B, R=H, 5
igzamide 3
Figure 1. Indole-enamide natural products.
H
O
R1
[(cod)2Ru(met)2]
H
N
H
dcypb, Yb(OTf)3
R1
R2
NEt3
3 Å mol. sieves
O
cis-enamide
H2N R2
trans-enamide
Δ
, 24h
Scheme 1. Ruthium complex mediated enamide formation.
substituted indole-3-alkynes with primary amides would allow
rapid synthetic entry to cis-enamide natural products.
To test this theory, we were initially required to synthesise
indole 3-acetylenes. Gold(I) chloride catalysed alkynylation6 of
indole 6a, 5-bromoindole 6b and 6-bromoindole 6c with
⇑
Corresponding author. Tel.: +64 9 373 7599; fax: +64 64 373 7422.
E-mail address: d.barker@auckland.ac.nz (D. Barker).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.081

5240
E. Dickson et al. / Tetrahedron Letters 54 (2013) 5239–5242
SiiPr3
H
O
R1
R1
R2
R1
R2
(i)
(ii)
O
R2
N
H
I
N
H
N
H
R1 = R2 = H, 8a
R1 = R2 = H, 9a
Sii Pr3
R1 = R2 = H, 6a
R1 = Br, R2 = H, 8b
R1 = H, R2 = Br, 8c
R1 = R2 = Br, 8d
R1 = Br, R2 = H, 9b
R1 = H, R2 = Br, 9c
R1 = R2 = Br, 9d
R1 = Br, R2 = H, 6b
R1 = H, R2 = Br, 6c
R1 = R2 = Br, 6d
7
(iii)
O
R1
R2
R1
R2
O
O
(iv)
NH2
OEt
HN
HN
N
N
H
O
H
R1 = R2 = H, 12a
R1 = R2 = H, 11a
R1 = Br, R2 = H, 12b
R1 = H, R2 = Br, 3
R1 = R2 = Br, 12d
R1 = Br, R2 = H, 11b
R1 = H, R2 = Br, 11c
R1 = R2 = Br, 11d
Scheme 2. Reagents and conditions: (i) compound 7 (1.2 equiv), AuCl (5 mol %), Et2O, rt, 12 h, 8a 81%, 8b 77%, 8c 88%, 8d 86%; (ii) TBAF (2 equiv), THF, rt, 18 h, 9a 85%, 9b 82%,
9c 85%, 9d 89%; (iii) compound 9a–d (1 equiv), 10 (0.5 equiv), [(cod)2Ru(met)2] (5 mol %), Yb(OTf)3 (4 mol %), dcypb (6 mol %), DMF, 60 °C, 6 h, 11a 43%, 11b 39%, 11c 41%, 11d
32%; (iv) 1:1 concd NH4OH/MeOH, rt, 2 h, 12a 95%, 12b 90%, 3 (12c) 91%, 12d 86%.
O
O
H2N
R1
R2
NH
HN
R1
R2
(i)
O
O
N
H
N
H
N
H
R1 = R2 = H, 9a
13
R1 = R2 = H, 14 [(Z)-5]
R1 = Br, R2 = H, 15
R1 = H, R2 = Br, 16 [(Z)-4]
R1 = R2 = Br, 17
R1 = Br, R2 = H, 9b
R1 = H, R2 = Br, 9c
R1 = R2 = Br, 9d
Scheme 3. Reagents and conditions: (i) compounds 9a–d (1 equiv), 13 (0.5 equiv), [(cod)2Ru(met)2] (5 mol %), Yb(OTf)3 (4 mol %), dcypb (6 mol %), DMF, 60 °C, 6 h, 14 35%, 15
38%, 16 32%, 17 35%.
benziodoxole 7 gave silyl-protected acetylenes 8a–8c in good
yields (Scheme 1). 5,6-Dibromoindole 6d was prepared from
methyl indole-3-carboxylate,7 and alkynylation gave acetylene
8d in 86% yield. Desilylation of 8a–d using TBAF in THF gave termi-
nal acetylenes 9a–d in good yields.8 Hydroamidation of alkynes
9a–9d was first attempted with ethyl oxamate (10) using 5 mol %
molecular sieves5 did not however afford the expected trans-ena-
mide, coscinamide A (4), but gave exclusively the cis-enamide,
Z-coscinamide A (16) in 32% yield (Scheme 3).12 Attempted conver-
sion of 16 into trans-enamide 4 by additional treatment with base5
or by heating in DMSO2a did not alter the cis- to trans-enamide ra-
tio. Hydroamidation of acetylenes 9a, 9b and 9d with glyoxylamide
13 gave Z-coscinamide B (14) and bromo analogues 15 and 17,
respectively, in 32–43% yields. Again these compounds did not
isomerise into the trans-enamide using literature conditions,5
showing the unusually robust nature of indolic cis-enamides.
Igzamide (3) has previously been reported to be cytotoxic to-
wards the murine leukaemia L1210 cell line,1b whilst coscinamide
B (5) has activity against the prostate cancer DU1451a cell line.
Compounds 3, 12a, 12b, 12d and 14–17 were evaluated for anti-
proliferative activity at the National Cancer Institute (NCI).13 Igza-
mide (3) and analogues 12a, 12b and 12d were considered inactive
bis(2-methylallyl)cycloocta-1,5-diene
ruthenium(II)
[(cod)2
Ru(met)2]5a to afford cis-enamides 11a–d in 32–43% yields
(Scheme 2).9 Only the cis-enamides 11a–d were obtained with
none of the isomeric trans-enamide products detected. Treatment
of 11a–d with 1:1 concd NH4OH/MeOH gave igzamide (3) and ana-
logues 12a, 12b and 12d in excellent yields.10 The spectroscopic
data obtained for igzamide (3) matched literature values.1b The
successful use of this methodology with bromoindole acetylenes
allowed the synthesis of igzamide (3) in four steps and in 16% over-
all yield, representing a considerable improvement over previously
reported dehydrative methods, which gave igzamide in 4.2% (over
nine steps)4 and 2.6% (over six steps)2a yields.
in single dose (10 lM) testing. The four alkaloids exhibited modest
sub-panel selectivity towards breast cancer cell lines MCF7, MDA-
MB-231/ATCC and MDA-MB-468 and the CNS cancer cell line SNB-
75, and a general trend was observed whereby antiproliferative
activity increased with increasing bromine substitution. Of the cos-
cinamide analogues 14–17, non-brominated 15 was inactive (in
single dose 10 lM testing), whilst the brominated compounds
14, 16 and 17 were more active, especially against the melanoma
cell line MDA-MB-435. In five-dose testing against this cell line,
We next explored the synthesis of coscinamides A 4 and B 5
using this methodology. In this case, the geometry of the enamide
in the natural products is trans and would thus require enamide
isomerisation. Our synthesis began with the preparation of in-
dole-3-glyoxylamide (13) from indole 6a using reported
methods.11 Hydroamidation of acetylene 9c with glyoxylamide
13, followed immediately by refluxing with triethylamine and

E. Dickson et al. / Tetrahedron Letters 54 (2013) 5239–5242
5241
J = 1.7, 8.5 Hz, H-5), 7.35 (1H, d, J = 2.6 Hz, H-2), 7.46 (1H, d, J = 1.7 Hz, H-7),
7.58 (1H, d, J = 8.5 Hz, H-4), 8.23 (1H, br s, NH-1); dC (100 MHz, CDCl3) 76.7
(CBCH), 79.3 (CBCH), 97.9 (C-3), 114.5 (C-7), 116.7 (C-6), 121.1 (C-4), 124.2 (C-
Z-coscinamide A 14 exhibited growth inhibition with a GI50 value
of 1.2 M and a TGI value of 6.63 M whilst 5,6-dibromo analogue
17 had a GI50 value of 2.3 M and a TGI of 5.8 M.
l
l
5), 127.4 (C-3a), 129.2 (C-2), 135.7 (C-7a); m
max cmꢀ1; 3400, 3256, 2105, 1522,
l
l
1450, 1233, 738; HRMS(ESI+) found (MH+): 219.9757, C10H679BrN requires
219.9756. Data for 9d: mp 129–131 °C; dH (400 MHz, CDCl3) 3.22 (1H, s,
CBCH), 7.41 (1H, d, J = 2.7 Hz, H-2), 7.64 (1H, s, H-7), 7.98 (1H, s, H-4), 8.22 (1H,
br s, NH-1); dC (100 MHz, CDCl3) 76.0 (CBCH), 79.7 (CBCH), 97.6 (C-3), 116.1
(C-7), 116.5 (C-5), 118.5 (C-6), 124.2 (C-4), 129.3 (C-3a), 130.2 (C-2), 135.6 (C-
7a); mmax cmꢀ1 3386, 3265, 2099, 1522, 1441, 1254, 1108, 835; HRMS(ESI+)
found (MNa+): 319.8686, C10H579Br2NNa requires 319.8681.
In summary, the selective synthesis of indolic cis-enamides has
been achieved using a ruthenium-catalysed hydroamidation of
indole acetylenes with primary amides. This method has allowed
rapid entry to igzamide and un-natural coscinamide analogues.
Cytotoxicity measurements with both the igzamide and the cosi-
namide series indicated that increased levels of bromination
improved bioactivity. We are currently exploring the application
of this methodology to the synthesis of more complex cis-
enamides and the results will be reported in due course.
9. Synthesis and data for cis-amides 11: To a solution of bis(2-methallyl)(cycloocta-
1,5-diene)ruthenium(II) (16.0 mg, 0.05 mmol), ethyl oxamate 10 (117 mg,
1.00 mmol),
1,4-Bis(dicyclohexylphosphino)butane
(dcypb)
(27.0 mg,
0.06 mmol) and Yb(OTf)3 (24.8 mg, 0.04 mmol) in dry DMF (3.0 mL), under
an atmosphere of nitrogen, were added the required indole acetylene 9,
(2.00 mmol) and water (108 lL, 6.00 mmol) and the mixture stirred at 60 °C for
6 h. Aqueous satd NaHCO3 (20 mL) was added and the mixture extracted twice
with ethyl acetate. The combined organic extracts were washed with water,
brine, dried (MgSO4) and concentrated in vacuo to give the crude product
which was purified by flash chromatography to give cis-enamides 11 as tan
solids. Data for 11c: mp 167–169 °C; dH (400 MHz, CDCl3) 1.38 (3H, t, J = 7.2 Hz,
OCH2CH3), 4.37 (2H, q, J = 7.2 Hz, OCH2CH3), 6.13 (1H, d, J = 9.2 Hz, ArCH@CHN),
6.95 (1H, dd, J = 9.2, 10.5 Hz, ArCH@CHN), 7.28–7.31 (2H, m, H-2, H-5), 7.48
(1H, d, J = 8.5 Hz, H-4), 7.58 (1H, d, J = 1.5 Hz, H-7), 8.40 (1H, br s, NH-1), 9.08
(1H, d, J = 10.5 Hz, NHCO); dC (100 MHz, CDCl3) 13.9 (OCH2CH3), 63.6
(OCH2CH3), 105.8 (ArCH@CHN), 111.3 (C-3), 114.3 (C-7), 116.8 (C-6), 119.5
(ArCH@CHN), 120.4 (C-4), 122.6 (C-2), 123.8 (C-5), 125.3 (C-3a), 136.7 (C-7a),
153.4 (NC@O), 160.5 (CO2Et); mmax cmꢀ1 3285, 2991, 1697, 1530, 1496, 1282,
1187, 1038, 788; HRMS(ESI+) found (MNa+): 359.0007, C14H1379BrN2NaO3
requires 359.0002. Data for 11d: mp 151–154 °C; dH (400 MHz, CDCl3) 1.38
(3H, t, J = 7.2 Hz, OCH2CH3), 4.73 (2H, q, J = 7.2 Hz, OCH2CH3), 6.05 (1H, d,
J = 9.1 Hz, ArCH@CHN), 6.95 (1H, dd, J = 9.1, 11.0 Hz, ArCH@CHN), 7.30 (1H, d,
J = 2.5 Hz, H-2), 7.72 (1H, s, H-7), 7.87 (1H, s, H-4), 8.40 (1H, br s, NH-1), 9.03
(1H, d, J = 11.0 Hz, NHCO); dC (100 MHz, CDCl3) 13.9 (OCH2CH3), 63.7
(OCH2CH3), 105.1 (ArCH@CHN), 110.7 (C-3), 116.0 (C-5), 116.1 (C-7), 118.5
(C-6), 120.0 (ArCH@CHN), 123.6 (C-4), 123.7 (C-2), 127.3 (C-3a), 135.5 (C-7a),
153.6 (NC@O), 160.4 (CO2Et); mmax cmꢀ1 3346, 1691, 1351, 1445, 1273, 1104,
859, 732; HRMS(ESI+) found (MNa+): 436.9103, C14H1279Br2N2NaO3 requires
436.9107.
Acknowledgments
We acknowledge the University of Auckland for funding and a
doctoral scholarship (E.A.D.). We also acknowledge the National
Cancer Institute for biological assays.
Supplementary data
Supplementary data (the NCI antiproliferative data and MOL
files for compounds 3, 12a–d and 14–17) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.07.081. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
References and notes
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10. Data for 3: mp 189–191 °C; dH (400 MHz; DMSO-d6) 6.16 (1H, d, J = 9.0 Hz,
ArCH@CHN), 6.70 (1H, dd, J = 9.0 Hz, 11.4, ArCH@CHN), 7.19 (1H, dd, J = 1.8,
8.5 Hz, H-5), 7.55 (1H, s, H-2), 7.56 (1H, d, J = 8.5 Hz, H-4), 7.62 (1H, d,
J = 1.8 Hz, H-7), 8.07 and 8.37 (2 ꢁ 1H, s, NH2), 9.48 (1H, d, J = 11.7 Hz, NHCO),
11.54 (1H, br s, NH-1); dC (100 MHz; DMSO-d6) 105.3 (ArCH@CHN), 109.8 (C-
3), 114.3 (C-7), 114.7 (C-6), 118.0 (ArCH@CHN), 120.3 (C-4), 122.3 (C-5), 124.4
(C-2), 125.3 (C-3a), 136.6 (C-7a), 157.2 (NHCO), 161.4 (CONH2); mmax cmꢀ1
3328, 1674, 1536, 800; HRMS (ESI+) found [MNa]+ 329.9855.
C
12H1079BrN3NaO2 requires 329.9849. Data for 12a: mp 190–192 °C; dH
(400 MHz; DMSO-d6) 6.19 (1H, d, J = 9.0 Hz, ArCH@CHN), 6.69 (1H, dd, J = 9.0,
11.4 Hz, ArCH@CHN), 7.07 (1H, t, J = 7.6 Hz, H-5), 7.17 (1H, t, J = 7.6 Hz, H-6),
7.44 (1H, d, J = 7.6 Hz, H-7), 7.52 (1H, d, J = 2.5 Hz, H-2), 7.60 (1H, d, J = 7.6 Hz,
H-4), 8.08 and 8.38 (2 ꢁ 1H, s, NH2), 9.50 (1H, d, J = 11.4 Hz, NHCO), 11.4 (1H, s,
NH-1); dC (100 MHz; DMSO-d6) 105.9 (ArCH@CHN), 109.5 (C-3), 111.7 (C-7),
117.3 (ArCH@CHN), 118.4 (C-4), 119.4 (C-5), 122.0 (C-6), 123.3 (C-2), 126.2 (C-
3a), 135.8 (C-7a), 157.1 (NHCO), 161.4 (CONH2); mmax cmꢀ1 3392, 2922, 1661,
1525, 1230, 736; HRMS (ESI+) found [MNa]+ 252.0749. C12H11N3NaO2 requires
252.0743. Data for 12b: mp 220–222 °C; dH (400 MHz; DMSO-d6) 6.19 (1H, d,
J = 9.0 Hz, ArCH@CHN), 6.67 (1H, dd, J = 9.0, 11.2 Hz, ArCH@CHN), 7.27 (1H, dd,
J = 2.0, 8.7 Hz, H-6), 7.40 (1H, d, J = 8.7, H-7), 7.58 (1H, d, J = 2.5 Hz, H-2), 7.80
(1H, d, J = 2.0 Hz, H-4), 8.07 and 8.37 (2 ꢁ 1H, s, NH2), 9.49 (1H, d, J = 11.2 Hz,
NHCO), 11.61 (1H, s, NH-1); dC (100 MHz; DMSO-d6) 105.3 (ArCH@CHN), 109.3
(C-3), 113.7 (C-7), 117.7 (ArCH@CHN), 118.4 (C-5), 120.9 (C-4), 124.5 (C-6),
124.8 (C-2), 128.1 (C-3a), 134.5 (C-7a), 157.2 (NHCO), 161.4 (CONH2); mmax
cmꢀ1 3326, 2977, 1657, 1533, 1228, 883; HRMS (ESI+) found [MNa]+ 329.9858.
C
12H1079BrN3NaO2 requires 329.9849. Data for 12d: mp 228–230 °C; dH
(400 MHz; DMSO-d6) 6.17 (1H, d, J = 9.2 Hz, ArCH@CHN), 6.68 (1H, dd,
J = 9.2, 11.2 Hz, ArCH@CHN), 7.63 (1H, s, H-2), 7.83 (1H, s, H-7), 8.03 (1H, s,
H-4), 8.07 and 8.37 (2 ꢁ 1H, s, NH2), 9.50 (1H, dd, J = 11.2 Hz, NHCO), 11.66
(1H, br s, NH-1); dC (100 MHz; DMSO-d6) 105.0 (ArCH@CHN), 109.4 (C-3),
113.7 (C-5), 116.1 (C-6), 116.4 (C-7), 118.2 (ArCH@CHN), 123.1 (C-4), 125.8 (C-
2), 127.3 (C-3a), 135.5 (C-7a), 157.3 (NHCO), 161.4 (CONH2); mmax cmꢀ1 3334,
1654, 1532, 1222, 868; HRMS (ESI+) found [MNa]+ 409.8940.
8. Synthesis and data for bromo acetylenes 9: To a solution of 8a–d (1 equiv) in THF
(10 mL/mmol of 8) was added tetrabutylammonium fluoride (1 M in THF,
2.0 equiv) and the mixture stirred at rt for 18 h. Saturated aqueous NH4Cl was
added and the mixture extracted three times with Et2O. The combined organic
layers were washed with aq satd NaHCO3, brine, dried (MgSO4) and
concentrated in vacuo to give the crude product which was purified by flash
chromatography to afford the acetylenes as brown solids. Data for 9b: mp 122–
124 °C; dH (400 MHz, CDCl3) 3.21 (1H, s, CBCH), 7.17 (1H, d, J = 8.5 Hz, H-7),
7.29 (1H, dd, J = 1.9, 8.5 Hz, H-6), 7.36 (1H, d, J = 2.7 Hz, H-2), 7.87 (1H, d,
J = 1.9 Hz, H-4), 8.23 (1H, br s, NH-1); dC (100 MHz, CDCl3) 76.7 (CBCH), 79.3
(CBCH), 97.3 (C-3), 112.8 (C-7), 114.2 (C-5), 122.4 (C-4), 126.1 (C-6), 129.7 (C-
C
12H979Br2N3NaO2 requires 409.8931.
11. Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283–1289.
12. Data for 14: mp 167–169 °C; dH (400 MHz; DMSO-d6) 6.24 (1H, d, J = 9.2 Hz,
ArCH@CHN), 6.82 (1H, dd, J = 9.2, 11.1 Hz, ArCH@CHN), 7.08 (1H, t, J = 7.8 Hz,
H-5), 7.18 (1H, t, J = 7.8 Hz, H-6), 7.25–7.32 (2H, m, H-50 and H-60), 7.45 (1H,
d, J = 7.8 Hz, H-7), 7.54–7.58 (1H, m, H-70), 7.62–7.67 (2H, m, H-2 and H-4),
8.23–8.26 (1H, m, H-40), 8.94 (1H, s, H-20), 9.69 (1H, d, J = 11.1 Hz, NHCO)
11.45 (1H, br s, NH-1), 12.38 (1H, br s, NH-10); dC (100 MHz; DMSO-d6) 105.9
(ArCH@CHN), 109.7 (C-3), 111.7 (C-7), 111.9 (C-30), 112.7 (C-70), 117.3
(ArCH@CHN), 118.4 (C-4), 119.4 (C-5), 1211.3 (C-40), 121.9 (C-6), 122.8 (C-2),
123.7 (C-50 and C-60), 126.2 (C-3a0), 126.41 (C-3a), 135.8 (C-7a), 136.3 (C-7a0),
2), 130.2 (C-3a), 135.6 (C-7a); m
max cmꢀ1; 3402, 3256, 2103, 1524, 1454, 1235,
m
139.2 (C-20), 159.8 (CONH), 179.7 (COAr); max cmꢀ1 3280, 2923, 1661, 1626,
1429, 1122, 734; HRMS (ESI+) found [MK]+ 368.0802. C20H15KN3O2 requires
739; HRMS(ESI+) found (MH+): 219.9758, C10H779BrN requires 219.9756. Data
for 9c: mp 111–113 °C; dH (400 MHz, CDCl3) 3.22 (1H, s, CBCH), 7.28 (1H, dd,

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E. Dickson et al. / Tetrahedron Letters 54 (2013) 5239–5242
368.0796. Data for 15: mp 158–161 °C; dH (400 MHz; DMSO-d6) 6.23 (1H, d,
(C-7), 114.7 (C-6), 118.0 (ArCH@CHN), 120.3 (C-4), 121.3 (C-40), 122.2 (C-5),
122.8 (C-50), 123.7 (C-60), 124.7 (C-2), 125.4 (C-3a0), 126.2 (C-3a), 136.3 (C-
7a), 136.6 (C-7a0), 139.1 (C-20), 160.0 (NHCO), 179.8 (COAr); mmax cmꢀ1 3300,
2922, 1670, 1534, 1438, 1125, 794; HRMS (ESI+) Found [MNa]+ 430.0164.
J = 9.2 Hz, ArC@CHN), 6.81 (1H, dd, J = 9.2, 10.8 Hz, ArCH@CHN), 7.25–7.32
(3H, m, H-6, H-50, H-60), 7.42 (1H, d, J = 8.5 Hz, H-7), 7.54–7.58 (1H, m, H-70),
7.73 (1H, d, J = 1.8 Hz, H-2), 7.85 (1H, d, J = 1.7 Hz, H-4), 8.22–8.27 (1H, m, H-
40), 8.90 (1H, s, H-20), 9.70 (1H, d, J = 10.8 Hz, CONH), 11.64 (1H, br s, NH-1),
12.38 (1H, br s, NH-10); dC (100 MHz; DMSO-d6) 105.3 (ArCH@CHN), 109.5 (C-
3), 111.9, 112.0 (C-5 and C-30), 112.7 (C-70), 113.7 (C-7), 117.8 (ArCH@CHN),
120.9 (C-4), 121.3 (C-40), 122.7 (C-50), 123.7 (C-60), 124.4 (C-6), 125.2 (C-2),
126.4 (C-3a0), 128.3 (C-3a), 134.5 (C-7a), 136.3 (C-7a0), 139.1 (C-20), 160.1
(NHCO), 179.9 (ArCO); mmax cmꢀ1 3295, 2922, 1669, 1595, 1534, 1484, 1438,
1125, 793; HRMS (ESI+) found [MNa]+ 430.0162. C20H1479BrN3NaO2 requires
430.0162. Data for 16: mp 161–164 °C; dH (400 MHz; DMSO-d6) 6.20 (1H, d,
J = 9.2 Hz, ArCH@CHN), 6.83 (1H, dd, J = 9.2, 10.8 Hz, ArCH@CHN), 7.20 (1H,
dd, J = 1.6, 8.5 Hz, H-5), 7.24–7.31 (2H, m, H-50 and H-60), 7.54–7.57 (1H, m,
H-70), 7.61 (1H, d, J = 8.5 Hz, H-4), 7.63 (1H, d, J = 1.9 Hz, H-7), 7.68 (1H, d,
J = 2.5 Hz, H-2), 8.21–8.26 (1H, m, H-40), 8.90 (1H, s, H-20), 9.68 (1H, d,
J = 10.8 Hz, CONH), 11.55 (1H, s, NH-1), 12.37 (1H, s, NH-10); dC (100 MHz;
DMSO-d6) 105.3 (ArCH@CHN), 109.9 (C-3), 111.9 (C-30), 112.7 (C-70), 114.3
C
20H1479BrN3NaO2 requires 430.0162. Data for 17: mp 222–225 °C; dH
(400 MHz; DMSO-d6) 6.23 (1H, d, J = 9.3 Hz, ArCH@CHN), 6.82 (1H, dd,
J = 9.3, 11.1 Hz, ArCH@CHN), 7.25–7.33 (2H, m, H-50 and H-60), 7.54–7.58 (1H,
m, H-70), 7.77 (1H, d, J = 2.0 Hz, H-2), 7.84 (1H, s, H-4), 8.07 (1H, s, H-7), 8.22–
8.26 (1H, m, H-40), 8.88 (1H, d, J = 3.1 Hz, H-20), 9.74 (1H, d, J = 11.1 Hz,
CONH), 11.67 (1H, br s, NH-1), 12.38 (1H, br s, NH-10); dC (100 MHz; DMSO-
d6) 104.9 (ArCH@CHN), 109.6 (C-3), 111.9 (C-30), 112.7 (C-70), 113.7 (C-5),
116.0 (C-6), 116.4 (C-7), 118.3 (ArCH@CHN), 121.3 (C-40), 122.8 (C-4), 123.1,
123.7 (C-50 and C-60), 126.2 (C-2), 127.5 (C-3a and C-3a0), 135.4 (C-7a), 136.3
(C-7a0), 139.1 (C-20), 160.4 (NHCO), 179.9 (COAr); mmax cmꢀ1 3297, 2921,
1672, 1608, 1436, 1123, 739; HRMS (EI+) Found [MNa]+ 507.9270.
C
20H1379Br2N3NaO2 requires 507.9267.
13. See http://dtp.nci.nih.gov/index.html for specific details of the biological
testing.