2986
N. K. Manchukonda et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2983–2987
therefore may be preventing from the requisite substitution reac-
tion. A report from Ma and co-workers14 described to enhance rate
of aromatic substitution reaction of electron-rich aryl bromides
with copper catalysts by rising the reaction temperature. Taking
this clue, the reaction temperature was enhanced incrementally.
To our success, after series of experiments, 9-bromo noscapine 3
was successfully converted with CuI, NaN3 and proline at 130 °C
appropriate care and protection while using this method for large
scale conversions. Nonetheless, in view of its importance in medic-
inal chemistry the method is highly valuable for small scale prep-
arations of 9-amino-a-noscapine 5 for their onward use as potent
inhibitor of tubulin polymerization in clinical studies.
Acknowledgments
for 4 h to give moderate yield (30%) of 9-amino-a-noscapine 5
(Table 1, entry 7). At this stage we also observed debromination
of bromo noscapine 3 to give 22% of natural noscapine 1. The reac-
tion was best progressed when 9-bromo-a-noscapine 3 was re-
acted with CuI (2.0 equiv), sodium azide (2.0 equiv) and proline
(4.0 equiv) in DMSO at 130 °C for 3.0 h (Table 1, entry 9). The crude
reaction mixture was purified by triethyl amine treated silica gel
Authors are thankful to Dr. J.S. Yadav, Director, Dr. B.B. Gawali
and Dr. V.J. Rao, Chief scientists, Crop Protection Chemicals
Division, IICT, Hyderabad for their continuous support, encourage-
ment and assistance through MLP projects. N.K.M. (JRF) is thankful
to CSIR for financial assistance.
column chromatography to give 9-amino-
yield.
a-noscapine 5 in 62%
Supplementary data
Complete experimental details, copies of 1H, 13C NMR and mass
spectra (ESI and HR-MS) of synthesized products 3 and 5; single
crystal X-ray diffraction data for 9-amino-a-noscapine 5 (CCDC
854482) can be found free of charge from the Cambridge crystallo-
Supplementary data associated with this article can be found, in
Noscapine 1 (15%) was also isolated from this reaction. Heating
the bromo compound 3 at 130 °C in the absence of copper catalyst
but in the presence of 4 equiv of sodium azide and proline in DMSO
did not result any reaction (Table 1, entry 16), suggesting that the
present transformation is truly copper mediated. Changing of sol-
vent to DMF did show any significant changes in the course of reac-
tion or product yield (Table 1, entry 12). Addition of cesium
carbonate or potassium carbonate as base additive led to sluggish
and decomposed reaction mixtures. 9-Amino-a-noscapine 5 ob-
References and notes
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and HRMS) spectra data. 15 Single crystal X-ray analysis unambigu-
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Although the exact mechanism for the conversion of 9-bromo-
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mechanism is devised with the fact that Cu(I) form complex with
amino acid through carbonyl and amino groups (Fig. 2). The -pro-
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with 9-bromo- -noscapine 3 to give stabilized oxidative addition
a
-noscapine 5 (Fig. 1).16
a
a
L
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ring of noscapine may become somewhat electron deficient and
undergoes nucleophilic attack with azide, followed by in situ
reduction of azide to amine under the reaction conditions
employed.
In conclusion, we described here a copper mediated synthesis of
9-amino-
noscapine 3 obtained through bromination of natural
1, was reacted with sodium azide, in the presence of CuI &
at 130 °C in DMSO under neural conditions to give 9-amino-
capine 5 in 62% yield. The protocol developed here avoided isola-
tion of 9-azido- -noscapine and did not affect the sensitive C–C
a-noscapine 5 from natural
a
-noscapine 1. 9-Bromo-
-noscapine
-proline
-nos-
a-
a
L
a
a
bond between two heterocyclic units. Due to the ever present po-
tential for explosions when working with azides, we recommend
O
Br
O
O
CuI
N
N
N
H
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Pharmacol. 2006, 69(6), 1801.
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Noscapine analogues and their use in treating cancers, including drug
resistance cancers, US 2011/ 0294844, Dec 1, 2011.
H
H
DMSO
O
O
OH
Cu
Cu
II
I
X
NaN3
-NaX
X=Br or I
O
NH2
N3
N
H
8. (a) Vuppalapati, S. V. N.; Putapatri, S. R.; Kantevari, S. ARKIVOC 2009, XIV, 217;
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H
O
Cu
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N3
III
Br
3
9-bromo noscapine
Figure 2. Plausible mechanism for the formation of 9-amino-a-noscapine 5.