Two new approaches towards the synthesis of annomontine using Pictet-Spengler and aza-Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2013.05.026

Two new routes were established for the synthesis of biologically active natural product annomontine utilizing Pictet-Spengler and aza-Diels-Alder reactions as key steps.

Full text of DOI:10.1016/j.tetlet.2013.05.026

Tetrahedron Letters 54 (2013) 3715–3717
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Two new approaches towards the synthesis of annomontine using
Pictet–Spengler and aza-Diels–Alder reactions
Nilesh H. Naik a,b, Arun K. Sikder b, Radhika S. Kusurkar a,
⇑
a Department of Chemistry, University of Pune, Pune 411 007, India
b High Energy Materials Research Laboratory, Sutarwadi, Pune 411 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new routes were established for the synthesis of biologically active natural product annomontine
utilizing Pictet–Spengler and aza-Diels–Alder reactions as key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 March 2013
Revised 4 May 2013
Accepted 8 May 2013
Available online 16 May 2013
Keywords:
Annomontine
Pictet–Spengler reaction
Aza-Diels–Alder reaction
Microwave
Annomontine (1) was one of the first members of the class of 1-
(20-aminopyrimidin-4-yl)-b-carboline alka1oids. It has been iso-
lated from the trunk and root bark of Annona montana,1 A. foetida,2
A. reticulata3 and A. purpurea.4
methyl formamide dimethyl acetal in DMF at 110 °C (Scheme 2)
to produce 4-(dimethoxymethyl)pyrimidin-2-amine (2).8 The ami-
no group in the product was subsequently protected using benzyl
chloroformate to furnish Cbz-protected acetal 3. Further, deprotec-
tion of the acetal group using HCl afforded aldehyde 4. The last step
in this synthesis was the Pictet–Spengler reaction between alde-
hyde 4 and tryptamine 5. For this condensation various acid cata-
lysts such as trimethyl silyl chloride, sulfuric acid, acetic acid and
aluminium chloride were used at room temperature as well as at
elevated temperature. However, instead of the expected product,
starting material was recovered. Surprisingly, using TFA as a cata-
lyst at room temperature a solid product9 was obtained in 87%
yield. This was shown to be benzyl 4-(4,9-dihydro-3H-pyr-
ido[3,4-b]indol-1-yl)pyrimidin-2-ylcarbamate (6) from 1H NMR
and HRMS data. Further, in a one pot reaction sequence, compound
Annomontine possesses antiparasitic activity and was shown2
to be active against Leishmania braziliensis, with an IC50 of
34.8 lM. It exhibits analgesic and anti-inflammatory activity in
mice,4 antileishmanial activity against promastigote forms of L.
braziliensis2 and trypanocidal activity over Trypanosoma cruzi.5 Re-
cently, annomontine has shown anxiolytic-like effects in the ele-
vated plus-maze.4
In the literature, there are very few reports6 available for the
synthesis of annomontine. Considering the biological importance,
we herein report two new and convenient routes for its synthesis.
In one of the two routes, it was envisioned to construct the b-carb-
oline ring by using the conventional Pictet–Spengler reaction,
while in the other, use of an elegant strategy of indole as a dieno-
phile in an inverse electron demand aza-Diels–Alder reaction was
planned.
CHO
N
N
Route 1
NH2
NH2
N
H
+
N
N
H
N
NH2
In our earlier work, Pictet–Spengler condensation was utilized
for the synthesis of tetrahydrospiro-b-carbolines, tetrahydro-5-
azaindoles and b-carbolines.7 In continuation with this work, a
route having Pictet–Spengler condensation as a key step was
planned as shown by retrosynthetic analysis (Scheme 1, route 1).
This route started with three-component reaction using guani-
dine hydrochloride, pyruvic aldehyde dimethyl acetal and N,N-di-
N
1
Route 2
COOMe
N
CHO
N
N
N
N
N
+
N
H
N
NH2
N
NH2
N
NH2
⇑
Corresponding author.
E-mail address: rsk@chem.unipune.ac.in (R.S. Kusurkar).
Scheme 1. Retrosynthetic analysis for annomontine (1).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.026

3716
N. H. Naik et al. / Tetrahedron Letters 54 (2013) 3715–3717
MeO OMe
MeO OMe
O
N
O
OMe
NH2
HN NH2
HCl
+
a
b
+
MeO
N
O
N
H
N
Me
Me
MeO
N
OMe
H2N
N
Me
3
2
CHO
N
d
N
c
O
N
e
N
N
H
N
O
N
H
N
H
NH2
N
HN
O
N
H2N
N
N
H
O
6
4
1
5
Scheme 2. Reagents and conditions: (a) (i) DMF, 110 °C, 15 h; (ii) NaOH, 110 °C, 36 h, 70%; (b) CbzCl, EtOH, NaHCO3, dioxane, H2O, 5–10 °C, 12 h, 90%; (c) HCl, RT, 5 h, 85%; (d)
TFA, RT, 48 h, 87%; (e) IBX, TBAB, acetonitrile, DMSO (cat.), RT, 24 h, 65%.
CHO
N
COOH
N
COOCH3
N
CONHNH2
N
c
a
b
N
NH
O
N
NH
O
N
NH
O
N
NH
O
O
O
O
O
8
4
7
9
N
N
N
N
N
N
N
H
f
d
e
N
N
H
N
N
HN
O
N
HN
N
H2N
O
10
O
O
1
11
Scheme 3. Reagents and conditions: (a) KMnO4, DMSO, RT, 24 h, 82%; (b) CH3OH, H2SO4, reflux, 6 h, 76%; (c) NH2NH2ꢀH2O, THF, 150 °C, 20 min, 86%; (d) glyoxal, NH4OAc,
CH3COOH, 180 °C, MW, 10 min; (e) indole, 180 °C, MW, 30 min, 68% (over two steps); (f) H2, Pd/C, CH3OH, RT, 12 h, 78%.
6 was treated with 2-iodoxybenzoic acid (IBX) and tetrabutylam-
monium bromide (TBAB) in acetonitrile to furnish annomontine
(1) in good yield. Formation of the target molecule can be ex-
plained by dehydrogenation of compound 6, followed by deprotec-
tion of the carbobenzyloxy group in one pot. The spectral data of 1
were consistent with the reported values.10
sis of annomontine. For the aza-Diels–Alder reaction, widely used
microwave strategy was successfully applied. All new compounds
obtained in both the routes were characterized by 1H NMR, 13C
NMR and HRMS.
Acknowledgments
The other approach planned for the synthesis of annomontine
was based on inverse electron demand of the aza-Diels–Alder reac-
tion as a key step. There are very few reports for indole acting as a
dienophile in the inter11a and intra11b–d molecular Diels–Alder
reactions. In the present synthesis, (retrosynthetic analysis in
Scheme 1, route 2) 2,3 double bond of the indole ring has been suc-
cessfully used as a dienophile with 2-azadiene system present in
the substituted 1,2,4-triazine. Thus, to start with, aldehyde 4 was
oxidized using KMnO4 to acid 7 (Scheme 3). The methyl ester 8
was obtained using methanol in HCl, which was subsequently trea-
ted with hydrazine hydrate in tetrahydrofuran at elevated temper-
ature to achieve unstable hydrazide 9. Without any purification,
compound 9 was treated with glyoxal, in the presence of ammo-
nium acetate and acetic acid in microwave oven for 10 min. The
reaction mixture was further irradiated in microwave for 30 min
along with indole to get desired Cbz-protected annomontine12
11. In this reaction sequence an aza-Diels–Alder reaction and sub-
sequent chelotropic expulsion of N2 furnished Cbz-protected target
molecule 11. During this reaction of hydrazide 9 in microwave
oven, the initial formation of intermediate 10 was proved by sepa-
rately isolating and characterizing the substituted triazine 10. In
the last step, deprotection of compound 11 using H2, Pd/C in meth-
anol furnished annomontine 1 in good yield.
We are grateful to Mrs. J.P. Choudhary for NMR spectra. The
authors are thankful to BCUD, University of Pune, for financial
assistance.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.05.026.
References and notes
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2. Costa, E. V.; Pinheiro, M. L. B.; Xavier, C. M.; Silva, J. R. A.; Amaral, A. C. F.; Souza,
A. D. L.; Barison, A.; Campos, F. R.; Ferreira, A. G.; Machado, G. M. C.; Leon, L. L.
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Shumaila, A. M. A.; Puranik, V. G.; Kusurkar, R. S. Tetrahedron 2011, 67, 936; (c)
In summary, two new convenient routes using Pictet–Spengler
and aza-Diels–Alder reactions have been developed for the synthe-

N. H. Naik et al. / Tetrahedron Letters 54 (2013) 3715–3717
3717
Kusurkar, R. S.; Alkobati, N. A. H.; Gokule, A. S.; Puranik, V. G. Tetrahedron 2008,
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12. Synthesis of benzyl-(4-(9H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl)carbamate
(11): benzyl-(4-(hydrazinecarbonyl)pyrimidin-2-yl)carbamate (9) (0.2 g,
0.69 mmol), glyoxal (0.03 ml, 0.69 mmol), ammonium acetate (0.5 g,
6.9 mmol) and acetic acid (2 ml) were taken in a microwave vial. The vial
was then sealed and irradiated at 180 °C in CEM microwave reactor for 10 min.
Further, the reaction mixture was fast cooled under nitrogen by the
instrument. Indole (0.08 g, 0.69 mmol) was then added and the contents
were further irradiated for 30 min at 180 °C. The reaction was cooled and
poured on crushed ice to get a solid compound which was insoluble in general
organic solvents. Thus, the product was washed repeatedly with diethyl ether
and ethyl acetate to remove organic impurities. N-Protected annomontine 11
was obtained in 68% yield (0.18 g). Mp 185–187 °C; FTIR (KBr cmꢁ1) 3311,
3177, 1741, 1640, 1561, 1484, 1283, 1225, 1168, 1006; 1H NMR (300 MHz,
DMSO-d6) d: 5.36 (s, 2H, –CH2), 7.24–7.48 (m, 5H, ArH), 7.51–7.54 (m, 2H, ArH),
7.60–7.67 (m, 1H, ArH), 7.79 (d, 1H, J = 4.9 Hz, ArH), 8.12 (d, 1H, J = 4.9 Hz, ArH),
8.3–8.4 (m, 2H, ArH), 8.54 (d, 1H, J = 4.4 Hz, ArH), 11.02 (s, 1H, D2O
exchangeable, –NH), 12.55 (s, 1H, D2O exchangeable, –NH); 13C NMR
(75 MHz, DMSO-d6) d: 165.3, 160.9, 158.2, 157.1, 136.5, 128.6, 128.1, 127.9,
122.1, 121.6, 117.9, 115.5, 110.6, 103.3, 66.1; HRMS (ESI) (M+H) 396.1462;
calcd for C23H18N5O2 396.1460.
9. Synthesis of benzyl-(4-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-
yl)carbamate (6): tryptamine
5
(0.5 g, 3.1 mmol) and benzyl-(4-
formylpyrimidin-2-yl)carbamate
4 (0.8 g, 3.1 mmol) in TFA (10 ml) were
stirred at room temperature under nitrogen atmosphere for 48 h. The
reaction was then quenched by adding crushed ice. A yellow colored solid
precipitate was obtained which was then filtered and dried. The compound
was having poor solubility in common organic solvents. Thus, the product was
washed repeatedly with hot ethyl acetate to remove organic impurities.
Product 6 (1 g, 87%) was characterized by 1H NMR and HRMS. Mp 180 °C
(decomposed); FTIR (KBr cmꢁ1) 3231, 2912, 1736, 1605, 1563, 1529, 1184; 1H
NMR (300 MHz, DMSO-d6) d: 2.92 (t, 2H, J = 8.2 Hz, CH2), 4.09 (t, 2H, J = 8.2 Hz,
CH2), 5.36 (s, 2H, CH2), 7.07 (t, 1H, J = 7 Hz, ArH), 7.14–7.67 (m, 8H, ArH), 7.79
(d, 1H, J = 4.7 Hz, ArH), 8.77 (d, 1H, J = 5.3 Hz, ArH), 10.82 (br s, 1H, D2O
exchangeable, –NH), 12.36 (s, 1H, D2O exchangeable, –NH); HRMS (ESI) (M+H)
398.1614; calcd for C23H20N5O2 398.1617.
10. Costa, E. V.; Pinheiro, M. L. B.; de Souza, A. D. L.; dos Santos, A. G.; Campos, F. R.;
Ferreira, A. G.; Barison, A. Magn. Reson. Chem. 2008, 46, 69.
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Benson, S. C.; Li, J. H.; Snyder, J. K. J. Org. Chem. 1992, 57, 5285; (c) Lindsley, C.