C. Sanaboina et al. / Tetrahedron Letters 53 (2012) 5027–5029
5029
R3
N
References and notes
R
1. For application of cascade reaction in total synthesis of natural products see (a)
Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009, 74, 3491; (b) England,
D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792; (c) Flick, A. C.; Caballero, Maria
Jose´ A.; Padwa, A. Org. Lett. 1871, 2008, 10; (d) Zhang, H.; Boonsombat, J.;
Padwa, A. Org. Lett. 2007, 9, 279; (e) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63,
5341; (f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134; (g) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Gelin, C. F.
Tetrahedron 2008, 64, 4736; (h) Jones, S. B.; Simmons, B.; Mastracchio, A.;
MacMillan, D. W. C. Nature 2011, 475, 183; (i) Grondal, C.; Jeanty, M.; Enders, D.
Nat. Chem. 2010, 2, 167; (j) Xiong, Z.; Busch, R.; Corey, E. J. Org. Lett. 2010, 12,
1512; (k) Coldham, I.; Watson, L.; Adams, H.; Martin, N. G. J. Org. Chem. 2011,
76, 2360; (l) Burrell, A. J. M.; Coldham, I.; Oram, N. Org. Lett. 2009, 11, 1515.
2. (a) Bonjoch, J.; Sole, D. Chem. Rev. 2000, 100, 3455; (b) Scholz, U.; Winterfeldt, E.
Nat. Prod. Rep. 2000, 17, 349; (c) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 15,
327; (d)The Alkaloids; Saxon, J. E., Cordell, G. A., Eds.; Academic Press: New
York, 1998. Vol. 50 and 51.
CH3CN, TFA
90 °C, 12 h
4
5
+
n
R2
N
H
R1
6
n = 1, 2; R = H, OMe; R1 =H, Me; R2 = H, Me, Ph; R3 = H, Me
Scheme 2. Synthesis of heterofused indoles 6.
O
Condensation
NH2
N
+
N
H
N
H
3. Kam, T. S.; Sim, K. M. Phytochemistry 1998, 47, 145.
Cl
5e
4. (a) Allin, S. M.; Thomas, C. I.; Doyle, K.; Elsegood, M. R. J. J. Org. Chem. 2005, 70,
357; (b) Da Silva, W. A.; Rodrigues, M. T., Jr.; Shankaraiah, N.; Ferreira, R. B.;
Andrade, Carlos K. Z.; Pilli, R. A.; Santos, L. S. Org. Lett. 2009, 11, 3238; (c)
Takasu, K.; Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70, 3957.
5. (a) Chbani, M.; Païs, M.; Delauneux, J. M.; Debitus, C. J. Nat. Prod. 1993, 56, 99;
(b) Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283.
6. Saha, S.; Reddy, V. R.; Patro, B. Tetrahedron Lett. 2011, 52, 4014.
Cl
4a
7
Intramolecular
N-alkylation
Pictet-Spengler
Reaction
N
N
N
N
7. Reaction conditions: 4 (1 equiv), 5 (1.5 equiv), TFA (1 equiv), CH3CN, 90 °C,
H
H
12 h.
8
1
8. For the synthesis of 5a, 5c and 5d see (a) Coldham, I.; Jana, S.; Watson, L.;
Pilgram, C. D. Tetrahedron Lett. 2008, 49, 5408; (b) Coldham, I.; Jana, S.; Watson,
L.; Martin, N. G. Org. Biomol. Chem. 2009, 7, 1674. Compound 5b was prepared
as reported for the preparation of 5a..
Scheme 3. Synthesis of harmicine. Reagents and conditions: CH3CN, TFA, 90 °C,
12 h, 48%.
9. For synthesis of harmicine see (a) Knolker, H. J.; Agarwal, S. Synlett 2004, 1767;
(b) Allin, S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P. Tetrahedron Lett.
2007, 48, 5669; (c) Szawkało, J.; Czarnocki, S. J.; Zawadzka, A.; Szawkało, J.;
Czarnocki, S. J.; Zawadzka, A.; Maurin, J. K.; Czarnockia, Z.; Drabowicz, J.
Tetrahedron Assym. 2007, 18, 406; (d) Gonzalez-Gomez, A.; Domınguez, G.;
Perez-Castells, J. Tetrahedron 2009, 65, 3378; (e) King, F. D. J. Heterocycl. Chem.
2007, 44, 1459; (f) Chiou, W. H.; Lin, G. H.; Hsu, C. C.; Chaterpaul, S. J.; Ojima, I.
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10. Witiak, D. T.; Tomita, K.; Patch, R. J.; Enna, S. J. J. Med. Chem. 1981, 24, 788.
11. Experimental procedure for synthesis of ( )-harmicine (1): Tryptamine 4a
(250 mg, 1.56 mmol) and 4-chloro butyraldehyde 5e (825 mg, 7.81 mmol) in
acetonitrile (5 mL) were stirred at room temperature under inert atmosphere.
After 10 min, trifluoro acetic acid (0.11 mL, 1.56 mmol) was added slowly, and
stirring was continued for 10 min at room temperature. Then reaction mixture
was heated at 90 °C for 12 h, cooled to room temperature, diluted with CH2Cl2
(20 mL), washed sequentially with 10% sodium bicarbonate solution
(2 Â 5 mL), water (5 mL) and brine (2 Â 5 mL) and dried over Na2SO4. The
organic solution was evaporated under reduced pressure and the resultant
crude mass was purified by flash chromatography (MeOH/CH2Cl2 2:98 to
MeOH/CH2Cl2 1:9) to obtain a pure material 1 (160 mg, 48%) as light yellow
solid. Mp 170–172 °C [lit.6 171–174 °C]. 1H NMR (400 MHz, CDCl3): d 1.80–1.95
(m, 3H), 2.25–2.33 (m, 1H), 2.60–2.70 (m, 1H), 2.82–3.00 (m, 3H), 3.04–3.10
(m, 1H), 3.30–3.33 (m, 1H), 4.23 (br s, 1H), 7.07–7.15 (m, 2H), 7.30 (d,
J = 7.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.91 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 17.8, 23.4, 29.4, 45.9, 49.3, 56.9, 107.8, 110.7, 118.1, 119.3, 121.4,
127.3, 135.4, 136.0; HRMS calcd for C14H17N2: 213.1313, found: 213.1378.
Spectral data are in agreement to those reported in literature.9g
cascade-type methodology. Thus, we are pleased to report the one-
step synthesis of ( )-harmicine in good yields using the commer-
cially available tryptamine 4a and 4-chlorobutyraldehyde 5e.
In summary, we have described a cascade reaction methodol-
ogy for the synthesis of indole alkaloid related compounds in an
efficient way. The synthesis of ( )-harmicine has been accom-
plished in a shortest route applying this cascade-type chemistry
as a key step. Syntheses of other indole alkaloids are in progress
in our laboratory recently and will be reported in due course.
Acknowledgments
We are grateful to GVK BioSciences Private Limited, India for
financial and analytical support during this program. C.S. thanks
JNTU, Hyderabad, India for continuous encouragement.
Supplementary data
Supplementary data (experimental procedures and character-
ization data of all new compounds) associated with this article
12. Kropp, R. U.S. Patent 4565870, 1986.