1996
G. K. Jana, S. Sinha / Tetrahedron Letters 51 (2010) 1994–1996
Compound 4a. To a mixture of N-Boc-2-iodoaniline (450 mg, 1.41 mmol), 6a
Acknowledgments
(370 mg, 1.69 mmol), Pd(PPh3)2Cl2 (49 mg, 0.071 mmol), and CuI (27 mg,
0.141 mmol) were added Et3N (3 mL) and anhydrous benzene (6 mL) under an
argon atmosphere. The reaction mixture was stirred at room temperature for
12 h. Tetrabutylammonium fluoride (TBAF) (1.0 M in THF, 4.23 mmol) was
added dropwise to the reaction mixture. The reaction mixture was refluxed for
12 h and concentrated in vacuo. The resulting residue was partitioned between
water and dichloromethane. The aqueous layer was further extracted with
dichloromethane (2 Â 10 mL). The combined organic extracts were dried over
Na2SO4 and evaporated in vacuo to give the crude product which was purified
by flash column chromatography on silica gel (PE:EtOAc, 5:1) to afford the
isoquinuclidine-containing indole 4a (367 mg, 63.4%) as a light yellow oil.
Rf = 0.52 (PE:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3): d 8.06 (d, J = 7.8 Hz, 1H),
7.44 (m, 1H), 7.24–7.14 (m, 2H), 6.47 (t, J = 6.6 Hz, 1H), 6.37 (s, 1H), 6.27 (m,
1H), 3.90 (ddd, J = 5.7, 2.7, 1.2 Hz, 1H), 3.60 (s, 3H), 3.20 (dd, J = 9.0, 2.1 Hz, 1H),
3.12–3.10 (m, 2H), 2.82–2.78 (m, 1H), 2.57 (br s, 1H), 2.47–2.41 (m, 2H), 2.18
(ddd, J = 12.6, 4.2, 2.4 Hz, 1H), 1.93 (dt, J = 9.3, 2.4 Hz, 1H), 1.69 (s, 9H), 1.44–
1.34 (ddt, J = 12.9, 11.1, 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 174.8, 150.5,
140.5, 136.4, 135.1, 130.0, 129.5, 123.1, 122.5, 119.7, 115.5, 107.5, 83.6, 57.1,
S.S. thanks DST, India, for financial support by a grant [SR/S1/
OC-38/2007]. G.K.J. is thankful to CSIR for his fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. (a) Alper, K. R. Alkaloids 2001, 56, 1; (b) Sundberg, R. J.; Smith, S. Q. Alkaloids
2002, 59, 281.
2. (a) Mash, D. C.; Staley, J. K.; Baumann, M. H.; Rothmann, R. B.; Hearn, W. L.
LifeSciences 1995, 57, 45; (b) Lotsof, H. S. Maps 1995, 5, 16; (c) Touchette, N. Nat.
Med. 1995, 1, 288; (d) Popik, P.; Layer, R. T.; Skolnick, P. Pharmacol. Rev. 1995,
47, 235.
3. Glick, S. D.; Rossman, K.; Rao, N. C.; Maisonneuve, I. M.; Carlson, J. N.
Neuropharmacology 1992, 31, 497.
4. O’Hearn, E.; Molliver, M. E. J. Neurosci. 1997, 17, 8828.
5. (a) Delorenzi, J. C.; Freire-de-Lima, L.; Gattass, C. R.; de Andrade, C. D.; He, L.;
Kuehne, M. E.; Saraival, E. M. B. Antimicrob. Agents Chemother. 2002, 46, 2111;
(b) Andrade, M. T.; Lima, J. A.; Pinto, A. C.; Rezende, C. M.; Carvalho, M. P.;
Epifanio, R. A. Bioorg. Med. Chem. 2005, 13, 4092.
55.0, 54.9, 51.7, 45.3, 31.1, 28.9, 28.3, 24.4; IR (neat):
m
2947, 1732, 1454,
1329 cmÀ1
411.2274.
;
HRMS (ESI) (M+H)+ calcd for C24H30N2O4H+ 411.2278, found
Compound 4b. The procedure was same as reported for the synthesis of 4a
(above). The crude product was purified by flash column chromatography on
silica gel (PE:EtOAc, 3:1) to afford the isoquinuclidine-containing indole 4b
(354 mg, 61%) as
a
light yellow oil. Rf = 0.52 (PE:EtOAc, 1:1); 1H NMR
(300 MHz, CDCl3): d 8.06 (d, J = 8.4 Hz, 1H), 7.43 (dm, J = 6.6 Hz, 1H), 7.21 (td,
J = 8.1, 1.5 Hz, 1H), 7.16 (td, J = 7.2, 1.5 Hz, 1H), 6.42 (t, J = 6.9 Hz, 1H), 6.36 (s,
1H); 6.20 (ddd, J = 8, 5.4,1.2 Hz, 1H), 3.87 (ddd, J = 5.4, 3.3, 1.2 Hz, 1H), 3.64 (s,
3H), 3.23–3.10 (m, 3H), 3.03–2.99 (dd, J = 9.3, 1.8 Hz, 1H), 2.93–2.86 (m, 1H),
2.64–2.55 (m, 2H), 2.11–2.03 (dt, J = 9.3, 2.4 Hz, 1H), 1.80–1.71 (m, 2H), 1.68 (s,
9H); 13C NMR (75 MHz, CDCl3): d 174.5, 150.5, 140.2, 136.5, 134.8, 129.6,
129.4, 123.3, 122.6, 119.8, 115.6, 107.5, 83.8, 57.2, 54.6, 54.2, 51.8, 43.9, 30.8,
6. Analogues: (a) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836; (b)
Sundberg, R. J.; Cherney, R. J. J. Org. Chem. 1990, 55, 6028; (c) Sundberg, R. J.;
Hong, J.; Smith, S. Q.; Sabat, M. Tetrahedron 1998, 54, 6259; Congeners: (d)
Repke, D. B.; Artis, D. R.; Nelson, J. T.; Wong, E. H. F. J. Org. Chem. 1994, 59, 2164;
(e) Efange, S. M. N.; Mash, D. C.; Khare, A. B.; Ouyang, Q. J. Med. Chem. 1998, 41,
4486; (f) Passarella, D.; Favia, R.; Giardini, A.; Lesma, G.; Martinelli, M.; Silvani,
A.; Danieli, B.; Efange, S. M. N.; Mash, D. C. Bioorg. Med. Chem. 2003, 11, 1007.
7. (a) Cordell, G. A.. In The Alkaloids: Chemistry and Biology; Elsevier, 2001; Vol. 56.
pp 1–313 and 2002, 59, 281–376; (b) He, D.-Y.; McGough, N. N. H.;
Ravindranathan, A.; Jeanblanc, J.; Logrip, M. L.; Phamluong, K.; Janak, P. H.;
ꢀ
29.17, 28.44, 28.35, 28.24, 26.1; IR (neat):
HRMS (ESI) (M+H)+ calcd for C24H30N2O4H+ 411.2278, found 411.2275.
Compound 3a. To a slurry of bis(acetonitrile)palladium dichloride (179 mg,
0.70 mmol) in CH3CN (1.5 mL) was added Et3N (46 L, 0.35 mmol) under an
m ;
2926, 2949, 1732, 1454 cmÀ1
l
argon atmosphere. Silver tetrafluoroborate (275 mg, 1.40 mmol) was added
and the orange heterogeneous mixture immediately became yellow. After
10 min, a solution of dehydroisoquinuclidine 4a (144 mg, 0.35 mmol) in CH3CN
(2.0 mL) was added. The deep red solution was then stirred for 1 h at room
temperature and then heated at 70 °C for 10 h. The reaction mixture was
cooled to 0 °C and MeOH (1.5 mL) was added followed by NaBH4 (13 mg,
0.35 mmol) in portions. The solution was stirred for 1 h at 0 °C, water (1 mL)
was added, and the solution was acidified with cold 2 N aq HCl. The mixture
was filtered through a pad of Celite to remove palladium black, extracted with
ether (20 mL), and then basified with cold concentrated aq NH4OH. The basic
aq solution was extracted with ethyl acetate (3 Â 15 mL). The organic extracts
were combined, dried, and concentrated in vacuo to give N-Boc-protected and
deprotected crude mixture which was used in the next step without
purification.
ˇ
ˇ
Ron, D. J. Neurosci. 2005, 25, 619; (c) Maciulaitis, R.; Kontrimaviciute˙ , V.;
Bressolle, F. M. M.; Briedis, V. Hum. Exp. Toxicol. 2008, 27, 181.
8. Bandarage, U. K.; Kuehne, M. E.; Glick, S. D. Tetrahedron 1999, 55, 9405.
9. Büchi, G.; Coffin, D. L.; Kocsisi, K.; Sonnet, P. E.; Ziegler, F. E. J. Am. Chem. Soc.
1965, 87, 2073.
10. Ye, Z.; Guo, L.; Barakat, K. J.; Pollard, P. G.; Palucki, B. L.; Sebhat, I. K.; Bakshi, R.
K.; Tang, R.; Kalyani, R. N.; Vongs, A.; Chen, A. S.; Chen, H. Y.; Rosenblum, C. I.;
MacNeil, T.; Weinberg, D. H.; Peng, Q.; Tamvakopoulos, C.; Miller, R. R.; Stearns,
R. A.; Cashen, D. E.; Martin, W. J.; Metzger, J. M.; Strack, A. M.; MacIntyre, D. E.;
Ploeg, L. H. T. V.; Patchett, A. A.; Wyvratta, M. J.; Nargunda, R. P. Bioorg. Med.
Chem. Lett. 2005, 15, 3501.
11. (a) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T. H. Chem. Pharm. Bull. 1988,
36, 1305; (b) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856; (c) Hiroya,
K.; Itoh, S.; Sakamoto, T. Tetrahedron 2005, 61, 10958; (d) Sakai, N.; Annaka, K.;
Konakahara, T. Tetrahedron Lett. 2006, 47, 631.
12. Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm Bull. 2003, 51,
1170.
13. Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978, 100, 3930.
14. Sripha, K.; Zlotos, D. P.; Buller, S.; Mohr, K. Tetrahedron Lett. 2003, 44, 7183.
15. Experimental section and spectral data for some key compounds (PE stands for
The crude mixture was treated with 20% TFA in CH2Cl2 (2 mL) at 0 °C and then
the reaction mixture was stirred for 3 h at room temperature. CH2Cl2 and
volatiles were removed in vacuo and then saturated aq NaHCO3 solution (3 mL)
and ethyl acetate (5 mL) were added to the residue. The aqueous phase was
extracted with ethyl acetate (3 Â 10 mL); the combined organic extracts were
washed with brine (10 mL) and the solvent was removed by rotary
evaporation. The crude product was subjected for purification by column
chromatography on silica gel. Elution with 0.5–0.7% MeOH in CH2Cl2 gave the
exo-analogue 3a (52 mg, 48%) as a light brown solid. Rf = 0.54 (CH2Cl2:MeOH,
20:1); mp 99–100 °C; 1H NMR (300 MHz, CDCl3): d 7.75 (br s, 1H), 7.45 (dd,
J = 6.6, 1.8 Hz, 1H), 7.25 (dd, J = 6.6, 1.8 Hz, 1H), 7.16–7.07 (m, 2H), 3.73 (s, 3H),
3.62–3.57 (m, 1H), 3.48 (t, J = 1.8 Hz, 1H), 3.34–3.28 (ddd, J = 11.1, 4.5, 1.5 Hz,
1H), 3.24–3.20 (m, 2H), 3.10–3.08 (dt, J = 9.3, 2.7 Hz, 1H), 3.02 (dt, J = 9.0,
1.8 Hz, 1H), 2.83–2.79 (ddd, J = 11.1, 5.4, 2.4 Hz, 1H), 2.48–2.42 (dt, J = 16.5,
2.7 Hz, 1H), 2.40–2.32 (m, J = 13.5 Hz, 1H), 2.21–2.11 (ddt, J = 12.9, 12.3, 2.7 Hz,
1H), 2.00–1.96 (m, 1H), 1.80 (ddt, J = 13.0, 10.2, 3.0 Hz, 1H), 1.57–1.51 (ddd,
J = 13.2, 7.5, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 175.7, 134.7, 133.2, 128.6,
121.1, 119.1, 117.5, 110.2, 58.3, 52.4, 51.9, 49.6, 46.4, 35.1, 34.7, 26.1, 26.0,
petroleum ether): Compounds 6a and 6b.
A suspension of K2CO3 (1.84 g,
13.28 mmol) in anhydrous CH3CN (10 mL) containing the compound 8 (1.64 g,
6.64 mmol) and alkyne 6 (1.48 g, 6.64 mmol) was refluxed for 10 h, then cooled
to room temperature, filtered through a Celite pad, and washed with EtOAc
(10 mL). The combined organic extracts were concentrated in vacuo and
purified by column chromatography on silica using EtOAc in petroleum ether
(initially with 4% EtOAc and then with 10% EtOAc in PE) as eluent to give
isoquinuclidine-containing alkynes 6a (549 mg, 37.5%) as a pale yellow oil
(Rf = 0.38, PE:EtOAc, 9:1) and 6b (595 mg, 41%) as a pale yellow oil (Rf = 0.32,
PE:EtOAc, 4:1).
Exo 6a. 1H NMR (300 MHz, CDCl3): d 6.40 (dd, J = 7.7, 6.85 Hz, 1H), 6.20–6.16
(ddd, J = 7, 5.4, 1.35 Hz, 1H), 3.75 (ddd, J = 5.3, 2.65, 1.4 Hz, 1H), 3.67 (s, 3H),
3.10–3.06 (dd, J = 9, 2.2 Hz, 1H), 2.61–2.53 (m, 1H), 2.50 (br m, 1H), 2.38–2.34
(m, 1H), 2.28–2.22 (m, 1H), 2.18–2.12 (m, 2H), 2.07 (m, 1H), 1.87 (dd, J = 2.5,
2.45 Hz, 1H), 1.82–1.77 (dt, J = 9, 2.5 Hz, 1H), 1.36–1.28 (ddt, J = 12.0, 9.8,
2.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 174.7, 135.2, 129.7, 83.0, 68.5, 56.5,
25.32; IR (KBr):
m
3396, 2928, 2858, 1728, 1460.1 cmÀ1; HRMS (ESI) (M+H)+
calcd for C19H22N2O2H+ 311.1754, found 311.1754; Anal. Calcd for C19H22N2O2:
C, 73.52; H, 7.14; N, 9.03. Found: C, 73.28; H, 7.02; N, 8.59.
Compound 3b. The procedure was same as reported for the synthesis of 3a
(above).The crude product was subjected for purification by column
chromatography on silica gel. Elution with 0.5–0.7% MeOH in CH2Cl2 gave
54.7, 54.6, 51.8, 45.2, 30.9, 24.2, 18.3; IR (neat):
m
3296, 2939, 2118, 1736,
the endo-analogue 3b (40 mg, 37%) as
a light brown solid, Rf = 0.42
1435 cmÀ1
220.1337.
;
HRMS (ESI) (M+H)+ calcd for C13H17NO2H+ 220.1332, found
(CH2Cl2:MeOH, 20:1); mp 149–151 °C; 1H NMR (300 MHz, CDCl3): d 7.83 (br
s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.09 (m, 2H), 3.71 (s, 3H),
3.66–3.58 (m, 1H), 3.35 (m, 3H), 3.24–3.12 (m, 3H), 3.24–3.04 (m, 4H), 2.55–
2.49 (dt, J = 16.5, 2.7 Hz, 1H), 2.27–2.19 (m, 2H), 2.00 (m, 1H), 1.91 (ddt,
J = 13.8, 11.1, 3.0 Hz, 1H), 1.52–1.46 (m, 1H); 13C NMR (75 MHz, CDCl3): d
175.0, 134.6, 133.3, 128.5, 121.3, 119.3, 119.0, 117.6, 110.2, 57.2, 52.7, 52.0,
Endo 6b. 1H NMR (300 MHz, CDCl3): d 6.39 (td, J = 7.4, 1.1 Hz, 1H), 6.13 (ddd,
J = 8, 5.3, 1.3 Hz, 1H), 3.75 (ddd, J = 6, 3.3, 1.4 Hz, 1H), 3.59 (s, 3H), 3.06–3.0 (m,
1H), 2.92–2.88 (dd, J = 9.4, 2.0 Hz, 1H), 2.70–2.65 (m, 1H), 2.55 (br m, 1H),
2.44–2.37 (m, 1H), 2.29–2.25 (m, 2H), 1.96 (t, J = 2.5 Hz, 1H), 1.93 (m, 1H),
1.73–1.67 (m, 2H); 13C NMR (75 MHz, CDCl3): d 174.3, 134.7, 129.5, 82.8, 68.9,
49.54, 46.2, 35.2, 30.7, 26.0, 25.8, 25.0; IR (KBr):
m
3339, 2931, 1732,
1458 cmÀ1
311.1759.
;
HRMS (ESI) (M+H)+ calcd for C19H22N2O2H+ 311.1754, found
56.6, 54.4, 54.1, 51.8, 43.9, 30.7, 25.9, 18.4; IR (neat):
m 3300, 3053, 2949, 2116,
1736, 1435 cmÀ1; HRMS (ESI) (M+H)+ calcd for C13H17NO2H+ 220.1332, found
220.1336.