complicated mixtures. We tried optimizing the reaction
conditions by varying time, temperature, and concentration.
Ultimately, a dimeric species was isolated in 45% yield, and
the structure was determined to be 7a. To reconcile the
divergent results from TFA- and BF3-promoted cyclization
experiments, we prepared the substrates 5 containing various
substitution patterns on the indole cores. These results are
summarized in Table 1.8 Generally, regardless of the strength
of the electron-withdrawing groups on the silyl tryptophols
5, condensation with acetone under TFA promotion to
produce tetrahydro-pyrano[3,4-b]indoles 6 proceeded in
moderate to good yields without detection of the dimers 7
(entries 1, 7, 10, 12, 14, and 18). Benzophenone under these
reaction conditions failed to give any cyclization adduct
probably due to the steric hindrance (entry 13). Instead, the
desilylated product 8a was obtained after workup. Similarly,
the uncyclized adducts 9a and 9b were obtained when the
electron-deficient trytophols 5g and 5h were employed for
the condensations with cyclohexanone under identical condi-
tions (entries 15 and 19). It is worth noting that 10 could be
generated from the reaction of homotryptophol 5i with CH3-
CHO in satisfactory yield (entry 21, 54%), though the similar
reaction with acetone only gave the desilylated product 8b
without any cyclization (entry 20).
Scheme 1
to prepare a series of electron-withdrawing group-substituted
tetrahydro-pyrano[3,4-b]indoles. Here, we describe an ef-
ficient methodology for syntheses of various electron-
demanding tetrahydro-pyrano[3,4-b]indoles using Larock’s
palladium-catalyzed indole synthesis followed by silicon-
directed oxa-Pictet-Spengler cyclization of resultant tryp-
tophols with ketones or aldehydes. The scope and limitation
of this methodology are also discussed.
The required tryptophol components, 2-(2-trimethylsilanyl-
1H-indol-3-yl)-ethanols, and 2-(2-trimethylsilanyl-1H-indol-
3-yl)-propanols 5 were easily prepared in two steps as
described by Larock (Scheme 1).6 First, selective ortho
iodinations of anilines 3 afforded the 2-iodinated products 4
in modest to good yields.7 Palladium-catalyzed heteroannu-
lation of ortho-iodoanilines with 4-(trimethylsilanyl)-3-butyn-
1-ol or 5-(trimethylsilanyl)-4-pentyn-1-ol gave the corre-
sponding 2-(2-trimethylsilanyl-1H-indol-3-yl)-ethanols or
2-(2-trimethylsilanyl-1H-indol-3-yl)-propanols 5 with no
regioisomeric products isolated. Generally, this reaction
proceeded in reasonable yields, excellent regioselectivity, and
good tolerance for substitution on the indole cores.
A possible mechanism for the silicon-promoted formation
of the tetrahydro-pyrano[3,4-b]indoles 6 is shown in Scheme
2. Two pathways are likely involved in this process. Pathway
A involves the acid-catalyzed formation of the oxocarbenium
ion species 12, followed by intramolecular electrophilic
aromatic substitution on the activated position ipso to the
trimethylsilyl group of 12. Intermediate 13 is then believed
to form due to the stabilizing hyperconjugation of the TMS
group on the â-carbocation.9 Desilylation of 13 then affords
(8) (a) Typical Procedure for TFA-Promoted Oxa-Pictet-Spengler
Cyclization, Preparation of 6i. Acetone (0.2 mL) was added into 5f (100
mg, 0.35 mmoL) in 3 mL of 2:1 CH2Cl2/trifluoroacetic acid solution at 0
°C. The reaction was stirred for 2 h from 0 °C to rt. The reaction was then
quenched with saturated NaHCO3 solution and extracted 3x with CH2Cl2.
The organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, concentrated, and purified by column chromatography (silica gel,
hexanes/ EtOAc from 2:1 as the eluent) to give 6i as a white solid (75 mg,
81%): 1H NMR (CDCl3) δ 7.60 (br, s, 1H), 7.16 (d, J ) 3.5 Hz, 1H), 7.04
(d, J ) 8.5 Hz, 1H), 3.92 (t, J ) 8.5 Hz, 2H), 2.62 (t, J ) 8.5 Hz, 2H),
1.42 (s, 6H); 13C NMR (CDCl3) δ 154.2, 151.8, 141.2, 131.8, 114.7, 112.3,
106.9, 104.4, 71.6, 60.2, 27.6, 22.1; MS (m/z) MH- 284. Anal. Calcd for
C13H13ClFNO: C, 61.54; H, 5.16. Found: C, 61.23; H, 5.09. (b) Typical
Procedure for BF3-Promoted Dimerization, Preparation of 7c. BF3
etherate (0.23 mL, 3.70 mmoL) was added dropwise into the mixture of 5f
(480 mg, 1.68 mmoL) and acetone (0.14 mL, 1.85 mmoL) in 5 mL of
dichloromethane at 0 °C. The reaction was slowly warmed to rt over 2 h,
and stirring was continued for another 4 h. The mixture was then poured
into saturated NaHCO3 solution and extracted three times with CH2Cl2.
The organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, concentrated, and purified by column chromatography (silica gel,
hexanes/EtOAc from 3:1 to 1:1 as the eluent) to give the dimer 7c as a
white solid (285 mg, 67%): 1H NMR (CDCl3) δ 7.66 (br, s, 1H), 7.28 (d,
J ) 9.0 Hz, 1H), 7.24 (d, J ) 4.0 Hz, 1H), 7.20 (d, J ) 8.5 Hz, 1H), 7.01
(d, J ) 4.5 Hz, 1H), 3.88 (m, 2H), 3.76 (m, 1H), 3.52 (m, 1H), 3.05 (t, J
) 8.5 Hz, 2H), 2.98 (abq, J ) 13.5 Hz, 1H), 2.85 (m, 2H), 2.62 (abq, J )
13.5 Hz, 1H), 2.11 (s, 3H), 1.53 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3)
δ 152.9, 150.6, 149.8, 139.4, 131.4, 129.2, 127.3, 125.8, 115.6, 114.3, 113.3,
112.3, 111.0, 109.8, 109.0, 106.0, 104.2, 103.3, 101.1, 61.6, 60.8, 56.0,
37.0, 28.4, 27.5, 26.4, 26.0; IR (film, cm-1) 3362, 3290, 1470; MS (m/z)
MH+ 507, MNa+ 529. HRMS calcd for C26H26F2N2O2Cl2 506.1339, found
506.1342.
Our initial study on the oxa-Pictet-Spengler cyclization
started with 2-(2-trimethylsilanyl-1H-indol-3-yl)-ethanol 5a
(entries 1 and 2). As expected on the basis of the well
documented behavior of tryptophol, the tetrahydro-pyrano-
[3,4-b]indole 6a was obtained in reasonable yield when 5a
was condensed with acetone in trifluoroacetic acid (TFA).
To our surprise, when BF3 etherate was employed as the
promoter the reaction of 5a with acetone always produced
(4) For references regarding other uses of the oxa-Pictet-Splengler
cyclization, see: (a) Bianchi, D. A.; Cipulli, M. A.; Kaufman, T. S. Eur. J.
Org. Chem. 2003, 24, 4731. (b) Bianchi, D. A.; Rua, F.; Kaufman, T. S.
Tetrahedron Lett. 2004, 45, 411. (c) Guiso, M.; Bianco, A.; Marra, C.;
Cavarischia, C. Eur. J. Org. Chem. 2003, 17, 3407. (d) Miles, W. H.;
Heinsohn, S. K.; Brennan, M. K.; Swarr, D. T.; Eidam, P. M.; Gelato, K.
A. Synthesis 2002, 11, 1541. (e) Guiso, M.; Marra, C.; Cavarischia, C.
Tetrahedron Lett. 2001, 42, 6531. (f) Wuensch, B.; Zott, M.; Hoefner, G.;
Bauschke, G. Arch. Pharm. 1995, 328, 487. (g) Wuensch, B.; Zott, M.
Tetrahedron: Asymmetry 1993, 4, 2309. (h) Wuensch, B.; Zott, M. Liebigs
Ann. Chem. 1992, 1, 39.
(5) (a) Willette, R. E. AdV. Heterocycl. Chem. 1968, 9, 27. (b) Yakhonto,
L. N.; Prokopov, A. A. Russ. Chem. ReV. 1980, 49, 428. (c) Snieckus, V.
Chem. ReV. 1990, 90, 879.
(6) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355. (c) Walsh,
T.; Toupence, R.; Ujjainwalla, F.; Young, J.; Goulet, M. Tetrahedron 2001,
57, 5233.
(9) (a) Wierschke, S. G.; Chandrasekhar, J.; Jorgensen, W. J. Am. Chem.
Soc. 1985, 107, 1496. (b) Lambert, J. B.; Wang, G.; Finzel, R. B.; Teramura,
D. H. J. Am. Chem. Soc. 1987, 109, 7838.
(7) Iodo-4,5-dichloroaniline and 2-iodo-4-fluoro-5-chloroaniline were
obtained along with their regioisomers.
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Org. Lett., Vol. 7, No. 10, 2005