instantly in methanol. The reaction of MTAD with N-acetyl
indole 8 required 4 h for completion in CH2Cl2, but occurred
within 10 min in MeOH and 1 min in CF3CH2OH. BF3‚
Et2O accelerated the reaction of MTAD and 8, but a different
ene product resulted from attachment of MTAD to C(2).
These results provide clear evidence of protic or Lewis acid
catalysis of these ene reactions. Indole 5 reacted rapidly with
MTAD to give imine 6, which isomerized upon standing in
CDCl3 to eneamine 7. Indole 15 reacted with MTAD
selectively at the indole site rather than the nearby enophilic
double bond. The structure of 4 was confirmed via X-ray
crystallography, as depicted in Figure 2.
reducing conditions failed to convert these tryptophan-
derived urazole adducts to the parent indoles.
Acceleration of the ene reaction by polar, protic media
(e.g. MeOH) indicates that the addition of MTAD to indoles
may proceed through a zwitterionic intermediate as depicted
in Figure 3. In most cases, if an excess amount of MTAD is
Figure 3. Formation of urazole-indole adducts might proceed via
a two-step mechanism.
Figure 2. ORTEP representation of the crystalline adduct 4.
added, electrophilic aromatic substitution takes place on the
indole aromatic ring. Even carbazole reacts with MTAD
slowly to afford a mixture of MTAD adducts. More than
one equivalent (1.2) of MTAD is sometimes necessary due
to this competing reaction, which accounts for the less than
quantitative yield of urazole adduct in most cases.
Differences in reactivity of different indole subunits toward
MTAD, as described above, are greater in CH2Cl2 than in
MeOH. This difference in reactivity was useful since it
permitted selective reaction to the N-unsubstituted indole in
1 with CH2Cl2 as solvent, a key step in the synthesis of
okaramine N.1
In conclusion, the first general method for protection of
the 2,3-π double bond of indoles has been developed. The
method is chemoselective for indoles in the presence of
double bonds. Electron-rich indoles react faster than electron-
deficient ones. The process of protection and deprotection
is both rapid and operationally simple.
In the cases where the MTAD ene-reaction led to a final
imine product (e.g. 1, 3, and 19), the thermal retro-ene
process was generally facile at 110-150 °C. Eneamine-type
adducts (7, 9, and 11) and urazole-substituted pyrroloindo-
lines (14, 16, and 18) were less reactive and required higher
temperatures (250-280 °C, in vacuo), but the retro-ene
process proceeded smoothly with short contact times in a
heated tube flow reactor. Thus, a flask was charged with
urazole-indole adduct and connected to a long Pyrex tube
(55 × 1 cm, 14/20 joints, which was enclosed in the furnace
(20 cm) and connected to an evacuated receiver). Condensa-
tion of the pure parent indoles occurred rapidly on the surface
of the tube outside of the hot zone in 65-95% yield. With
the exception of urazole adduct 11, this thermolysis proce-
dure simply and routinely furnished the starting parent
indoles. It appears that the tertiary carbamate subunit of 11
was eliminated leading to pyrido-indole 12 after the retro-
ene reaction and subsequent aromatization. However, ene-
amine 11 could be converted to the starting indole 10 upon
exposure to acid (0.21 equiv of MeSO3H, CH2Cl2, 0-23 °C,
30 h, 68% brsm). The high temperatures necessary to excise
the urazole residue from 14, 16, and 18 are likely a
consequence of the difficult ring-chain tautomerization
preceding the retro-ene. A variety of acidic, basic, and
Acknowledgment. We are grateful to the NIH for a
Postdoctoral Fellowship to P.S.B., to the Undergraduate
Harvard College Research Program for a summer fellowship
to C.A.G, and to Drs. Richard Staples and D.-H. Ryu for
expert assistance.
Supporting Information Available: Detailed experi-
mental procedures for all compounds and full characterization
of new compounds. This material is available free of charge
(4) Hall, J. H.; Kaler, L.; Herring, R. J. Org. Chem. 1984, 49, 2579-
2582.
(5) MTAD is commercially available from Aldrich, Inc.
OL034634X
Org. Lett., Vol. 5, No. 11, 2003
2001