G. Wu, T. Li, F. Liu et al.
Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Important indole compounds and bioactive indole compounds containing C-3 diaryl-methine substituent.
eas C2, C3 and squaric acids C4, C5) were also tested in place of C1
and they were all less effective and gave the desired 3aa in a lower
yield and racemic form (Table 1). The less effectiveness in enan-
tioselective induction might attribute to the poor basic character
of tertiary amine group which couldn’t form a tight interfered com-
plex with indoles. And the optimal reaction conditions at this time
turned out to be performing the reaction in CH2Cl2 or THF at ambi-
ent temperature using 10 mol% C1 as catalyst.
Scheme 1. p-QMs and their resonance structures.
With the optimal reaction conditions in hand, the scope of p-
QMs was firstly explored. As shown in Table 2, a variety of p-
QMs bearing a single electron-donating or electron-withdrawing
substituent at the aryl ring were readily converted to the corre-
sponding 1,6-adducts in modest to high yields indicating that the
electronic properties of p-QMs did not have a significant impact
on the reaction outcome (Table 2, 3aa–3na). p-QM 1e with 3,4-
dimethoxyl phenyl substitute gave the corresponding 1,6-adduct
3ea in a little lower yield compared with its analogues with a sin-
gle methoxyl substitutes 1a and 1f (Table 2, 3ea vs 3aa, 3fa). And
the ortho-OMe phenyl substituted p-QM 1f gave the corresponding
1,6-adduct 3fa in 91% yield which were slightly lower than 1a
(with a p-OMe substitute) and 1 g (with a m-OMe substitute)
revealed the 1,6-conjugate addition reaction was somewhat sensi-
tive to the steric factors. And more importantly, heteroaryl substi-
tuted p-QMs were also compatible with the reaction conditions,
leading to the corresponding indole derivatives 3oa-3ra in high
yields which excellently demonstrate the mildness of the reaction
conditions and wide potential applicability.
Then the scope of indoles were accessed which results were
summarized in Table 3. Indoles 2a-2g with an electron-donating
methyl group located at the N1, C2, C4, C5, C6 or C7 positions
(Table 3, 3aa–3ag) and 2h with stronger donating methoxyl group
at the C4 (Table 3, 3ah) all proceeded well under the optimal con-
ditions affording the corresponding 1,6-adducts in high yields.
Indole 2i with an electron-withdrawing methoxyl carbonyl substi-
tute at the C4 position didn’t react at all which indicated that the
of p-QMs with various nucleophiles (Scheme 2, e) [11]. Although
the above demonstrated works are elegant and effective to afford
the substituted indoles in chiral or racemic form, they are limited
in the specific substituted pattern in the substrates or harsh reac-
tion condition. Herein we reported a thiourea catalyzed 1,6-conju-
gate addition of indoles to p-QMs in which p-QMs was activated by
a weak hydrogen-bond effect. The mild reaction conditions toler-
ated a wide substrate scope and a series of C-3 bisaryl methine
substituted indoles are prepared in high yields.
Results and discussion
Initially, p-QM 1a and indole 2a were chose as model substrates
to test the feasibility and screening the optimal reaction conditions
of this 1,6-conjugate addition reaction which results are depicted
in Table 1. MeCN soon proved to be a suitable solvent and the
desired 1,6-conjugative addition product 3aa was obtained in
73% isolated yield (Table 1, entry 1). No desired reaction occurred
in more polar DMF or DMSO (Table 1, entries 2–3). An alternative
1,6-conjugate reaction product 4a was obtained in 42% yield when
MeOH was used as solvent (Table 1, entry 4). Ethyl acetate and
toluene were both less effective than MeCN (Table 1, entries 5–
6). And finally CH2Cl2 and THF proved to be more suitable solvents
than MeCN and in both cases the corresponding 1,6-adduct 3aa
was obtained in 97% high yield (Table 1, entries 7–13). Four com-
mon chiral H-bond donor catalysts (commercially available thiour-
2
Wu, Guangmiao
