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(KHMDS) and phenyl[(trimethylsilyl)ethynyl]iodonium tri-
flate,[11] the corresponding ynamides 6a–d were obtained in
45–79% yield.[12] Subsequent treatment of ynamide 6a with
iPrMgCl·LiCl[13] provided the corresponding magnesium
reagent 7a within 0.5 h at À108C in over 90% yield.[14] In
the presence of a catalytic amount of CuCN·2LiCl[15]
(30 mol%) 7a underwent a smooth cyclization (258C,
24 h)[16] producing a 2-metalated indole derivative (of type
3; Scheme 1). A subsequent allylation reaction with ethyl 2-
(bromomethyl)acrylate[17] (0.9 equiv) afforded the polyfunc-
tional indole 8a in 92% yield (Scheme 2).[18] Similarly,
acylation of 7e with 3-chlorobenzoyl chloride furnished the
2-acylated indole 8b in 92% yield. The CF3-substituted
ynamide 6b reacted smoothly with iPrMgCl·LiCl (À208C,
15 min) to give the corresponding magnesium reagent 7b.
However, in this case the addition of one equivalent of
CuCN·2LiCl was necessary to achieve complete ring closure
(258C, 8 h). Alternatively, with microwave irradiation[19] of
the reaction mixture (508C, max. 100 W) the ring closure
reaches completion within 1.5 h. The resulting 2-metalated
indole reacted with various electrophiles in good yields. Thus,
acylations with cyclopropanecarbonyl chloride and 4-methyl-
benzoyl chloride provided the desired ketones 8c and 8d in
yields of 85 and 78%, respectively. Similarly, the allylation
with 3-bromocyclohexene afforded the functionalized indole
8e in 65% yield.
In the case of the cyano-substituted ynamide 6c, the Br/
Mg exchange with iPrMgCl·LiCl was complete at À58C in
0.5 h and for the more sensitive ester-substituted ynamide 6d,
the exchange was carried out at À208C in 1 h. The use of
stoichiometric amounts of CuCN·2LiCl avoids side reactions
in both cases. Again when microwave irradiation (508C, max.
100 W) was applied, the ring closure was complete within
0.75–1 h (instead of 258C, 16 h). Subsequent acylation of the
corresponding cyano-substituted 2-metalated heterocycle
gave indole 8 f in 68% yield. Likewise, allylation and
acylation of reagent 7d afforded indoles 8g and 8h in yields
of 62 and 93%, respectively (Scheme 3).
dole 9 undergoes Negishi cross-coupling reactions[21] with
various zinc reagents[22] in the presence of 3 mol% PEPPSI-
iPr[23] to provide the 2,3-disubstituted indoles 10a–c in 63–
89% yield (Scheme 3).
Remarkably, this versatile indole synthesis was success-
fully extended to the preparation of 4-, 5-, 6-, and 7-
azaindoles. For the synthesis of 7-azaindoles, we used
commercial 2-amino-3-bromopyridine (11) as the starting
material. The synthesis of the corresponding ynamide 12 was
achieved in two steps as described above (66% overall yield).
Treatment of ynamide 12 with iPrMgCl·LiCl (1.1 equiv,
À458C, 1 h) provided the heteroarylmagnesium reagent 13
in roughly 91% yield. Upon subsequent microwave irradi-
Scheme 4. Preparation of functionalized 7-azaindoles of type 14 by the
copper-mediated carbomagnesiation of ynamide 12. Reagents and
conditions: a) PhSO2Cl (1.2 equiv), pyridine (3.0 equiv), CH2Cl2, 258C,
72 h, 80%; b) KHMDS (1.0 equiv), toluene, 08C, 1 h, then phenyl-
[(trimethylsilyl)ethynyl]iodonium triflate (1.2 equiv), 258C, 16 h, 82%.
ation and reaction with CuCN·2LiCl (1.0 equiv) at 508C the
ring closure yielding 14 was complete within 1 h (Scheme 4).
After quenching with water the corresponding 7-azain-
dole 14a was isolated in 79% yield (Table 1, entry 1).
Alternatively, allylation or acylation can be readily performed
with ethyl 2-(bromomethyl)acrylate, furoyl chloride, or cyclo-
propanecarbonyl chloride to provide the desired 7-azaindoles
14b–d in 69–84% yield (Table 1, entries 2–4).
Further functionalization of 7-azaindoles 14b and 14d
could be achieved by transformation of the TMS group using
ICl (1.1 equiv) (CH2Cl2, 08C, 5 min, 64–72%) to provide the
corresponding iodides 15a and 15b. Subsequent I/Mg
exchange with MeMgCl (1.1 equiv, À788C, 0.5 h)[24] followed
by transmetalation with ZnCl2 (1.1 equiv) furnished the
functionalized Zn reagents 16a–b which reacted smoothly
with 3-chlorobenzoyl chloride, cyclohexanecarbonyl chloride,
and cyclopropanecarbonyl chloride to give the respective 2,3-
disubstituted azaindoles 17a–c in 74–85% yield (Scheme 5).
The subclass of 4- and 6-azaindoles is readily available
using this new method. The standard two-step conversion of
the commercial 2-bromopyridin-3-amine (18) provides the
desired ynamide 19 in 56% overall yield. This precursor 19
undergoes a Br/Mg exchange reaction with iPrMgCl·LiCl
(1.5 equiv, À408C, 24 h) at position 2 providing, after copper-
mediated ring closure, 4-azaindole 20 in 52% yield
(Scheme 6).[25] Remarkably, starting from the same ynamide
19, the present methodology can be used to prepare 6-
The TMS substituent in indoles of type 8 can be used as
a handle for further functionalization in position 3. Thus, the
TMS-substituted indole 8a was converted into iodide 9 (ICl
(1.1 equiv), CH2Cl2, 08C, 5 min, 90%;[20] Scheme 3). Iodoin-
Scheme 3. Transformation of the TMS-substituted indole 8a into the
3-iodoindole 9 and subsequent Negishi cross-couplings.
À
azaindoles by means of selective C H activation mediated by
2
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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