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Organic Letters
Letter
Figure 2. Intramolecular hydroamidationa challenging task.
Copper-catalyzed cycloisomerization of 2-alkynyl benza-
mides in the presence of ionic liquid to produce (Z)-3-
alkylideneisoindolinones was reported by Mancuso et al.17
Recently, Brahmchari and co-workers achieved the synthesis of
isoindolin-1-ones through iodoaminocyclization of 2-alkynyl-
benzamides by n-BuLi-I2/ICl.18 In most of the cases, reaction
conditions have been tuned to afford either exo-dig- or endo-
dig-products, and, in many cases, afforded a mixture. Because
of the ambident nature of amides resulting in O-nucleophile
and N-nucleophile, and the availability of two electrophilic
sites at the alkyne bond in the same system, the chemo-
selectivity and regioselectivity scenario is intricate19 (see
Scheme 1). In this context, a chemoselective- and regiose-
Figure 3. ORTEP diagram of 2a and 3a. (Atomic displacement
ellipsoids are drawn at the 50% probability level.)
conformation, whereas structure of 3a is present in chair
conformation. Next, we attempted to synthesize 2a and 3a in a
regiodivergent and chemodivergent manner through the
assistance of various metal catalysts and found that Pd and
Ag catalysts could be crucial in achieving the desired goal. We
then examined a series of Pd catalysts to tune the
regioselectivity of the cyclization of 1a toward the formation
of 2a.
Scheme 1. Intramolecular Cycloamidation for the Synthesis
of Fused Heterocycles
Evaluation of solvents revealed their significant influence on
the reaction and CH3CN was found to be the best choice.
Accordingly, treatment of 1a with 10 mol % of Pd(PPh3)4, 3
equiv of K2CO3 in CH3CN in sealed tube at 110 °C for 16 h
furnished the desired seven-membered product 2a, which was
resulted from 7-exo-dig cyclization in 82% yield (Table 1,
entries 1−5). Switching to other bases such as Et3N and KOH
was futile (Table 1, entries 6 and 7). The screening of Pd(II)
catalysts in the absence of a base did not afford any product,
whereas poor regioselectivity was observed in the presence of
K2CO3 (Table 1, entries 8−10). The combination of
Pd(OAc)2 and a small monodentate phosphine ligand P(o-
tol)3 provided the 2a and 3a in 51% and 49% yields,
respectively (Table 1, entry 11). Ligand-based Pd(II) catalysts
were less effective (Table 1, entries 12−15).
With the optimized conditions in hand, scope of this
regioselective 7-exo-dig cyclohydroamidation reaction for the
synthesis of 2 was investigated in CH3CN (5 mL) using 10
mol % of Pd(PPh3)4, 3 equiv of K2CO3 at 110 °C in sealed
tube for 16 h (see Table 2).
Various 4-substituted triazol-1-ylbenzamides (1) with
electron-withdrawing and electron-donating groups afforded
desired products in excellent yields. Moreover, the substrate
1n, prepared from 3-amino-2-naphthoic acid, provided the
corresponding product 2n in 84% yield. A wide range of
alkynes having alkyl, aryl and heteroaryl substituents (R2 and
R3) on aromatic ring were successfully participated in the
reaction. Amines having aliphatic and aromatic substituents
(R2) successfully participated in the reaction to yield
corresponding products in excellent yields.
lective-controlled approach by merely changing a metal catalyst
in intramolecular cycloamidation is a powerful tool to
synthesize medium-sized ring compounds.
Herein, we report an unprecedented Ag- and Pd-mediated
chemoselective and regioselective cyclization of triazol-1-
ylbenzamides for the synthesis of seven- and eight-membered
triazole-fused heterocycles.
The required triazol-1-yl benzamides 1 were prepared by
modifying the previously reported procedure in the liter-
ature.20 With the required precursor amides 1 in hand, we
chose benzamide 1a as a model substrate to study the
intramolecular cyclization with various bases and metal
catalysts (see Table S1 in the Supporting Information (SI)).
Accordingly, when 1a was treated with 3 equiv of DBU in a
sealed tube at 110 °C for 16 h, a mixture of benzylidene
diazepin-6-one 2a and triazolo[1,5-a][1,5]diazocin-7(6H)-one
3a, in yields of 62% and 37%, respectively (Table S1, entry 2),
was isolated. The proton NMR of 2a and 3a showed a singlet
at 6.57 and 6.68 ppm, corresponding to the CC−H proton.
Finally, the absolute structures of 2a and 3a were confirmed by
single-crystal X-ray analysis (Figure 3). The ORTEP diagram
of 2a exhibited that the seven-membered ring adopted a boat
Having realized the regioselective synthesis of benzotriazlo-
lodiazepin-7-ones 2, we next examined the 8-endo-dig
cyclization of triazol-1-ylbenzamide 1 toward synthesis of
benzotriazolodiazocin-8-ones 3. Recently, silver(I) salts
became prevalent reagents for the cycloisomerization reactions,
because of their mild Lewis acidity and carbophilicity.21 In
B
DOI: 10.1021/acs.orglett.9b04162
Org. Lett. XXXX, XXX, XXX−XXX
Chen, Kai-Chi
