Organic Letters
Letter
substrate 1bn lacking the amide chain provided the 1,6-
annulated 2-pyridone 2bn in 85% yield. Then this gold-
catalyzed hydroamination/cycloisomerization process was also
applied to the Ugi adducts 1bo−bt derived from 2-(2-
ethynylphenyl)acetaldehydes with the aim of constructing a
library of pyrido[2,1-a]isoquinolin-4-ones (n = 1, Table 2). To
our satisfaction, this process worked well with various aliphatic
and aromatic substituents on the 2-ynamide moiety, affording
the targeted 1,6-annulated 2-pyridones 2bo−bt in good yields of
71−89%.
2ac in 92% yield (Scheme 2). This indicates that the first step of
this tandem process is a hydroamination of the alkyne or cyanide
a
Scheme 2. Mechanism Study
For the synthesis of diverse 2,3-annulated 4-pyrimidinones,
we next planned to use the Ugi adducts 1ca−cm assembled from
2-formylbenzonitrile and 2-(2-oxoethyl)benzonitrile. As sum-
marized in Table 3, treatment of various substrates under the
Table 3. Scope of Tandem Cyclization Process for the
Synthesis of 2,3-Annulated 4-Pyrimidinones
a
b
a
The reaction was run on a 0.05 mmol scale. Isolated yield. TMB =
1,1,3,3-tetramethylbutyl.
and the compound 3ac is an intermediate of the tandem process.
When AgOTf was utilized as a catalyst, the reaction delivered
2ac in only a moderated yield (Condition B). No conversion
was observed when IPrAuCl was utilized as catalyst (Condition
C). Neither HOTf (5 mol %) nor NaOTf (5 mol %) can catalyze
the reaction (Condition D, E). These results indicate that the
cationic gold catalyst is the real catalyst for the cyclo-
isomerization.
Based on these observations and previous reports,15,16
a
plausible mechanism for this gold(I)-catalyzed tandem hydro-
amination/cycloisomerization process is depicted in Scheme 3.
Scheme 3. Plausible Mechanism of Gold(I)-Catalyzed
Hydroamination/Cycloisomerization Process
a
Unless otherwise stated, all reactions were run with 1ca−cm, (0.1
mmol), 5 mol % of IPrAuCl/AgOTf, and 2.0 mL of DCE at 60 °C in
a sealed flask for 12 h; all yields are isolated yields. TMB = 1,1,3,3-
tetramethylbutyl.
optimal conditions smoothly produced the desired fused 2,3-
annulated 4-pyrimidinones 2ca−cm in moderate to good yields.
In particular, substrates bearing an alkyl or an aryl substituent on
the 2-ynamide are compatible, yielding the products 2cc−ch in
62−82%. A high tolerance for halides (F and Br) on the
benzonitrile moiety was observed (2ci−ck). The substrates 1cl
and 1cm derived from the 2-(2-oxoethyl)benzonitrile, success-
fully gave 2cl and 2 cm in 61% and 72% yield, respectively. The
structure of compound 2cb was confirmed by X-ray
crystallography.
We propose compound 3ac is an intermediate for the tandem
cyclization. To shed light on the reaction process, treatment of
compound 3ac with IPrAuCl/AgOTf (5 mol %) in DCE (1,2-
dichloroethane) at 60 °C for 12 h delivered the desired product
First, the intramolecular hydroamination of the gold π- activated
terminal alkyne (X = CH) or nitrile group (X = N) occurs in an
exo-dig fashion producing the isoindoline (n = 0) or
isoquinolinone (n = 1) intermediate B, which upon proto-
deauration gives N-alkenyl or N-(iminomethyl) alkynylamide
intermediate C.11 Subsequently, the second annulation of the
newly formed double bond with the cationic gold π-activated
alkyne of the 2-ynamide occurs, delivering iminium intermediate
D,12 which after isomerization and protodeauration affords 1,6-
annulated 2-pyridones or 2,3-annulated 4-pyrimidinones.
C
Org. Lett. XXXX, XXX, XXX−XXX