Angewandte
Chemie
Table 1: Catalytic reactions over gold catalysts.
Table 2: Catalytic cycloadditions with various ynamides.
Entry
Catalyst[a]
Solvent[b]
t [h]
Yields [%][c]
1a
3a
1
2
3
4
5
6
7
8
9
AuCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
C6H5Cl
1,4-dioxane
12
9
10.5
4
65
–
–
–
–
–
75
–
–
–
20
75
73
95
89
93
–
84
86
65
[LAuCl]/AgNTf2
[IPrAuCl/AgNTf2
[Ph3PAuCl]/AgNTf2
[Ph3PAuCl]/AgSbF6
[Ph3PAuCl]/AgOTf
AgNTf2
[Ph3PAuCl]/AgNTf2
[Ph3PAuCl]/AgNTf2
[Ph3PAuCl]/AgNTf2
4
3.5
12
7.5
2.5
9
10
[a] 2a (4 equiv). [b] [1a]=0.20m. [c] Product yields are reported after
purification using a silica column. IPr=1,3-bis(diisopropyl phenyl)-
imidazol-2-ylidene, L=P(tBu)2(o-biphenyl), Ms=methanesulfonyl,
Tf =trifluoromethansesulfonyl.
Table 1 shows the realization of a catalytic synthesis of the
pyrimidine species 3a using the ynamide 1a and benzonitrile
(2a; 4 equiv). We first tested the reaction with AuCl3
(5 mol%) in hot 1,2-dichloroethane (DCE, 758C, 12 h),
from which 3a and unreacted 1a were obtained in 20 and
65%, respectively (entry 1). The cationic gold catalysts
[P(tBu)2(o- biphenyl)AuCl]/AgNTf2 and [IPrAuCl]/AgNTf2
enabled complete consumption of 1a in hot DCE (758C, 9–
10.5 h) to afford 3a in 75 and 73% yield, respectively
(entries 2 and 3). The yield of 3a was greatly improved to
95% with [PPh3AuCl]/AgNTf2 within a brief period (4 h,
entry 4). Other anions in [PPh3AuCl]/AgX (X = SbF6 and
OTf) maintained high yields (89–93%) of 3a (entries 5 and
6). AgNTf2 alone was found to be inactive in hot DCE (758C)
for a prolonged period (entry 7). With [PPh3AuCl]/AgNTf2 in
other solvents, the yields of 3a were 84%, 86%, and 65%,
respectively, in toluene, chlorobenzene, and 1,4-dioxane
(entries 8–10). The molecular structure of 3a was confirmed
with X-ray diffraction.[14]
We prepared additional ynamides (1b–r) to assess the
substrate scope (Table 2). Most reactions were performed
with [PPh3AuNTf2] (5 mol%), ynamides, and benzonitrile
(4 equiv) in hot DCE (758C; 1b–m) whereas in the cases of
1n–r the reactions were run at 288C. For the ynamides 1b–d,
bearing various sulfonamide substituents (R’ = n-butyl,
phenyl, and benzyl), the corresponding pyrimidine products
3b–d were obtained in 75–89% yields. The cycloadditions
were applicable also to the ynamides 1e and 1 f comprising
tosyl-substituted and cyclic sulfonamides, thus giving the
desired 3e (93%) and 3 f (74%), respectively. We tested the
reactions on the ynamides 1g–i in which the phenyl group
bears different substituents (X = OMe, Cl and CO2Me), thus
yielding the desired 3g–i in satisfactory yields. The reactions
were compatible with 2- and 3-thienyl-substituted ynamides
(1j and 1k), thus yielding the corresponding pyrimidine
derivatives 3j (79%) and 3k (81%), respectively. For other
[a] [1]=0.20m, [Ph3PAuCl]/AgNTf2 (5 mol%), benzonitrile (4.0 equiv).
[b] Product yields are reported after purification on a silica column.
[c] Reactions were carried out at 758C for 1b–m and at 288C for 1n–r.
heteroaryl-substituted ynamides, 1l and 1m, the correspond-
ing cycloadducts 3l and 3m were produced efficiently. The
alkyl-substituted ynamides 1n and 1o (R = cyclopropyl and n-
butyl) were also amenable to this reaction at 288C, thus
yielding pyrimidines 3n and 3o in 65 and 61% yield,
respectively. Such cycloadditions were extended to the
alkenyl-substituted ynamides 1p–r, thus giving compounds
3p–r in reasonable yields.
Table 3 depicts the nitriles 2b–l which are compatible with
our catalytic cycloadditions. For the 4-substituted benzoni-
triles 2b,c, bearing electron-donating groups (X = OMe and
Me), the gold-catalyzed cycloadditions proceeded smoothly
to yield the pyrimidine products 4b,c in excellent yields. This
synthetic method was also feasible for the electron-deficient
benzonitriles 2d–g (X = CO2Me, F, Cl and Br), thus providing
the desired 4d–g in 72–84% yields. For 3-thienylnitrile, the
resulting product 4h was obtained in 53% yield. We also
examined the reactions on two alkenylniriles, 2i and 2j (R’’ =
H and Ph), thus yielding the desired 4i and 4j in 65 and 74%
yield, respectively. To our delight, this method was also
compatible with the aliphatic nitriles 2k and 2l, thus yielding
the desired pyrimidine species 4k and 4l, respectively in 62–
Angew. Chem. Int. Ed. 2014, 53, 9072 –9076
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