elimination to give 1-tosyl-1,2,3,4-tetrahydropyridine were
never detected. We then set out to explore the scope of this
endo-selective gold-catalyzed aminohydroxylation reaction
(Table 2). First, we examined the effect of substituents in the
backbone of the aminopentene substrates. N-Tosyl-(2,2-
diphenylpent-4-enyl) amine (1b) reacted efficiently under
through slight modifications of the reaction conditions. 2,2-
Dimethyl- and 2-cyclohexyl-substituted substrates 1c–d
afforded 1,3-aminoalcohols 2c–d in 85 and 80% yield,
respectively, as single regioisomers under the standard con-
ditions (Table 2, entries 5 and 8). The reaction of 1c in the
presence of EtOH afforded 4c’ in 77% yield whereas with
PhI(OAc)2 as oxidant aminoacetate 6c was isolated in 80%
yield (Table 2, entries 6 and 7). In the case of aniline 1e, an
unseparable 1.5:1 mixture of 6-endo and 5-exo aminohydrox-
ylation products 2e and 3e was obtained in 50% yield
(Table 2, entry 9). We then evaluated the influence of the N-
protecting groups in the reaction. N-methyl- and N-mesityl-
(2,2-dimethyl-pent-4-enyl) sulfonamides (1 f, 1g) were effi-
ciently converted into the corresponding 1,3-aminoalcohols in
good yields and complete regioselectivity (Table 2, entries 10
and 11) whereas substrate 1h bearing an o-nitro-benzenesul-
fonyl group failed to react (Table 2, entry 12). Interestingly,
the N-Cbz-protected substrate 1i reacted smoothly to give the
Table 2: Scope of the gold-catalyzed aminooxygenation reaction.
Entry React.
cond.[a]
Substrate, R, R1
Products
(Ratio)[b]
Yield
[%][c]
corresponding
1,3-aminoalcohol
2i
and
6,6-
1
2
3
4
5
6
7
8
A
A
B
C
A
B’
C
A
1a: R=Ts, R1 =H
2a/3a (9:1)
2b/3b (9:1)
4b/5b (9:1)
6b/7b (4:1)
2c
4c’
6c
2d
78[d]
85
87
76
85
77
80
80
dimethyltetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (3i’’) in a
2:1 ratio and 82% yield (Table 2, entry 13).[13] Internal
substituted alkenes were efficiently transformed into the
corresponding tertiary acetates (Table 2, entry 14).
1b: R=Ts, R1 =Ph
1b
1b
1c: R=Ts, R1 =Me
To our surprise, when scaling up the reaction of 1b, traces
of N-(5,5-diphenyl-1-tosylpiperidin-3-yl)acetamide (8b) were
detected in the mixture. In this case, the acetonitrile used as
solvent reacts as a nucleophile, followed by hydrolysis to the
corresponding amide. Due to the broad range of biological
activities reported for N-piperidin-3-yl carboxamides we
decided to further pursue this synthetically useful trans-
formation.[14] After an additional short screening of reaction
conditions, aminoamidation products could be selectively
obtained by reducing the amount of water in the reaction to
only 2 equivalents. With these new optimized conditions we
studied the scope of this transformation (Table 3). Substrate
1a afforded 1,3-aminoamide 8a in 68% yield (Table 3,
entry 1). 2,2-Diphenyl-, 2,2-dimethyl-, and 2-cyclohexyl-sub-
stituted substrates 1b–d were efficiently transformed under
these conditions into the corresponding cyclic 1,3-amino-
amidation products 8b–d in 72, 70, and 74% yield, respec-
tively (Table 3, entries 2, 3, and 6). Aminoamide 8c could be
crystallized, thus confirming the structure of these novel
derivatives (Figure 1b in the Supporting Information).
Propio- and butyronitrile could also be employed (Table 3,
entries 4 and 5). The reactions proved to be highly regiose-
lective except for aniline 1e which afforded a 1:1 mixture of
regioisomers 8e and 9e in 70% combined yield (Table 3,
entry 7). N-methyl and N-mesityl sulfonamides 1 f and 1g
afforded the corresponding products 8 f and 8g in 64 and 46%
yield, respectively, upon heating for 15 hours (Table 3,
entries 8 and 9).
1c
1c
1d: R=Ts, R1 =-(CH2)5-
9
A
2e/3e (1.5:1) 50[d]
10
11
A
A
1 f: R=Ms, R1 =Me
1g: R=mesitylsulfonyl,
R1 =Me
2 f
2g
80[e]
77[e]
12
13
14
A
A
C
1h: R=o-NO2C6H4,
–
–
R1 =Me
1i: R=Cbz, R1 =Me
2i/3i’’ (1:2)
82[13]
79
2j
15
A, B
–
–
[a] Reaction conditions A: Same as Table 1, entry 3; Cond. B: Selectfluor
(2 equiv), CH3CN/MeOH (20:1), 0.02m; Cond. B’: as B but with EtOH;
Cond. C: PhI(OAc)2 (2 equiv), DCE, 0.1m, 12 h. [b] Determined by
1H NMR analysis of the crude reaction mixture. [c] Yield of the isolated
major regioisomer. [d] Yield of the mixture of regioisomers. [e] Reaction
time: 12 h. Cbz=benzyloxycarbonyl.
the optimized conditions to give 1,3-amino alcohol 2b in 85%
yield (Table 2, entry 2).[12] When the reaction was performed
in a mixture of CH3CN/MeOH (20:1), the corresponding
aminomethoxylated product 4b could be obtained in 87%
yield (Table 2, entry 3).[2e] Switching to PhI(OAc)2 as stoi-
chiometric oxidant in 1,2-dichloroethane (DCE) as solvent,
the corresponding aminoacetoxylation product 6b was
obtained in 76% yield, although lower regioselectivity was
detected still favoring the piperidine product (4:1; Table 2,
entry 4).
The 1,2-substitution pattern on the olefin seemed to be an
intrinsic limitation for these gold-catalyzed aminooxygena-
tion/amidation reactions (Table 2, entry 15 and Table 3,
entry 10). However, the reaction of 1k in the presence of a
phthaloyl-based iodosobenzene afforded tricyclic 3-benzaze-
pine 10k[15] in a diastereomerically pure form as a result of the
activation of one of the aromatic rings at the C2 position of the
pentene backbone (Scheme 1).[16] The reaction was extended
These results highlight the synthetic utility of this gold-
catalyzed process, since 1,3-aminoalcohols, ethers, or acetates
can be selectively obtained in a highly efficient manner
Angew. Chem. Int. Ed. 2011, 50, 906 –910
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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