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R. Giles et al. / Tetrahedron Letters 54 (2013) 4083–4085
Table 3
NHSO2Ph
Effect of catalyst and acid at different temperaturesa
Entry
1
p-TsOH
(mol %)
Temp
(°C)
4 Yield
(%)
4:5 (mol
ratio)
4
(mol %)
2
Pd catalyst
+
1
2
3
4
5
5
10
5
5
5
5
5
10
10
10
60
60
60
40
100
55
30
93
80
91
55:1
30:1
13:1
40:1
7:1
+
acid, solvent
40-100 oC, 18 h
PhSO2NH2
3
5
a
All reactions were run using 0.25 mmol of benzenesulfonamide and 0.75 mmol
Scheme 1. Hydroamination of 4-methylstyrene.
of 4-methylstyrene in toluene.
Table 1
Effect of acids and palladium complexes on hydroamination of 4-methylstyrenea
10 mol % of the acid and 2–5 mol % of the Pd catalyst, we observed
reasonably high yield and selectivity in favor of the hydroamina-
tion product (entry 3). Lower temperature improved the selectivity
despite slightly lower yield (entry 4) while higher temperatures
gave comparable yields with slightly lower selectivity (entry 5).
Thus depending on the nature of the substrate, the temperature
can be varied to improve either selectivity or yield as desired.
Under the optimized catalytic conditions, the substrate scope of
this methodology was examined by screening various different vi-
nyl arenes (Scheme 2 and Table 4).11 Electron-rich vinyl arenes,
including 4-methylstyrene (entry 1), 2,4-dimethylstyrene (entry
2), and 4-methoxystyrene (entry 3), furnished the hydroamination
products in good yields and selectivities at relatively low temper-
atures (40–60 °C). 2,4-Dimethylstyrene in particular reacted in
essentially quantitative yield under these conditions. 4-Methoxy-
styrene, in comparison, was much more sensitive to polymeriza-
tion than any other substrates and required very mild conditions,
including increased catalyst loading and a lower temperature, to
give the hydroamination product in a decent yield. When the sub-
stitution pattern was changed from 4-methoxy to 3-methoxy (en-
try 4), the reactivity decreased dramatically and higher
temperatures were required to afford comparable yields. 3-Meth-
oxystyrene behaved similarly to unsubstituted and electron-neu-
tral substrates encompassing styrene (entry 5) and 2-
vinylnaphthalene (entry 6), which reacted smoothly at higher tem-
peratures than electron-rich styrenes. Higher temperatures or in-
creased amounts of p-TsOH resulted in significantly lower
chemoselectivities, yielding increased amounts of homocoupled
product 8.
4-F-, Cl-, and Br-substituted vinyl arenes were subjected to the
developed catalytic conditions and each of these substrates pro-
vided high yields and selectivities under conditions similar to
those used for electron-neutral examples (entries 7–9).
As expected based on the aforementioned examples, the reac-
tivities dropped significantly when the substitution pattern was
changed from para to ortho. These substrates required higher tem-
peratures in chlorobenzene solvent with higher loading of p-TsOH
(entries 10–12). 2-Fluoro- and 2-bromostyrenes provided decent
yields and selectivities at 130 °C. In contrast, 2-chlorostyrene
underwent significant polymerization as well as hydroamination
and dimerization (entry 11). 3-Chlorostyrene was a poor substrate
Entry
Pd catalystb
Acid
4 Yield (%)
4:5 (mol ratio)
1
2
3
4
5
––
p-TsOH
p-TsOH
p-TsOH
p-TsOH
MeSO3H
71
81
71
95
91
1:1.6
1:1.6
1:1.7
7.9:1
5.1:1
Pd(PPh3)2Cl2
Pd(OAc)2
1
1
a
All reactions were run using 0.25 mmol of benzenesulfonamide, 0.75 mmol of
4-methylstyrene, and 20 mol % of acids in toluene at 60 °C.
b
10 mol % of Pd catalysts were used.
most effective for hydroamination but still gave the dimer 5 as the
major product (entry 1). We then investigated the use of palladium
complexes as co-catalysts. When known palladium complexes
were used (entries 2 and 3), both the yield of hydroamination
product and the chemoselectivity remained similar to those of
the acid-only conditions (entry 1). In sharp contrast, the addition
of catalyst 1 led to a great improvement in hydroamination conver-
sion and considerable reversal of chemoselectivity. Comparable re-
sults were observed with MeSO3H (entry 5). Unlike known
catalysts, our catalyst 1 inhibited undesired Brønsted acid-cata-
lyzed homocoupling of the olefin while promoting the desired
hydroamination, implying that the structure and electronic prop-
erties of the ligand, rather than the simple presence of a palladium
salt, could be the driving force behind the unique reactivity and
selectivity.
With these trends noted, we endeavored to determine the influ-
ence of several other factors including solvent and substrate ratios
(Table 2). Three distinct outcomes based on solvent effects were
observed; the reaction was very active but not selective (1,2-
dichloroethane, entry 1), no reaction occurred (dioxane, entry 2),
and the reaction was efficient and highly selective toward the
hydroamination product (toluene, entry 3). When we decreased
the amount of the olefin to limit formation of dimer 5, we observed
much higher selectivities as anticipated. However, the yields of 4
diminished significantly, revealing the importance of using an ex-
cess of the olefin for optimal results (entries 4 and 5).
Subsequently, we investigated the effect of lowering catalyst 1
and acid loading at different temperatures (Table 3). When we
used 5 mol % of p-TsOH, the chemoselectivities improved dramat-
ically but the reactions were sluggish and provided much lower
yields of the hydroamination product (entries 1 and 2). With
NHSO2Ph
Table 2
Effect of solvents and substrate ratiosa
7
6
Entry
Ratio (2:3)
Solvent
4 Yield (%)
4:5 (mol ratio)
1 (5 mol%)
R
R
+
+
1
2
3
4
5
3:1
3:1
3:1
1:1
1:3
DCE
81
0
81
67
61
1.2:1
0:0
20:1
67:1
61:1
p-TsOH, solvent
40-130 oC, 18 h
Dioxane
Toluene
Toluene
Toluene
PhSO2NH2
3
8
R
R
a
All reactions were run using 10 mol % of the catalyst and acid each at 60 °C.
Scheme 2. Hydroamination of vinyl arenes.
Giles, Richard
