Organic Letters
Letter
(
2) for carbonyl−olefin metathesis. The best yields of 2 were
However, catalyst loadings of 30 mol % FeCl were tolerated
3
obtained in a sequence relying on the initial conversion of the
well and resulted in the formation of 6 in 89% yield with 99%
conversion of starting material, which was ultimately
established as the optimal set of reaction conditions (entry
11, Table 1). When the reaction was conducted relying on
toluene as the solvent under otherwise optimal reaction
Electronically differentiated sulfonamides were then exam-
ined as nitrogen protecting groups in the carbonyl−olefin
metathesis, respectively (Table 2). Our previous efforts toward
16
amino acids to the corresponding Weinreb amides, followed
by the addition of an aryllithium or Grignard reagent and the
final alkylation of the amine functionality with either
homoprenyl bromide or iodide. Importantly, this sequence
was amenable to the gram scale and proved viable for all
natural and unnatural amino acids evaluated in the course of
this work. With a robust substrate synthesis in hand, we turned
our attention to the evaluation of distinct Lewis acids for their
ability to promote the desired carbonyl−olefin metathesis
reaction (Table 1). We first evaluated stronger Lewis acids as
a
Table 2. Evaluation of Protecting Groups
a
Table 1. Evaluation of Reaction Conditions
R1
R2
σp
yield (%)
b
b
entry
substrate
entry
Lewis acid
mol % time (h) yield (%)
conversion (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Bn
CF3
0.54
0.37
0.0
−0.17
−0.27
−0.27
0.54
84
80
78
72
47
1
2
3
4
5
6
7
8
9
AlCl3
TiCl4
SnCl4
BCl3
50
50
50
50
50
50
50
50
50
50
30
10
10
50
50
24
24
24
24
24
24
24
24
12
24
24
24
72
24
24
7
0
45
99
45
49
99
95
97
99
99
99
99
10
40
91
97
Cl
H
Me
OMe
OMe
10
11
12
12
5
43
48
58
52
40
68
69
88
89
6
GaCl3
b
78
89
BF ·OEt2
3
CF3
FeBr3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Fe(OTf)3
Fe(OTf)3
c
a
Conditions: All reactions were performed using 0.1 mmol of
substrate and FeCl (30 mol %) in DCE (0.01 M) at 84 °C for 24 h.
3
Reaction was stirred for 48 h.
b
1
1
1
1
1
1
0
1
2
3
4
5
the development of a synthetic approach toward 3-pyrrolines
revealed that sulfonamides can function as competitive binders
to FeCl , which sequesters the catalyst and results in lower
39
30
37
3
15b
overall yields. By utilizing more electron-deficient protecting
groups, the reactivity of the Lewis basic site was attenuated,
and the carbonyl−olefin metathesis reaction was able to
proceed in excellent yield. Similar observations were made
in the present study toward tetrahydropyridines, in which
electron-deficient sulfonamides resulted in the desired meta-
thesis products in yields of up to 89% (entries 1, 2, and 7,
Table 2). However, more electron-rich sulfonamides also
proved to be viable substrates and resulted in good yields of up
to 78% of the desired tetrahydropyridines, albeit requiring
a
Conditions: All reactions were performed using 0.02 mmol of
substrate in DCE (0.01 M) at 84 °C for the indicated time. Yield and
conversion determined by H NMR using dimethyl terephthalate as
an internal standard. Lewis acid was added at 0 °C, and the reaction
was allowed to warm to room temperature.
b
1
5b
1
c
catalysts for the metathesis reaction of substrate 5. When aryl
ketone 5 was converted with 50 mol % of AlCl , the desired
tetrahydropyridine 6 was formed in only 7% yield (entry 1,
Table 1). Similarly, TiCl4 did not provide the desired
heterocycle 6, albeit the complete conversion of aryl ketone
was observed (entry 2, Table 1). In comparison, the use of
0 mol % SnCl or BiCl provided the desired product 6 in 43
and 48% yield, respectively (entries 3 and 4, Table 1).
Improved yields of 6 in 58% were observed with GaCl3,
whereas utilizing BF ·OEt2 resulted in 52% yield. The
complete consumption of substrate 5 was observed in both
cases (entries 5 and 6, Table 1). Diminished yields of
tetrahydropyridine 6 were obtained when FeBr was selected
3
17
prolonged reaction times of 48 h (entries 4−6, Table 2).
This is in stark contrast with observations made in our
previous studies toward chiral 3-pyrrolines in which electron-
deficient sulfonamides were essential to obtain high yields of
the carbonyl−olefin metathesis product.
5
5
4
3
Next, we evaluated the effect of olefin substitution (Table
3). Whereas both prenyl- or styrenyl-derived olefins were
previously shown to be suitable reaction partners for catalytic
3
1
2
carbonyl−olefin ring-closing metathesis reactions, aryl
ketones bearing a prenyl substituent were found to be superior
in the synthesis of tetrahydropyridines, resulting in up to 89%
yield of the desired product (entry 1, Table 3). Importantly,
the corresponding styrenyl derivatives either failed or provided
the desired tetrahydropyridines in low yields (entries 2, 3, 5,
and 6, Table 3). The addition of superstoichiometric
allyltrimethylsilane to the carbonyl−olefin metathesis reactions
of styrene derivatives was previously shown to be beneficial for
3
as the Lewis acid catalyst, whereas FeCl (50 mol %) proved
3
superior and resulted in 88% yield (entries 7 and 10, Table 1).
Attempts to lower the reaction temperature to ambient
conditions or shorten the reaction time to 12 h led to lower
yields of tetrahydropyridine 6 of 68 and 69%, respectively
(
entries 8 and 9, Table 1). Iron- and scandium-based metal
triflates similarly resulted in the formation of the desired
carbonyl−olefin metathesis products, albeit in diminished
yields of 30 and 37%, respectively (entries 14 and 15, Table 1).
1
5b
high yields and conversions. However, the addition of 5.0
equiv of allytrimethylsilane to 18 under otherwise identical
1
5a
B
Org. Lett. XXXX, XXX, XXX−XXX
Gaviria, Mario A.
