Journal of the American Chemical Society
Article
a
Table 1. Screening of Reaction Conditions
c
entry
2
cat. (5 mol %)
base (equiv)
solvent (M)
T (°C) t (min)
additive
4 (%)
11
5 (%) 6 (%)
1
2
3
4
5
6
7
8
9
10
2a (R = SO2Tol)
2a (R = SO2Tol)
2a (R = SO2Tol)
2a (R = SO2Tol)
2a (R = SO2Tol)
2a (R = SO2Tol)
2a (R = SO2Tol)
2b (R = SO2t-Bu)
2c (R = SO2Me)
2d (R = COC6H4-p-CF3)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
DBU (1.2)
DBU (1.2)
DABCO (1.2)
TMG (1.2)
DBU (1.2)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DMF (0.1)
80
80
80
80
80
120
120
120
120
120
180
180
180
180
180
10
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
-
ZnI2
ZnI2
ZnI2
ZnI2
56
12
-
-
-
-
toluene (0.1)
toluene (0.1)
toluene (0.1)
toluene (0.1)
xylenes (0.4)
xylenes (0.4)
xylenes (0.4)
xylenes (0.4)
xylenes (0.4)
44
-
-
-
-
43
60
23
9
-
-
10
-
b
10
10
72 (68 )
44
44
-
-
-
10
10
-
-
-
23
a
Conditions for entries 1−5: 2 (0.1 mmol), 1-phenylethyne (0.12 mmol), cat. (5 mol %), 4 Å MS (40 mg), solvent (1.0 mL). Conditions for
entries 6−10: 2 (0.2 mmol), 1-phenylethyne (0.24 mmol), cat. (0.05 mol %), ZnI2 (0.04 mmol) except for entry 6, solvent (0.5 mL). See Tables S-
b
c
1−S-3 in the Supporting Information for details. 3 g scale after recrystallization. Abbreviations: DABCO, 1,4-diazabicyclo[2.2.2]octane; DBU,
1,8-diazabicyclo[5.4.0]undec-7-ene; TMG, 1,1,3,3-tetramethylguanidine.
dimerized to disiloxane 5a in 56% yield. In contrast, the
formation of 4a (44%) was significantly favored in nonpolar
toluene, while the generation of the undesired byproduct 5a
was significantly inhibited (12%; entry 2). Among the tested
bases, DBU was the most effective, as the less basic DABCO
was ineffective for N−H deprotonation (entry 3), while the
stronger base TMG promoted the decomposition of 3a (entry
4). Screening of Pt-, Ni-, or Rh-centered catalysts as well as
other Pd catalysts revealed that Pd(PPh3)2Cl2 was as effective
as Pd(PPh3)4 (entry 5). However, the overall formation
efficiency of 3-silaazetidine 3a was higher with Pd(PPh3)2Cl2
than with Pd(PPh3)4 (67% vs 56%), identifying Pd(PPh3)2Cl2
as the optimal reaction catalyst.
Furthermore, with an increase in the temperature from 80 to
120 °C, the concentration of 2a to 0.4 M, and the loading of
DBU to 2.0 equiv, while the solvent was also changed to
xylenes, favored the ring expansion of 3a, giving 4a in 60%
yield (Table 1, entry 6). The additive 4 Å MS, which was used
for absorption of water in the reaction at 80 °C (entries 1−5),
was no longer needed at 120 °C due to the much faster ring
expansion of 3a toward 4a. However, the new byproduct 6a
was also formed in 10% yield, resulting from the nucleophilic
substitution of the 1-phenylethyne anion with 2a. In order to
inhibit this side reaction, various Lewis acids were tested to
reduce the nucleophilicity of 1-phenylethyne. ZnI2 proved to
be the most effective,101 affording 4a in 72% yield and
completely eliminating the formation of 5a and 6a (entry 7).
Under these optimized conditions, 4a could also be prepared
on a 3 g scale with a comparably high yield of 68% (entry 7). A
series of N-substituents were also tested to examine their effect
on the formation efficiency of 4. Similar to the case for 2a,
sulfonamide precursors 2b,c gave compounds 4b,c, respec-
tively, in 44% yield (entries 8 and 9). In contrast, 2d bearing
the less electron-withdrawing p-CF3-C6H4CO group could not
be deprotonated, affording only 6d in 23% yield (entry 10).
2.3. Scope of Alkynes. The scope of alkynes was
examined using the 3-silaazetidine precursor 2a (Table 2).
Aryl alkynes bearing a phenyl ring substituted with various
electron-donating or electron-withdrawing groups gave 3-
silatetrahydropyridines 4e−x in generally good yields. The
higher yield of the 4-Me-C6H4-substituted analogue 4g (75%)
in comparison to that of 2-Me-C6H4-substituted 4e (59%)
suggested that the ortho substitution sterically hindered the
alkyne insertion. A primary amine and a secondary amide were
also tolerated, yielding 4n,o in respective yields of 38% and
57%. However, aryl bromide, a typical moiety used in Pd-
catalyzed cross-coupling reactions, interfered with our process,
giving 4t in only 12% yield. The formation of 4aa indicated the
potential utility of the approach in developing ferrocene-type
ligands. Alkynes substituted with heterocycles bearing one or
more N, O, or S heteroatoms served as good substrates for
4ab−am. The basic N-heterocycle moiety in the substrates did
not interfere with the basic function of DBU.
Functionalized alkyl alkynes, including those derived from
propargyl alcohol or thiol (4an−aw), were also well tolerated,
except for 4aq containing a free hydroxyl group. The yield
differences among 4an−ap indicated a certain steric bias
against alkynes. Extensive examination of a wide range of
propargyl amines and amides indicated that free secondary or
tertiary amines (4ax−az and 4ba−bf), either in chainlike
substrates or in ring structures with three or five to seven
members, can function well in this approach without affecting
the chirality of the functional groups (4ay). Good applicability
was also observed for secondary and tertiary propargyl amides
and lactams (4bg−bp), while rings with three to eight
members or spirocyclic rings were well tolerated. Analogues
4bq−bu bearing a diene moiety from the corresponding
enynes were also successfully synthesized in good yields.
However, the reaction failed to give 4bv from the
corresponding diyne, in which both terminal and internal
alkynes were inactive under these conditions. An inefficiency
was also observed for ring expansion with 1-phenyl-1-propyne,
indicating that the reaction was unsuitable for more sterically
demanding internal alkynes. Although methyl propiolate
proved to be a more challenging substrate in comparison to
inactivated alkynes, because the aza-Michael addition signifi-
cantly interfered with the ring expansion, the analogue 4bw
was successfully prepared in 32% yield using 5 mol % of
PdCp(η3-C3H5) as the catalyst and 10 mol % of PPh3 as the
ligand by forming the intermediate 3a prior to the alkyne
11143
J. Am. Chem. Soc. 2021, 143, 11141−11151