Journal of the American Chemical Society
Article
a
Table 2. Reaction Optimization
b
c
entry
Cu
base (mol %)
A (20)
A (20), CsF (100)
CsF (150)
“
solvent
yield (SM %)
ee (%)
1
2
3
4
5
6
7
8
9
Cu(MeCN) BF
PhMe
50% (49)
83% (13)
75% (11)
39% (48)
65% (20)
50% (31)
75% (10)
74% (<1)
82% (4)
90
90
91
74
91
87
92
91
90
90
4
4
4
“
“
“
“
Cu(MeCN) BF
THF
dioxane
cyclohexane
MTBE
4
“
“
“
“
“
“
d
“
“
“
“
“
d
Cu(MeCN) OTf
“
4
1
1
0
CuOTf· / C H
CsF (160)
98% (−)
2
6
6
a
Standard conditions: 1a (0.10 mmol, 1.0 equiv), 2 (0.135 mmol, 1.35 equiv), [Cu] (5 mol %), L (6 mol %), solvent (1.5 mL), 32 °C, 24 h. A =
b
19
c
NaO(2-OMeC H ). Yield was determined by F NMR of crude reaction, using PhF as an internal standard. Determined by HPLC with a chiral
stationary phase. MeCN removed before reaction.
6
4
d
1
Switching to CuOTf· / C H as the copper source afforded
To explore the scalability of this method, 1b was synthesized
on a 6 mmol scale without a significant loss in enantiose-
lectivity or chemical yield. It was discovered that other
silylboranes could be utilized for this transformation when
(R,S)-3,5-Trip-Josiphos was employed as the ligand (1b-
BnMe Si, 1b-CyMe Si, and 1b-Et Si). These allenyl silanes
2
6
6
the desired allene in almost quantitative yield (entry 10).
With the optimal conditions established, an alternative
synthetic route employing readily available material to prepare
propargylic difluorides was developed (Scheme 2). The
2
2
3
Scheme 2. Improved Synthesis of Propargylic Difluorides
were synthesized on gram scales with comparable yields and
enantioselectivities to 1b-PhMe Si.
2
Determination of the absolute configuration of allene 10b
22
Information for details) at four levels of theory, B3LYP/6-
3
1G(d), B3PW91/6-31G(d), B3LYP/cc-pVTZ, and B3PW91/
23
cc-pVTZ, the resulting conformers were Boltzmann averaged
and plotted with a line width of 5 cm to produce the final
−
1
theoretical spectra. The IR and VCD spectra were then
23
frequency scaled for comparison to the experimental data.
Calculations at all four levels of theory matched well, proving
the absolute configuration of 10b to be S. Of the four methods
employed, the best agreement with experimental data was from
the B3PW91/cc-pVTZ level. The comparison of experimental
2
4
and theoretical spectra was quantified using BioTools
Jupiter, FL) CompareVOA software, with high neighborhood
similarity for IR (90.4) and VCD (69.6), ESI (enantiomeric
decarboxylative bromination of difluorocarboxylic acids and
the copper-catalyzed Sonogashira cross-coupling of terminal
alkynes with difluorobenzyl bromides afforded difluoroalkynes,
which were subjected to defluorosilylation under the optimized
conditions. A range of functional groups were tolerated in the
copper catalyzed transformation, affording the desired allenes
(
similarity index) for VCD (62.9), and a confidence level of
9
9%. Of particular note was the asymmetric allene C−C−C
−1
stretch observed at 1933 cm , which was one of many closely
correlated bands between experiment and theory. In addition
1
−24b in high yields (83−98%) and in good enantioselectiv-
to allene 10b, the absolute configuration of 1b-Et Si, 12b, 17b,
ities (82−98%) after isolation (Table 3). Notably, alkynes
3
(
(
19b), alkenes (20b), enynes (24b), aldehydes (8b), ketones
9b), propargylic acetates (23b) as well as alkyl and aryl
1
2c,e,16a,21,25
On the basis of previous reports regarding CuF
halides (3b and 6b) were tolerated. Coordinating heterocycles
1
5b,f,17d,26
(
14−16b, 18b, and 25b), amides (7b, 11−13b), and nitriles
and copper silyl species,
we propose the following
(5b and 10b) also did not hamper catalysis. Although changing
mechanism for the copper-catalyzed reaction (Figure 1). First,
a complex between Josiphos and [CuOTf] undergoes salt
the electronics of the aryl ring slightly decreased the
enantiomeric excess of the reaction (1−6b), increasing the
steric bulk of the aryl group was well tolerated (25b). Although
many functional groups were tolerated, the reaction proved
more sensitive to alterations of the substituents directly
attached to the allene, which could affect the barrier of
silylation of the alkyne (26−27b) or impact the C−F bond
strength (28−29b).
16a,21,25d
metathesis with CsF to generate JosiphosCuF (Cu1).
σ-Bond metathesis with PhMe SiBpin (2) generates Josipho-
sCuSiMe Ph (Cu2) and releases FBpin.
2
12c−e
Subsequent
2
coordination and silylation of the triple bond generates an
1
5a,e,27
12g
alkenyl Cu species (Cu3).
A β-fluoride elimination
19,28 15c
regenerates Cu1, which is trapped by FBpin,
2
or
decomposes the formed allenylsilane (c). As FBpin is more
1
3761
J. Am. Chem. Soc. 2021, 143, 13759−13768