Asymmetric synthesis of protected α-amino boronic acid derivatives with an air- and moisture-stable Cu(II) catalyst

Article abstract of DOI:10.1021/jo500300t

The asymmetric borylation of N-tert-butanesulfinyl imines with bis(pinacolato)diboron is achieved using a Cu(II) catalyst and provides access to synthetically useful and pharmaceutically relevant α-amino boronic acid derivatives. The Cu(II)-catalyzed reaction is performed on the benchtop in air at room temperature using commercially available, inexpensive reagents at low catalyst loadings. A variety of N-tert-butanesulfinyl imines, including ketimines, react readily to provide α-sulfinamido boronate esters in good yields and with high stereoselectivity. In addition, this transformation is applied to the straightforward, telescoped synthesis of α-sulfinamido trifluoroborates.

Full text of DOI:10.1021/jo500300t

Note
pubs.acs.org/joc
Asymmetric Synthesis of Protected α‑Amino Boronic Acid
Derivatives with an Air- and Moisture-Stable Cu(II) Catalyst
Andrew W. Buesking, Vlad Bacauanu, Irene Cai, and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: The asymmetric borylation of N-tert-butanesulfinyl imines with bis(pinacolato)diboron is achieved using a Cu(II)
catalyst and provides access to synthetically useful and pharmaceutically relevant α-amino boronic acid derivatives. The Cu(II)-
catalyzed reaction is performed on the benchtop in air at room temperature using commercially available, inexpensive reagents at
low catalyst loadings. A variety of N-tert-butanesulfinyl imines, including ketimines, react readily to provide α-sulfinamido
boronate esters in good yields and with high stereoselectivity. In addition, this transformation is applied to the straightforward,
telescoped synthesis of α-sulfinamido trifluoroborates.
α-Amino boronic acids have significant utility as pharmaco-
phores for protease inhibition as best exemplified by the cancer
drug bortezomib (Velcade).1 More recently, α-amino boronic
acid derivatives have also been shown to be competent coupling
partners in transition-metal-catalyzed reactions, providing
convergent, asymmetric assembly of chiral amine products.2,3
These applications have inspired the development of a number
of methods for the asymmetric synthesis of α-amino boronic
acid derivatives.4−8 We previously reported the Cu(I)-catalyzed
asymmetric borylation of N-tert-butanesulfinyl imines with
bis(pinacolato)diboron9 to provide one of the most efficient
asymmetric methods to prepare homochiral α-amino boronic
acid derivatives (eq 1).4,10 However, the utility of this
modest yield and selectivity in the borylation of N-tert-
butanesulfinyl ketimines. We instead chose to develop a Cu(II)
catalyst system, in response to a number of recent reports of
Cu(II)-catalyzed conjugate borylation, which takes place in
water and open to air.11−15 Herein, we report the first Cu(II)-
catalyzed borylation of N-tert-butanesulfinyl imines for the
asymmetric synthesis of protected α-amino boronic acids. The
reaction proceeds under aqueous conditions in air at room
temperature and consequently is extremely convenient to
perform. Moreover, the reaction proceeds at very low loading
of CuSO4 and PCy3 with the ligand introduced as the
commercially available and completely air-stable HBF4 salt.
Our investigation began with the borylation of imine 1a
(Table 1). In water and with picoline as an additive, conditions
initially developed by Santos and co-workers for the borylation
of α,β-unsaturated ketones and esters,12 we observed good
reactivity but poor diastereoselectivity (entry 1). Using instead
a biphasic toluene/H2O system greatly improved the
diastereoselectivity, with a 5:1 toluene/H2O ratio providing
optimal selectivity (entries 2 and 3). Notably, the sense of
induction for this transformation was opposite that of our
previously reported Cu(I) system.4 A range of tertiary,
secondary, and primary amine additives (e.g., entries 4−6)
provided results similar to those observed with 4-picoline.
However, only benzylamine afforded marked improvement
(entry 7).
methodology was limited by the Cu(I) catalyst, which is
particularly air- and moisture-sensitive and necessitated use of a
glovebox. Thus, we sought to develop a catalyst system with
improved stability to air and moisture.
Parallel to our efforts, Sun and co-workers have reported a
metal-free, N-heterocyclic carbene (NHC) catalyzed method
that proceeds open to air and without need for rigorous drying,
providing facile entry to α-sulfinamido boronate esters in good
yield and with moderate to excellent diastereoselectivity.6
However, this method suffers from relatively high loading (10
mol %) of 1,3-bis(1-naphthyl)benzimidazolium chloride, which
is not commercially available, as the catalyst and provides
Both NHC and phosphorus ligands have previously been
utilized in Cu(I)-catalyzed borylations of α,β-unsaturated
systems, aldehydes, and imines.4,10,16−18 Thus, a number of
Received: February 8, 2014
Published: March 31, 2014
© 2014 American Chemical Society
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Note
a
Table 1. Evaluation of Reaction Parameters
b
c
entry
solvent/cosolvent
base
ligand
none
yield (%)
dr (2aa:2ab)
d
1
H2O
4-picoline
4-picoline
4-picoline
Et3N
41
34
29
35
27
38
51
46
1:1
2
3
4
5
6
7
8
9
1:5 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
5:1 toluene/H2O
none
5:1
none
>9:1
>9:1
>9:1
>9:1
>9:1
4:1
none
piperidine
CyNH2
BnNH2
BnNH2
BnNH2
BnNH2
none
none
none
none
ICy·HBF4
P(OPh)3
P(OPh)3
P(OPh)3
PCy3
e
85 (46 )
95:5
f
g
10
0
11
12
13
14
4
>9:1
10:90
92:8
6:94
6:94
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
none
94
31
POCy3
e
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PEt3·HBF4
PtBu3·HBF4
89 (84 )
h
15
84
f
g
16
0
17
18
19
92
16
66
6:94
15:85
5:95
none
none
a
b
d
Reagents and conditions: 1a (1.0 equiv), B2pin2 (2.0 equiv), CuSO4 (1.2 mol %), ligand (1.2 mol %), amine (5.0 mol %) in solvent (0.42 M).
c
1
1
Determined by H NMR of crude material relative to 1,3,5-trimethoxybenzene as an external standard. Based on H NMR of crude material.
e
f
g
1
Reaction time of 3 h. Isolated yield after column chromatography. Reaction conducted in the absence of CuSO4. No product observed by H
h
NMR. Reaction conducted with CuSO4 (0.6 mol %), PCy3·HBF4 (0.6 mol %), and BnNH2 (2.5 mol %).
potential ligands were next evaluated (entries 8−19). The
NHC that we previously employed in our Cu(I)-catalyzed
imine borylation4 failed to improve the yield and resulted in
diminished diastereoselectivity (entry 8). However, phosphorus
ligands demonstrated more promising results, with P(OPh)3
providing the α-sulfinamido boronate ester with excellent
conversion and good diastereoselectivity (entry 9).19 From a
mechanistic perspective, both CuSO4 and BnNH2 were
essential; reactions conducted without either of these
components resulted in no more than trace product (entries
10 and 11).
Among the commercially available phosphines evaluated, the
electron-rich phosphine PCy3 afforded the highest yield and
diastereoselectivity (entry 12). Still, variability in yield and
stereoselectivity was observed for this ligand likely due to its
contamination with phosphine oxide,20 which could diminish
the yield and erode the diastereoselectivity (entry 13).
Therefore, the commercially available, air-stable HBF4 salt
served as the more convenient ligand source (entry 14). It is
noteworthy that the sense of induction for this addition was
opposite that observed with P(OPh)3 (entry 9), which
highlights the importance of the phosphorus ligand for
controlling asymmetric induction. Because diastereomer 2ab
was more stable than diastereomer 2aa to chromatographic
isolation (compare entries 9 and 14), we chose to employ
PCy3·HBF4 in further studies.
reaction (15−51% yield, ≥95:5 dr) was observed in the absence
of exogenous CuSO4. However, rigorous exclusion of trace
copper as well as other metal contaminants by use of new vials,
stir bars, and high-purity water (total ion concentration 30 ppb)
demonstrated that addition of CuSO4 is important for achieving
an effective catalyst system (entry 16).21 Although benzylamine
was necessary when P(OPh)3 was employed (entry 11), it was
not essential for the PCy3·HBF4 system (entry 17). However, in
exploration of the scope, benzylamine proved beneficial
particularly in the borylation of more challenging substrates
(vida infra). The less and more hindered electron-rich
trialkylphosphine salts PEt3·HBF4 and PtBu3·HBF4 were also
investigated but exhibited lower selectivity and/or yield (entries
18 and 19).22
Finally, varying the ligand to copper ratio established that
≥1:1 stoichiometry is optimal (Table 2). Using excess copper
resulted in comparable yield but diminished diastereoselectivity
(entry 1) likely arising from the competitive ligand-free
reaction. When excess ligand was employed, the yields and
selectivity remained comparable to those observed with a 1:1
ratio (entries 2−4).
The scope of the reaction with respect to the N-tert-
butanesulfinyl imine substrates was next explored (Table 3). A
variety of alkyl imines reacted readily under the optimized
conditions to afford the desired α-sulfinamido boronate esters;
products possessing α- and β-branching (2ab and 2b) as well as
linear alkyl chains (2c) could be prepared in good yield and
with high diastereoselectivity. Highlighting the functional group
compatibility of this method, a carboxybenzyl-protected amine
was compatible with the reaction conditions (2d). Aryl imines
also reacted readily under these conditions, with para and ortho
A number of experiments were conducted to probe the
CuSO4/PCy3·HBF4 catalyst system. First, a comparable yield
and selectivity of 2ab were obtained when the catalyst loading
was dropped 2-fold to 0.6 mol % (entry 15). Consistent with
this high catalyst activity, variable but significant background
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Note
a
boronate esters (see Table 3, compounds 2ab, 2e, and 2f).
Additionally, electron-rich and electron-poor functionalities,
including the methoxy, chloro, and trifluoromethyl groups,
were compatible with this reaction sequence, providing the
products in good yield and selectivity (3d−3f). While electron-
rich 3d was isolated in moderate yield, the corresponding
potassium salt 3d′ was isolated in excellent yield via
precipitation, demonstrating that chromatographic isolation
and not poor reactivity was responsible for the diminished yield
of this ammonium trifluoroborate. Additionally, the trifluor-
omethyl-substituted trifluoroborate (3f), which was not stable
to chromatographic isolation as the corresponding boronate
ester (2g), could be isolated in good yield.
Table 2. Effect of the Ligand:Cu(II) Ratio
b
c
entry
CuSO4/PCy3
yield (%)
dr
1
2
3
4
2:1
1:1
1:2
1:4
89
88
89
91
75:25
94:6
93:7
95:5
a
N-tert-Butanesulfinyl ketimines also react readily at higher
concentration (1.2 M compared to 0.42 M), and this method
represents the first highly diastereoselective borylation of this
substrate class. Dialkyl N-tert-butanesulfinyl ketimine 4a could
be readily borylated to provide the protected α,α-disubstituted
α-amino boronate ester 5a in moderate yield but with good
selectivity (Scheme 1). Additionally, α,α-disubstituted α-amino
trifluoroborate 6 could be synthesized in good yield and
excellent diastereoselectivity (Scheme 2). Notably, in the
absence of BnNH2, a significantly lower yield of 6 was
observed due to poor conversion to intermediate 5b in the
borylation step.
In conclusion, we have developed an air- and moisture-
tolerant Cu(II) catalyst system for the borylation of N-tert-
butanesulfinyl imines. The borylation of aldimines occurs at low
catalyst loadings (1.2 mol %) and provides α-amino boronic
acid derivatives in good yield and stereoselectivity. In addition,
the corresponding α-sulfinamido trifluoroborates can be
prepared in good yield through a telescoped sequence. Finally,
we have demonstrated the first highly diastereoselective
borylation of N-tert-butanesulfinyl ketimines to provide access
Reagents and conditions: 1a (1.0 equiv), B2pin2 (2.0 equiv), CuSO4
(1.2 mol %), PCy3·HBF4 (0.76−4.8 mol %), BnNH2 (5.0 mol %) in
b
solvent (0.42 M). Determined by 1H NMR of crude material relative
c
to 1,3,5-trimethoxybenzene as an external standard. Based on 1H
NMR of crude material.
substitution being well tolerated (2e and 2f, respectively).
Finally, the reaction tolerated the electron-deficient trifluor-
omethyl substituent (2g). For boronate ester 2g, the NMR
rather than an isolated yield is reported as a measure of reaction
efficiency because highly electron-deficient benzyl boronate
esters partially degrade during chromatographic isolation.4
Given the improved stability of trifluoroborates over the
corresponding boronate esters23−25 and our interest in α-
sulfinamido trifluoroborates as coupling partners in transition-
metal-catalyzed reactions,3 we also developed a telescoped
synthesis of these reagents employing the newly developed
Cu(II) catalyst system (Table 4). Importantly, all steps in this
process are tolerant of aqueous conditions and can be set up on
the benchtop in air. The trifluoroborates 3a, 3b, and 3c could
be isolated in yields comparable to those of the corresponding
a b
,
Table 3. Substrate Scope of the Cu(II)-Catalyzed Borylation
a
Reagents and conditions: 1 (1.0 equiv), B2pin2 (2.0 equiv), CuSO4 (1.2 mol %), PCy3·HBF4 (1.2 mol %), BnNH2 (5.0 mol %) in 5:1 toluene/H2O
b
(0.42 M). Unless noted, isolated yield of mixture of diastereomers after column chromatography. Diastereomeric ratio determined by 1H NMR of
c
d
the crude product. Reaction conducted without BnNH2; see the Experimental Section for details. Reaction conducted from 0 °C to rt; see the
e
f
Experimental Section for details. Diastereomeric ratio determined upon isolation. Determined by 1H NMR relative to 1,3,5-trimethoxybenzene as
an external standard. Product could not be isolated via silica gel chromatography.
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Note
a b
,
Table 4. Substrate Scope for the Telescoped Synthesis of α-Sulfinamido Trifluoroborates
a
b
For detailed reaction conditions, see the Experimental Section. Isolated yield of mixture of diastereomers after column chromatography.
c
1
Diastereomeric ratio determined by H NMR of the crude boronate ester. Reaction conducted without BnNH2; see the Experimental Section for
details. Product isolated as the potassium trifluoroborate via precipitation.
d
capped with polypropylene caps equipped with PTFE/silicone septa.
Unless noted, diastereomeric ratios were determined by H NMR of
Scheme 1. Borylation of a Dialkyl N-tert-Butanesulfinyl
Ketimine
1
the crude boronate ester. Products were isolated as a mixture of
diastereomers. NMR spectra were obtained at room temperature.
Chemical shifts are reported in parts per million relative to the peak
1
for CHCl3 (7.26 ppm for H and 77.2 ppm for 13C) or DMSO (2.50
ppm for 1H and 39.5 ppm for 13C). C6F6 (−162.5 ppm in DMSO-d6)
was used to standardize 19F NMR chemical shifts. 11B NMR spectra in
DMSO-d6 are reported uncorrected. IR spectra were collected on an
FT-IR spectrometer possessing an ATR attachment with an anvil; only
partial data are provided. Melting points are reported uncorrected.
High-resolution mass spectrometry (HRMS) was performed using
electrospray ionization (ESI) on a time-of-flight (TOF) mass
spectrometer.
(R,E)-Benzyl (3-((tert-Butanesulfinyl)imino)propyl)carbamate
(1d). The reaction was conducted in flame-dried glassware under an
inert atmosphere. A round-bottom flask was charged with a magnetic
stir bar, 3-[(benzyloxycarbonyl)amino]propionaldehyde (0.251 g, 1.21
mmol), (R)-(+)-tert-butanesulfinamide (0.29 g, 2.4 mmol), pyridinium
p-toluenesulfonate (17.5 mg, 0.0696 mmol), and magnesium sulfate
(0.74 g, 6.1 mmol). CH2Cl2 (2.4 mL) was then added, and the
resulting suspension was stirred rapidly for 17 h. The reaction mixture
was then filtered through Celite, rinsing with CH2Cl2. The resulting
solution was concentrated under reduced pressure. Purification by
flash chromatography (silica gel, 30% EtOAc/CH2Cl2) afforded imine
to the corresponding trisubstituted organoboron compounds in
good to moderate yield and with good selectivity.
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise noted, imine
substrates 1 were prepared using previously reported methods.26,27
Bis(pinacolato)diboron was recrystallized from pentane prior to use.
Toluene was passed through a column of activated alumina under
nitrogen; it could be collected and stored on the benchtop in a glass
bottle for >1 month without the reactivity being affected. All other
reagents were obtained from commercial suppliers and used without
further purification. Aqueous solutions of CuSO4 were prepared from
CuSO4·5H2O and deionized water. Unless noted, all reactions were set
up on the benchtop and were not set up under an inert atmosphere or
using dried glassware. Reactions conducted in 1 dram vials were
Scheme 2. Telescoped Synthesis of an α,α-Disubstituted α-Sulfinamido Trifluoroborate
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Note
1d (0.329 g, 88%) as a clear oil. Analytical data were consistent with
those of previous literature reports.28
15−25% EtOAc/CH2Cl2. The desired product 2c was isolated as a
white solid (149 mg, 81%). Analytical data were consistent with those
of previous literature reports.4
Pinacol (S)-1-((R)-tert-Butanesulfinamido)-3-methylbutylboro-
nate (2aa). To a 1 dram vial equipped with a magnetic stir bar
were added a solution of P(OPh)3 in toluene (0.10 mL, 100 mM, 6.0
μmol), aqueous CuSO4 (0.20 mL, 30 mM, 6.0 μmol), and
benzylamine (2.7 μL, 25 μmol), sequentially. The vial was capped,
and the catalyst mixture was stirred for 10 min. The vial was uncapped,
and a solution of aldimine 1a (94.7 mg, 0.500 mmol) in toluene (0.90
mL) and then bis(pinacolato)diboron (254 mg, 1.00 mmol, 1.2 equiv)
were added. The vial was recapped, and the mixture was stirred rapidly
for 22 h. The reaction mixture was diluted with EtOAc and filtered
through a deactivated silica gel plug (100:35 SiO2/H2O) eluting with
EtOAc. The resulting solution was concentrated under reduced
pressure. The crude material was purified by rapid column
chromatography on deactivated silica gel (100:35 silica/H2O) eluting
with 5−15% EtOAc/CH2Cl2 to provide 2aa as a clear oil (73.0 mg,
Pinacol (R)-3-(((Benzyloxy)carbonyl)amino)-1-((R)-tert-
butanesulfinamido)propylboronate (2d). The general procedure
was followed with aldimine 1d (195 mg, 0.628 mmol) and
bis(pinacolato)diboron (321 mg, 1.26 mmol). The catalyst and
solvent were scaled accordingly: aqueous CuSO4 (0.25 mL, 30 mM,
7.5 μmol), PCy3·HBF4 (2.8 mg, 7.5 μmol), benzylamine (3.4 μL, 31
μmol), and toluene (1.23 mL). The crude material was purified by
column chromatography on deactivated silica gel eluting with 30−50%
EtOAc/CH2Cl2 to yield the desired product 2d as a light brown oil
1
(169 mg, 60%). IR: 3283, 2977, 1704, 1141, 1041 cm−1. H NMR
(400 MHz, CDCl3): δ 7.38−7.25 (m, 5H), 5.47 (s, 1H), 5.12 (d, J =
12.3 Hz, 1H), 5.05 (d, J = 12.3 Hz, 1H), 3.47−3.26 (m, 3H), 3.11 (dd,
J = 13.9, 6.6 H z, 1H), 2.03−1.95 (m, 1H), 1.90−1.76 (m, 1H), 1.24
(s, 15H), 1.20 (s, 6H). 13C NMR (126 MHz, CDCl3): δ 156.6, 136.9,
128.5, 128.1, 128.0, 84.4, 66.6, 56.2, 41.4 (br), 38.7, 32.8, 25.1, 24.7,
1
46%). IR: 2956, 1365, 1331, 1143, 1067 cm−1. H NMR (400 MHz,
+
22.7. HRMS: m/z calcd for C42H70B2N4NaO10S2 [2M + Na]+,
CDCl3): δ 3.45 (d, J = 4.5 Hz, 1H), 3.07 (m, 1H), 1.77 (m, 1H), 1.46
(m, 2H), 1.24 (s, 12H), 1.20 (s, 9H), 0.89 (d, J = 6.6 Hz, 6H). 13C
NMR (126 MHz, CDCl3): δ 84.2, 55.4, 41.4, 24.9, 24.8, 24.7, 22.8,
22.7, 22.2. HRMS: m/z calcd for C15H33BNO3S [M + H]+, 318.2269;
found, 318.2245.
899.4612; found, 899.4599.
Pinacol (R)-((R)-tert-Butanesulfinamido)(4-methylphenyl)-
methylboronate (2e). The general procedure was followed with
(R,E)-2-methyl-N-(4-methylbenzylidene)propane-2-sulfinamide (1e)
(112 mg, 0.500 mmol). The crude material was purified by column
chromatography on deactivated silica gel eluting with 5−15% EtOAc/
CH2Cl2. Mixed fractions were combined and purified by a second
column eluting with 5−15% EtOAc/CH2Cl. The desired product 2e
was isolated as a white solid (132 mg, 75%). Analytical data were
consistent with those of previous literature reports.10
General Procedure for Borylation of N-tert-Butanesulfinyl
Aldimines. To a 1 dram vial charged with PCy3·HBF4 (2.2 mg, 6.0
μmol, 1.2 mol %) and equipped with a magnetic stir bar were added
toluene (0.10 mL), aqueous CuSO4 (0.20 mL, 30 mM, 6.0 μmol, 1.2
mol %), and benzylamine (2.7 μL, 25 μmol, 5.0 mol %), sequentially.
The vial was capped, and the catalyst mixture was stirred for 10 min.
The vial was uncapped, and then toluene (0.90 mL), the appropriate
aldimine (0.500 mmol, 1.0 equiv), and bis(pinacolato)diboron (254
mg, 1.00 mmol, 2.0 equiv) were added. The reaction vial was recapped,
and the reaction mixture was stirred rapidly for 20−24 h. The reaction
mixture was diluted with EtOAc and filtered through a deactivated
silica gel plug (100:35 SiO2/H2O) eluting with EtOAc. The resulting
solution was concentrated under reduced pressure. The product was
isolated by rapid silica gel chromatography on deactivated silica gel
(100:35 SiO2/H2O) using EtOAc/CH2Cl2 mixtures. Products were
visualized on TLC via UV and CMA or KMnO4 stain. CMA stain was
prepared by dissolving ammonium molybdate (25 g) and Ce(SO4)2 (5
g) in H2O (450 mL) and then slowly adding concd H2SO4 (50 mL).
Pinacol (R)-1-((R)-tert-Butanesulfinamido)-3-methylbutylboro-
nate (2ab). The general procedure was followed with aldimine 1a
(95.1 mg, 0.502 mmol). The crude material was purified by column
chromatography on deactivated silica gel eluting with 10−20%
EtOAc/CH2Cl2 to yield the desired product 2ab as a white solid
(131 mg, 82%). Analytical data were consistent with those of previous
literature reports.4
Without Benzylamine. The general procedure was followed with
aldimine 1a (94.7 mg, 0.500 mmol) except benzylamine was not
added. The crude material was purified by column chromatography on
deactivated silica gel eluting with 10−20% EtOAc/CH2Cl2 to yield the
desired product 2ab as an off-white solid (132 mg, 83%). Analytical
data were consistent with those of previous literature reports.4
P i n a c o l ( R ) - 1 - ( ( R ) - t e r t - B u t a n e s u l fi n a m i d o ) -
cyclohexylmethylboronate (2b). The general procedure was followed
with (R,E)-N-(cyclohexylmethylene)-2-methylpropane-2-sulfinamide
(1b) (106 mg, 0.494 mmol) except the vial was placed in a 0 °C
bath before addition of B2pin2. The bath was allowed to come to room
temperature over the course of the reaction. The crude material was
purified by column chromatography on deactivated silica gel eluting
with 15% EtOAc/CH2Cl2 to yield the desired 2b product as a white
solid (146 mg, 86%). Analytical data were consistent with those of
previous literature reports.4
Pinacol (R)-((R)-tert-Butanesulfinamido)(2-methylphenyl)-
methylboronate (2f). The general procedure was followed with
(R,E)-2-methyl-N-(2-methylbenzylidene)propane-2-sulfinamide (1f)
(112 mg, 0.502 mmol). The crude material was purified by column
chromatography on deactivated silica gel eluting with 5−15% EtOAc
in CH2Cl2. Mixed fractions were combined and purified by a second
column on deactivated silica gel eluting with 2.5%−10% EtOAc/
CH2Cl2 to yield the desired product 2f as a white solid (106 mg, 60%).
1
Mp: >80 °C dec. IR: 2983, 1344, 1139, 1064 cm−1. H NMR (400
MHz, CDCl3): δ 7.42 (d, J = 7.2 Hz, 1H), 7.19−7.13 (m, 1H), 7.13−
7.10 (m, 2H), 4.48 (d, J = 3.9 Hz, 1H), 3.50 (d, J = 3.9 Hz, 1H), 2.37
(s, 3H), 1.22 (s, 9H), 1.18 (s, 6H), 1.14 (s, 6H). 13C NMR (126 MHz,
CDCl3): δ 138.5, 135.8, 130.6, 127.8, 126.8, 126.3, 84.3, 56.4, 43.8
(br), 24.8, 24.4, 22.8, 19.9. HRMS: m/z calcd for C18H31BNO3S+ [M +
H]+, 352.2112; found, 352.2137.
General Procedure for the Telescoped Synthesis of α-
Sulfinamido Trifluoroborates. Cu(II)-Catalyzed Borylation. To a 1
dram vial charged with PCy3·HBF4 (2.2 mg, 6.0 μmol, 1.2 mol %) and
equipped with a magnetic stir bar were added toluene (0.10 mL),
aqueous CuSO4 (0.20 mL, 30 mM, 6.0 μmol, 1.2 mol %), and
benzylamine (2.7 μL, 25 μmol, 5.0 mol %), sequentially. The vial was
capped, and the catalyst mixture was stirred for 10 min. The vial was
uncapped, and then toluene (0.90 mL), the appropriate aldimine
(0.500 mmol, 1.0 equiv), and bis(pinacolato)diboron (254 mg, 1.00
mmol, 2.0 equiv) were added. The reaction vial was recapped, and the
reaction mixture was stirred rapidly for 20−24 h. The reaction mixture
was diluted with EtOAc and filtered through a silica gel plug (100:35
silica/H2O) eluting with EtOAc. The resulting solution was
concentrated under reduced pressure to afford the crude boronate
ester.
Trifluoroborate Formation. To a 100 mL round-bottom flask
containing the crude boronate ester and a magnetic stir bar was added
MeOH (5.0 mL). The resulting solution was cooled to 0 °C, and
aqueous KHF2 (1.8 mL, ∼4.5M, 8.1 mmol) was added dropwise. The
reaction mixture was allowed to warm to room temperature and then
heated to 65 °C. The reaction mixture was stirred for 1 h and
subsequently cooled to room temperature. The reaction mixture was
concentrated by rotary evaporation and then high vacuum overnight.
The resulting solid was triturated with acetone (∼45 mL) to remove
inorganic salts, and the filtrate was concentrated by rotary evaporation.
The ammonium trifluoroborate was isolated by silica gel chromatog-
Pinacol (R)-1-((R)-tert-Butanesulfinamido)-2-phenylpropylboro-
nate (2c). The general procedure was followed with (R,E)-2-methyl-
N-(3-phenylpropylidene)propane-2-sulfinamide (1c) (119 mg, 0.500
mmol). The crude material was purified by column chromatography
on deactivated silica gel eluting with 15−25% EtOAc/CH2Cl2. Mixed
fractions were combined and purified by a second column eluting with
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Note
raphy using CH2Cl2/MeOH/NH4OH mixtures and visualized on TLC
by UV and KMnO4 stain.
(1h) (123 mg, 0.505 mmol). The crude trifluoroborate was purified
by silica gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/
MeOH/NH4OH to yield the desired product 3e as a white solid (130
mg, 78%). Mp: >90 °C dec. IR: 3272, 2967, 1440, 976 cm−1. 1H NMR
(400 MHz, DMSO-d6): δ 7.23−7.14 (m, 4H), 7.08 (br s, 4H), 4.13 (d,
J = 5.2 Hz, 1H), 3.29 (s, 1H), 1.08 (s, 9H). 13C NMR (101 MHz,
DMSO-d6): δ 147.0, 128.5, 128.0, 126.7, 55.5, 22.1.29 19F NMR (376
MHz, DMSO-d6): δ −145.6. 11B NMR (128 MHz, DMSO-d6): δ 2.68.
HRMS: m/z calcd for C11H19BClF2N2OS+ [M − F]+, 311.0968;
found, 311.0956.
Ammonium (R)-((R)-tert-Butanesulfinamido)(4-(trifluoromethyl)-
phenyl)methyltrifluoroborate (3f). The general procedure was
followed with (R,E)-N-(4-(trifluoromethyl)benzylidene)-2-methylpro-
pane-2-sulfinamide (1i) (123 mg, 0.505 mmol) except the Cu(II)-
catalyzed borylation was worked up after 1 h. The crude
trifluoroborate was purified by silica gel chromatography eluting
with 99:10:1 to 44:10:1 CH2Cl2/MeOH/NH4OH to yield the desired
product 3f as a white solid (135 mg, 73%). Mp: >130 °C dec. IR:
3283, 2968, 1322, 996, 845 cm−1. 1H NMR (400 MHz, DMSO-d6): δ
7.47 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (br s, 4H), 4.23
(d, J = 5.0 Hz, 1H), 3.42 (s, 1H), 1.09 (s, 9H). 13C NMR (151 MHz,
DMSO-d6): δ 153.36, 127.19, 125.0 (q, J = 272 Hz), 124.4 (q, J = 32
Hz), 123.7 (q, J = 4.5 Hz), 55.61, 22.12.29 19F NMR (376 MHz,
DMSO-d6): δ −60.1 (s, 3F), −145.6 (br s, 3F). 11B NMR (128 MHz,
DMSO-d6): δ 2.74. HRMS: m/z calcd for C12H15BF5NNaOS+ [M −
NH4F + Na]+, 350.0780; found, 350.0755.
Ammonium (R)-1-((R)-tert-Butanesulfinamido)-3-methylbutyltri-
fluoroborate (3a). The general procedure was followed with aldimine
1a (95.1 mg, 0.502 mmol). The crude trifluoroborate was purified by
silica gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/
MeOH/NH4OH to yield the desired product 3a as a white solid (121
1
mg, 87%). Mp: >90 °C dec. IR: 3267, 2952, 1449, 992, 929 cm−1. H
NMR (600 MHz, DMSO-d6): δ 7.08 (br s, 4H), 3.27 (d, J = 7.1 Hz,
1H), 2.09 (s, 1H), 1.90−1.80 (m, 1H), 1.26−1.19 (m, 1H), 1.17−1.06
(m, 1H), 1.03 (s, 9H), 0.81 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz,
3H). 13C NMR (151 MHz, DMSO-d6): δ 55.0, 44.0, 24.2, 24.0, 22.3,
22.2.24 19F NMR (376 MHz, DMSO-d6): major, δ −145.5; minor, δ
−146.3. 11B NMR (128 MHz, DMSO-d6): δ 3.57. HRMS: m/z calcd
for C9H24BF2N2OS+ [M − F]+, 257.1665; found, 257.1692.
Ammonium (R)-((R)-tert-Butanesulfinamido)(4-methylphenyl)-
methyltrifluoroborate (3b). The general procedure was followed
with 1e (112 mg, 0.500 mmol). The crude trifluoroborate was purified
by silica gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/
MeOH/NH4OH to yield the desired product 3b as a white solid (137
mg, 88%). Analytical data were consistent with those of previous
literature reports.3
Without Benzylamine. The general procedure was followed with
aldimine 1e (112 mg, 0.500 mmol) except benzylamine was not added
during the Cu(II)-catalyzed borylation. The crude trifluoroborate was
purified by silica gel chromatography eluting with 99:10:1 to 44:10:1
CH2Cl2/MeOH/NH4OH to yield the desired product 3b as a white
solid (132 mg, 85%). Analytical data were consistent with those of
previous literature reports.3
Ammonium (R)-((R)-tert-Butanesulfinamido)(2-methylphenyl)-
methyltrifluoroborate (3c). The general procedure was followed
with 1f (111 mg, 0.497 mmol). The crude trifluoroborate was purified
by silica gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/
MeOH/NH4OH to yield the desired product 3c as a white solid (95.3
mg, 62%). Analytical data were consistent with those of previous
literature reports.3
Ammonium (R)-((R)-tert-Butanesulfinamido)(4-methoxyphenyl)-
methyltrifluoroborate (3d). The general procedure was followed with
(R,E)-N-(4-methoxybenzylidene)-2-methylpropane-2-sulfinamide
(1g) (121 mg, 0.506 mmol). The crude trifluoroborate was purified by
silica gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/
MeOH/NH4OH to yield the desired product 3d as a white solid (84.1
mg, 51%). Mp: >70 °C dec. IR: 3275, 2965, 1510, 1441, 1243, 970
cm−1. 1H NMR (400 MHz, DMSO-d6): δ 7.08 (apparent d, J = 8.2 Hz,
6H), 6.71 (d, J = 8.5 Hz, 2H), 3.98 (d, J = 5.0 Hz, 1H), 3.69 (s, 3H),
3.21 (s, 1H), 1.07 (s, 9H). 13C NMR (101 MHz, DMSO-d6): δ 156.2,
139.7, 127.8, 112.4, 55.3, 54.9, 22.1.29 19F NMR (376 MHz, DMSO-
d6): δ −145.4. 11B NMR (128 MHz, DMSO-d6): δ 2.94. HRMS: m/z
calcd for C12H22BF2N2O2S+ [M − F]+, 307.1458; found, 307.1462.
Potassium (R)-((R)-tert-Butanesulfinamido)(4-methoxyphenyl)-
methyltrifluoroborate (3d′). The general procedure was followed
with 1g (479 mg, 2.00 mmol) and bis(pinacolato)diboron (1.02 g,
4.00 mmol). The catalyst, reagents, and solvent were scaled
accordingly: aqueous CuSO4 (0.80 mL, 30 mM, 24 μmol), PCy3·
HBF4 (8.7 mg, 24 μmol), benzylamine (10.9 μL, 0.100 mmol), toluene
(4.0 mL), KHF2 (7.1 mL, ∼4.5 M, 32 mmol), and MeOH (20 mL).
The crude trifluoroborate was dissolved in CPME (22 mL), pentane
(50 mL), and acetone (10 mL). The volatile components of the
solvent were removed by rotary evaporation. To the remaining
solution was added pentane (50 mL), resulting in the precipitation of a
white solid. The solid was collected via filtration with a fine-fritted
funnel, washing with pentane (3 × 30 mL). Until the final wash, the
entirety of the solvent was not allowed to pass through the frit; doing
so resulted in the formation of an oily solid, which was difficult to
manipulate. Upon evaporation of trace solvent, the product 3d′ was
obtained as a powdery, white solid (542 mg, 78%). Analytical data
were consistent with those of previous literature reports.3
Pinacol 1-((R)-tert-Butanesulfinamido)-4-methylpentyl-2-boro-
nate (5a). To a 1 dram vial charged with PCy3·HBF4 (2.2 mg, 6.0
μmol) were added toluene (35 μL), aqueous CuSO4 (67 μL, 90 mM,
6.0 μmol), and benzylamine (2.7 μL, 25 μmol), sequentially. The vial
was capped, and the catalyst mixture was stirred for 10 min. The vial
was uncapped, and then ketimine 4a (102 mg, 0.500 mmol) in toluene
(0.30 mL) and bis(pinacolato)diboron (254 mg, 1.00 mmol) were
added. The reaction vial was recapped, and the reaction mixture was
stirred rapidly for 24 h. The reaction mixture was diluted with EtOAc
and filtered through a deactivated silica gel plug (100:35 SiO2/H2O)
eluting with EtOAc. The resulting solution was concentrated under
reduced pressure. The crude product was purified by rapid silica gel
chromatography on deactivated silica gel (100:35 SiO2/H2O) eluting
with 0−10−20% EtOAc/CH2Cl2 to yield the desired product 5a as a
1
clear oil (95.9 mg, 58%). IR: 2955, 1325, 1136, 1065, 833 cm−1. H
NMR (400 MHz, CDCl3): δ 3.64 (s, 1H), 1.78−1.69 (apparent d, J =
11.2 Hz, 2H), 1.45 (dd, J = 14.9, 9.7 Hz, 1H), 1.38 (s, 3H), 1.24 (s,
12H), 1.20 (s, 9H), 0.89 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H).
13C NMR (151 MHz, CDCl3): δ 84.4, 55.9, 47.5, 26.9, 25.0, 24.83,
24.77, 24.2, 23.0, 22.8. HRMS: m/z calcd for C16H35BNO3S+ [M +
H]+, 332.2425; found, 332.2397. To ascertain the diastereomeric ratio,
the authentic diastereomers were prepared as previously described.30
1
Diagnostic peaks in H NMR (600 MHz, CDCl3): major, δ 3.66 (s,
1H, NH) 1.38 (s, 3H, CH3); minor, δ 3.24 (s, 1H, NH), 1.31 (s, 3H,
CH3).
Ammonium 1-((R)-tert-Butanesulfinamido)-1-phenylethyltri-
fluoroborate (6). To a 1 dram vial charged with PCy3·HBF4 (2.2
mg, 6.0 μmol) and equipped with a magnetic stir bar were added
toluene (35 μL), aqueous CuSO4 (67 μL, 90 mM, 6.0 μmol), and
benzylamine (2.7 μL, 25 μmol, 5.0 mol %), sequentially. The vial was
capped, and the catalyst mixture was stirred for 10 min. The vial was
uncapped, and then ketimine 4b (112 mg, 0.500 mmol) in toluene
(0.30 mL) and bis(pinacolato)diboron (254 mg, 1.00 mmol) were
added. The reaction vial was recapped, and the reaction mixture was
stirred rapidly for 24 h. The reaction mixture was diluted with EtOAc
and filtered through a deactivated silica gel plug (100:35 SiO2/H2O)
eluting with EtOAc. The resulting solution was concentrated under
reduced pressure to afford the crude boronate ester. To a 100 mL
round-bottom flask containing the crude boronate ester and a
magnetic stir bar was added MeOH (5.0 mL). The resulting solution
was cooled to 0 °C, and aqueous KHF2 (1.8 mL, ∼4.5 M, 8.1 mmol)
was added dropwise. The reaction mixture was allowed to warm to
room temperature and then heated to 65 °C. The reaction mixture was
stirred for 1 h and subsequently cooled to room temperature. The
Ammonium (R)-((R)-tert-Butanesulfinamido)(4-chlorophenyl)-
methyltrifluoroborate (3e). The general procedure was followed
with (R,E)-N-(4-chlorobenzylidene)-2-methylpropane-2-sulfinamide
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The Journal of Organic Chemistry
Note
reaction mixture was concentrated by rotary evaporation and then high
vacuum overnight. The resulting solid was triturated with acetone
(∼45 mL) to remove inorganic salts, and the filtrate was concentrated
by rotary evaporation. The crude trifluoroborate was purified by silica
gel chromatography eluting with 99:10:1 to 44:10:1 CH2Cl2/MeOH/
NH4OH to yield the desired product 6 as a white solid (130 mg, 84%).
Without Benzylamine. The aforementioned procedure was followed
with ketimine 4b (112 mg, 0.500 mmol) except benzylamine was not
added during the Cu(II)-catalyzed borylation. The crude trifluor-
oborate was purified by silica gel chromatography eluting with 99:10:1
to 44:10:1 CH2Cl2/MeOH/NH4OH to yield the desired product 6 as
a white solid (17.0 mg, 11%). Mp: >70 °C dec. IR: 3266, 2964, 1443,
1167, 978, 701 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 7.30 (d, J =
7.9 Hz, 2H), 7.17−7.04 (m, 6H), 6.95 (t, J = 7.2 Hz, 1H), 3.76 (s,
1H), 1.48 (s, 3H), 1.07 (s, 9H). 13C NMR (101 MHz, DMSO-d6): δ
149.9, 127.4, 126.3, 123.2, 54.5, 24.9, 22.6.29 19F NMR (376 MHz,
DMSO-d6): δ −151.4. 11B NMR (128 MHz, DMSO-d6): δ 3.06.
HRMS: m/z calcd for C12H19BF2NOS+ [M − NH4F + H]+, 274.1243;
found, 274.1244.
(11) Chea, H.-S.; Sim, H.-S.; Yun, J.-S. Bull. Korean Chem. Soc. 2010,
31, 551.
(12) Thorpe, S. B.; Calderone, J. A.; Santos, W. L. Org. Lett. 2012, 14,
1918.
(13) Kobayashi, S.; Xu, P.; Endo, T.; Ueno, M.; Kitanosono, T.
Angew. Chem., Int. Ed. 2012, 51, 12763.
(14) Kitanosono, T.; Xu, P.; Kobayashi, S. Chem. Commun. 2013, 49,
8184.
(15) Stavber, G.; Casar, Z. Appl. Organomet. Chem. 2013, 27, 159.
(16) Calow, A. D. J.; Whiting, A. Org. Biomol. Chem. 2012, 10, 5485.
(17) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem., Int. Ed.
̈
2010, 49, 1194.
(18) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036.
(19) Isolation of boronate ester 2aa was possible, but a low isolated
yield was obtained due to the apparent instability of this diastereomer
to silica gel chromatography.
(20) In commercial PCy3 that had been stored on the benchtop, a
signal corresponding to POCy3 was observed by 31P NMR.
(21) A number of other commercially available Cu(II) salts (e.g.,
CuCl2, Cu(OAc)2, and CuO) were also investigated as copper sources,
and while many were capable of catalyzing the reaction, none proved
superior to CuSO4.
(22) Stoichiometry of the CuSO4/PtBu3 system was also evaluated.
Improved yield but comparable diastereoselectivity was observed with
a 1:2 ratio of CuSO4/PtBu3·HBF4 (78%, 6:94 dr).
(23) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(24) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(25) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240.
(26) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(27) Collodos, J. F.; Toledano, E.; Guijarro, D.; Yus, M. J. Org. Chem.
2012, 77, 5744.
(28) Fandrick, D. R.; Johnson, C. S.; Fandrick, K. R.; Reeves, J. T.;
Tan, Z.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett.
2010, 12, 748.
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic data for all compounds shown in Tables 3 and 4
and Schemes 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation.
V.B. gratefully acknowledges the support of a Yale College
Freshman Summer Research Fellowship in Science and
Engineering. I.C. acknowledges the support of a Yale College
STARS II fellowship.
(29) As with other trifluoroborates reported in the literature, the
carbon attached to boron is not observed. For selected recent
examples, see: (a) Presset, M.; Oehlrich, D.; Rombouts, F.; Molander,
G. A. Org. Lett. 2013, 15, 1528. (b) Joliton, A.; Carreira, E. M. Org.
Lett. 2013, 15, 5147. (c) Molander, G. A.; Ryu, D.; Hosseini-Sarvari,
M.; Devulapally, R.; Seapy, D. G. J. Org. Chem. 2013, 78, 6648.
(30) Brak, K.; Barrett, K. T.; Ellman, J. A. J. Org. Chem. 2009, 74,
3606.
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