Improving carbene-copper-catalyzed asymmetric synthesis of α-aminoboronic esters using benzimidazole-based precursors

Article abstract of DOI:10.1021/jo4000477

By using a benzimidazole core and N-substitutions to tune the electronic properties of the corresponding N-heterocyclic carbenes, a one-pot protocol for efficient synthesis of α-aminoboronic esters without the need of a glovebox was developed in this work. The starting materials for the transformation can also be extended from aldehydes to ketones. An alternative protocol with short reaction time using preformed carbene-copper chloride is also described.

Full text of DOI:10.1021/jo4000477

Note
pubs.acs.org/joc
Improving Carbene−Copper-Catalyzed Asymmetric Synthesis of
α‑Aminoboronic Esters Using Benzimidazole-Based Precursors
Kun Wen,†,§ Han Wang,†,§ Jinbo Chen,† He Zhang,† Xiaodan Cui,† Chao Wei,† Erkang Fan,‡
and Zhihua Sun*,†
†College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, China
‡Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: By using a benzimidazole core and N-substitutions to
tune the electronic properties of the corresponding N-heterocyclic
carbenes, a one-pot protocol for efficient synthesis of α-aminoboronic
esters without the need of a glovebox was developed in this work. The
starting materials for the transformation can also be extended from
aldehydes to ketones. An alternative protocol with short reaction time
using preformed carbene−copper chloride is also described.
ecently, the use of α-aminoboronic acid as a key
see Figure 1). NHCs are widely used as transition metal ligands
Rpharmacophore in the design of protease inhibitors has for catalysis in modern organic synthesis.26−33 To improve
attracted increasing attention. For example, bortezomib is an
FDA-approved anticancer drug that contains a C-terminal α-
aminoboronic acid moiety and targets 26S proteasome.1−5 For
the development of antidiabetic drugs, α-aminoboronic acid has
been incorporated in inhibitors that target dipeptidyl peptidase
4.6−9 An early stereoselective synthetic method for α-
aminoboronic acid, via Matteson’s protocol, starts from
alkylboronic acid.10 However, the lack of commercially available
alkylboronic acids limits the practical application of this
method. A major breakthrough in asymmetric synthesis of α-
aminoboronic acid was achieved by the Ellman group. The
Ellman protocol utilized Sadighi’s catalyst11 to facilitate direct
addition of a boryl group, generated from bis(pinacolato)-
diboron (B2pin2), to N-butanesulfinyl aldimines.12 Activation of
boron reagents for addition to double bonds in either 1,2 and
1,4 fashion has also attracted increased research attention.13−22
In a related study,23 α-chloroboronic esters were prepared
through catalytic hydrogenation of borolane-substituted vinylic
chlorides. A more recent advance for direct borylation of N-
sulfonyl-protected aldimines used phosphine activation, and
stereoselectivity was achieved through chiral phosphines.24
Although the Ellman method has a great advantage over
Matteson’s approach in using widely available aldehydes as
starting materials to form sulfinyl aldimines and has excellent
stereocontrol due to the use of chiral N-butanesulfinyl
activation/protection, it also has its own drawbacks as the
reaction has to be carried out in a glovebox due to the
preparation, storage, and handling of Sadighi’s catalyst. In
continuation to our studies with N-heterocyclic carbenes,25 we
report herein an improved protocol for asymmetric synthesis of
α-aminoboronic esters by tuning the properties of NHC
catalysts.
Figure 1. NHC ligand precursors 1−7, Sadighi’s catalyst, and NHC−
Cu−Cl complex 8.
upon Ellman’s protocol, we reasoned that tuning the NHC
ligand property would most likely lead to efficient catalysts that
allow the desired reactions to occur under normal laboratory
moisture- and oxygen-free conditions, for example, in a one-pot
setting so that one can avoid preparation and storage of the
active catalysts. For a given NHC, there are logically two major
areas one can modify to achieve significant impact on its
electronic properties: one is the substitutions on the nitrogen
atoms of the central ring, and the other is the substitution on
Sadighi’s catalyst is an imidazole-based N-heterocyclic
Received: January 15, 2013
carbene (NHC)−copper complex (from ligand precursor 2;
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4000477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the central N-heterocyclic ring itself. Therefore, we chose to
investigate precursors (1−7) by varying (a) either an alkyl or
an aromatic substitution on the nitrogen and/or (b) a
benzimidazole central ring to alter the electronic features of
carbenes when generated with base treatment. Initial screening
of reaction conditions with B2pin2 is summarized in Table 1.
considering the disadvantages of benzene and in anticipation
that our new catalyst may improve the reaction sufficiently, we
tested the reactions in less toxic toluene. As shown in Table 1,
the imidazole-based ligand precursor 2 corresponding to the
original Sadighi’s catalyst did not produce desirable results
under our screening conditions with 1 equiv of base. When 2
equiv of base was used to facilitate the generation of Sadighi’s
catalyst, a low yield of 18% was achieved without the use of a
glovebox to isolate the pure catalytic agent. An NHC precursor
with an imidazole core and two aromatic N-substitutions (3)
gave moderate product yields depending on the amount of base
used (23−45%, entries 4 and 5). NHC precursor 5 with a
benzimidazole core and two N-cyclohexyl substitutions did not
perform well either. A benzimidazole core plus at least one N-
aromatic substitution (precursors 4, 6, and 7) gave better
outcomes with precursor 7 producing desirable yields in
toluene. From this initial screening, it can be concluded that
aromatic substitution on at least one nitrogen atom in the NHC
is critical for efficient catalysis in this one-pot protocol. A fused
benzene ring to the imidazole core also improves catalytic
efficiency.
It is notable that most of the screening conditions only
involve the use of 1 equiv of base to generate NHC from the
precursor; as a consequence, Sadighi’s catalyst (NHC−copper
t-butoxide) or its benzimidazole analogues may not form
significantly during the reaction (although one may not
completely rule out this possibility due to the heterogeneous
nature of the reaction). To investigate if NHC−Cu chloride
could catalyze the reaction as it may be the most likely
intermediate in our 1 equiv base protocol, we isolated such
Table 1. Screening NHCs for One-Pot Synthesis of α-
Aminoboronic Esters
a
entry
ligand precursor
base
yield
1
2
3
4
5
6
7
8
9
0.1 equiv of 1
0.1 equiv of 2
0.1 equiv of 2
0.1 equiv of 3
0.1 equiv of 3
0.1 equiv of 4
0.1 equiv of 5
0.1 equiv of 6
0.1 equiv of 7
0.1 equiv of NaOtBu
0.1 equiv of NaOtBu
0.2 equiv of NaOtBu
0.1 equiv of NaOtBu
0.2 equiv of NaOtBu
0.1 equiv of NaOtBu
0.1 equiv of NaOtBu
0.1 equiv of NaOtBu
0.1 equiv of NaOtBu
none
none
18%
23%
45%
65%
none
52%
88%
a
Isolated yield at 2 mmol scale.
In Ellman’s original report, benzene was the optimal solvent.
Using toluene led to a significant drop in yields. However,
Table 2. Additional Examples of α-Aminoboronic Esters Using Two Protocols
a
b
entry
1
R1
R2
product
yield (method)
dr
(CH3)3C−
H
9b
86% (A)
89% (B)
89% (A)
90% (B)
83% (A)
85% (B)
85% (A)
88% (B)
88% (A)
91% (B)
82% (A)
84% (B)
79% (A)
86% (B)
80% (A)
85% (B)
75% (A)
83% (B)
48% (A)
56% (B)
66% (A)
75% (B)
>99:1
99:1
2
(CH3)2CHCH2−
(4-MeO-Ph) CH2O(CH2)3−
PhCH2−
H
9c
9d
9e
9f
3
H
>99:1
98:2
4
H
5
(4-F-Ph)CH2−
4-Me-Ph−
H
99:1
6
H
9g
9h
9i
>99:1
>99:1
99:1
7
4-Cl-Ph−
H
8
4-MeO-Ph−
naphtha-2-yl−
Ph−
H
9
H
9j
98:2
10
11
CH3
CH3
9k
9l
71:29
74:26
CH3CH2−
a
b
Isolated yield in 2 mmol scale reaction. Diastereomeric ratio measurements are described in the main text.
B
dx.doi.org/10.1021/jo4000477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
hydrochloric acid and then recrystallized from the solution after
water was added.
species (compound 8 from precursor 7, Figure 1) in a glovebox.
However, incubation of 8 with diboron and an aldimine did not
lead to the formation of the desired product. The product was
only formed with the addition of more base (additional 1 or
more equiv to NHC) including a non-nucleophilic base such as
NaH. This certainly ruled out the formation of the Sadighi’s
catalyst but may suggest that, if a catalytic intermediate such as
NHC−Cu−B(pin) is formed,11,12,22 base activation of diboron
is still required. More detailed studies of the reaction
mechanism are currently underway. One significant difference
between the NHC−Cu chloride protocol and our one-pot
protocol is that using preformed NHC−Cu chloride and
additional base allowed the entire reaction can to be complete
in a few hours rather than 48 h in the one-pot protocol. Isolated
yields using the two methods are very similar (in 2 mmol scale
for 9a, 88% for one-pot and 92% for preformed 8 with NaH).
Additional examples of asymmetric synthesis of α-amino-
boronic esters are listed in Table 2, using precursor 7 to
generate NHC in situ for the one-pot 48 h protocol (method
A) or using preformed 8 for a 4 h protocol (method B). These
examples cover a wide variety of functional groups in the N-tert-
butanesulfinyl aldimine substrates. Entries 1−5 cover aliphatic
aldimines. For those substrates, using either protocol gave
comparable results with yields generally in the 80−90% range.
Entries 6−9 cover aromatic substrates. In these cases, using
method B with preformed NHC−Cu chloride and shorter
reaction time produced slightly better results. Although the
overall yields are slightly worse than with aliphatic substrates,
we did not suffer much significant loss in product stability as
reported by the Ellman group.12 Entries 10 and 11 cover
substrates derived initially from ketones rather than aldehydes
with moderate yields (48−75%). Ellman’s initial report did not
cover ketimine substrates, although one would expect the
catalytic system to work with ketimines with less efficiency due
to the lower electrophilic properties of ketimines than
aldimines. We now confirmed this with experimental data.
Similar to the original Ellman report, the stereoselectivity of
this NHC−Cu-catalyzed reaction was high for aldimine
substrates. We measured the diastereoselectivity ratio of the
reaction using the method reported by the Ellman group.12 For
all aldimine substrates (entries 1−9), the diastereoselectivity
ratios are greater than 98:2. For the two ketimine substrates
(entries 10 and 11), the diastereoselectivity ratios dropped to
around 70:30 in the worst case. This drop in stereospecificity
with ketimine substrates was not unexpected as the size
difference between the two groups on a ketimine moiety would
be smaller than that of an aldimine.
Representative Procedure with Ligand Precursor 7 for
Product 9a. (Method A): Under argon, ligand precursor 7 (81 mg,
0.2 mmol) was mixed with CuCl (20 mg, 0.2 mmol) and NaOBu-t (19
mg, 0.2 mmol) in 10 mL of toluene. The mixture was stirred at room
temperature for 4 h, during which time the reaction solution turned
from colorless to green then to light black color. To this were then
added in one portion a solution of N-tert-butylsulfinyl butaldimine
(350 mg, 2.0 mmol) and bis(pinacolato)diboron (559 mg, 2.2 mmol)
in 10 mL of toluene. The reaction was stirred under argon at room
temperature for 48 h. Then the solution was diluted with 30 mL of
ethyl acetate and quenched with saturated K2CO3 solution. After
separation and washing the aqueous layer with ethyl acetate (2 × 30
mL), the combined organic solution was dried over anhydrous Na2SO4
and then concentrated. Purification using water-inactivated silica gel
(CH2Cl2/MeOH as eluent) gave 9a as colorless oil: 533 mg (yield
88%); 1H NMR (400 MHz, CD3OD, δ) 2.97 (t, J = 7.2 Hz, 1H), 1.66
(m, 2H), 1.45 (m, 2H), 1.29 (d, J = 3.2 Hz, 12H), 1.23 (s, 9H), 0.96
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD, δ) 83.9, 55.9, 43.4,
35.3, 23.9, 23.6, 21.6, 19.6, 13.1; MS (ESI-TOF) m/z 304.2 [M + H]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H31BNSO3 304.2112;
found 304.2117.
Preparation of Catalyst 8.34 In a nitrogen-filled glovebox, a
round-bottomed flask equipped with a Teflon-coated stir bar was
charged with copper(I) chloride (1.30 g, 13.13 mmol) and sodium
tert-butoxide (1.20 g, 12.53 mmol). Tetrahydrofuran (100 mL) was
added, and the mixture was stirred for 2 h. 1,3-Bis(2,6-dinaphthyl)-
imidazolinium chloride25 (4.87 g, 12 mmol) was added, and the
mixture was stirred for an additional 12 h. The mixture was filtered
through Celite, washed with dichloromethane (5 × 30 mL), and then
transferred out of glovebox to dry in vacuo to give the title complex
(4.77g, 85%). Final product was transferred back and stored in the
glovebox: 1H NMR (400 MHz, DMSO-d6, δ) 8.31 (d, J = 8.4 Hz, 2H),
8.25 (dd, J1 = 4.8 Hz, J2 = 8.0 Hz, 2H), 8.14 (d, J = 7.2 Hz, 1H), 8.03
(d, J = 6.8 Hz, 1H), 7.84 (m, 2H), 7.73 (m, 2H), 7.64 (m, 4H), 7.41
(m, 2H), 7.14 (m, 2H); 13C NMR (100 MHz, DMSO-d6, δ) 135.1,
134.5, 133.7, 133.6, 131.0, 131.0, 129.7, 129.5, 129.2, 129.1, 128.6,
128.4, 127.7, 127.7, 127.2, 127.1, 126.4, 126.4, 125.6, 125.5, 122.8,
122.6, 112.8. Anal. Calcd for C27H18ClCuN2: C, 69.08; H, 3.86.
Found: C, 68.94; H, 3.99.
Representative Procedure with Preformed 8 for Product 9a.
(Method B): In a glovebox filled with nitrogen, N-tert-butylsulfinyl
butaldimine (350 mg, 2.0 mmol) was mixed with bis(pinacolato)-
diboron (559 mg, 2.2 mmol), complex 8 (94 mg, 0.2 mmol), and NaH
(5 mg, 0.2 mmol) in 10 mL of toluene. The reaction vessel was sealed
and then transferred out of the glovebox. The reaction was stirred at
room temperature for 4 h. Then the solution was diluted with 30 mL
of ethyl acetate and quenched with saturated K2CO3 solution. After
separation and washing the aqueous layer with ethyl acetate (2 × 30
mL), the combined organic solution was dried over anhydrous Na2SO4
and then concentrated. Purification using water-inactivated silica gel
(CH2Cl2/MeOH as eluent) gave 9a as colorless oil: 558 mg (yield
92%).
Representative Procedure for the Determination of
Diastereomeric Ratio of Product 9a. Compound 9a was dissolved
in dioxane in an oven-dried vial equipped with a Teflon-coated stir bar
under nitrogen. Freshly distilled MeOH (10 equiv) was added to the
solution, followed by the dropwise addition of 4.0 M HCl in dioxane
(1 equiv). The reaction mixture was stirred at rt for 45 min to 1 h
before it was directly concentrated under reduced pressure. The
resulting amine hydrochloride salt was triturated with a 2:1 mixture of
hexanes to Et2O. The amine hydrochloride (1.0 equiv) was then
dissolved in CH2Cl2 and cooled to 0 °C. DIPEA (4.0 equiv) was then
added followed by the addition of >99% ee (+) or >99% (−) MTPA
chloride (∼2.0 equiv), and the resulting mixture was stirred for 1 h at 0
°C. The reaction mixture was diluted with EtOAc and then washed
with 1 N sodium bisulfate. The organic layer was then washed with 1
N NaHCO3 and brine. The organic layer was dried over Na2SO4 and
concentrated. Diastereomeric ratios were determined by 19F NMR of
In summary, by changing the electronic properties of NHC
as a ligand to a copper complex, we were able to find new
benzimidazole-based NHC precursors that allow the establish-
ment of a simplified one-pot protocol for the NHC−copper-
catalyzed asymmetric synthesis of α-aminoboronic esters
without the use of a glovebox to isolate the catalytic agent.
This new procedure is applicable to a range of aromatic and
aliphatic N-sulfinyl aldimine or ketimine substrates, which can
be generated from widely available aldehydes or ketones. We
expect the new NHC precursors will offer improved access to
α-aminoboronic esters in drug discovery and industrial
applications.
EXPERIMENTAL SECTION
Purification of Raw Materials. Toluene was refluxed with sodium
under argon before use. CuCl was dissolved in concentrated
■
C
dx.doi.org/10.1021/jo4000477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the unpurified material,35,36 dr > 99:1, and the diastereomeric ratio was
determined by 19F NMR (376 MHz, DMSO-d6): (R)-MTPA
derivative of major diastereomer δ = −68.42, minor diastereomer δ
= −68.56.
m/z 372.2 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C17H28BNSClO3 372.1566; found 372.1574.
9i: Colorless oil; 587 mg (yield 80%) (method A); 624 mg (yield
85%) (method B); dr = 99:1; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.53, minor
9b: White solid; 545 mg (yield 86%); mp 98.6−100.7 °C (method
A); 564 mg (yield 89%) (method B); dr > 99:1; 19F NMR (376 MHz,
DMSO-d6) (R)-MTPA derivative of major diastereomer δ = −68,
1
diastereomer δ = −68.80; H NMR (400 MHz, DMSO-d6, δ) 7.23
(d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.27 (d, J = 5.2 Hz, 1H),
3.99 (d, J = 5.2 Hz, 1H), 3.72 (s, 3H), 1.13 (s, 15H), 1.11 (s, 6H); 13C
NMR (100 MHz, DMSO-d6, δ) 158.4, 133.1, 128.9, 114.1, 84.0, 56.1,
55.5, 46.8, 24.9, 24.5, 23.1; MS (ESI-TOF) m/z 368.2 [M + H]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H31BNSO4 368.2061;
found 368.2054.
1
minor diastereomer δ = −68.16; H NMR (400 MHz, DMSO-d6, δ)
4.31 (d, J = 8.0 Hz, 1H), 2.54 (d, J = 8.0 Hz, 1H), 1.22 (d, J = 2.4 Hz,
12H), 1.10 (s, 9H), 0.93 (s, 9H); 13C NMR (100 MHz, DMSO-d6, δ)
83.9, 56.2, 54.1, 34.2, 28.1, 25.2, 24.9, 22.9; MS (ESI-TOF) m/z 318.2
[M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H33BNSO3
318.2269; found 318.2266.
9j: Colorless oil; 581 mg (yield 75%) (method A); 642 mg (yield
83%) (method B); dr = 98:2; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.38, minor
9c: White solid; 564 mg (yield 89%); mp 153.4−154.9 °C (method
A); 570 mg, (yield 90%) (method B); dr = 99:1; 19F NMR (376 MHz,
DMSO-d6) (R)-MTPA derivative of major diastereomer δ = −68.51,
1
diastereomer δ = −68.45; H NMR (400 MHz, DMSO-d6, δ) 8.08
1
(m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.66 (m, 1H), 7.53 (m, 4H),
5.55 (d, J = 5.6 Hz, 1H), 4.76 (d, J = 5.6 Hz, 1H), 1.18 (s, 9H), 1.08
(d, J = 9.6 Hz, 12H); 13C NMR (100 MHz, DMSO-d6, δ) 137.6, 133.7,
130.8, 129.0, 127.2, 126.2, 126.0, 125.3, 123.9, 84.3, 56.3, 43.8, 24.9,
24.5, 23.2; MS (ESI-TOF) m/z 388.2 [M + H]+; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C21H31BNSO3 388.2112; found 388.2120.
9k: Colorless oil; 318 mg (yield 48%) (method A); 371 mg (yield
56%) (method B); dr = 71:29; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.81, minor
minor diastereomer δ = −68.56; H NMR (400 MHz, DMSO-d6, δ)
4.67 (d, J = 6.0 Hz, 1H), 2.80 (dd, J1 = 8.0 Hz, J2 = 14.4 Hz, 1H), 1.67
(m, 1H), 1.41 (m, 2H), 1.19 (d, J = 5.2 Hz, 12H), 1.09 (s, 9H), 0.86
(dd, J1 = 6.8 Hz, J2 = 2.4 Hz, 6H); 13C NMR (100 MHz, DMSO-d6, δ)
83.7, 55.6, 42.2, 25.4, 25.1, 24.8, 23.1, 23.1, 23.0; MS (ESI-TOF) m/z
318.2 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C15H33BNSO3 318.2269; found 318.2274.
9d: Colorless oil; 729 mg (yield 83%) (method A); 746 mg (yield
85%) (method B); dr > 99:1; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.55, minor
1
diastereomer δ = −69.16; H NMR (400 MHz, DMSO-d6, δ) 7.40
1
(m, 2H), 7.31 (m, 2H), 7.18 (m, 1H), 5.18 (s, 0.34H), 5.15 (s, 0.51H),
1.64 (s, 1.22H), 1.58 (s, 1.78H), 1.20 (s, 9H), 1.16 (s, 12H), 1.13 (s,
6H); 13C NMR (100 MHz, DMSO-d6, δ) 146.2, 146.1, 128.3, 128.2,
127.2, 126.3, 126.2, 84.4, 84.2, 56.7, 55.8, 25.0, 24.9, 24.9, 24.6, 24.4,
23.4, 23.2; MS (ESI-TOF) m/z 352.2 [M + H]+; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C18H31BNSO3 352.2112; found 352.2119.
9l: Colorless oil; 374 mg (yield 66%) (method A); 425 mg (yield
75%) (method B); dr = 74:26; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.64, minor
diastereomer δ = −68.63; H NMR (400 MHz, DMSO-d6, δ) 7.24
(d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.77 (d, J = 6.4 Hz, 1H),
4.36 (s, 2H), 3.74 (s, 3H), 3.36 (m, 2H), 2.76 (d, J = 6.4 Hz, 1H), 1.57
(m, 4H), 1.19 (d, J = 2.8 Hz, 12H), 1.08 (s, 9H); 13C NMR (100
MHz, DMSO-d6, δ) 159.1, 131.1, 129.5, 114.1, 83.8, 71.9, 69.7, 55.4,
55.5, 42.4, 29.8, 27.1, 25.1, 24.8, 23.1; MS (ESI-TOF) m/z 440.2 [M +
H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H39BNSO5
440.2637; found 440.2640.
9e: Colorless oil; 597 mg (yield 85%) (method A); 618 mg (yield
88%) (method B); dr = 98:2; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.34, minor
1
diastereomer δ = −68.88; H NMR (400 MHz, DMSO-d6, δ) 4.34
(s, 0.65H), 1.63 (m, 1H), 1.51 (m, 1H), 1.21 (d, J = 3.2 Hz, 12H),
1.13 (m, 12H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, δ) 84.1, 55.4, 32.7, 25.1, 24.9, 24.0, 23.0, 22.2; MS (ESI-
TOF) m/z 304.2 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C14H31BNSO3 304.2112; found 304.2105.
1
diastereomer δ = −68.45; H NMR (400 MHz, DMSO-d6, δ) 7.24
(m, 5H), 4.83 (d, J = 5.2 Hz, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 2.79
(m, 1H), 1.10 (s, 15H), 1.04 (s, 6H); 13C NMR (100 MHz, DMSO-d6,
δ) 139.2, 129.6, 128.6, 126.7, 83.8, 55.7, 55.4, 43.6, 25.1, 24.7, 23.0;
MS (ESI-TOF) m/z 352.2 [M + H]+; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C18H31BNSO3 352.2112; found 352.2118.
ASSOCIATED CONTENT
* Supporting Information
■
9f: Light yellow oil; 649 mg (yield 88%) (method A); 672 mg
(yield 91%) (method B); dr = 99:1, 19F NMR (376 MHz, DMSO-d6)
(R)-MTPA derivative of major diastereomer δ = −68.41, minor
S
General methods and NMR spectra of all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
diastereomer δ = −68.49; H NMR (400 MHz, DMSO-d6, δ) 7.25
(dd, J1 = 8.4 Hz, J2 = 6.0 Hz, 2H), 7.10 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz,
2H), 4.90 (d, J = 5.6 Hz, 1H), 3.05 (m, 1H), 2.92 (m, 1H), 2.78 (m,
1H), 1.11 (s, 6H), 1.08 (s, 9H), 1.04 (s, 6H); 13C NMR (100 MHz,
DMSO-d6, δ) 161.3, 135.4, 131.4, 115.2, 83.8, 55.7, 43.8, 38.2, 25.1,
24.7, 23.0; MS (ESI-TOF) m/z 370.2 [M + H]+; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C18H30BNSO3F 370.2018; found 370.2015.
9g: Colorless oil; 576 mg (yield 82%) (method A); 590 mg (yield
84%) (method B); dr > 99:1; 19F NMR (376 MHz, DMSO-d6) (R)-
MTPA derivative of major diastereomer δ = −68.21, minor
AUTHOR INFORMATION
Corresponding Author
*E-mail: sungaris@gmail.com.
■
Author Contributions
§These authors contributed equally to this work.
Notes
1
diastereomer δ = −68.71; H NMR (400 MHz, DMSO-d6, δ) 7.20
The authors declare no competing financial interest.
(d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.33 (d, J = 4.2 Hz, 1H),
4.01 (d, J = 4.2 Hz, 1H), 2.27 (s, 3H), 1.13 (s, 15H), 1.10 (s, 6H); 13C
NMR (100 MHz, DMSO-d6, δ) 138.2, 135.7, 129.2, 127.6, 84.0, 56.1,
46.8, 24.9, 24.5, 23.2, 21.1; MS (ESI-TOF) m/z 352.2 [M + H]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H31BNSO3 352.2112;
found 352.2110.
ACKNOWLEDGMENTS
This work was supported by the Shanghai Saijia Chemicals
Company Ltd.
■
9h: White solid; 586 mg (yield 79%); mp 85.6−87.5 °C (method
A); 638 mg (yield 86%) (method B); dr > 99:1; 19F NMR (376 MHz,
DMSO-d6) (R)-MTPA derivative of major diastereomer δ = −68.58,
REFERENCES
■
(1) Young, M. M.; Takahashi, Y.; Khan, O.; Park, S.; Hori, T.; Yun, J.;
Sharma, A. K.; Amin, S.; Hu, C.-D.; Zhang, J.; Kester, M.; Wang, H.-G.
J. Biol. Chem. 2012, 287, 12455.
1
minor diastereomer δ = −68.89; H NMR (400 MHz, DMSO-d6, δ)
7.36 (m, 4H), 5.57 (d, J = 5.6 Hz, 1H), 4.08 (d, J = 5.6 Hz, 1H), 1.14
(s, 15H), 1.12 (s, 6H); 13C NMR (100 MHz, DMSO-d6, δ) 104.7,
131.3, 129.4, 128.5, 84.3, 56.2, 46.8, 24.9, 24.5, 23.1; MS (ESI-TOF)
(2) Dalla Via, L.; Nardon, C.; Fregona, D. Future Med. Chem. 2012, 4,
525.
D
dx.doi.org/10.1021/jo4000477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(3) Kisselev, A. F.; van der Linden, W. A.; Overkleeft, H. S. Chem.
Biol. 2012, 19, 99.
(36) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1996, 34,
2543.
(4) Frankland-Searby, S.; Bhaumik, S. R. Biochim. Biophys. Acta 2012,
1825, 64.
(5) Sub, K. S.; Goy, A. Future Oncol. 2008, 4, 149.
(6) Milo, L. J., Jr.; Lai, J. H.; Wu, W.; Liu, Y.; Maw, H.; Li, Y.; Jin, Z.;
Shu, Y.; Poplawski, S. E.; Wu, Y.; Sanford, D. G.; Sudmeier, J. L.;
Bachovchin, W. W. J. Med. Chem. 2011, 54, 4365.
(7) Poplawski, S. E.; Lai, J. H.; Sanford, D. C.; Sudmeier, J. L.; Wu,
W.; Bachovchin, W. W. J. Med. Chem. 2011, 54, 2022.
(8) Connolly, B. A.; Sanford, D. G.; Chiluwal, A. K.; Healey, S. E.;
Peters, D. E.; Dimare, M. T.; Wu, W.; Liu, Y.; Maw, H.; Zhou, Y.; Li,
Y.; Jin, Z.; Sudmeier, J. L.; Lai, J. H.; Bachovchin, W. W. J. Med. Chem.
2008, 51, 6005.
(9) Lai, J. H.; Wu, W.; Zhou, Y.; Maw, H. H.; Liu, Y.; Milo, L. J.;
Poplawski, S. E.; Henry, G. D.; Sudmeier, J. L.; Sanford, D. G.;
Bachovchin, W. W. J. Med. Chem. 2007, 50, 2391.
(10) Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am. Chem. Soc.
1981, 103, 5241.
(11) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036.
(12) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
6910.
(13) Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253.
(14) Bonet, A.; Pubill-Ulldemolins, C.; Bo, C.; Gulyas
Fernandez, E. Angew. Chem., Int. Ed. 2011, 50, 7158.
(15) Pubill-Ulldemolins, C.; Bonet, A.; Bo, C.; Gulyas
Fernan
(16) Dang, L.; Zhao, H. T.; Lin, Z. Y. Organometallics 2007, 26, 2824.
(17) Lam, K. C.; Lin, Z. Y.; Marder, T. B. Organometallics 2007, 26,
3149.
́
, H.;
, H.;
́
́
́
dez, E. Chem.Eur. J. 2012, 18, 1121.
(18) Dang, L.; Lin, Z.; Marder, T. B. Chem. Commun. 2009, 3987.
(19) Gao, M.; Thorpe, S. B.; Kleeberg, C.; Slebodnick, C.; Marder, T.
B.; Santos, W. J. Org. Chem. 2011, 76, 3997.
(20) Kleeberg, C.; Crawford, A. G.; Batsanov, A. S.; Hodgkinson, P.;
Apperley, D. C.; Cheung, M. S.; Lin, Z. Y.; Marder, T. B. J. Org. Chem.
2012, 77, 785.
(21) Cid, J.; Gulyas
2012, 41, 3558.
́ ́ ́
, H.; Carbo, J. J.; Fernandez, E. Chem. Soc. Rev.
(22) Zhao, H. T.; Dang, L.; Marder, T. B.; Lin, Z. Y. J. Am. Chem. Soc.
2008, 130, 5586.
(23) Gazic
U.; Zanotti-Gerosa, A.; Kovace
2012, 51, 1014.
(24) Sole, C.; Gulyas
3769.
́
Smilovic,
́
I.; Casas-Arce,
́
E.; Roseblade, S. J.; Nettekoven,
̌
̌
̌
vic, M.; Casar, Z. Angew. Chem., Int. Ed.
́
́ ́
, H.; Fernandez, E. Chem. Commun. 2012, 48,
(25) Wang, H.; Xia, Y.; Lv, S.; Xu, J.; Sun, Z. Facial and Practical
Synthesis of Benzimidazole-Based N-Heterocyclic Carbenes. Tetrahe-
dron Lett., 2013, DOI: 10.1016/j.tetlet.2013.02.006.
(26) http://www.sciencedircet.com/science/article/pii/
S00404039103002177 (Accessed Feb 13, 2013).
(27) Herrmann, W. A.; Reisinger, C. P.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93.
(28) Zhang, C. M.; Huang, J. K.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804.
(29) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119.
(30) Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387.
(31) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(32) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119.
(33) Stauffer, S. R.; Lee, S. W.; Stambuli, J. P.; Hauck, S. I.; Hartwig,
J. F. Org. Lett. 2000, 2, 1423.
(34) Jian, T. Y.; He, L.; Tang, C.; Ye, S. Angew. Chem., Int. Ed. 2011,
50, 9104.
(35) Laitar, D. S. Synthetic and Catalytic Studies of Group 11 N-
Heterocyclic Carbene Complexes. Ph.D. Thesis, Massachusetts
Institute of Technology, 2006.
E
dx.doi.org/10.1021/jo4000477 | J. Org. Chem. XXXX, XXX, XXX−XXX