Stereoselective Chiral Recognition of Amino Alcohols with 2,2′-Dihydroxybenzil

Article abstract of DOI:10.1021/acs.joc.7b00600

2,2′-Dihydroxybenzil is demonstrated to be a highly diastereoselective stereodynamic receptor for the chiral recognition of amino alcohols. The receptor by forming diimine compounds with amino alcohols showed good (11:1) to excellent (>50:1) diastereoselectivity in chloroform. The existence of intramolecular hydrogen bonding with amino alcohols only in an axial conformer is demonstrated by ¹H NMR and CD spectroscopy, X-ray crystallography, and DFT computations. The exciton chirality method can be used with diazo-attached 2,2′-dihydroxybenzil.

Full text of DOI:10.1021/acs.joc.7b00600

Article
pubs.acs.org/joc
Stereoselective Chiral Recognition of Amino Alcohols with
2,2′‑Dihydroxybenzil
Min-Seob Seo, Daeyoung Sun, and Hyunwoo Kim*
Department of Chemistry, KAIST, Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: 2,2′-Dihydroxybenzil is demonstrated to be a highly diastereoselective stereodynamic receptor for the chiral
recognition of amino alcohols. The receptor by forming diimine compounds with amino alcohols showed good (11:1) to
excellent (>50:1) diastereoselectivity in chloroform. The existence of intramolecular hydrogen bonding with amino alcohols only
1
in an axial conformer is demonstrated by H NMR and CD spectroscopy, X-ray crystallography, and DFT computations. The
exciton chirality method can be used with diazo-attached 2,2′-dihydroxybenzil.
INTRODUCTION
■
Amino alcohols are among the important classes of compounds
widely used for the synthesis of bioactive compounds.1a,b
Moreover, natural or unnatural amino alcohols have been
widely applied for the development of chiral ligands, auxiliaries,
and catalysts.1c−f Due to the importance of amino alcohols, it is
highly desirable to develop simple, accurate, and practical
methods for the stereochemical analysis of amino alcohols. In
recent years, the induced circular dichroism (ICD) analysis2 has
been used for chiral analyses, such as the determination of the
configuration and enantiomeric excess (ee) of chiral com-
pounds, such as amines,3 alcohols,4 carboxylic acids,5 and
others,6 and tests of high-throughput screening applications.2b,d
For amino alcohols, several stereodynamic probes have been
reported, including diarylnaphthalenes,7 arylacetylenes,8 bi-
naphtolate borons,9 palladium complexes,10 and others11
(Figure 1a). Although several types of stereodynamic receptors
have been developed, it remains challenging to achieve a high
level of diastereoselectivity upon the formation of diastereo-
meric complexes between a stereodynamic receptor and an
amino alcohol. Thus, ICD signals are often weak and variable
with regard to the analyte structure due to the low level of
diastereoselectivity. To ensure an accurate and sensitive chiral
analysis, it is crucial to develop highly diastereoselective
stereodynamic receptors.
Figure 1. (a) Reported chiroptical probes and (b) 2,2′-dihydrox-
ybenzil (1) for the chirality sensing of amino alcohols.
We recently reported a stereodynamic probe, 2,2′-dihydrox-
ybenzil (1), which can be used for the chiral amplification of
monodentate primary amines.3b Although 2,2′-dihydroxybenzil
exhibits minimal structural requirements for the generation of
axial chirality, this probe showed low to moderate diaster-
eoselectivity of 1.4 to 4.7 controlled by the steric strain. We
demonstrate here that intramolecular hydrogen bonding
interaction can improve the diastereoselectivity to achieve a
highly stereoselective recognition of amino alcohols.
Received: March 13, 2017
Published: June 5, 2017
© 2017 American Chemical Society
6586
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591

The Journal of Organic Chemistry
Article
are three intramolecular H-bonds: two H-bonds between
phenolic hydrogens and imine nitrogens as well as one H-
bond between the hydroxyl groups of L-valinol. It is remarkable
that all hydroxyl groups in SS-2 are involved in the
intramolecular H-bonds to establish axial chirality of the P
form.
RESULTS AND DISCUSSION
■
2,2′-Dihydroxybenzil (1), readily prepared by coupling between
oxalyl chloride and phenol, exhibits a 1,1′-binaphthalene-like
axial arrangement with two internal hydrogen bonds and exists
as an equal mixture of rapidly interconverting P and M forms
(Figure 1b). The stereodynamic nature of 1 was confirmed in
our previous report, which showed that diimines formed from 1
and chiral monodentate amines become diastereomers.3b In
such cases, low (1.4:1) to moderate (4.7:1) stereoselectivity can
be observed. We then questioned whether additional intra-
molecular interactions, such as hydrogen bonding enhance the
diastereoselectivity of diimines. In order to test this idea, we
first reacted L-valinol and 1 to form diimine 2, resulting in two
diastereomeric mixtures P-SS-2 and M-SS-2 (Figure 1b).
When 5 equiv of L-valinol was heated with 1 in EtOH at 80
°C for 6 h, a clean product of diimine (2) was obtained. The 1H
NMR spectra of the crude mixture showed that the
diastereomeric ratio was 15:1 in CDCl3. Indeed, the
diastereoselectivity for 3-methyl-2-butylamine (2.1:1)3b was
significantly improved when a hydroxyl group was attached to
the methyl group.
The DFT calculation also supports the contention that
additional H-bonding between the hydroxyl groups of L-valinol
can increase the energy difference between P-SS-2 and M-SS-2,
resulting in an increase in the diastereoselectivity. The DFT
calculation showed that both energy minimum structures of P-
SS-2 and M-SS-2 exhibit two intramolecular H-bonds between
the phenolic hydrogens and the imine nitrogens, forming a class
of strong resonance-assisted hydrogen bonds (RAHBs).12 In
both the P- and M-conformers, the hydrogens on the chiral
carbons face each other in order to minimize the steric
repulsion. However, in P-SS-2, both hydroxymethyl groups are
positioned in the same direction, whereas in M-SS-2, both
hydroxymethyl groups are positioned in opposite directions.
Accordingly, the third intramolecular H-bond is found not in
the M-form but in the P-form due to the relative arrangement
of the isopropyl and hydroxymethyl groups. It is remarkable
that the crystal and optimized structures of P-SS-2 are in
excellent agreement (Figures 2 and 3). As expected, P-SS-2 due
to the additional H-bond is approximately 4.31 kcal/mol more
stable than M-SS-2. In the case of imine 2′ formed from (R)-3-
methyl-2-butylamine, the M-form is more stable than the P-
form by about 0.64 kcal/mol because the steric repulsion
between the isopropyl groups and the phenol groups increases
the energy of the P-form (Figure 3). Accordingly, the DFT
computation indicates that the intramolecular H-bond between
the hydroxyl groups provide sufficient stabilization energy of
approximately 4.95 kcal/mol, favoring an axial conformer,
which is a minor axial conformer with respect to the repulsive
steric interactions.
In order to verify the existence of the intramolecular H-bond
interactions with the hydroxyl groups of amino alcohols, we
initially determined the crystal structure of 2. Although the
diastereoselectivity for SS-2 was found to be 15:1 in CDCl3 as
determined by the 1H NMR spectra, the crystal structure
indicated that the SS-2 with the P-configuration was selectively
crystallized (Figure 2). In the crystal structure of P-SS-2, there
In order to verify the existence of H-bonding not only in the
solid state but also in the solution state, we examined the
solvent effect on the stereoselectivity of SS-2. The measured
values of the diastereoselectivity for SS-2 were 15:1 in CDCl3,
5.3:1 in CD3CN, and 3.4:1 in CD3OD (Scheme 1a). The
intramolecular H-bonds are generally reinforced in aprotic
solvents, such as CDCl3, but are disrupted in protic solvents,
Figure 2. Crystal structure (50% ellipsoid probability) of P-SS-2. All
hydrogens except for phenols, alcohols, and chirality carbon centers
are omitted for clarity.
Figure 3. Calculated global energy minimum structures of (a) P-SS-2 and M-SS-2 as well as (b) P-RR-2′ and M-RR-2′, an imine (2′) formed between
1 and (R)-3-methyl-2-butylamine.
6587
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591

The Journal of Organic Chemistry
Article
Scheme 1. Solvent Effects on the Stereoselectivity of
Diimines Formed from (a) L-Valinol and (b) (R)-3,3-
Dimethyl-2-butylamine
Figure 5. Measured CD spectrum and UV−vis spectrum (75 μM, 10
mm cell, at 20 °C) of SS-2 in EtOH (a and b), CH3CN (c and d), and
CHCl3 (e and f) and simulated CD spectrum of P-SS-2 (g).
observed. Instead, we simulated the CD spectra by performing
a TD-DFT calculation (Figure 5).14 When the simulated CD
curves are overlapped, the CD signals of P-SS-2 are in very
good agreement with the experimental CD signals of SS-2. In
addition, the CD signals of SS-2 are stronger in CHCl3 and
CH3CN than in EtOH, in agreeing with the solvent effect.
However, the signal intensity in CHCl3 is not significantly
greater than that in CH3CN although the diastereoselectivity in
CHCl3 (15:1) is much greater than that in CH3CN (5.3:1).
The observed CD spectra of SS-2 in three solvents also indicate
that the major axial conformer is also the P-form in a protic
solvent because the intramolecular H-bonds still play a crucial
role to favor the equilibrium to the P-form of SS-2.
such as CD3OD. Thus, the decreased stereoselectivity of SS-2
by a polar solvent or protic solvent supports the presence of
intramolecular H-bonds. In addition, we measured the 1H
NMR spectra of SS-4 formed from L-phenylglycinol in various
concentrations (CDCl3, 38−50 mM). The signal of the
phenolic proton at 14.5 ppm was almost constant to the
various concentrations because this hydrogen bond is a strong
resonance-assisted hydrogen bond. However, the proton signal
of the hydroxyl groups around 3.7 ppm was quite variable
(Figure 4). We found that an addition of 4 Å molecular sieves
In order to investigate the analytical scope for our
stereodynamic probe 1, we prepared imine compounds by
the reaction between 1 and a variety of L-amino alcohols with i-
Pr (2), phenyl (4), ethyl (5), methyl (6), iso-butyl (7), and
benzyl (8) substituents (Table 1). We could isolate the desired
imines in 67−87% yields and their diastereoselectivity was
1
determined by H NMR spectroscopy in CDCl3, CD3CN, and
CD3OD. In all cases, good (11:1) to excellent (>50:1)
diastereomeric ratios were obtained in CHCl3 but the
diastereoselectivity decreased in CD3CN (3.7:1 ∼ > 50:1)
and CD3OD (2.5:1−26:1). In order to understand the
observed diastereoselectivity of various imines, we calculated
the equilibrium energies between the P-form and the M-form of
the imines in a range of 3.1 to 7.0 kcal/mol, but there is no
linear relationship between the calculated equilibrium energy
and the observed diastereoselectivity (Table 1).
Imine compounds 2 and 4−8 as a crude mixture showed
strong CD signals in EtOH (Table 1). Our analysis by
comparing the experimental and simulated CD spectra by TD-
DFT calculations indicates that the signal of the first Cotton
effect at 330−340 nm can be used for assigning the absolute
chirality of amino alcohols. The negative first Cotton effects by
(S)-amino alcohols can be rationalized to form P-axial
conformers. Thus, the experimental CD spectra together with
a CD simulation can be used to determine the absolute chirality
of amino alcohols. In addition to the determination of the
absolute chirality, the CD spectra can be used to determine
enantiomeric excess (ee), as observed optical response may
exist in a linear relationship with the ee of chiral amino alcohols.
Indeed, there is an excellent linear relationship between the
enantiopurities of valinol and the observed CD signal (Figure
6).
Figure 4. Concentration effect for the chemical shifts of the phenolic
OH and the hydroxyl OH of SS-4 in CDCl3.
decreased the peak shift of the hydroxyl OH signal to within 0.1
ppm, suggesting that the hydroxyl groups form a weak
intramolecular H-bond and can be partially disrupted by
residual water in the CDCl3. On the other hand, in an imine
(RR-3) formed from 1 and (R)-3,3-dimethyl-2-butylamine, the
stereoselectivity was measured to be 1:4.5, 1:4.3, and 1:4.7 in
CDCl3, CD3CN, and CD3OD, respectively (Scheme 1b). In
RR-3, the stereoselectivity was maintained independent of the
solvent because its stereoselectivity originated from the relative
steric bulkiness of the methyl and tert-butyl groups.
The axial arrangement of a diimine can be verified by circular
dichroism (CD) spectroscopy.13 The CD spectra of the crude
mixtures of SS-2 were measured without any purification
procedures. As shown in Figure 5, there are strong Cotton
effects in the CD spectra of SS-2, but the exciton chiral
method2e,13 is not applicable when determining the absolute
chirality, as because bisignate CD curves are not clearly
6588
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591

The Journal of Organic Chemistry
Article
Table 1. Stereoselective Chirality Transfer from Amino Alcohols to 2,2′-Dihydroxybenzil (1)
a
b
1
Determined by the H NMR spectra of the isolated products. 75 μM in ethanol, 10 mm cell, at 20 °C.
Figure 6. (a) Circular dichroism spectra of 2 with various enantiopurities of valinol and (b) a linear plot between the CD/UV−vis ratios and the
enantiopurities of valinol (75 μM in ethanol, 10 mm cell, at 20 °C).
Figure 7. (a) Procedure for the formation of diazo attached 2,2′-dihydroxybenzil (9). (b) Structure of the imine complex formed between the new
probe and amino alcohol, and (c) measured CD and UV−vis spectra (75 μM in ethanol, 10 mm cell, at 20 °C) of P-SS-10 (blue) and P-SS-11 (red).
Although 2,2′-dihydroxybenzil (1) can be used to ascertain
the absolute chirality and enantiomeric excess, as previously
demonstrated, this stereodynamic probe shows weak CD
signals for amino alcohols with alkyl substituents, and a TD-
DFT calculation is required to determine the absolute chirality
instead of the more intuitively simple exciton chirality method.
In order to overcome these challenges, we designed a new
probe (9) by attaching the diazo group to the 5-position of the
6589
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591

The Journal of Organic Chemistry
Article
in EtOH (0.125 mL) was added 5 equiv of chiral amino alcohol
(0.3125 mmol). The solution was stirred for 6 h at 80 °C, and then all
volatile residues were removed in vacuo. The resulting crude mixture
was used for CD analysis without further purification. The isolated
product was used for NMR analysis.
phenol group of 2,2′-dihydroxybenzil. Because the UV signals
of diazo groups may appear in regions separated from those of
other chromophores, a spatial arrangement of two diazo groups
can be used for the determination of the absolute chirality by
the exciton chirality method. Indeed, when imines 10 and 11
were formed by a reaction between the new probe and L-valinol
or L-phenylglycinol, respectively, the UV signals at 370 nm were
observed to have similar patterns, indicating that the diazo
groups can be an independent signal unit regardless of the
functional groups of the analytes. To our surprise, in both cases
the first positive and the second negative Cotton effects were
observed, and the absolute chirality was determined as the P-
configuration, in agreement with the crystallographic and DFT
calculation data (Figure 7).
P-SS-2. Yellow solid (21.9 mg, 85%); 1H NMR (400 MHz, CDCl3)
δ 14.89 (br, 2H), 7.31 (ddd, J = 8.7, 7.2, 1.6 Hz, 2H), 7.09 (dd, J = 8.0,
1.6 Hz, 2H), 7.02 (dd, J = 8.4, 1.1 Hz, 2H), 6.71 (ddd, J = 8.2, 7.2, 1.2
Hz, 2H), 3.95−3.82 (m, 4H), 3.82 (br, 2H), 3.63 (dt, J = 8.1, 3.8 Hz,
2H), 1.71−1.63 (m, 2H), 0.91 (d, J = 7.0 Hz, 6H), 0.74 (d, J = 7.1 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 167.0, 162.3, 133.3, 130.9,
118.4, 118.3, 117.8, 68.3, 62.9, 31.6, 19.7, 16.8; HRMS (ESI-TOF) m/
z: [M+Na]+ Calcd for C24H32N2O4Na 435.2254; Found: 435.2265.
P-SS-4. Yellow solid (22.0 mg, 78%); 1H NMR (400 MHz, CDCl3)
δ 14.55 (br, 2H), 7.19−7.06 (m, 8H), 7.00−6.99 (m, 6H), 6.41 (dd, J
= 8.0, 1.6 Hz, 2H), 6.12 (ddd, J = 8.3, 7.2, 1.2 Hz, 2H), 4.84 (dd, J =
9.9, 3.3 Hz, 2H), 4.17 (t, J = 10.6 Hz, 2H), 4.04 (br, 2H), 3.89 (dd, J =
9.1, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 168.5, 161.6, 137.9,
133.3, 131.1, 128.6, 127.8, 127.5, 118.4, 117.8, 116.7, 69.3, 68.9;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C30H28N2O4Na
503.1941; Found 503.1962.
CONCLUSION
■
In summary, we have demonstrated the highly stereoselective
recognition of amino alcohols using 2,2′-dihydroxybenzil as a
stereodynamic receptor. The axial chirality is controlled via the
formation of diimines with a series of amino alcohols that have
good (11:1) to excellent (>50:1) stereoselectivity. The origin of
the high diastereoselectivity and the existence of H-bond
interactions were verified by combining the experimental data
P-SS-5. Yellow solid (18.1 mg, 75%); 1H NMR (400 MHz, CDCl3)
δ 14.64 (br, 2H), 7.32 (ddd, J = 8.6, 7.2, 1.6 Hz, 2H), 7.09 (dd, J = 8.0,
1.6 Hz, 2H), 7.02 (dd, J = 8.4, 1.2 Hz, 2H), 6.73 (ddd, J = 8.1, 7.2, 1.0
Hz, 2H), 4.00−3.77 (m, 4H), 3.71−3.64 (m, 2H), 3.51 (br, 2H),
1.60−1.26 (m, 4H), 0.74 (t, J = 7.5 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.2, 162.2, 133.4, 130.7, 118.4, 118.4, 117.6, 66.2, 64.7,
25.6, 9.5; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H28N2O4Na
407.1941; Found: 407.1940.
1
of H NMR and CD spectroscopy and X-ray crystallography
with computational data. The experimental CD spectra can be
used to determine the absolute chirality of amino alcohols by
comparing simulated CD spectra, and there is an excellent
linear relationship between the enantiopurity of amino alcohols
and the observed CD signals. In addition, diazo-attached 2,2′-
dihydroxybenzil is feasible for use with the exciton chirality
method. Thus, 2,2′-dihydroxybenzil is a highly stereoselective
stereodynamic probe which can be utilized for the determi-
nation of the absolute configurations and ee values of amino
alcohols.
P-SS-6. Yellow solid (15.0 mg, 67%); 1H NMR (400 MHz, CDCl3)
δ 14.55 (br, 2H), 7.32 (ddd, J = 8.3, 7.2, 1.6 Hz, 2H), 7.09 (dd, J = 8.0,
1.6 Hz, 2H), 7.02 (dd, J = 8.4, 1.1 Hz, 2H), 6.74 (ddd, J = 8.2, 7.2, 1.2
Hz, 2H), 4.01−3.57 (m, 8H), 0.94 (d, J = 5.9 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 167.2, 162.1, 133.4, 130.7, 118.5, 118.4, 117.4, 68.5,
59.7, 17.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H24N2O4Na 379.1628; Found: 379.1630.
P-SS-7. Yellow solid (20.1 mg, 73%); 1H NMR (400 MHz, CDCl3)
δ 14.59 (br, 2H), 7.32 (ddd, J = 8.6, 7.2, 1.6 Hz, 2H), 7.14 (dd, J = 8.0,
1.6 Hz, 2H), 7.01 (dd, J = 8.4, 1.2 Hz, 2H), 6.75 (ddd, J = 8.2, 7.2, 1.2
Hz, 2H), 3.97−3.77 (m, 2H), 3.78−3.65 (m, 4H), 3.68 (br, 2H),
1.60−1.24 (m, 4H), 1.14−0.87 (m, 2H), 0.64 (d, J = 6.5 Hz, 6H), 0.35
(d, J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.0, 162.2,
133.3, 130.9, 118.3, 118.3, 117.6, 66.9, 62.6, 41.8, 25.1, 23.8, 21.2;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H36N2O4Na
463.2567; Found: 463.2579.
EXPERIMENTAL SECTION
■
General Information. Commercially available compounds were
used without further purification or drying. The H and 13C NMR
1
spectra were recorded on a Bruker Ascend 400 spectrometer (400
1
MHz for H and 100 MHz for 13C) and are reported in ppm, relative
to residual protonated solvent peak (CDCl3, CD3CN, and CD3OD).
The high-resolution mass spectra (HRMS) were obtained on a Bruker
Daltonik microTOF-QII spectrometer. Circular dichroism (CD) and
UV−vis spectra were performed on a JASCO J-815 spectrometer. All
calculations were performed using Gaussian 09. 2,2′-Dihydroxybenzil
was prepared according to the reported procedure.3b
P-SS-8. Yellow solid (27.7 mg, 87%); 1H NMR (400 MHz, CDCl3)
δ 14.41 (br, 2H), 7.40 (ddd, J = 8.6, 7.2, 1.6 Hz, 2H), 7.30 (dd, J = 7.9,
1.6 Hz, 2H), 7.15 (dd, J = 8.4. 1.1 Hz, 2H), 7.13−7.08 (m, 6H), 6.81
(ddd, J = 8.2, 7.2, 1.2 Hz, 2H), 6.71−6.57 (m, 4H), 3.85 (tdd, J = 8.3,
5.0, 3.4 Hz, 2H), 3.72 (dd, J = 11.1, 8.9 Hz, 2H), 3.62 (dd, J = 11.1, 3.3
Hz, 2H), 3.13 (br, 2H), 2.76−2.52 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 167.8, 162.1, 136.8, 133.7, 130.7, 129.3, 128.6, 126.8, 118.9,
118.5, 117.5, 65.8, 65.5, 39.2; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C32H32N2O4Na 531.2254; Found: 531.2281.
Procedure for Formation of Diazo Attached 2,2′-Dihydrox-
ybenzil. A cooled solution containing NaNO2 (145 mg, 2.1 mmol)
and water (1.5 mL) was slowly added to a cooled solution of p-
toluidine (225 mg, 2.1 mmol), 6 M HCl (0.7 mL), and water (0.7 mL)
to form the diazonium salt. The diazonium salt solution was then
added dropwise to a cooled solution of 2,2′-dihydroxybenzil (242 mg,
1 mmol) dissolved in dilute sodium hydroxide (100 mg in 1.5 mL).
The resulting solution was stirred for 2 h. To precipitate the axo-dye,
the solution was acidified with 6 M HCl. The precipitate was filtered
off and reslurry from MeOH (5 mL) to give the compound 9.
9. Dark orange solid (234 mg, 49%); 1H NMR (400 MHz, CDCl3)
δ 11.61 (s, 2H), 8.23 (dd, J = 9.1, 2.4 Hz, 2H), 8.14 (dd, J = 2.4, 0.4
Hz, 2H), 7.86−7.55 (m, 4H), 7.31−7.26 (m, 4H), 7.25 (dd, J = 9.1,
0.4 Hz, 2H), 2.41 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 195.9,
165.9, 150.5, 145.7, 142.0, 130.4, 130.1, 129.9, 123.0, 120.0, 116.3,
Procedure for Formation of 2,2′-Dihydroxybenzil.3b To a
suspension of AlCl3 (11.2 g, 84 mmol) in CH2Cl2 (75 mL), a solution
of phenol (3.95 g, 42 mmol) in CH2Cl2 (12.5 mL) was added
dropwise at room temperature and the mixture was stirred for 30 min.
A solution of oxalyl chloride (1.72 mL, 20 mmol) in CH2Cl2 (12.5
mL) was added dropwise to the reaction mixture at room temperature.
After 3 h, the reaction was quenched by the addition of 12 M HCl
solution. The layers were separated, and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layers were
washed with water, dried (MgSO4), filtered, and concentrated. The
residue was purified by recrystallization from EtOH (10 mL) to afford
the product, 2,2′-dihydroxybenzil (1).
1
2,2′-Dihydroxybenzil (1). Greenish yellow solid (1.54 g, 32%); H
NMR (400 MHz, CDCl3) δ 11.28 (s, 2H), 7.59 (ddd, J = 8.6, 7.4, 1.6
Hz, 2H), 7.47 (dd, J = 8.0, 1.6 Hz, 2H), 7.10 (dd, J = 8.5, 1.0 Hz, 2H),
6.92 (ddd, J = 8.2, 7.3, 1.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
196.6, 163.7, 138.5, 132.5, 120.0, 119.0, 116.8; HRMS (ESI-TOF) m/
z: [M+Na]+ Calcd for C14H10O4Na 265.0471; Found: 265.0453.
General Procedure for the Diimine Formation of 2,2′-
Dihydroxybenzil. To a stirred solution of 1 (15.1 mg, 0.0625 mmol)
6590
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591

The Journal of Organic Chemistry
Article
21.6; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H22N4O4Na+
501.1533; Found: 501.1539.
C.; Benet-Buchholz, J.; Kleij, A. W. Angew. Chem., Int. Ed. 2011, 50,
713. (c) Joyce, L. A.; Maynor, M. S.; Dragna, J. M.; da Cruz, G. M.;
Lynch, V. M.; Canary, J. W.; Anslyn, E. V. J. Am. Chem. Soc. 2011, 133,
13746. (d) Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita, A.; Rosini,
C. J. Am. Chem. Soc. 2006, 128, 6893.
General Procedure for the Diimine Formation of Diazo
Attached 2,2′-Dihydroxybenzil. To a stirred solution of 9 (29.9
mg, 0.0625 mmol) in EtOH (0.125 mL) was added 5 equiv of chiral
amino alcohol (0.3125 mmol). The solution was stirred for 6 h at 80
°C, and then all volatile residues were removed in vacuo. The resulting
crude mixture was used for CD analysis without further purification.
(6) (a) Iwaniuk, D. P.; Wolf, C. Chem. Commun. 2012, 48, 11226.
(b) Leung, D.; Anslyn, E. V. Org. Lett. 2011, 13, 2298. (c) Katoono,
R.; Kawai, H.; Fujiwara, K.; Suzuki, T. J. Am. Chem. Soc. 2009, 131,
́
16896. (d) Sciebura, J.; Skowronek, P.; Gawronski, J. Angew. Chem.,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00600.
Int. Ed. 2009, 48, 7069.
■
(7) (a) Bentley, K. W.; Wolf, C. J. Org. Chem. 2014, 79, 6517.
(b) Bentley, K. W.; Wolf, C. J. Am. Chem. Soc. 2013, 135, 12200.
(c) Ghosn, M. W.; Wolf, C. J. Org. Chem. 2011, 76, 3888. (d) Ghosn,
M. W.; Wolf, C. J. Am. Chem. Soc. 2009, 131, 16360.
S
Spectroscopic and calculation data and crystallographic
details (PDF)
X-ray crystallographic details for P-SS-2 (CIF)
(8) Iwaniuk, D. P.; Bentley, K. W.; Wolf, C. Chirality 2012, 24, 584.
(9) Bentley, K. W.; Nam, Y. G.; Murphy, J. M.; Wolf, C. J. Am. Chem.
Soc. 2013, 135, 18052.
(10) Zhang, P.; Wolf, C. Chem. Commun. 2013, 49, 7010.
(11) (a) Hasan, M.; Khose, V. N.; Pandey, A. D.; Borovkov, V.;
Karnik, A. V. Org. Lett. 2016, 18, 440. (b) Ikbal, S. A.; Dhamija, A.;
Brahma, S.; Rath, S. P. J. Org. Chem. 2016, 81, 5440. (c) De los Santos,
Z. A.; Ding, R.; Wolf, C. Org. Biomol. Chem. 2016, 14, 1934. (d) Joyce,
L. A.; Sherer, E. C.; Welch, C. J. Chem. Sci. 2014, 5, 2855.
AUTHOR INFORMATION
Corresponding Author
*hwkim@kaist.edu
ORCID
■
(e) Escar
Escudero-Adan
́
cega-Bobadilla, M. V.; Salassa, G.; Belmonte, M. M.;
Hyunwoo Kim: 0000-0001-5030-9610
́
, E. C.; Kleij, A. W. Chem. - Eur. J. 2012, 18, 6805.
(12) (a) Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough, A. J.;
Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. (b) Gilli, P.;
Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405.
(13) Circular Dichroism: Principles and Applications, 2nd ed.; Berova,
N., Nakanishi, K., Woody, R. W., Eds.; Wiley-VCH: New York, 2000.
(14) The Gaussian 09 was used for all calculations. We used the
B3LYP/ 6-31G(d,p) or CAM-B3LYP/ 6-31G(d,p) basis for all atoms.
TD-SCF method was used for electronic CD simulation and CD
spectra were generated using the program SpecDis v. 1.61.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
Samsung Science and Technology Foundation (SSTF-BA1601-
10). The authors thank Dr. Alan J. Lough (University of
Toronto) for his X-ray analysis.
REFERENCES
■
(1) (a) Patel, R. N. Biomolecules 2013, 3, 741. (b) Klingler, F. D. Acc.
Chem. Res. 2007, 40, 1367. (c) Karjalainen, O. K.; Koskinen, A. M. P.
Org. Biomol. Chem. 2012, 10, 4311. (d) Donohoe, T. J.; Callens, C. K.
A.; Flores, A.; Lacy, A. R.; Rathi, A. H. Chem. - Eur. J. 2011, 17, 58.
(e) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (f) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
(2) For recent reviews, see: (a) You, L.; Zha, D.; Anslyn, E. V. Chem.
Rev. 2015, 115, 7840. (b) Jo, H. H.; Lin, C.-Y.; Anslyn, E. V. Acc.
Chem. Res. 2014, 47, 2212. (c) Wolf, C.; Bentley, K. W. Chem. Soc. Rev.
2013, 42, 5408. (d) Leung, D.; Kang, S. O.; Anslyn, E. V. Chem. Soc.
Rev. 2012, 41, 448. (e) Berova, N.; Bari, L. D.; Pescitelli, G. Chem. Soc.
Rev. 2007, 36, 914.
(3) (a) De los Santos, Z. A.; Wolf, C. J. Am. Chem. Soc. 2016, 138,
13517. (b) Seo, M.-S.; Lee, A.; Kim, H. Org. Lett. 2014, 16, 2950.
(c) Kuwahara, S.; Nakamura, M.; Yamaguchi, A.; Ikeda, M.; Habata, Y.
Org. Lett. 2013, 15, 5738. (d) Dragna, J. M.; Pescitelli, G.; Tran, L.;
Lynch, V. M.; Anslyn, E. V.; Di Bari, L. J. Am. Chem. Soc. 2012, 134,
4398. (e) Iwaniuk, D. P.; Wolf, C. J. Am. Chem. Soc. 2011, 133, 2414.
(f) Iwaniuk, D. P.; Wolf, C. Org. Lett. 2011, 13, 2602. (g) Kim, H.; So,
S. M.; Yen, C. P.-H.; Vinhato, E.; Lough, A. J.; Hong, J.-I.; Kim, H.-J.;
Chin, J. Angew. Chem., Int. Ed. 2008, 47, 8657. (h) Borovkov, V. V.;
Hembury, G. A.; Inoue, Y. Acc. Chem. Res. 2004, 37, 449.
(4) (a) Wang, L.; Zhang, T.; Redden, B. K.; Sheppard, C. I.; Clark, R.
W.; Smith, M. D.; Wiskur, S. L. J. Org. Chem. 2016, 81, 8187. (b) Li,
X.; Burrell, C. E.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2012, 134,
9026. (c) You, L.; Berman, J. S.; Lucksanawichien, A.; Anslyn, E. V. J.
Am. Chem. Soc. 2012, 134, 7126. (d) You, L.; Pescitelli, G.; Anslyn, E.
V.; Di Bari, L. J. Am. Chem. Soc. 2012, 134, 7117. (e) You, L.; Berman,
J. S.; Anslyn, E. V. Nat. Chem. 2011, 3, 943. (f) Tartaglia, S.; Padula,
D.; Scafato, P.; Chiummiento, L.; Rosini, C. J. Org. Chem. 2008, 73,
4865.
(5) (a) Tanasova, M.; Anyika, M.; Borhan, B. Angew. Chem., Int. Ed.
2015, 54, 4274. (b) Wezenberg, S. J.; Salassa, G.; Escudero-Adan, E.
́
6591
DOI: 10.1021/acs.joc.7b00600
J. Org. Chem. 2017, 82, 6586−6591