Hydrogen-Bonding-Assisted Ketimine Formation of Benzophenone Derivatives

Article abstract of DOI:10.1021/acs.joc.8b01908

The favorable effect of 2-hydroxyphenyl groups for ketimine formation with benzophenone was demonstrated by combining computational and experimental studies. Although direct imine formation between benzophenone and primary amines is challenging, 2-hydroxy

Full text of DOI:10.1021/acs.joc.8b01908

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Hydrogen-Bonding-Assisted Ketimine Formation of Benzophenone
Derivatives
Min-Seob Seo,† Sumin Jang,† Hoimin Jung, and Hyunwoo Kim*
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: The favorable effect of 2-hydroxyphenyl groups for ketimine
formation with benzophenone was demonstrated by combining computational
and experimental studies. Although direct imine formation between
benzophenone and primary amines is challenging, 2-hydroxybenzophenone
or 2,2′-dihydroxybenzophenone was readily used for ketimine formation with
various primary alkyl amines and anilines. Measured activation parameters and
calculated energy profiles indicated that the 2-hydroxyphenyl group can lower
both activation barriers and equilibrium energies by establishing intra-
molecular and intermolecular hydrogen-bonding interactions.
known to be inactive for the imine formation with amines in
the absence of additives. Interestingly, the 2-hydroxyphenyl
group enables the benzophenone to directly react with amines
to form the imines (Scheme 1c). We have reported that 2,2′-
dihydroxybenzophenone readily reacts with a series of primary
amines to form imines to further prepare new phosphorus
ligands (briphos)19−22 and chiral solvating agents (CASA
reagents).23,24 With successful utilization of 2,2′-dihydrox-
ybenzophenone for designing ligands and chiral solvating
agents, we investigate the effect of the 2-hydroxyphenyl group
for ketimine formation with benzophenone derivatives by
combining computational and experimental approaches in this
study.
INTRODUCTION
■
The imine formation between carbonyl compounds and
amines is one of the fundamental organic transformations. In
the metabolism of amino acids, imine compounds formed from
amino acids and pyridoxal phosphate (PLP) are the key
intermediates for transamination, decarboxylation, deamina-
tion, and racemization reactions.1−3 In the field of asymmetric
synthesis, a variety of amine-based organocatalysts have been
developed, where the imine or iminium salt that is formed or
the enamine that is subsequently formed is used to activate
carbonyl compounds.4−8 Thus, given the popularity of the
imine compounds in biology and chemistry, understanding and
controlling the reactivity of the imine formation is highly
important.
The imine formation is dependent on the substrate or
product structures. In general, alkyl amines are more reactive
than aryl amines because of improved nucleophilicity and
basicity.9 Aldehydes are more reactive than ketones because of
less steric repulsion in the imine structures.9 Moreover, in the
case of salicylaldehydes, the intramolecular hydrogen bonding
due to the 2-hydroxyphenyl group provides additional
thermodynamic energy to stabilize the imine products.10
Thus, the facile aldimine formation between primary amines
and salicylaldehydes has been widely used to develop ligands,
such as N,N′-bis(salicylidene)diamines (salen, Scheme
1a).11−14 The direct formation of ketimines, however, has
been challenging. An imine formed from benzophenone and
glycine tert-butyl ester is a useful substrate for the synthesis of
chiral unnatural amino acid derivatives by the asymmetric
phase-transfer alkylation reaction,15 but the imine can be
formed by a sequential process involving the Lewis-acid-
catalyzed imine formation with ammonia followed by the
transamination reaction (Scheme 1b).16−18 Benzophenone is
RESULTS AND DISCUSSION
■
To systematically investigate the effect of the 2-hydroxyphenyl
group on ketimine formation, we compared the reactivity of
five ketones: acetophenone (AP), 2-hydroxyacetophenone
(HAP), benzophenone (BP), 2-hydroxybenzophenone
(HBP), and 2,2′-dihydroxybenzophenone (DHBP) as shown
in Figure 1. When the ketone was mixed with 10 equiv of
cyclohexylamine in DMSO-d6 at 50 °C, a complete imine
formation was observed for both HAP and DHBP after 30 min.
Under the same reaction conditions, HBP gave the imine
product with 66% yield, while AP and BP gave no product at
all. Imine formation with AP and BP was not observed, even
when the mixture was kept at high temperature (>150 °C) for
>48 h. The experimental results indicated that the 2-
hydroxyphenyl group is essential for the ketimine formation.
Received: July 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Direct Formation of Aldimines and Ketimines
role in obtaining reliable energies for the imine formation.
Indeed, the addition of a water molecule significantly affected
the calculated equilibrium energies for the ketimine formation.
First, all of the equilibrium energies were lowered by 3−11
kcal/mol, indicating stabilization of the ketimines by
intermolecular hydrogen bonding with the water molecule.
Second, the 2-hydroxyphenyl group provided additional
stabilization energies for the ketimine formation as expected.
In the case of AP and HAP, the stabilization energy by the 2-
hydroxyl group was calculated to be 4.7 kcal/mol. In the case
of BP, HBP, and DHBP, the 2-hydroxyl group appears to
additionally stabilize the ketimine by about 2.5 kcal/mol. The
calculated equilibrium energies for HAP, HBP, and DHBP
were still slightly endothermic, but it is evident that the
ketimine formation becomes favorable by hydrogen bonds
involving the 2-hydroxyphenyl group and the water molecule.
For a further understanding of the reaction mechanism, the
kinetic effect of the 2-hydroxyphenyl group was investigated by
measuring the activation parameters (Figure 2). The kinetic
data were recorded by 1H NMR spectroscopy at various
Figure 1. Experimental and computational data for ketimine
formation.
For an explanation of the experimental results, DFT
computation was performed to calculate the equilibrium
energies for the ketimine formation (Figure 1). For direct
conversion of the ketone and cyclohexylamine to the
corresponding ketimine and water, the equilibrium energies
were calculated to be highly endothermic in all cases (>7 kcal/
mol). Although the 2-hydroxyphenyl group lowered the
equilibrium energies by 4.2 kcal/mol in the results for AP
and HAP, the equilibrium energies for HBP and DHBP were
not substantially lower than that of BP. However, as described
in a previous report,25 water molecules can play a significant
Figure 2. Activation parameters for the formation of ketimines.
B
DOI: 10.1021/acs.joc.8b01908
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Figure 3. Free energy profile of the imine formation with benzophenone (BP).
temperatures (30−50 °C) in DMSO-d6 (10 mM). The
pseudo-first-order rate equations were obtained when an
excess amount of cyclohexylamine was used (10 equiv). For
the reaction with HAP, an Eyring plot gave ΔH‡ and ΔS‡
values of 9.2 kcal/mol and −40.2 cal/(mol K), respectively.
The calculated ΔG‡ value for the ketimine formation with
HAP at 25 °C is 21.2 kcal/mol. A linear relationship in the
Eyring plot was also obtained for HBP and DHBP. For the
ketimine formation with HBP, the measured ΔH‡, ΔS‡, and
ΔG‡ (25 °C) values are 13.8 kcal/mol, −30.2 cal/(mol K), and
22.8 kcal/mol, respectively, whereas these values for DHBP are
10.3 kcal/mol, −36.0 cal/(mol K), and 21.0 kcal/mol,
respectively. Indeed, compatible ΔG‡ values for HAP and
DHBP (21.2 and 21.0 kcal/mol, respectively) and a slightly
higher ΔG‡ value for HBP (22.8 kcal/mol) were obtained,
consistent with our initial observation.
imine formation consists of two major steps: (1) the
nucleophilic addition of the amine to the carbonyl carbon to
form a carbinolamine intermediate and (2) the elimination of
water from the carbinolamine to form the imine product. For
the first carbinolamine formation, the proton transfer from
amine N−H to carbonyl oxygen is necessary. We first
calculated the energy profile for the ketimine formation
between BP and cyclohexylamine. In our calculations, the
direct bimolecular conversion from BP and cyclohexylamine to
the imine product gave very high transition states of about >60
kcal/mol. Because the high potential barriers can be reduced
by consideration of the solvent in the nucleophilic approach on
carbonyl carbons,26 we then introduced auxiliary water
molecules to reduce the energies for transition states and
intermediates. The calculation indicated that one water
molecule reduced the transition state energies to about 45
kcal/mol. As shown in Figure 3, the addition of two water
molecules gave the first transition state 1-TS for the
carbinolamine formation and the second transition state 3-
TS for the dehydration being reasonably located at 19.8 and
28.4 kcal/mol, respectively. Although experimental data are
not available to verify the calculated energy profile, the poor
reactivity of BP for the ketimine formation agrees with the
calculated high activation barrier. In addition, the calculated
results with BP (Figure 3) can be directly compared with those
with HBP and DHBP (Figure 4) because the similar number
of atoms were involved in inter- and intramolecular hydrogen
bonds.
The energy profiles for HBP and DHBP were calculated
with one auxiliary water molecule, as shown in Figure 4. The 2-
hydroxyphenyl groups are found to be involved in intra-
molecular hydrogen bonding in all intermediates and transition
states. Remarkably, the zwitterionic intermediate 6 was found
between phenolic O−H and ammonium N−H bonds because
of the comparable acidity, and this zwitterionic form was
previously described in an aldimine formation using pyridoxal
phosphate (PLP) analogs.27 The carbinolamine 7 was formed
from the zwitterionic intermediate 6 through transition state 6-
TS. HBP and DHBP showed similar energy values for 6-TS
and 7 (19.0 and 15.5 kcal/mol for HBP and 19.0 and 15.2
The measured kinetic parameters indicate the enthalpic and
entropic contribution of the substituents to the transition
states. By comparing HAP and HBP, the substitution of the
methyl group with the phenyl group results in an increase of
the ΔH‡ and ΔS‡ values by 4.6 kcal/mol and 10 cal/(mol K),
respectively. Thus, in the presence of the sterically bulky
phenyl group, the activation barrier for the ketimine formation
becomes higher with an increase of ΔH‡ (4.6 kcal/mol), but it
becomes lower with an increase of ΔS‡ (TΔS‡ = 3.0 kcal/mol,
at 298 K). Overall, the ΔG‡ value is slightly increased by 1.6
kcal/mol. The phenyl substituent increases the activation free
energy for the ketimine formation by combining unfavorable
enthalpic and favorable entropic effects. Interestingly, the
opposite substituent effect was observed for the hydroxyphenyl
group, as shown by the kinetic parameters for HBP and DHBP.
The hydrogen bonding with the second hydroxyl group in
DHBP lowered the activation enthalpies by 3.5 kcal/mol,
whereas the ordered transition state (ΔΔS‡ = 5.8 cal/(mol K))
increased the ΔG‡ value by 1.7 kcal/mol due to the entropic
contribution (TΔS‡ at 298 K), resulting in a net decrease of
the ΔG‡ value of 1.8 kcal/mol.
After establishing the favorable kinetic effect of the 2-
hydroxyphenyl group, we calculated the energy profiles to
understand the origin of the 2-hydroxyphenyl group effect. The
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DOI: 10.1021/acs.joc.8b01908
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Figure 4. Free energy profile of the imine formation with 2-hydroxybenzophenone (HBP black line) and 2,2′-dihydroxybenzophenone (DHBP,
blue line)
Figure 5. Synthesis of ketimines with (a) 2-hydroxybenzophenone and (b) 2,2′-dihydroxybenzophenone.
kcal/mol for DHBP, respectively), indicating that the first 2-
hydroxyphenyl group was crucial to stabilize the carbinolamine
structure, and the second group was not effective. However, for
the dehydration step, the transition state 7-TS and the
intermediate 8 were calculated to be 23.5 and 12.9 kcal/mol
for HBP and 18.6 and 8.0 kcal/mol for DHBP, respectively.
The energy states for DHBP were 4.9 kcal/mol lower than
those for HBP. It was found that the second 2-hydroxyphenyl
group in DHBP significantly stabilized the dehydration process
in the ketimine formation. In 7b-TS, together with the first 2-
hydroxyphenyl group, the second 2-hydroxyphenyl group
establishes intramolecular hydrogen bonds with the OH
group of the carbinolamine to facilitate the generation of a
water molecule. According to the calculated energy profiles, it
D
DOI: 10.1021/acs.joc.8b01908
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Article
is proposed that the 2-hydroxyphenyl group has the following
effects on the ketimine formation: (1) stabilization of
carbinolamine formation by forming zwitterionic intermediates
and (2) stabilization of the dehydration process by intra-
molecular hydrogen bonds.
anilines were used to synthesize ketimines with HBP and
DHBP in moderate to good yields (30−96%). Because the
benzophenone derivatives can be directly used for ketimine
formation assisted by hydrogen bonds, the ketimine products
will be further used for the design of ligands and sensors.
Because the water molecules play a significant role in
computation to stabilize the transition states and intermediates
for the ketimine formation, we investigated the effect of water
on the rate of ketimine formation (Supporting Information).
Interestingly, the addition of water actually slowed or
prevented the ketimine formation, implying that the addition
of water would make the reaction thermodynamically
unfavorable. However, the relative reaction rates are quite
similar in a water concentration of 0−1.1 M, showing that the
kinetic barriers are not significantly affected by the water
concentration. It appeared that the kinetic effect of water
cannot be clearly determined in the ketimine formation
because (1) water affects both kinetic barriers and thermody-
namic energies, and (2) both the amine and water can be used
to relay the proton transfer.
After the kinetic and computational evaluation of the 2-
hydroxyphenyl group, the reaction scope for the ketimine
formation with HBP and DHBP was investigated (Figure 5).
Although the 2-hydroxyphenyl group provides both kinetic and
thermodynamic stabilization energies, the ketimine formation
is still highly dependent on the amine structure. For reactive
alkyl amines, the ketimine formation with HBP and DHBP
proceeded in MeOH. Several alkyl amines with DHBP
provided the desired ketimines 10a−d in high yields (85−
93%), but the ketimines with HBP 11a−d were obtained in
variable yields (30−97%) due to reduced reactivity (Method
A). For aryl amines, the electronic properties of the aryl group
are crucial. In the cases of aniline and electron-donating aryl
amines, the ketimine formation with HBP and DHBP
proceeded in toluene at 110 °C to provide the desired
ketimines 10e−g and 11e−g in good to moderate yields (73−
88%, Method B). However, in the cases of electron-
withdrawing aryl amines, the ketimine formation with HBP
and DHBP was not observed in toluene. Thus, microwave
irradiation at 180 °C was applied to obtain ketimines 11h and
11i in moderate yields of 45% and 56%, respectively (Method
C), but the corresponding products 10h and 10i with HBP
were not detected. Accordingly, direct ketimine formation with
HBP and DHBP can be achieved in proper reaction conditions
based on the reactivity of the amines.
EXPERIMENTAL SECTION
■
General Information. Commercially available compounds were
used without further purification or drying. The 1H and 13C{1H}
NMR spectra were recorded on a Bruker Ascend 400 spectrometer
1
(400 MHz for H and 100 MHz for 13C) and are reported in ppm,
relative to residual protonated solvent peak (DMSO-d6). The high-
resolution mass spectra (HRMS) were obtained on a Bruker Daltonik
micro TOF-QII spectrometer. All calculations were performed using
Gaussian 09. Monowave 300 from Anton Parr was used for
microwave irradiation.
General Procedure for the Preparation of Imines. Method A.
A 1.2 equiv portion of amine (0.6 mmol) was added to a stirred
solution of 2-hydroxybenzophenone (HBP, 99.1 mg, 0.5 mmol) or
2,2′-dihydroxybenzophenone (DHBP, 107 mg, 0.5 mmol) in MeOH
(1 mL). The solution was stirred at 50 °C until the clean formation of
imine was confirmed by crude 1H NMR spectra of aliquots in DMSO-
d6. After cooling to ambient temperature, all volatile residues were
removed in vacuum. The residue was purified by column
chromatography with ethyl acetate and n-hexane (1:10) to afford
the product as a yellow solid.
Method B. A 3 equiv portion of amine (6 mmol) was added to a
stirred solution of HBP (396 mg, 2 mmol) or DHBP (428 mg, 2
mmol) in toluene (4 mL). The solution was stirred at 110 °C for 48
1
h. The clean formation of imine was confirmed by crude H NMR
spectra of aliquots in DMSO-d6. After cooling to ambient temper-
ature, all volatile residues were removed in vacuo. The residue was
purified by column chromatography with ethyl acetate and n-hexane
(1:10) to afford the product as yellow solid.
Method C. DHBP (214 mg, 1 mmol) and amine (3 equiv, 3 mmol)
were mixed in a sealed microwave reaction vessel. Microwave
radiation directly heated the flask from 25 to 180 °C, and the mixture
was stirred for 2 h at external surface temperature of 180 °C in a
microwave reactor. After cooling to ambient temperature, the residue
was purified by crystallization from Et2O (10 mL) to afford the
product as a yellow solid.
E-2-{(Cyclohexylimino)(phenyl)methyl}phenol (10a). Yellow
solid (134 mg, 96%). 1H NMR (400 MHz, CDCl3): δ 7.67−7.38 (m,
3H), 7.30−7.21 (m, 1H), 7.23−7.16 (m, 2H), 6.97 (dd, J = 8.4, 1.2
Hz, 1H), 6.73 (dd, J = 8.0, 1.7 Hz, 1H), 6.59 (ddd, J = 8.1, 7.1, 1.2
Hz, 1H), 3.23 (tt, J = 9.1, 3.8 Hz, 1H), 1.87−1.64 (m, 4H), 1.64−
1.46 (m, 3H), 1.44−1.25 (m, 1H), 1.24−1.06 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 171.9, 164.5, 133.9, 132.5, 131.6, 129.0,
128.7, 127.4, 119.7, 118.4, 116.9, 58.8, 34.0, 25.0, 24.0. HRMS (EI)
m/z: [M + H]+ calcd for C19H22NO+, 280.1696; found, 280.1699.
(R,E)-2-[{(2,3-Dihydro-1H-inden-1-yl)imino}(phenyl)methyl]-
CONCLUSION
■
1
phenol (10b). Yellow solid (149 mg, 95%). H NMR (400 MHz,
The ketimine formation with benzophenone was greatly
facilitated by 2-hydroxyphenyl groups. The 2-hydroxybenzo-
phenone (HBP) and 2,2′-dihydroxybenzophenone (DHBP)
reacted with cyclohexylamine to provide the resulting
ketimines, whereas benzophenone (BP) gave no product.
The kinetic study indicated that the 2-hydroxyphenyl group
lowered the activation free energies by combining favorable
enthalpic and unfavorable entropic contributions. DFT
computation revealed that intermolecular and intramolecular
hydrogen bonds involving 2-hydroxyphenyl groups and water
molecules significantly stabilized all reaction intermediates and
transition states for the ketimine formation. Specifically, the
first 2-hydroxyphenyl group greatly stabilized the transition
state for the carbinolamine formation, while the second 2-
hydroxyphenyl group lowered the activation barrier for the
dehydration step. Accordingly, several alkyl amines and
CDCl3): δ 15.47 (s, 1H), 7.68−7.43 (m, 3H), 7.40−7.08 (m, 8H),
6.97 (dd, J = 8.2, 1.2 Hz, 1H), 6.83 (ddd, J = 7.9, 1.8, 0.4 Hz, 1H),
6.67 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 4.86 (t, J = 7.5 Hz, 1H), 3.50−
2.93 (m, 1H), 2.95−2.63 (m, 1H), 2.46−2.24 (m, 1H), 2.26−2.11
(m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 163.2, 144.4,
143.3, 134.2, 132.5, 131.9, 129.1, 128.9, 127.7, 126.7, 124.8, 124.0,
120.0, 118.1, 117.5, 65.6, 35.3, 30.9. HRMS (EI) m/z: [M + H]+
calcd for C22H20NO+, 314.1539; found, 314.1531. [α]D26 + 49 (c 1.0,
THF).
(S,E)-2-[{(1-Hydroxy-3-methylbutan-2-yl)imino}(phenyl)-
methyl]phenol (10c). Yellow solid (89 mg, 63%). H NMR (400
1
MHz, CDCl3): δ 15.86 (s, 1H), 7.49−7.41 (m, 3H), 7.30−7.18 (m,
3H), 6.97 (dd, J = 8.4, 1.0 Hz, 1H), 6.75 (dd, J = 8.0, 1.7 Hz, 1H),
6.61 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 4.01−3.62 (m, 2H), 3.34 (ddd, J
= 7.5, 5.6, 4.7 Hz, 1H), 2.13 (br, 1H), 1.99−1.63 (m, 1H), 0.95 (d, J
= 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 175.6, 164.3, 133.7, 132.9, 132.1, 129.1, 128.6, 128.3,
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119.7, 118.4, 117.3, 67.6, 64.9, 30.4, 19.8, 18.6. HRMS (EI) m/z: [M
133.8, 131.9, 131.2, 129.3, 121.1, 120.5, 119.1, 118.8, 118.6, 117.1,
+
+ H]+ calcd for C18H22NO2 , 284.1653; found, 284.1645. [α]D26 + 13
67.8, 64.3, 30.7, 19.9, 18.6. HRMS (EI) m/z: [M + H]+ calcd for
+
26
(c 1.0, THF).
C18H22NO3 , 300.1594; found, 300.1594. [α]D + 14 (c 1.0, THF).
2,2′,2″,2″′-([{(1S,2S)-1,2-Diphenylethane-1,2-diyl}bis-
(azaneylylidene)]bis(methanediyl ylidene))tetraphenol (11d).
2,2′-{(1E,1′E)-[{(1S,2S)-1,2-Diphenylethane-1,2-diyl}bis-
(azaneylylidene)]bis(phenylmeth aneylylidene)}diphenol
1
1
(10d). Yellow solid (86 mg, 30%). H NMR (400 MHz, DMSO-
Yellow solid (281 mg, 93%). H NMR (400 MHz, DMSO-d6): δ
d6): δ 15.14 (s, 2H), 7.57−7.46 (m, 2H), 7.48−7.39 (m, 4H), 7.32
(ddd, J = 8.5, 7.1, 1.7 Hz, 2H), 7.26−7.13 (m, 6H), 7.01 (dd, J = 8.3,
1.1 Hz, 2H), 6.91−6.83 (m, 4H), 6.72−6.59 (m, 6H), 6.55 (dd, J =
8.0, 1.7 Hz, 2H), 4.78 (s, 2H). 13C{1H} NMR (100 MHz, DMSO-
d6): δ 174.7, 161.9, 139.6, 133.1, 132.9, 131.5, 129.2, 128.6, 128.4,
127.4, 127.3, 126.6, 119.3, 117.9, 117.4, 71.3. HRMS (EI) m/z: [M +
15.39−15.32 (br, 2H), 9.40 (br, 2H), 7.31−7.22 (m, 4H), 7.18−6.80
(m, 14 H), 6.74−6.50 (m, 6H), 6.21−6.08 (m, 2H), 4.95−4.84 (m,
2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 172.8, 161.9, 154.0,
139.8, 132.4, 131.1, 130.5, 128.0, 127.7, 127.0, 119.8, 119.5, 118.6,
117.7, 117.5, 117.2, 115.3, 71.8. HRMS (EI) m/z: [M]+ calcd for
C40H32N2O2, 604.2362; found, 604.2360. [α]D26 + 136 (c 1.0, THF).
2,2′-{(Phenylimino)methylene}diphenol (11e). Yellow solid
+
26
H]+ calcd for C40H33N2O2 , 573.2537; found, 573.2540. [α]D + 21
1
(c 1.0, THF).
(457 mg, 79%). H NMR (400 MHz, DMSO-d6): δ 14.41 (s, 1H),
E-2-{Phenyl(phenylimino)methyl}phenol (10e). Yellow solid
(480 mg, 88%). 1H NMR (400 MHz, CDCl3): δ 14.54 (br, 1H), 7.37
(ddd, J = 8.3, 7.2, 1.7 Hz, 1H), 7.37−7.27 (m, 3H), 7.21−7.10 (m,
4H), 7.08 (dt, J = 8.0, 1.4 Hz, 2H), 7.03−6.85 (m, 1H), 6.81−6.66
(m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.5, 162.7, 147.0,
134.3, 133.4, 132.4, 129.0, 128.9, 128.6, 128.3, 124.6, 122.6, 120.1,
118.1, 118.1. HRMS (EI) m/z: [M + H]+ calcd for C19H16NO+,
274.1226; found, 274.1225.
9.89 (s, 1H), 7.38 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.27−7.10 (m, 3H),
7.06−6.89 (m, 6H), 6.84 (d, J = 1.0 Hz, 1H), 6.83−6.69 (m, 2H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 172.4, 161.4, 154.3, 147.0,
133.2, 131.6, 130.4, 129.0, 128.5, 124.7, 121.4, 121.3, 119.7, 118.8,
118.3, 117.3, 115.4. HRMS (EI) m/z: [M + H]+ calcd for
+
C19H16NO2 , 290.1176; found, 290.1178.
2,2′-[{(3,5-Dimethylphenyl)imino}methylene]diphenol
(11f). Yellow solid (538 mg, 85%). 1H NMR (400 MHz, DMSO-d6):
δ 14.53 (s, 1H), 9.89 (s, 1H), 7.36 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H),
7.19 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 6.98 (dd, J = 8.3, 1.2 Hz, 1H),
6.94 (ddd, J = 8.5, 6.8, 1.7 Hz, 2H), 6.87 (dd, J = 8.3, 1.0 Hz, 1H),
6.80−6.72 (m, 2H), 6.64 (t, J = 1.6 Hz, 1H), 6.55 (d, J = 1.7 Hz, 2H),
2.12 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 171.9, 161.5,
154.5, 146.8, 137.4, 133.0, 131.5, 130.4, 128.9, 126.3, 121.5, 119.7,
119.1, 118.8, 118.2, 117.4, 115.3, 20.9. HRMS (EI) m/z: [M + H]+
E-2-[{(3,5-Dimethylphenyl)imino}(phenyl)methyl]phenol
1
(10f). Yellow solid (493 mg, 82%). H NMR (400 MHz, CDCl3): δ
14.68 (br, 1H), 7.43−7.29 (m, 4H), 7.21−7.14 (m, 2H), 7.13−7.02
(m, 2H), 6.75 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 6.64 (s, 1H), 6.40 (s,
2H), 2.16 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 172.9,
162.8, 146.6, 138.1, 134.3, 133.2, 132.3, 128.9, 128.8, 128.2, 126.4,
120.4, 120.1, 118.1, 118.0, 21.3. HRMS (EI) m/z: [M + H]+ calcd for
C21H20NO+, 302.1539; found, 302.1546.
+
calcd for C21H20NO2 , 318.1489; found, 318.1479.
E-2-[{(3,5-Dimethoxyphenyl)imino}(phenyl)methyl]phenol
1
2,2′-[{(3,5-Dimethoxyphenyl)imino}methylene]diphenol
(11g). Yellow solid (540 mg, 77%). 1H NMR (400 MHz, DMSO-d6):
δ 14.25 (s, 1H), 9.95 (s, 1H), 7.38 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H),
7.20 (ddd, J = 8.3, 7.3, 1.7 Hz, 1H), 7.05−6.94 (m, 2H), 6.93 (dd, J =
8.0, 1.7 Hz, 2H), 6.88 (dd, J = 8.2, 1.0 Hz, 2H), 6.15 (s, 3H), 3.61 (s,
6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 172.5, 161.3, 160.2,
154.4, 148.8, 133.2, 131.6, 130.4, 128.7, 121.6, 119.6, 118.9, 118.3,
117.3, 115.3, 99.6, 96.9, 55.0. HRMS (EI) m/z: [M + H]+ calcd for
(10g). Yellow solid (488 mg, 73%). H NMR (400 MHz, CDCl3): δ
14.39 (s, 1H), 7.48−7.30 (m, 4H), 7.23−7.12 (m, 2H), 7.12−7.03
(m, 2H), 6.75 (ddd, J = 7.9, 7.2, 1.2 Hz, 1H), 6.72 (t, J = 2.3 Hz, 1H),
5.95 (d, J = 2.2 Hz, 2H), 3.62 (s, 6H). 13C{1H} NMR (100 MHz,
DMSO-d6): δ 173.4, 162.6, 160.7, 148.6, 134.3, 133.5, 132.5, 129.1,
128.7, 128.3, 119.9, 118.2, 118.1, 101.0, 97.3, 55.4. HRMS (EI) m/z:
+
[M + H]+ calcd for C21H20NO3 , 334.1438; found, 334.1439.
2,2′-{(Cyclohexylimino)methylene}diphenol (11a). Yellow
+
1
C21H20NO4 , 350.1387; found, 350.1390.
solid (130 mg, 88%). H NMR (400 MHz, DMSO-d6): δ 16.00 (s,
2,2′-([{3,5-Bis(trifluoromethyl)phenyl}imino]methylene)-
1H), 9.79 (s, 1H), 7.33 (ddd, J = 8.2, 7.3, 1.8 Hz, 1H), 7.25 (ddd, J =
8.3, 7.0, 1.9 Hz, 1H), 7.06 (dd, J = 7.5, 1.6 Hz, 1H), 6.99 (dd, J = 8.3,
0.7 Hz, 1H), 6.94 (td, J = 7.4, 1.0 Hz, 1H), 6.84 (dd, J = 8.3, 1.1 Hz,
1H), 6.70 (dd, J = 7.9, 1.8 Hz, 1H), 6.63 (ddd, J = 8.0, 7.0, 1.2 Hz,
1H), 3.26−3.08 (m, 1H), 1.85−1.56 (m, 4H), 1.55−1.36 (m, 3H),
1.36−1.23 (m, 1H), 1.23−1.03 (m, 2H). 13C{1H} NMR (100 MHz,
DMSO-d6): δ 169.9, 163.0, 153.8, 132.0, 130.6, 130.5, 128.4, 120.3,
119.4, 119.1, 117.5, 117.0, 115.7, 58.7, 33.2, 32.8, 25.1, 23.5. HRMS
1
diphenol (11h). Yellow solid (192 mg, 45%). H NMR (400 MHz,
DMSO-d6): δ 13.42 (s, 1H), 10.06 (s, 1H), 7.71 (dt, J = 1.8, 0.9 Hz,
1H), 7.57 (dd, J = 1.7, 0.8 Hz, 2H), 7.45 (ddd, J = 8.3, 7.2, 1.7 Hz,
1H), 7.19 (ddd, J = 8.3, 7.3, 1.7 Hz, 1H), 7.10 (dd, J = 7.6, 1.7 Hz,
1H), 7.03 (ddd, J = 8.4, 7.3, 1.4 Hz, 2H), 6.84 (ddd, J = 8.1, 7.2, 1.2
Hz, 1H), 6.82 (dd, J = 8.3, 1.0 Hz, 1H), 6.78 (td, J = 7.5, 1.0 Hz, 1H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 174.8, 161.2, 154.0, 149.4,
134.1, 132.1, 130.9, 130.4, 130.1, 129.1, 124.4, 121.7, 120.5, 119.3,
118.9, 117.5, 115.4. HRMS (EI) m/z: [M + H]+ calcd for
+
(EI) m/z: [M + H]+ calcd for C19H22NO2 , 296.1645; found,
296.1644.
+
C21H14NO2 , 426.0923; found, 426.0934.
(R)-2,2′-[{(2,3-Dihydro-1H-inden-1-yl)imino}methylene]-
1
diphenol (11b). Yellow solid (130 mg, 88%). H NMR (400 MHz,
2,2′-[{(3,5-Difluorophenyl)imino}methylene]diphenol (11i).
1
DMSO-d6): δ 16.00 (s, 1H), 9.79 (s, 1H), 7.33 (ddd, J = 8.2, 7.3, 1.8
Hz, 1H), 7.25 (ddd, J = 8.3, 7.0, 1.9 Hz, 1H), 7.06 (dd, J = 7.5, 1.6
Hz, 1H), 6.99 (dd, J = 8.3, 0.7 Hz, 1H), 6.94 (td, J = 7.4, 1.0 Hz, 1H),
6.84 (dd, J = 8.3, 1.1 Hz, 1H), 6.70 (dd, J = 7.9, 1.8 Hz, 1H), 6.63
(ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 3.26−3.08 (m, 1H), 1.85−1.56 (m,
4H), 1.55−1.36 (m, 3H), 1.36−1.23 (m, 1H), 1.23−1.03 (m, 2H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 171.8, 162.2, 153.9, 144.2,
143.0, 132.2, 130.9, 130.7, 128.8, 127.6, 126.5, 124.6, 123.9, 120.5,
119.6, 119.3, 117.6, 117.3, 115.8, 65.4, 34.4, 30.3. HRMS (EI) m/z:
Yellow solid (182 mg, 56%). H NMR (400 MHz, DMSO-d6): δ
13.54 (s, 1H), 9.99 (s, 1H), 7.43 (ddd, J = 8.3, 7.2, 1.7 Hz, 1H), 7.21
(ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.06 (dd, J = 7.6, 1.7 Hz, 1H), 7.01
(dd, J = 8.3, 1.1 Hz, 1H), 6.96 (dd, J = 8.0, 1.7 Hz, 1H), 6.93−6.75
(m, 4H), 6.69−6.61 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6):
δ 173.9, 161.1, 154.0, 150.3, 133.8, 131.9, 130.8, 128.9, 121.0, 119.4,
118.6, 117.4, 115.5, 105.1, 104.8, 99.8. HRMS (EI) m/z: [M ]+ calcd
for C19H13F2NO2, 325.0914; found, 325.0915.
+
[M + H]+ calcd for C22H20NO2 , 330.1489; found, 330.1488.
ASSOCIATED CONTENT
(S)-2,2′-[{(1-Hydroxy-3-methylbutan-2-yl)imino}-
methylene]diphenol (11c). Yellow solid (127 mg, 85%). 1H NMR
(400 MHz, CDCl3): δ 7.35 (ddd, J = 8.3, 6.1, 2.9 Hz, 1H), 7.20 (ddd,
J = 8.4, 7.1, 1.8 Hz, 1H), 7.13−7.04 (m, 1H), 7.04−6.96 (m, 2H),
6.86 (dd, J = 8.4, 1.2 Hz, 1H), 6.74 (dd, J = 8.1, 1.7 Hz, 1H), 6.54
(ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.89−3.65 (m, 2H), 3.43−3.15 (m,
1H), 1.96−1.67 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 166.3, 152.9,
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01908.
Spectroscopic and calculation data including 1H and 13
NMR (PDF)
C
F
DOI: 10.1021/acs.joc.8b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
́
(17) Esteban, F.; Cieslik, W.; Arpa, E. M.; Guerrero-Corella, A.;
AUTHOR INFORMATION
Corresponding Author
*E-mail: hwkim@kaist.edu.
ORCID
■
́
́
Díaz-Tendero, S.; Perles, J.; Fernandez-Salas, J. A.; Fraile, A.; Aleman,
J. Intramolecular Hydrogen Bond Activation: Thiourea-Organo-
catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylalde-
hyde-Derived Azomethine Ylides with Nitroalkenes. ACS Catal. 2018,
8, 1884−1890.
Hyunwoo Kim: 0000-0001-5030-9610
(18) Guerrero-Corella, A.; Esterban, F.; Iniesta, M.; Martín-Somer,
A.; Parra, M.; Díaz-Tendero, S.; Fraile, A.; Aleman, J. 2-
Hydroxybenzophenone as a Chemical Auxiliary for the Activation
of Ketiminoesters for Highly Enantioselective Addition to Nitro-
alkenes under Bifunctional Catalysis. Angew. Chem., Int. Ed. 2018, 57,
5350−5354.
Author Contributions
́
†M.-S.S. and S.J. contributed equally.
Notes
The authors declare no competing financial interest.
(19) Jung, H.; Lee, A.; Kim, J.; Kim, H.; Baik, M.-H. Regiodivergent
Conjugate Addition Controlled by Rhodium(I) and Palladium(II)
Catalysts: A Combined Computational and Experimental Study. Adv.
Synth. Catal. 2017, 359, 3160−3175.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
Samsung Science and Technology Foundation (SSTF-
BA1601-10).
(20) Lee, A.; Kim, H. Chiral Bicyclic Bridgehead Phosphoramidite
(Briphos) Ligands for Asymmetric Rhodium-Catalyzed 1,2- and 1,4-
Addition. J. Org. Chem. 2016, 81, 3520−3527.
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DOI: 10.1021/acs.joc.8b01908
J. Org. Chem. XXXX, XXX, XXX−XXX