Axially Chiral Bifunctional 8,8′-Biquinolyl: Synthesis of 7,7′-Dihydroxymethyl-8,8′-biquinolyl via Pd-Catalyzed Double C-H Oxidation of 7,7′-Dimethyl-8,8′-biquinolyl

Article abstract of DOI:10.1021/acs.joc.6b00534

Bifunctional C₂-symmetric 7,7′-dihydroxymethyl-8,8′-biquinolyl (2) was synthesized in short steps via (i) Cu/Pd-catalyzed homo coupling of 7-methyl-8-bromoquinoline and (ii) Pd(II)-catalyzed double C-H oxidation. Axial chirality of 2 and its synthetic precursor 7,7′-dimethyl-8,8′-biquinolyl (3) is stable. Optically active 2 was obtained through separation of racemic 2 by chiral column HPLC or Pd(II)-catalyzed double C-H oxidation of optically active 3. The absolute stereochemistry of enantiomers of 2 and 3 was determined using the exciton chirality method.

Full text of DOI:10.1021/acs.joc.6b00534

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Note
Axially Chiral Bifunctional 8,8#-Biquinolyl: Synthesis of
,7#-dihydroxymethyl-8,8#-biquinolyl via Pd-catalyzed
7
Double C–H Oxidation of 7,7#-Dimethyl-8,8#-biquinolyl
Mitsuru Kitamura, Hiroaki Fukuma, Mitsuaki Kobayashi, Shinya Okayama, and Tatsuo Okauchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00534 • Publication Date (Web): 04 Apr 2016
Downloaded from http://pubs.acs.org on April 6, 2016
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Axially Chiral Bifunctional 8,8′ꢀBiquinolyl: Synthesis of 7,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl
via Pdꢀcatalyzed Double C–H Oxidation of 7,7′ꢀDimethylꢀ8,8′ꢀbiquinolyl
Mitsuru Kitamura,* Hiroaki Fukuma, Mitsuaki Kobayashi, Shinya Okayama, and Tatsuo
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Okauchi
Department of Applied Chemistry, Kyushu Institute of Technology, 1ꢀ1 Sensuicho, Tobata,
Kitakyushu, 804ꢀ8550 Japan
Corresponding authors' email address
kita@che.kyutech.ac.jp
Table of Contents/Abstract Graphic
Abstract: Bifunctional
synthesized in short steps via i) Cu/Pdꢀcatalyzed homo coupling of
ꢀmethylꢀ8ꢀbromoquinoline, and ii) Pd(II)ꢀcatalyzed double C–H oxidation. Axial chirality of 2
2
C ꢀsymmetric 7,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl (2) was
7
and its synthetic precursor 7,7′ꢀdimethylꢀ8,8′ꢀbiquinolyl (3) is stable. Optically active 2 was
obtained through separation of racemic 2 by chiral column HPLC or Pd(II)ꢀcatalyzed double
C–H oxidation of optically active 3. The absolute stereochemistry of enantiomers of 2 and 3
was determined using the exciton chirality method.
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2,2′ꢀDisubstitutedꢀ1,1′ꢀbinaphthyl is an efficient scaffold for chiral ligands because the
1
axial chirality of the biaryl bond is stable. 1,1′ꢀBinaphthylꢀ2,2′ꢀdiol (BINOL) is known to be
one of the most effective asymmetric ligands and is used in various fields such as chiral
2
recognition and for chiral materials (Figure 1). For the stability of axial chirality in BINOL, the
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peri C–H bonds in the 8,8′ꢀpositions on the 1,1′ꢀbinaphthyl skeleton are important for inducing
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a high rotational barrier around the biaryl bond. Various modifications of BINOL have been
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examined to increase the efficiency of chiral reagents, such as partial hydrolysis or the
4
introduction of fluorine
to BINOL. The azaꢀanalogue
1
(azaꢀBINOL,
7
,7′ꢀdihydroxyꢀ8,8′ꢀbiquinolyl), wherein the 8,8′ꢀC–H positions in BINOL are replaced by
nitrogen, is expected to be a bifunctional chiral source; however, it has not been used for this
5
purpose because of the low rotational barrier around the azaꢀBINOL biaryl bond. The low
2
rotational barrier of 1 is due to the low repulsion between the sp nitrogen atoms and between
2
the sp nitrogen and hydroxy group.
Figure 1. BINOL and bifunctionalbiquinolinediol 1 and 2
We envisioned that 7,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl (2), where the hydroxy
groups are replaced by hydroxymethyl groups in azaꢀBINOL 1, is a configurationally stable
bifunctional biquinoline with the potential to be a new chiral reagent. We then examined the
synthesis of biquinolinediol 2 and its configurational stability.
We planned to synthesize biquinolinediol 2 by the oxidation of dimethylbiquinoline 3
(
Scheme 1). Optically active 2 could be synthesized from optically active 3 if 3 is
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configurationally stable or it could be obtained by the optical resolution of a racemic mixture of
2
.
Scheme 1. Synthetic plan of optically active biquinolinediol 2
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Dimethylbiquinoline 3 was synthesized from oꢀtoluidine in 7 steps by reported
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procedures (Scheme 2).
a
Scheme 2. Synthesis of dimethylbiquinoline 3 from oꢀtoluidine
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We developed an alternative synthetic method for dimethylbiquinoline 3 from
commercially available 7ꢀmethylquinoline (8) in 2 steps via homoꢀcoupling of bromoquinoline
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(Scheme 3). Bromoquinoline 9 was synthesized quantitatively by the bromination of 8 with
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NBS in sulfuric acid. When Ullmann coupling of 9 was attempted by treatment with Cu
powder in DMF at reflux temperature, reduction product 8 was primarily obtained, and the
desired homoꢀcoupled product 3 was obtained in 33% yield. The yield of 3 increased to 56%
8
yield by treating with Cu powder in the presence of a catalytic amount of Pd(OAc)
2
, and the
yield of the reduction product 8 decreased to 20%. Although homoꢀcoupling of
2
ꢀunsubstitutedꢀ8ꢀhaloꢀquinoline has been successful by treating with a Ni catalyst (cat. NiCl ,
7
9
,10
PPh , Zn), it was not efficient for the homoꢀcoupling of 9.
3
Scheme 3. Preparation of dimethylbiquinoline 3 from 7ꢀmethylquinoline (8)
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Chiral column HPLC analysis of 3 (DAICEL CHIRALPAK ADꢀH (4.6 mm × 250
mm), hexane/iPrOH = 9/1, 0.2 mL/min, retention time: 1st eluent 38.5 min, 2nd eluent 45.3
min) showed the existence of two rotamers, and each rotamer was collected by preparative
chiral column HPLC (DAICEL CHIRALPAK ADꢀH). The configuration of the first and second
eluates were assigned as (S)ꢀ3 (92% ee) and (R)ꢀ3 (98% ee), respectively, using the exciton
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chirality method (vide infra).
Next, we conducted the transformation of dimethylbiquinoline
,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl 2 using the racemic compound. First, we intended to
3
to
7
synthesize 2 by bromination of the benzylic positions of 3 followed by successive substitution
of the bromide with oxygen nucleophiles, similar to the synthesis of
1
2
2
,2'ꢀdihydroxymethylꢀ1,1′ꢀbinaphthyl from 2,2'ꢀdimethylꢀ1,1′ꢀbinaphthyl. Although radical
bromination was attempted for 3 under various reaction conditions, the formation of dibromide
0 failed and highꢀpolar compounds were formed (Eq. 1). The highꢀpolar compounds could be
quinolinium salts such as 11 and 12, formed by the benzylic bromination of 3 followed by
1
1
3
intramolecular cyclization.
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The recent developments in heteroatomꢀdirected metalꢀcatalyzed oxidation of C–H
14
bonds are remarkable. Pd(OAc)
2
ꢀcatalyzed oxidation combined with PhI(OAc)
2
as a
reꢀoxidant is recognized as a reliable method which enables the introduction of an acetoxy
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2 2
group. Various directing groups are utilized for the Pd(OAc) /PhI(OAc) oxidation. Among
1
5a
them, the pyridyl group is an efficient directing group. Recently, Blakemore succeeded in the
synthesis of the diacetate of azaꢀBINOL 1 by the double aryl C–H bond oxidation of
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2 2
,8′ꢀbiquinolyl with Pd(OAc) /PhI(OAc) which proceeds via a 6ꢀmembered palladacycle
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intermediate. We expected that acetoxy groups could be introduced at the benzylic positions
of 3 if a similar quinolineꢀnitrogen directed C–H bond oxidation proceeded at one of the
extended carbon positions.
Oxidation of dimethylbiquinoline 3 was examined by treatment with 20 mol%
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2 2
Pd(OAc) and 2.5 equiv of PhI(OAc) in acetic acid at reflux temperature (Table 1, Run 1).
The desired diacetate 14 was obtained in 16% yield after stirring the mixture for 18 h, and the
monoꢀacetate 13 was obtained in 44% yield. The yield of diacetate 14 increased with increasing
amounts of PhI(OAc) (Runs 1–3). Diacetate 14 was obtained in 63% yield with 8 equiv of
2
PhI(OAc)
2
for a prolonged reaction time (38 h, Run 4). A lower loading of Pd(OAc)
2
led to a
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decrease in the yield of the desired double C–H activation product 14, and 3 was recovered
(
Runs 5 and 6). In the Pd(OAc) /PhI(OAc) ꢀmediated reaction of 3, the color of the reaction
2 2
mixture gradually turned black, and the reaction rate slowed as measured by TLC monitoring.
When additional PhI(OAc) was added to the black reaction mixture, the color of the mixture
changed to orange, and the progress of the reaction was monitored by TLC. The oxidation
reaction was then conducted by adding an extra 2.0 equiv. of PhI(OAc) whenever the reaction
mixture turned black, and 14 was obtained in 74% yield by treating with an overall 20 equiv. of
PhI(OAc) (Run 7).
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2
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Table 1. Double C–H oxidation of 3 with Pd(OAc) /PhI(OAc)
Run
Pd(OAc)2 PhI(OAc)2
Time
(h)
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16
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38
38
38
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Yield (%)
(mol%)
20
(equiv.)
3
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44
63
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The desired 7,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl (2) was obtained in quantitative
yields by the hydrolysis of 14 with methanolic KOH (rt, 2 h).
Two rotamers of 2 were detected by chiral column HPLC (DAICEL CHIRALPAK
ADꢀH (4.6 mm × 250 mm), hexane/iPrOH= 4/1, 0.6 mL/min, retention time: 1st eluent 33.9
min, 2nd eluent 51.6 min), and each of the rotamers was collected as enantiomerically pure
form, by preparative chiral column HPLC (DAICEL CHIRALPAK ADꢀH). The configuration
of the first and second eluted rotamers of 2 were assigned (S) and (R), respectively, using the
exciton chirality method (vide infra).
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Next, double Pd(OAc) /PhI(OAc) oxidation of enantiomer of dimethylbiquinoline 3
and the successive hydrolysis were examined (Scheme 4). (R)ꢀ3 (98% ee) was successfully
transformed to (R)ꢀ2 (98% ee) without racemization.
Scheme 4. Reaction with optically active 3
We determined the absolute stereochemistry of separated enantiomers 2 and 3 using
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the exciton chirality method, which is one of the efficient methods for chirality determination.
To apply the exciton chirality method to binaphtylꢀtype compounds, information of the ground
state dihedral angle of the biaryl parts is required because the sign of spritꢀtype Cotton effects is
17
sensitive to the dihedral angle.
We employed a geometry optimization of 2 and 3 with a semiꢀempirical PM3
18
method, and dihedral angles of two quinoline planes in 2 and 3 were found to be less than 90°
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(2: 87 and 85° for the dihedral C(7)–C(8)–C(8′)–C(7′) and C(8a)–C(8)–C(8′)–C(8a′),
respectively; 3: 88 and 87° for the dihedral C(7)–C(8)–C(8′)–C(7′) and C(8a)–C(8)–C(8′)–
C(8a′), respectively; carbon numbering is shown in Scheme 4), allowing 2 and 3 to be studied
using the exciton chirality method.
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In Figures S1 and S2 (See, supporting information), CD and UV spectra for 3 and 2 are
shown, respectively. In the UV spectrum of 3, absorption was observed at 233 nm, assigned to a
1
Platt singlet transition state of B
b
(Figure S1). In the CD spectrum of enantiomers of 3, exciton
1
coupling between longꢀaxes polarized B
b
was observed, and two extrema with opposite signs
were detected at 238 and 227 nm. In the CD spectrum of the first chiral column HPLC (vide
supra) eluted compound of 3 (92% ee), a positive Cotton effect was observed (split CD
extrema: ꢀε238 +129; ꢀε227 –82). Therefore, its absolute configuration was assigned to (S), and
the second eluted compound of 3 (98% ee) was assigned to the (R)ꢀisomer, which showed a
negative Cotton effect.
The absolute configuration of 2 was assigned in a similar fashion to 3. In the UV
spectrum of 2, the absorption observed at 233 nm was assigned to the Platt singlet transition
1
state of B
b
(Figure S2). In the CD spectrum of enantiomerically pure 2, exciton coupling
1
between longꢀaxes polarized B
b
was observed, and two extrema with opposite signs were
detected at 238 and 226 nm. In the CD spectra of the first chiral column HPLC (vide supra)
1
eluted compound of 2, a positive Cotton effect induced by exciton coupling between B
b
was
observed (split CD extrema: ꢀε238 +117; ꢀε226 –74); therefore, its absolute configuration was
assigned as (S), and the second eluted compound 2 was assigned to the (R)ꢀisomer, which
showed a negative Cotton effect.
The axial chirality of 2 and 3 was found to be stable at room temperature for at least 2
months, and racemization of separated optically active 2 and 3 was not observed in toluene at
reflux temperature for 48 h.
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In conclusion, we achieved the synthesis of bifunctional C
2
symmetric
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,7′ꢀdihydroxymethylꢀ8,8′ꢀbiquinolyl (2) via i) Cu/Pdꢀcatalyzed homo coupling of
ꢀbromoquinoline, and ii) Pd(II)ꢀcatalyzed double C–H oxidation. Axial chirality of 2 is stable,
8
and optically active
2
was obtained by the separation of racemic
2
or
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,7′ꢀdimethylꢀ8,8′ꢀbiquinolyl (3), the precursor of the Pd(II)ꢀcatalyzed C–H functionalization,
by chiral column HPLC. Pdꢀcatalyzed CꢀH activation reaction enables to synthesize 2 which
could not be synthesized by traditional method.
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Experimental Section
General Methods
1
All reactions were carried out under a nitrogen atmosphere. H NMR (400 MHz, 500 MHz) and
1
3
1
1
C{ H} NMR (100 MHz, 126 MHz) spectra were recorded in CDCl
3
[TMS (for H, δ = 0) or
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1
3
CDCl
3
(for C, δ = 77.0) was used as an internal standard]. HRMSꢀFAB spectra were obtained
with a double focusing sector detector. Enantiomeric excess were determined by HPLC
analysis using chiral column (DICEL CHIRALPAK ADꢀH) with hexane/2ꢀpropanol as the
solvent. PM3 calculation was conducted with Spartan 14.
Materials
DMF and Toluene were distilled from CaH
2
and stored over 4A molecular sieves. Acetic acid
was distilled from KMnO . PhI(OAc) was recrystallized with hexane.
4
2
Typical procedure and spectroscopic data of products
6
Preparation of 7,7’-dimethyl-8,8’-biquinoline (3) by reported procedure (Scheme 2)
oꢀToluidine (9.96 g, 94.1 mmol) was added in acetic anhydryde (65 mL) at 0 °C and the mixture
was stirred for 2 h at 0 °C. Then, nitric acid (12.6 mL, 188 mmol) was added slowly for 1 h and
the mixture was stirred for 3 h. The mixture was poured into ice and thus formed solid was
2
collected by vacuum filtration. The residue was solved in the solutiomn of H O (540 mL),
EtOH (119 mL), KOH (60.0 g) and the mixture was stirred for 1 h at room temperature. Solid
was separated by vacuum filtration and the filtrate was purified by recrystallization
(
hexane/EtOAc) to give 2ꢀacetylamideꢀ3ꢀmethyl nitrobenzene (4) (11.5 g, 70.6 mmol) in 75%
1
yield. H NMR (400 MHz, CDCl
3
) δ 8.32 (br, 1H), 7.83 (d, 1H, J = 8.1 Hz), 7.51 (d, 1H, J = 8.1
1
3
1
3
Hz), 7.28 (dd, 1H, J = 8.0, 7.9 Hz), 2.32 (s, 3H), 2.23 (s, 3H); C{ H} NMR (100 MHz, CDCl )
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2
2
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δ 168.3, 144.9, 138.3, 136.1, 129.7, 126.4, 122.8, 23.8, 19.8. A solution of 4 (22.9 g, 141 mmol)
in conc. HCl (150 mL) was heated at 85 °C and the mixture was stirred for 6 h. The reaction
flask was cooled to 0 °C and was added dropwise solution of NaNO
2
(12.1 g, 176 mmol) in H
44 mL) for 1 h. After stirring the mixture for 1 h, the mixture was poured into solution of KI
34.1 g, 200 mmol) in ice water and the mixture was stirred for 2 h. Aqueous NaHSO was
2
O
(
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
added to the mixture, and the mixture was stirred for 1 h. Solid was separated by vacuum
filtration, and was purified by recrystallization (Hexane/EtOAc) to give 2ꢀiodoꢀ3ꢀmethyl
1
nitrobenzene (5) (28.5 g, 109 mmol) in 77% yield. H NMR (400 MHz, CDCl
3
) δ 7.43 (d, 2H, J
) δ
13
1
=
7.4 Hz), 7.35 (dd, 1H, J = 8.0, 7.2 Hz), 2.58 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
145.2, 132.3, 128.6, 121.8, 92.4, 29.7. To a solution of 5 (1.52 g, 5.78 mmol) in DMF (12 mL)
was added Cu powder (1.51 g, 23.7 mmol) and the mixture was stirred for 2 h at reflux. The
reaction quenched with sat. NaHCO aq. and basified with 2 M NaOH aq. The mixture was
3
filtered through a celite pad. The organic materials were extracted with EtOAc (3 × 20 mL),
washed with H
2
O (3 × 50 mL), and dried over anhydrous sodium sulfate. The solvent was
removed in vacuo to afford crude compound, which was purified by recrystallization
(hexane/EtOAc) to give 3,3’ꢀdimethylꢀ2,2’ꢀbinitrobenzene (6) (692 mg, 2.54 mmol) in 88%
1
yield. H NMR (400 MHz, CDCl ) δ 7.98 (d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 7.5 Hz), 7.46 (dd,
3
1
3
1
2
3
H, J = 8.0, 7.9 Hz), 1.98 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 148.1, 138.3, 135.2,
131.4, 128.6, 122.3, 19.8. To a solution of 6 (400 mg, 1.47 mmol) in conc. HCl (9.6 mL) and
EtOH (5.0 mL) was added Sn powder (994 mg, 8.82 mmol), and the mixture was stirred for 2 h
at reflux. The reaction mixture was poured into ice water and basified with 2 M NaOH aq. After
removing EtOH in vacuo. The resulting suspention was filtered through a Celite pad. Organic
2 2
materials were extracted with CH Cl (3×30 mL) from the filtrate, and the organic layer was
washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed in
vacuo to afford crude compound, which was purified by recrystallization (hexane/EtOAc) to
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8
9
1
give 3,3’ꢀdimethylꢀ2,2’ꢀbianiline (7) (311 mg, 1.47 mmol), quantitatively. H NMR (500 MHz,
CDCl ) δ 7.08 (dd, 2H, J = 8.0, 7.5 Hz), 6.72 (d, 2H, J = 7.5 Hz), 6.64 (d, 2H, J = 8.0 Hz), 3.45
3
13
1
(
brs, 4H), 1.97 (s, 6H); C{ H} NMR (126 MHz, CDCl
12.8, 19.5. To a solution of 7 (2.81 g, 13.2 mmol) in nitrobenzene (10 mL) and conc. H
2.8 mL) was added FeSO (H O) (1.83 g, 6.50 mmol) and glycerol (4.86 g, 53.0 mmol), the
3
) δ 144.2, 137.9, 128.4, 122.2, 120.1,
1
2
SO
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
4
2
7
mixture was stirred for 6 h at reflux. The reaction mixture was poured into ice water, basified
with sat. NaHCO aq., and filtered through a celite pad. The filtrate was acidified with 2 M HCl
3
2
aq. and extracted with H O (3 × 50 mL). After the aqueous layer was basified with 2 M NaOH
aq., the layer was extracted with EtOAc (3 × 50 mL) and the combined organic extracts were
dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford crude
compound, which was purified by column chlomatography (silica gel, hexane/EtOAc = 2/1) to
give 3 (2.14 g, 7.52 mmol) in 57% yield.
Separation of 3 by chiral column HPLC
Chiral column HPLC analysis of 3 (DAICEL CHIRALPAK ADꢀH (4.6 mm × 250 mm),
hexane/iPrOH = 9/1, 0.2 mL/min, retention time: 1st eluent 38.5 min, 2nd eluent 45.3 min)
showed the existence of two rotamers. Racemic 3 (ca 1 mg) was solved in mixed solvent
(hexane/iPrOH = 9/1, 5 mL) and was separated two enantiomers (S)ꢀ3 and (R)ꢀ3 by chiral
column preparative HPLC (column: DAICEL CHIRAL PAK ADꢀH; eluent: hexane/iPrOH =
9
/1). The configuration of the first and second eluates were assigned as (S)ꢀ3 (92% ee) and
(
R)ꢀ3 (98% ee), respectively, using the exciton chirality method (see, Text).
7,7’-Dimethyl-8,8’-biquinoline (3)
1
m.p. 219ꢀ223 °C (dec). H NMR (400 MHz, CDCl
3
) δ 8.71 (dd, 2H, J = 4.2, 1.8 Hz), 8.16 (dd,
2
H, J = 8.2, 1.8 Hz), 7.82 (d, 2H, J = 8.3 Hz), 7.57 (d, 2H, J = 8.3 Hz), 7.28 (dd, 2H, J = 8.2, 4.2
13
1
Hz), 2.06 (s, 6H). C{ H} NMR (100 MHz, CDCl
3
) 150.2, 147.3, 138.1, 137.1, 135.9, 129.4,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
127.1, 126.8, 119.9, 20.6. IR (ATR) 3028, 1489, 802. HRMS(FAB ) m/z (M+H) Calcd for
20 17 2
C H N
285.1392, Found 285.1384. UVꢀVis (MeOH) λmax 320 nm (ɛ 6400), 233 (43600), 208
(45200).
2
5
For (S)ꢀ3 (92% ee): [α]D =ꢀ34 (c 1.0, CHCl
3
). CD (MeOH) λext 238 nm (ꢀε +129), 227 (ꢀ82).
). CD (MeOH) λext 238 nm (ꢀε ꢀ155), 227 (+74).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
D
For (R)ꢀ3 (98% ee): [α] =+44 (c 1.0, CHCl
3
7
8-Bromo-7-methylquinoline (9)
2 4
To a solution of 7ꢀmethylquinoline (8) (10.8 g, 75 mmol) in conc. H SO (150 mL) was added
NBS (13.5 g, 75.3 mmol) at 0 °C, and the mixture was stirred for 2 h at room temperature. The
reaction flask poured into iced water, and basified with 2 M NaOH aq. The organic materials
were extracted with EtOAc (3 × 200 mL), and dried over anhydrous sodium sulfate. The solvent
was removed in vacuo to afford crude compound, which was purified by column
chlomatography (Silicagel, Hexane/EtOAc = 6/1) to give 9 (16.7 g, 75 mmol), quantitatively.
1
H NMR (400 MHz, CDCl ) δ 8.95 (dd, 1H, J = 4.2, 1.7 Hz), 7.89 (dd, 1H, J = 8.2, 1.7 Hz), 7.43
3
(
d, 1H, J = 8.3 Hz), 7.30 (dd, 1H, J = 8.2, 4.2 Hz), 7.29 (d, 1H, J = 8.3 Hz), 2.60 (s, 3H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 150.4, 150.3, 145.0, 139.6, 135.8, 128.8, 127.1, 126.1,
125.3, 120.4, 23.8.
Preparation of 7,7’-dimethyl-8,8’-biquinoline (3) by homo coupling of 9 (Scheme 3)
To a solution of 9 (1.05 g, 4.74 mmol) in DMF (11 mL) was added Pd(OAc) (56.0 mg, 0.25
mmol) and Cu powder (1.51 g, 24.8 mmol), and the mixture was stirred for 10 h at reflux
170 °C). The reaction was quenched with 2 M NaOH aq. and the organic materials were
2
(
extracted with EtOAc (3×50 mL) and dried with anhydrous sodium sulfate. The solvent was
removed in vacuo to afford crude compound, which was purified by column chlomatography
(Silicagel, hexane/EtOAc = 2/1) to give 3 (380 mg, 1.34 mmol) in 56% and 8 (138 mg, 0.96
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8
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mmol) in 20% yield.
Pd-catalyzed double C-H oxidation of 7,7’-dimethyl-8,8’-biquinoline (3)
2
To a solution of 3 (49.0 mg, 0.17 mmol) in AcOH (3.4 mL) was added Pd(OAc) (7.6 mg, 0.034
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2 2
mmol) and PhI(OAc) (354 mg, 1.1 mmol), and the mixture was stirred at reflux. PhI(OAc)
(113 mg, 0.35 mmol) was added 6 times by ca. 1 h to the reaction mixture when the color of
reaction mixture became black and the progress of the reaction was not observed by TLC. The
reaction lasted after 7 h, and was quenched with sat. NaHCO
extracted with CH Cl (3 × 10 mL), washed with brine, and dried over anhydrous sodium
sulfate. The solvent was removed in vacuo to afford crude compound, which was purified by
column chlomatography (silica gel, CHCl /MeOH = 19/1) to give 14 (51 mg, 0.13 mmol) in
4%.
3
aq. The organic materials were
2
2
3
7
7,7’-Diacethoxymethyl-8,8’-biquinoline (14)
1
m.p. 165ꢀ167°C (dec). H NMR δ 8.73, (dd, 2H, J = 4.2, 1.8 Hz), 8.20 (dd, 2H, J = 8.2, 1.7 Hz),
7.96 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.35 (dd, 2H, J = 8.2, 4.2 Hz), 4.90 (d, 2H, J
13
1
=
13.1 Hz), 4.78 (d, 2H, J = 13.1 Hz), 1.94 (s, 6H). C{ H} NMR (100 MHz, CDCl ) δ 170.5,
3
150.6, 147.0, 136.1, 135.6, 128.4, 128.1, 126.3, 121.1, 77.2, 64.6, 20.7. IR (KBr) 3051, 1740,
ꢀ1
+
+
21 2 4
1371 cm . HRMS (FAB ) m/z (M+H) Calcd for C24H N O 401.1501, Found: 401.1499.
7-Acethoxymethyl-7’-methyl-8,8’-biquinoline (13)
1
m.p. 169ꢀ172°C (dec). H NMR δ 8.75 (dd, 1H, J = 4.2, 1.8 Hz), 8.69 (dd, 1H, J = 4.2, 1.8 Hz),
8.20 (dd, 1H, J = 8.2, 1.7 Hz), 8.17 (dd, 1H, J = 8.2, 1.7 Hz), 7.94 (d, 1H, J = 8.5 Hz), 7.84 (d,
1H, J = 8.4 Hz), 7.77 (d, 1H, J = 8.5 Hz), 7.57 (d, 1H, J = 8.4 Hz), 7.34 (dd, 1H, J = 8.2, 4.2 Hz),
7.28 (dd, 1H, J = 8.2, 4.2 Hz), 4.88 (d, 1H, J = 13.0 Hz), 4.75 (d, 1H, J = 13.0 Hz), 2.08 (s, 3H)
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2
2
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2
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4
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5
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5
5
5
5
6
1
3
1
1.93 (s, 3H). C{ H} NMR (100 MHz, CDCl
3
) δ 170.5, 150.6, 150.2, 147.3, 146.9, 138.8,
1
2
3
37.7, 136.0, 136.0, 135.6, 135.1, 129.3, 128.1, 127.8, 127.6, 126.7, 126.5, 121.0, 120.0, 64.8,
ꢀ1
+
+
19 2 2
0.8, 20.7. IR (ATR) 2884, 1736, 842 cm . HRMS (FAB ) m/z (M+H) Calcd for C22H N O
43.1447, Found: 343.1478.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of 7,7’-dihydroxymethyl-8,8’-biquinoline (2) by hydrolysis of 14
To a solution of 14 (64.0 mg, 0.16 mmol) in MeOH (2.0 mL) was added KOH (53.0 mg, 0.96
mmol), and the mixture was stirred at room temperature for 2 h. The reaction was quenched
with sat. NH
4
Cl aq., and MeOH was removed in vacuo. The organic materials were extracted
with CH Cl
2
2
(3 × 10 mL) and dried with anhydrous sodium sulfate. The solvent was removed in
vacuo to afford crude compound, which was purified by column chromatography (silica gel,
CHCl /MeOH = 19/1) to give 2 (49.9 mg, 0.16 mmol), quantitatively.
3
Separation of 2 by chiral column HPLC
Chiral column HPLC analysis of 2 (DAICEL CHIRALPAK ADꢀH (4.6 mm × 250 mm),
hexane/iPrOH = 4/1, 0.6 mL/min, retention time: 1st eluent 33.9 min, 2nd eluent 51.6 min)
showed the existence of two rotamers. Racemic 2 (ca 1 mg) was solved in mixed solvent
(hexane/iPrOH = 4/1, 20 mL) and was separated two enantiomers (S)ꢀ3 and (R)ꢀ3 by chiral
column preparative HPLC (column: DAICEL CHIRAL PAK ADꢀH; eluent: hexane/iPrOH =
4
/1). The configuration of the first and second eluates were assigned as (S)ꢀ2 (>99% ee) and
(
R)ꢀ3 (>99%ee), respectively, using the exciton chirality method (see, Text).
7,7’-Dihydroxymethyl-8,8’-biquinoline (2)
1
m.p. 202ꢀ210 °C (dec). H NMR (400 MHz, CDCl
3
) δ 8.70 (dd, 2H, J = 4.2, 1.8 Hz), 8.26 (dd,
2
H, J = 8.2, 1.8 Hz), 8.01 (d, 2H, J = 8.4 Hz), 7.89 (d, 2H, J = 8.4 Hz), 7.38 (dd, 2H, J = 8.2, 4.2
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1
3
1
Hz), 4.28 (s, 4H), 3.19 (brs, 2H). C{ H} NMR (100 MHz, CDCl
3
) δ 150.6, 147.3, 141.3,
ꢀ1
+
1
36.8, 134.9, 128.6, 128.4, 128.2, 121.1, 64.1. IR (KBr) 3327, 2899, 1502 cm . HRMS (FAB )
+
m/z (M+H) Calcd for C20
17 2 2
H N O 317.1290, Found: 317.1299. UVꢀVis (MeOH) λmax 318 nm
(
ɛ 6500), 233 (46800), 208 (48800).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
5
For (S)ꢀ2 (92% ee): [α]D =ꢀ34 (c 1.0, CHCl ). CD (MeOH) λ 238 nm (ꢀε +117), 226 (ꢀ74).
3
ext
25
For (R)ꢀ2 (>99% ee): [α]D = +33 (c 1.0, CHCl
3
). CD (MeOH) λext 238 nm (ꢀε ꢀ116), 226
(+50).
Double C-H oxidation and successive hydrolysis of optically active biquinoline (R)ꢀ3
Scheme 4): to a solution of (R)ꢀ3 (98% ee, 5.0 mg, 0.017 mmol) in AcOH (1.0 mL) was added
Pd(OAc) (0.8 mg, 0.0036 mmol) and PhI(OAc) (43.8 mg, 0.136 mmol), and the mixture was
stirred at reflux. The reaction mixture was added PhI(OAc) (10.9 mg, 0.034 mmol) for each 1 h
(
2
2
2
and the reaction lasted for 7 h. The solvent was removed in vacuo to afford crude compound,
which was dissolved in MeOH (1.0 ml) was added KOH (9.5 mg, 0.16 mmol), and the mixture
was stirred at room temperature for 2 h. The reaction was quenched with sat. NH
MeOH was removed in vacuo. The organic materials were extracted with CH Cl
and dried with anhydrous sodium sulfate. The solvent was removed in vacuo to afford crude
4
Cl aq. and
2
2
(3×10 mL)
3
compound, which was purified by column chlomatography (Silicagel, CHCl /MeOH = 19/1) to
give (R)ꢀ2 (98% ee, 2.6 mg, 0.0082 mmol) in 48%.
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6
Acknowledgement
This work was supported by JSPS KAKENHI Grant Number 24655086. We thank Prof.
Katsuhiko Tomooka and Dr. Kazunobu Igawa (Kyushu University) for the separation of 2 and 3
by chiral HPLC. We thank Prof. Shigeori Takenaka and Dr. Shinobu Sato for the CD spectra
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Kyushu Institute of Technology).
Supporting Information Availability Statement
NMR spectra, chiral HPLC chart, CD/UV spectra, and Cartesian coordinates of computational
data. The Supporting Information is available free of charge on the ACS Publications website at
******
Notes
The authors declare no competing financial interest.
References
(1)
(a) Dashevskii, V. G.; Kitaigorodskii, A. I. Theor. Eksp. Khim. 1967, 3, 43. (b) Gamba,
A.; Rusconi, E.; Simonetta, M. Tetrahedron 1970, 26, 871. (c) Gustav, K.; Sühnel, J.; Wild, U.
P. Chem. Phys. 1978, 31, 59. (d) Carter, R. E.; Liljefors, T. Tetrahedron 1976, 32, 2915. (e)
Liljefors, T.; Carter, R. E. Tetrahedron 1978, 34, 1611. (f) Leister, D.; Kao, J. J. Mol. Struct.
1988, 168, 105. (g) Tsuzuki, S.; Tanabe, K.; Nagawa, Y.; Nakanishi, H. J. Mol. Struct. 1990,
216, 279. (h) Kranz, M.; Clark, T.; Schleyer, P. v. R. J. Org. Chem. 1993, 58, 3317. (i) Meca, L.;
Reha, D.; Havlas, Z. J. Org. Chem. 2003, 68, 5677.
2) For reviews, see: (a) Miyano, S.; Hashimoto, H. J. Synth. Org. Chem., Jpn. 1986, 44,
(
713. (b) Pu, L. Chem. Rev. 1998, 98, 2405. (c) Brunel, J. M. Chem. Rev. 2007, 107, 1. (d) Chen,
Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
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(3)
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In an initial study, we examined the Pd(OAc) ꢀcatalyzed reaction in various solvents
2
10
(AcOH, Ac
2
O, CHCl
3
/AcOH = 6/1, CH
3
CN, or toluene). Although AcOH or a mixed solvent
of CHCl
3
/AcOH was found to be efficient for the formation of 10, we chose AcOH as solvent
/AcOH.
Bari, L. D.; Pescitelli, G.; Salvadori, P. J. Am. Chem. Soc. 1999, 121, 7998.
Dihedral angles induced by PM3 level calculation are adaptable for the exciton
because the yield of 10 and mass balance in AcOH were better than that in CHCl
3
(
17)
18)
(
chirality method for various 2,2'ꢀhomosubstitutedꢀ1,1′ꢀbinaphthyls. See, Ref 17.
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