Ligand-accelerated stereoretentive Suzuki-Miyaura coupling of unprotected 3,3′-dibromo-BINOL

Article abstract of DOI:10.1021/acs.joc.5b02368

An efficient synthesis of the enantiomerically pure 3,3′-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3′-dibromo-BINOL with complete retention of enantiopurity. The active cata

Full text of DOI:10.1021/acs.joc.5b02368

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Ligand-Accelerated Stereoretentive Suzuki−Miyaura Coupling of
Unprotected 3,3′-Dibromo-BINOL
Bo Qu,* Nizar Haddad,* Sonia Rodriguez, Joshua D. Sieber, Jean-Nicolas Desrosiers,
Nitinchandra D. Patel, Yongda Zhang, Nelu Grinberg, Heewon Lee, Shengli Ma, Uwe Jorg Ries,
̈
Nathan K. Yee, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United
States
S
* Supporting Information
ABSTRACT: An efficient synthesis of the enantiomerically
pure 3,3′-bis-arylated BINOL derivatives is accomplished
through the palladium-catalyzed Suzuki−Miyaura coupling of
the unprotected 3,3′-dibromo-BINOL with complete retention
of enantiopurity. The active catalyst system Pd(OAc)2/BI-
DIME has enabled mild reaction conditions at palladium loads
as low as 500 ppm.
Scheme 1. Proposed Synthesis of Phosphoric Acid 1
INTRODUCTION
■
Organocatalysts derived from 1,1′-binaphthalene-2,2′-diol
(BINOL) are becoming increasingly versatile catalysts and
have been shown to catalyze a plethora of asymmetric
transformations using operationally simple and mild reaction
conditions with diverse functional group tolerance.1 Notably,
the aryl substitution at the 3- and 3′- positions of the BINOL
can significantly influence the catalytic activity by adjusting
both the steric and electronic properties with different
substituents.2,3 Even though the enantioselective transforma-
tions employing 3,3′-bis-arylated BINOLs have seen exponen-
tial growth, the strategies for their synthesis have remained the
same and require the cross coupling of an ether-protected 3,3′-
bis-boronic acid or 3,3′-dihalo-BINOL to construct the aryl
functionality. A deprotection step is then followed to generate
the 3,3′-bis-arylated BINOLs. Furthermore, high catalyst load
and prolonged reaction time are often required to achieve
acceptable conversions, which renders these BINOL-derived
catalysts not readily available for large-scale applications.
Chiu and co-workers observed diminished enantiomeric excess
(from >99% ee to 94% ee) with a low isolation yield when
coupling the enantiomerically pure 3,3′-dibromo-BINOL with
phenylboronic acid.6 Clark et al. have reported an elegant
synthesis of 3,3′-bis-arylated BINOL derivatives using a one-pot
C−H borylation/Suzuki−Miyaura coupling sequence, yet the
enantiopurity was preserved only for coupling of the phenyl
halides without any substitution.7 When coupling with the
substituted phenyl halides with either an electron-donating or
an electron-withdrawing group, the enantiopurities of the
resulting 3,3′-diaryl-BINOLs are in the range of 87−97% ee.7
Herein, we report an efficient synthesis to prepare enantiomeri-
cally pure 3,3′-bis-arylated BINOLs with the complete
retention of optical purity through a palladium-catalyzed
Suzuki−Miyaura coupling of the commercially available
unprotected (R)-3,3′-dibromo-BINOL (3).
Recently, the enantiomerically pure BINOL-based phos-
phoric acid (1) was required in one of our programs. To
identify an efficient and cost-effective synthetic strategy to
access the intermediate 3,3′-diaryl-BINOL (2a), a streamlined
protection-free Suzuki−Miyaura coupling process was sought
starting from 3,3′-dibromo-BINOL (3) (Scheme 1). Despite
the growing interest in these BINOL derivatives, coupling of
the unprotected 3,3′-dihalo-BINOL is scarce in literature. The
key challenge associated with this approach is the potential
racemization of BINOLs and the corresponding coupling
products, which is known to occur under both basic and acidic
conditions, especially at elevated temperature.4 As a result,
there are few reports of direct palladium-catalyzed Suzuki−
Miyaura coupling of the unprotected 3,3′-dibromo-BINOL.
RESULTS AND DISCUSSION
We have recently reported a privileged dihydrobenzophosphole
core structure (Scheme 2), and various effective chiral
■
Beller and Kockritz reported the successful Suzuki coupling of
Received: October 13, 2015
̈
partially hydrogenated 3,3′-dibromo-H8-BINOL.5 However,
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02368
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Scheme 2. BI-DIME Ligand and Derivatives
Scheme 3. Ligand Evaluation for Suzuki−Miyaura Coupling
a
of (R)-Dibromo-BINOL (3)
phosphine ligands were derived from this key building block.8
BI-DIME and derivatives have been demonstrated to be highly
effective ligands9 for palladium-catalyzed cross-coupling reac-
tions, especially the Suzuki−Miyaura reaction.10 It was
envisioned that these highly effective ligands could facilitate
the coupling of the unprotected dibromo-BINOL under mild
reaction conditions and therefore retain the stereoconfigura-
tion.
The reaction of (R)-3,3′-dibromo-BINOL (3) and 3,5-
bis(trifluoromethyl)phenylboronic acid was first examined with
Pd(OAc)2 (2 mol %) and (S)-BI-DIME ligand 5a (2.2 mol %)
in MeTHF/H2O at 70 °C using Na2CO3 as the base. To our
delight, the reaction completed in 30 min, and the desired
product 2a was isolated in 92% yield. Most importantly, the
coupling product was analyzed on chiral HPLC, and no
racemization was detected. The enantiomeric ratio of 2a is
>99.5:0.5, the same as that of the starting material 3.
Furthermore, the structural modification of the BIDIME ligand
at the 2-position with increased steric hindrance was reported
to increase the reactivity of the palladium-catalyzed Suzuki−
Miyaura coupling reactions.10a,c Ligands 5b−e were included
into the screening together with several structurally diverse
ligands. To compare the reactivity of the ligands, the reactions
were carried out with 0.1 mol % of Pd(OAc)2 (1000 ppm) as
the catalyst precursor at 70 °C for 20 h (Scheme 3).
In the presence of BI-DIME ligand 5a, desired product 2a
was observed in 92% yield together with the remaining
monocoupling intermediate and monocoupling des-Br impurity
(Scheme 3a).13 The reaction progress was monitored by HPLC
and is shown in Scheme 3b. Increasing the steric hindrance at
the 2-position of the ligand slows down the reaction. A 48%
yield was observed using the Me-BIDIME ligand with a methyl
substitution (5b, Scheme 3a) after 20 h, 22% for Bn-BIDIME
with a benzyl substitution (5c), and less than 5% for Me-Bn-
BIDIME (5d) and i-Pr-Bn-BIDIME11 (5e). The reactivity is
irrelevant to the chirality of the ligand; both (S)- and racemic-
BIDIME produced the same reaction profile. Racemic BI-
DIME was then applied for further studies. On the other hand,
S-Phos,12 X-Phos, P-t-Bu3·HBF4, and DPPF ligands were all
produced in less than 10% yield under 0.1 mol % catalyst load.
As revealed in the literature, racemization is an existing
challenge for Suzuki−Miyaura coupling of the unprotected 3,3′-
dibromo-BINOL; therefore, we evaluated whether any chiral
erosion would occur after extended heating under our reaction
a
(R)-Dibromobinol (3.0 g, 6.755 mmol), 3,5-bis(trifluoromethyl)-
phenylboronic acid (4.58 g, 16.887 mmol), catalyst stock solution
containing Pd(OAc)2 (1.52 mg, 0.0068 mmol) and ligand (0.0074
mmol), Na2CO3 (2.15 g, 20.26 mmol), MeTHF (22.5 mL), H2O (7.5
mL), 70 °C, 20 h. Product 2a is reported in HPLC area percent at 220
nm wavelength (see the Supporting Information for details). The plot
3b represents the reaction progress with ligand BI-DIME (5a) under
the same conditions.
conditions. The reaction mixture of (R)-dibromo-BINOL and
3,5-bis(trifluoromethyl)phenylboronic acid was heated for 48 h
at 70 °C after the reaction was completed. The desired product
2a was isolated again with an enantiomeric ratio of >99.5:0.5
(Table 1, entry 1). The high reactivity of the BI-DIME ligand
enables the coupling to occur under mild reaction conditions
with a weak base Na2CO3, which leads to high enantiopurity of
B
DOI: 10.1021/acs.joc.5b02368
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a
Table 1. Effect of Base on the Coupling Product 2a
c
entry
base
solvent
T (°C)
mono des-Br (%) (2 h)
yield (2a) (%) (2 h)
er (2 h)
er (48 h)
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
MeTHF
MeTHF
MeTHF
MeTHF
dioxane
dioxane
dioxane
dioxane
dioxane
70
70
2.4
5.5
97.6
94.5
93.5
80.0
97.5
90.3
97.7
94.0
82.0
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
K3PO4
70
6.5
b
NaO-t-Bu
Na2CO3
K3PO4
70
20.0
2.5
99.4:0.6
70
>99.5:0.5
>99.5:0.5
70
9.7
b
Na2CO3
K3PO4
100
100
100
2.3
99.2:0.8
b
6.0
99.2:0.8
b
NaO-t-Bu
18.0
98.2:1.8
94.2:5.8
a
Reaction conditions: (R)-dibromo-BINOL (0.5 g, 1.126 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (2.5 equiv), base (3.38 mmol), catalyst
solution containing Pd(OAc)2 (1.3 mg, 0.0056 mmol) and rac-BI-DIME (2.1 mg, 0.0062 mmol), 20 v% of H2O was added (total 5 mL of solvent
b
c
mixture). 20 h. Yield of product 2a is reported in HPLC area percent at 220 nm wavelength (see the Supporting Information for details).
the product even after prolonged heating. Most phosphine
ligands require the use of a stronger base to favor the coupling
reaction; however, in the meantime, chiral degradation of the
isolated products resulted.6,7 Furthermore, the effect of base on
the enantiopurity of the product was studied (Table 1). It was
shown that the enantiopurity of the product 2a remained the
same in the presence of K2CO3 and K3PO4 after heating at 70
°C for 48 h (entries 2, 3 and 5, 6) and started to degrade
slightly in the presence of NaO-t-Bu (entry 4). More
importantly, stronger base also favors the formation of the
monocoupling des-bromo impurity. The racemization starts to
occur at a higher temperature of 100 °C. An enantiomeric ratio
of 99.2:0.8 was obtained after 20 h in the presence of Na2CO3
and K3PO4, respectively (entries 7 and 8) and a ratio of 94.2:5.8
er with NaO-t-Bu as the base (entry 9).
The Pd(OAc)2/BI-DIME catalyst system was then applied
for the Suzuki coupling of unprotected (R)-3,3′-dibromo-
BINOL with various boronic acids with Na2CO3 as the base
(Table 2). At a catalyst load of 0.5 mol %, both electron-rich
and electron-poor boronic acids were coupled successfully with
dibromo-BINOL in 88−99% yields (entries 1−6). Catalyst
amount can be further decreased; with 0.05 mol % Pd(OAc)2
(500 ppm), the coupling of 3,3′-dibromo-BINOL with 3,5-
bis(trifluoromethyl)phenylboronic acid was completed within 7
h, and an isolation yield of 85% resulted (entry 1). Ortho-
substituted boronic acids were also obtained with 89−97%
yields (entries 7−10). The catalyst system is applicable to the
heteroaryl boronic acids as well. The Suzuki coupling with 1-
methyl 5-indole boronic acid, 5-benzofuran boronic acid and 3-
thiophene-ylboronic acid produced 86%, 81%, and 77% yield,
respectively (entries 11−13). Chiral purity of all the isolated
products has an enantiomeric ratio of >99:1. In contrast, Clark
observed a 93% ee for the compound 2d.7
The resulting 3,3′-diaryl-BINOLs can be conveniently
converted to chiral phosphoric acids (Scheme 4) and other
related BINOL Brønsted acids. The formation of the chiral
monophosphoric acid 1 completed within 1.5 h by increasing
the reaction temperature to 80 °C. A modified workup
procedure allowed the preparation of the (R)-phosphoric 1
on kilogram scale with a 71% isolated yield14 starting from the
commercially available (R)-3,3′-dibromo-BINOL. The two-step
synthesis significantly improves the efficiency of the overall
process for this important BINOL-derived Brønsted acid.
In summary, a straightforward efficient Suzuki−Miyaura
coupling process to prepare enantiomerically pure 3,3′-bis-aryl
substituted BINOLs starting from the unprotected 3,3′-
dibromo-BINOL is reported. The methodology eliminated
Scheme 4. Converting (R)-2a to Phosphoric Acid (R)-1
the deprotection process after the coupling step with an
increased overall yield and excellent enantiopurity. The Pd-BI-
DIME catalyst system enables low catalyst load of 500 ppm;
which constitutes a cost-effective, efficient and high yielding
process to access derivatives of substituted BINOLs, including
chiral monophosphoric acids.
EXPERIMENTAL SECTION
General Methods. Unless otherwise stated, all reactions were
carried out under strictly N2 inert atmosphere. MeTHF and HPLC-
■
1
grade water were used as received and N2-sparged before usage. H
1
and 13C NMR spectra were acquired in CDCl3 at 23 °C. The H and
13C chemical shifts are given in parts per million (δ) with respect to an
internal tetramethylsilane (TMS, δ 0.00 ppm) standard. High-
resolution mass spectroscopy was performed on a TOF instrument
with ESI positive or negative ionization modes. Flash chromatography
was performed on an automated system with silica columns. Melting
points of the crystalline compounds were measured on TA Instrument
DSC Q1000. All starting materials are commercially available and used
as received including (R)- and (S)-3,3′-dibromo-BINOL with chiral
purity of >99.5% ee.
General Procedure for Alkylation Reactions. Phosphine oxide
4a (1.0 g, 2.887 mmol) was dissolved in 15 mL of anhydrous THF
under argon in a three-neck flask. The mixture was cooled to −78 °C,
and 2.0 M LDA in THF/ethylbenzene (1.7 mL, 3.46 mmol) was
added dropwise. The temperature was maintained under −70 °C for 1
h. 2-(Bromomethyl)-1,3,5-trimethylbenzene (646 mg, 3.03 mmol) was
added, and the temperature was kept under −60 °C. The mixture was
stirred at −78 °C for 1 h and then warmed to 23 °C, and stirring
continued for 2 h. DCM (10 mL) and H2O (10 mL) were added to
quench the reaction. The layers were separated, and the organic layer
was extracted with 5 mL of CH2Cl2 and dried with Na2SO4, and
compound 4d was purified on silica with 10−35% EtOAc in hexanes
to give white crystalline solid after dryness.
(2S,3R)-3-tert-Butyl-4-(2,6-dimethoxyphenyl)-2-(2,4,6-trimethyl-
benzyl)-2H-benzo[d][1,3]oxaphosphole 3-oxide (4d): 0.84 g, 61%
yield; mp 210−212 °C; 1H NMR (500 MHz, CDCl3) δ 7.51 (t, J = 7.9
Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.96 (dd, J = 7.2, 3.2 Hz, 1H), 6.93
C
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(s, 2H), 6.88 (dd, J = 8.0, 3.2 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.61
(d, J = 8.2 Hz, 1H), 4.58−4.62 (m, 1H), 3.85 (s, 3H), 3.75 (s, 3H),
3.16−3.29 (m, 2H), 2.34 (s, 6H), 2.31 (s, 3H), 0.92 (d, J = 15.6 Hz,
9H); 31P NMR (202 MHz, CDCl3) δ 59.97 ppm; 13C NMR (125
MHz, CDCl3) δ 163.4 (d, JC−P = 19.5 Hz), 158.8, 157.4, 138.5 (d, JC−P
= 5.1 Hz), 137.0, 136.0, 134.2 (d, JC−P = 1.8 Hz), 132.2 (d, JC−P = 10.4
Hz), 129.8, 129.2, 125.0 (d, JC−P = 8.3 Hz), 117.3 (d, JC−P = 2.4 Hz),
114.3 (d, JC−P = 90.3 Hz), 112.6 (d, JC−P = 5.7 Hz), 104.5, 103.0, 74.5
(d, JC−P = 59.6 Hz), 56.2, 55.4, 33.8 (d, JC−P = 71.0 Hz), 29.0, 23.6,
20.9, 20.5 ppm; HRMS(EI) m/z calcd for C29H36O4P [M + H+]
479.2346, found 479.2329.
Table 2. Palladium-Catalyzed Suzuki Coupling of 3,3′-
a
Dibromo-BINOL (3)
(2S,3R)-3-tert-Butyl-4-(2,6-dimethoxyphenyl)-2-(2,4,6-triisopro-
pylbenzyl)-2H-benzo[d][1,3]oxaphosphole 3-oxide (4e): 1.023 g of
1
white crystalline solid, 63% yield; mp 232−233 °C; H NMR (500
MHz, CDCl3) δ 7.49 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 8.4 Hz, 1H), 7.04
(s, 2H), 6.94 (dd, J = 7.4, 3.1 Hz, 1H), 6.84 (dd, J = 8.4, 3.4 Hz, 1H),
6.69 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 4.45−4.50 (m, 1H),
3.83 (s, 3H), 3.72 (s, 3H), 3.27 (dd, J = 6.5, 3.4 Hz, 2H), 3.17 (sep, J =
6.8 Hz, 2H), 2.90 (sep, J = 6.8 Hz, 1H), 1.26−1.29 (m, 2H), 1.21 (d, J
= 6.8 Hz, 6H), 0.89 (d, J = 15.6 Hz, 9H); 31P NMR (202 MHz,
CDCl3) δ 59.8 ppm; 13C NMR (125 MHz, CDCl3) δ 163.4 (d, JC−P
=
19.7 Hz), 158.8, 157.4, 147.4, 147.0, 138.6 (d, JC−P = 5.0 Hz), 134.2
(d, JC−P = 1.8 Hz), 129.9, 129.4 (d, JC−P = 10.6 Hz), 125.0 (d, JC−P
=
8.4 Hz), 121.3, 117.3 (d, JC−P = 2.2 Hz), 114.5 (d, JC−P = 89.8 Hz),
112.6 (d, JC−P = 5.8 Hz), 104.5, 103.0, 76.0 (d, JC−P = 59.0 Hz), 56.2,
55.4, 34.1, 33.8 (d, JC−P = 71.0 Hz), 29.3, 26.9, 24.7, 24.2, 24.1, 24.0,
23.6 ppm (d, JC−P = 0.6 Hz); HRMS(EI) m/z calcd for C35H48O4P [M
+ H+] 563.3285, found 563.3242.
General Procedure for Reduction of the Phosphine Oxides.
To a Schlenk flask under argon were added 4d (500 mg, 1.045 mmol),
THF (10 mL), polymethylhydrosiloxane (1.5 g), and Ti(O-i-Pr)4 (742
mg, 2.61 mmol). The mixture was stirred at 65 °C for 14 h. Upon
complete conversion by 31P NMR analysis, the mixture was
concentrated under vacuum. Then the flask was cooled to 0 °C, and
20 mL of degassed 30% aqueous NaOH was added slowly with
caution. Extreme H2 gas evolution was observed in the beginning.
After complete addition, the mixture was heated to 60 °C after
addition of 10 mL of MeTHF and the mixture stirred for 1 h. The
mixture was cooled to 23 °C, and the product was extracted with
degassed MeTHF (3 × 10 mL) under argon. The combined organic
layer was filtered through a plug of neutral alumina with anhydrous
MgSO4 on the top. 5d was obtained as a white crystalline solid after
dryness.
(2S,3S)-3-tert-Butyl-4-(2,6-dimethoxyphenyl)-2-(2,4,6-trimethyl-
benzyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (5d): 425 mg, 88%
yield; mp 184−185 °C; 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J = 7.8
Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 6.82−6.85 (m, 4H), 6.65 (d, J = 8.2
Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 4.99 (dd, J = 10.5, 4.6 Hz, 1H), 3.77
(s, 3H), 3.69 (s, 3H), 3.04−3.11 (m, 1H), 2.84−2.89 (m, 1H), 2.28 (s,
6H), 2.24 (s, 3H), 0.68 (d, J = 12.2 Hz, 9H); 31P NMR (162 MHz,
CDCl3) δ 8.03 ppm; 13C NMR (100 MHz, CDCl3) δ 162.9, 157.8,
157.1, 138.8 (d, JC−P = 17.2 Hz), 136.7, 135.7, 132.8 (d, JC−P = 12.6
Hz), 130.5, 129.1, 129.0, 125.5, 124.5 (d, JC−P = 15.3 Hz), 123.7 (d,
JC−P = 4.0 Hz), 119.7, 110.1, 104.4, 103.6, 83.4 (d, JC−P = 26.0 Hz),
56.0, 55.4, 35.2 (d, JC−P = 31.0 Hz), 31.2 (d, JC−P = 18.5 Hz), 30.3,
26.7 (d, JC−P = 14.4 Hz), 20.9, 20.5 ppm (d, JC−P = 1.6 Hz);
HRMS(EI) m/z calcd for C29H36O3P [M + H+] 463.2397, found
463.2369.
(2S,3S)-3-tert-Butyl-4-(2,6-dimethoxyphenyl)-2-(2,4,6-triisopro-
pylbenzyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (5e): 442 mg of
1
white crystalline solid, 91% yield; mp 195−196 °C; H NMR (500
MHz, CDCl3) δ 7.32 (t, J = 7.8 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 6.99
(s, 2H), 6.87 (dd, J = 7.8, 3.2 Hz, 1H), 6.83 (dd, J = 8.3, 0.9 Hz, 1H),
6.66 (d, J = 8.5, 1H), 6.59 (d, J = 8.6 Hz, 1H), 4.88 (dd, J = 11.1, 3.0
Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.10−3.19 (m, 3H), 2.96 (ddd, J =
15.1, 6.8, 3.0 Hz, 1H), 2.88 (sep, J = 6.8 Hz, 1H), 1.24 (m, 12H), 1.18
(d, J = 6.8 Hz, 6H), 0.70 (d, J = 12.0 Hz, 9H); 31P NMR (202 MHz,
CDCl3) δ 9.59 ppm; 13C NMR (125 MHz, CDCl3) δ 162.8, 157.8,
a
Reaction conditions: (R)-3,3′-dibromo-BINOL (0.5 g, 1.126 mmol),
boronic acid (2.5 equiv), Na2CO3 (358 mg, 3.38 mmol), catalyst
solution containing Pd(OAc)2 (1.3 mg, 0.0056 mmol) and rac-BI-
DIME (2.1 mg, 0.0062 mmol), MeTHF/H2O 3/1 (5 mL), 70 °C, 2−4
b
c
h. Isolated yield of average two runs with (R)- and (S)-isomers. 500
157.1, 147.1, 146.8, 138.7 (d, JC−P = 16.8 Hz), 130.6, 130.5 (d, JC−P =
14.2 Hz), 129.1, 124.7 (d, JC−P = 14.9 Hz), 123.7 (d, JC−P = 4.1 Hz),
d
ppm Pd(OAc)2 at 10 g scale, 7 h. 14 h.
D
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121.1, 119.8, 110.0, 104.6, 103.7, 85.1 (d, JC−P = 26.1 Hz), 56.1 (d,
(R)-3,3′-Di-o-tolyl[1,1′-binaphthalene]-2,2′-diol (2h): purified on
silica with 0−20% EtOAc in hexanes, 470 mg of white solid isolated,
89% yield, >99.5% ee; spectral data were in complete agreement with
the published data.17
JC−P = 1.6 Hz), 55.4, 34.2, 33.3 (d, JC−P = 32.0 Hz), 31.1 (d, JC−P
=
19.0 Hz), 29.3, 26.6, 26.5, 24.7, 24.2, 24.1 ppm (d, JC−P = 4.6 Hz);
HRMS(EI) m/z calcd for C35H48O3P [M + H+] 547.3336, found
547.3348.
(R)-3,3′-Bis(2-isopropylphenyl)[1,1′-binaphthalene]-2,2′-diol (2i):
purified on silica with 5% EtOAc in hexanes, 535 mg of white
crystalline solid isolated, 91% yield, >99.5% ee; spectral data were in
complete agreement with the published data;18 mp 218−220 °C.
(R)-3-(1,9-Dihydropyren-4-yl)-3′-(pyren-4-yl)[1,1′-binaphtha-
lene]-2,2′-diol (2j): crystallized from 1:1 MeOH/water, 750 mg of off-
General Procedure for the Suzuki−Miyaura Coupling. (R)-
3,3′-Dibromo-BINOL (500 mg, 1.126 mmol), (3,5-bis-
(trifluoromethyl)phenyl)boronic acid (95%, 764.2 mg, 2.815 mmol),
Na2CO3 (378 mg, 3.38 mmol), MeTHF (3.75 mL), and H2O (1.25
mL) were charged to a 25 mL flask. The mixture was purged with Ar
for 10 min, and then catalyst stock solution containing Pd(OAc)2 (1.3
mg, 0.0056 mmol) and racemic BI-DIME (2.1 mg, 0.0062 mmol) was
added. The mixture was heated to 70 °C and stirred at this
temperature for 2−14 h under argon. The reaction was monitored by
LC−MS. After complete conversion to the desired product was
observed, the mixture was cooled and 5 mL of H2O was added. The
layers were separated, and the aqueous layer was extracted three times
with 10 mL of MeTHF. The organic layer was combined and dried
with Na2SO4 and purified on silica with 5% EtOAc in hexanes to yield
2a as white crystalline solid after dryness.
1
white crystalline solid, 97% yield; H NMR (400 MHz, CDCl3) δ
8.40−7.90 (m, 22H), 7.35−7.35 (m, 6H), 5.38−5.2 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 113.2, 113.3, 113.6, 124.50, 124.53, 124.74,
124.77, 124.82, 124.85, 124.87, 124.92, 124.94, 124.99, 125.03, 125.1,
125.31, 125.36, 125.41, 125.47, 125.49, 125.53, 126.1, 126.21, 126.24,
127.46, 127.49, 127.55, 127.59, 127.63, 127.87, 127.92, 127.94, 128.05,
128.12, 128.2, 128.38, 128.45, 128.6, 128.7, 129.4, 129.5, 129.63,
129.66, 129.7, 129.90, 129.99, 130.01, 130.07, 130.99, 131.02, 131.04,
131.39, 131.4, 132.17, 132.24, 132.27, 132.74, 132.77, 132.9, 133.7,
133.8, 150.78, 150.80, 150.82 ppm (rotamers not assigned);
HRMS(EI) m/z calcd for C52H29O2 [M − H+] 685.2173, found
685.2188.
(R)-3,3′-Bis(3,5-bis(trifluoromethyl)phenyl)[1,1′-binaphthalene]-
2,2′-diol (2a):15 760 mg of white crystalline solid, 92% yield, >99.5%
1
ee; mp 217−219 °C; H NMR (500 MHz, CDCl3) δ 8.16 (s, 4H),
(R)-3,3′-Bis(1-methyl-1H-indol-6-yl)[1,1′-binaphthalene]-2,2′-diol
8.04 (s, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.84 (s, 2H), 7.40 (dt, J = 7.2,
1.0 Hz, 2H), 7.34 (dt, J = 8.0, 1.4 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H),
5.28 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 149.8, 139.4, 133.2,
132.3, 131.7 (q, JC−F = 33.3 Hz), 129.9, 129.8, 129.4, 128.9, 128.6,
127.7, 125.2, 123.9, 122.3 (q, JC−F = 272.9 Hz), 121.3 (sep, JC−F = 3.8
Hz), 111.7 ppm.
(2k): purified on silica with 30% EtOAc in hexanes, 527 mg of white
1
solid isolated, 86% yield, 98.4% ee; H NMR (400 MHz, CDCl3) δ
8.03 (s, 2H), 7.96 (d, J = 1.1 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.58
(dd, J = 8.5, 1.6 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.34−7.40 (m, 2H),
7.27−7.33 (m, 2H), 7.11 (d, J = 3.1 Hz, 2H), 5.51 (s, 2H), 3.85 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 150.2, 136.3, 132.9, 131.8,
130.9, 129.5, 129.4, 128.8, 128.4, 128.2, 126.7, 124.5, 123.9, 123.3,
122.0, 113.2, 109.3, 101.4, 33.0 ppm; HRMS(EI) m/z calcd for
C38H29N2O2 [M + H+] 545.2224, found 545.2221.
(R)-3,3′-Bis(3,5-dimethoxyphenyl)[1,1′-binaphthalene]-2,2′-diol
(2b): crystallized from 1:1 MeOH/water, 597 mg of white crystalline
1
solid, 95% yield, >99.5% ee; mp 243−244 °C; H NMR (400 MHz,
CDCl3) δ 8.01 (s, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.38 (dt, J = 8.0, 2.0
Hz, 2H), 7.30 (dt, J = 8.0, 2.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.85
(d, J = 2.0 Hz, 2H), 6.52 (t, J = 2.0 Hz, 2H), 3.85 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.9, 149.8, 139.3, 133.1, 131.0, 130.5, 129.3,
128.4, 127.3, 124.4, 124.3, 112.9, 107.7, 100.2, 55.5 ppm; HRMS(EI)
m/z calcd for C36H31O6 [M + H+] 559.2115, found 559.2109.
(R)-3,3′-Bis(3,4,5-trifluorophenyl)[1,1′-binaphthalene]-2,2′-diol
(2c): purified on silica with 0−40% EtOAc in hexanes, 589 mg of white
crystalline solid, 93% yield, >99.5% ee; spectral data were in complete
agreement with the published data;3f mp 198−201 °C.
(R)-3,3′-Di(benzofuran-5-yl)[1,1′-binaphthalene]-2,2′-diol (2l):
purified with 30% EtOAc in hexanes, 450 mg of white crystalline
1
solid, 77% yield, 99.5% ee; mp 235−236 °C; H NMR (400 MHz,
CDCl3) δ 8.04 (s, 2H), 7.94 (d, J = 1.2 Hz, 2H), 7.91 (d, J = 8.0 Hz,
2H), 7.65 (dd, J = 8.8, 2.0 Hz, 4H), 7.61 (d, J = 8.8 Hz, 2H), 7.39 (td,
J = 8.4, 1.6 Hz, 2H), 7.32 (td, J = 8.0, 1.2 Hz, 2H), 7.26 (d, J = 8.4 Hz,
2H), 6.82 (dd, J = 2.4, 0.8 Hz, 2H), 5.40 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 154.6, 150.2, 145.6, 132.9, 132.2, 131.5, 130.9, 129.5,
128.4, 127.8, 127.2, 126.1, 124.37, 124.34, 122.3, 112.6, 111.4, 106.8
ppm; HRMS(EI) m/z calcd for C36H22O4 [M + H+] 519.1591, found
519.1584.
(R)-3,3′-Bis(4-(trifluoromethyl)phenyl)[1,1′-binaphthalene]-2,2′-
diol (2d): purified on silica with 0−10% EtOAc in hexanes, 567 mg of
white crystalline solid, 88% yield, >99.5% ee; spectral data were in
complete agreement with the published data;7 mp 203−206 °C.
(R)-6,6‴-Dimethoxy[2,2′:4′,1″:3″,2‴-quaternaphthalene]-2″,3′-
diol (2e): crystallized from 1:1 MeOH/water, 593 g of white crystalline
(R)-3,3′-Di(thiophene-3-yl)[1,1′-binaphthalene]-2,2′-diol (2m):
purified on silica with 4% EtOAc in hexanes, 391 mg of white solid
isolated, 77% yield, >99.5% ee; spectral data were in complete
agreement with the published data.19
1
(R)-3,3′-Bis[3,5-bis(trifluormethyl)phenyl]-1,1′-binaphthyl-2,2′-di-
hydrogen Phosphate (1). (R)-3,3′-Bis(3,5-bis(trifluoromethyl)-
phenyl)[1,1′-binaphthalene]-2,2′-diol (2a) (5.5 g, 7.40 mmol) and
15 mL of pyridine were added to a 250 mL reactor. A solution of
phosphorus oxychloride (1.71 g, 11.152 mmol) in 7.5 mL of pyridine
was slowly added while the reaction temperature was maintained
below 30 °C. The reaction mixture was stirred at 80 °C for 1.5 h,
cooled to 40 °C, and 7.5 mL of water was added followed after 10 min
by addition of 37 mL of 6 N HCl aqueous solution. The mixture was
heated to 100 °C for 1 h and cooled to 20 °C, and the solids were
filtered. The solids were washed with 15 mL of water and then
returned to the reactor. Toluene (60 mL) and 6 N HCl (15 mL) were
added. The mixture was heated to 40 °C for 20 min, and then the
aqueous fraction was separated. The organic layer was washed at 30−
40 °C with 15 mL of 6 N HCl two times and then with 20 mL of
water. The layer was distilled twice with toluene to reach 17 mL of the
product solution and heated to 60 °C, and then 60 mL of heptane was
added to crystallize the product. The mixture was cooled to 20 °C,
filtered, washed with heptane, and then dried under reduced pressure
at 70 °C for 20 h to yield 3.82 g of white crystalline solid, 66.4% yield,
ee >99.5%; spectral data were in complete agreement with the
published data;15 mp 192−194 °C.
solid, 88% yield, >99.5% ee; mp 153−154 °C; H NMR (400 MHz,
CDCl3) δ 8.60 (d, J = 9.6 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.88 (s,
4H), 7.84 (d, J = 10.0 Hz, 2H), 7.44 (dt, J = 6.7 Hz, 1.0 Hz, 2H), 7.37
(dt, J = 6.7 Hz, 1.0 Hz, 2H), 7.32 (d, J = 9.4 Hz, 2H), 7.24−7.20 (m,
4H), 5.49 (s, 2H), 3.98 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
158.0, 150.3, 134.0, 133.0, 132.7, 131.5, 130.7, 129.8, 129.6, 129.0,
128.5, 128.4, 128.2, 127.3, 126.9, 124.4, 124.4, 119.2, 112.6, 105.7, 55.4
ppm; HRMS(EI) m/z calcd for C42H31O4 [M + H+] 599.2217, found
599.2209.
(R)-3,3′-Bis(4-biphenyl)[1,1′-binaphthalene]-2,2′-diol (2f): puri-
fied on silica with 10% EtOAc in hexanes, 732 mg of white crystalline
solid, 99% yield, >99.5% ee; spectral data were in complete agreement
with the published data;16 mp 220−222 °C.
(R)-3,3′-Bis(2,4-difluorophenyl)[1,1′-binaphthalene]-2,2′-diol
(2g):3e purified on silica with 10% EtOAc in hexanes, 600 mg of white
1
solid isolated, 93% yield, >99.5% ee; H NMR (400 MHz, CDCl3) δ
5.22 (s, 2H), 6.92−7.03 (m, 4H), 7.24 (d, J = 8.4 Hz, 2H), 7.34−7.44
(m, 4H), 7.73 (ddd, J = 15.0, 6.4, 1.7 Hz, 2H), 7.92 (d, J = 8.2 Hz,
2H), 7.98 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 111.3, 111.4,
111.6, 121.3, 121.4, 121.5 (2), 124.2, 124.4, 124.6, 127.9, 128.6, 129.2
(2), 129.3, 132.6, 123.7 (2), 132.8, 150.6, 159.1, 159.2, 161.5, 161.6,
161.7 (2), 164.0, 164.1.
E
DOI: 10.1021/acs.joc.5b02368
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
A. G.; Wei, X.; Zhang, Y.; Gao, J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee,
N. K.; Senanayake, C. H. Org. Lett. 2012, 14, 2258. (d) Tang, W.;
Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. D.; Savoie, J.; Gao,
J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.; Krishnamurthy, D.;
Yee, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed. 2010, 49, 5879.
(11) (a) Lipshutz, B. et al. Unpublished work: iPr-Bn-BIDIME (5e)
referred to as Handaphos. (b) Lipshutz, B. Abstracts of Papers; 249th
National Meeting of the American Chemical Society, Denver, CO,
March 22−26, 2015; American Chemical Society: Washington, DC,
2015; BMGT-12.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02368.
■
S
1H and 13C NMR spectra and HPLC chromatograms of
the enantiomeric ratio analyses (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: bo.qu@boehringer-ingelheim.com.
*E-mail: nizar.haddad@boehringer-ingelheim.com.
Notes
■
(12) (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358. (b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
(13) See the Supporting Information.
(14) 71% was obtained on a kilogram scale for the two-step synthesis.
(15) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7,
2583.
The authors declare no competing financial interest.
(16) Simonsen, K. B.; Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem.
1998, 63, 7536.
REFERENCES
■
(1) (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047. (b) Chen, D.-F.; Han, Z.-Y.; Zhou, X. L.; Gong, L.-Z.
Acc. Chem. Res. 2014, 47, 2365. (c) List, B.; Reisinger, C. M.; Kampen,
D. Chiral Brønsted Acids for Asymmetric Organocatalysis; Springer Link,
2009; Vol. 291. (d) Brunel, J. M. Chem. Rev. 2005, 105, 857. (e) Chen,
Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
(17) Totland, K. M.; Boyd, T. J.; Lavoie, G. G.; Davis, W. M.;
Schrock, R. S. Macromolecules 1996, 29, 6114.
̌
́
(18) Kim, J. H.; Coric, I.; Vellalath, S.; List, B. Angew. Chem., Int. Ed.
2013, 52, 4474.
(19) Bleschke, C.; Schmidt, J.; Kundu, D. S.; Blechert, S.; Thomas, A.
Adv. Synth. Catal. 2011, 353, 3101.
(2) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I.
Angew. Chem., Int. Ed. 2013, 52, 11569.
(3) (a) Dumoulin, A.; Lalli, C.; Retailleau, P.; Masson, G. Chem.
Commun. 2015, 51, 5383. (b) Monaco, M. R.; Prevost, S.; List, B. J.
́
Am. Chem. Soc. 2014, 136, 16982. (c) Liao, L.; Shu, C.; Zhang, M.;
Liao, Y.; Hu, X.; Zhang, Y.; Wu, Z.; Yuan, W.; Zhang, X. Angew. Chem.,
Int. Ed. 2014, 53, 10471. (d) Monaco, M. R.; Poladura, B.; Diaz de los
Bernardos, M.; Leutzsch, M.; Goddard, R.; List, B. Angew. Chem., Int.
Ed. 2014, 53, 7063. (e) Chen, L.; Zhang, L.; Lv, J.; Cheng, J.-P.; Luo,
S. Chem. - Eur. J. 2012, 18, 8891. (f) Hatano, M.; Horibe, T.; Ishihara,
K. J. Am. Chem. Soc. 2010, 132, 56.
̌
(4) (a) Meca, L.; Reha, D.; Havlas, Z. J. Org. Chem. 2003, 68, 5677.
(b) Kyba, E. P.; Gokel, G. W.; de John, F.; Koga, K.; Sousa, L. R.;
Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. J. Org. Chem.
1977, 42, 4173.
(5) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Kockritz, A.;
̈
Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316.
(6) Li, B.; Chiu, P. Eur. J. Org. Chem. 2011, 2011, 3932.
(7) Ahmed, I.; Clark, D. A. Org. Lett. 2014, 16, 4332.
(8) (a) Qu, B.; Samankumara, L. P.; Savoie, J.; Fandrick, D. R.;
Haddad, N.; Wei, X.; Ma, S.; Lee, H.; Rodriguez, S.; Busacca, C. A.;
Yee, N. K.; Song, J. J.; Senanayake, C. H. J. Org. Chem. 2014, 79, 993.
(b) Qu, B.; Samankumara, L. P.; Ma, S.; Fandrick, K. R.; Desrosiers, J.-
N.; Rodriguez, S.; Li, Z.; Haddad, N.; Han, Z. S.; McKellop, K.;
Pennino, S.; Grinberg, N.; Gonnella, N. C.; Song, J. J.; Senanayake, C.
H. Angew. Chem., Int. Ed. 2014, 53, 14428. (c) Sieber, J. D.;
Chennamadhavuni, D.; Fandrick, K. R.; Qu, B.; Han, Z. S.; Savoie, J.;
Ma, S.; Samankumara, L. P.; Grinberg, N.; Lee, H.; Song, J. J.;
Senanayake, C. H. Org. Lett. 2014, 16, 5494. (d) Rodriguez, S.; Qu, B.;
Haddad, N.; Reeves, D.; Tang, W.; Krishnamurthy, D.; Senanayake, C.
H. Adv. Synth. Catal. 2011, 353, 533. (e) Tang, W.; Qu, B.; Capacci, A.
G.; Rodriguez, S.; Wei, X.; Haddad, N.; Narayanan, B.; Ma, S.;
Grinberg, N.; Yee, N. K.; Krishnamurthy, D.; Senanayake, C. H. Org.
Lett. 2010, 12, 176. (f) Tang, W.; Capacci, A. G.; White, A.; Ma, S.;
Rodriguez, S.; Qu, B.; Savoie, J.; Patel, N. D.; Wei, X.; Haddad, N.;
Grinberg, N.; Yee, N. K.; Krishnamurthy, D.; Senanayake, C. H. Org.
Lett. 2010, 12, 1104.
(9) (a) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am.
Chem. Soc. 2015, 137, 6746. (b) Fu, W.; Nie, M.; Wang, A.; Cao, Z.;
Tang, W. Angew. Chem., Int. Ed. 2015, 54, 2520. (c) Nie, M.; Fu, W.;
Cao, Z.; Tang, W. Org. Chem. Front. 2015, 2, 1322.
(10) (a) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W. J. Am.
Chem. Soc. 2014, 136, 570. (b) Zhao, Q.; Li, C.; Senanayake, C. H.;
Tang, W. Chem. - Eur. J. 2013, 19, 2261. (c) Tang, W.; Patel, N. D.;
Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci,
F
DOI: 10.1021/acs.joc.5b02368
J. Org. Chem. XXXX, XXX, XXX−XXX