Gram scale conversion of R-BINAM to R-NOBIN

Article abstract of DOI:10.1021/acs.joc.5b02663

A mild, operationally simple, and single-step transition-metal-free protocol for the synthesis of enantiomerically pure (R)-(+)-2′-amino-1,1′-binaphthalen-2-ol (R-NOBIN) from (R)-(+)-1,1′-binaphthyl-2,2′-diamine (R-BINAM) is reported. The one-pot conversion proceeds with good yield and shows no racemization. The hydroxyl on the R-NOBIN product was shown to have come from water in the reaction medium via an H₂¹⁸O study. The correct value of the specific rotation of R-NOBIN was reported.

Full text of DOI:10.1021/acs.joc.5b02663

This is an open access article published under an ACS AuthorChoice License, which permits
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Note
pubs.acs.org/joc
Gram Scale Conversion of R‑BINAM to R‑NOBIN
Darshan C. Patel, Zachary S. Breitbach, Ross M. Woods, Yeeun Lim, Andy Wang, Frank W. Foss Jr.,
and Daniel W. Armstrong*
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, United States
S
* Supporting Information
ABSTRACT: A mild, operationally simple, and single-step
transition-metal-free protocol for the synthesis of enantiomeri-
cally pure (R)-(+)-2′-amino-1,1′-binaphthalen-2-ol (R-NOBIN)
from (R)-(+)-1,1′-binaphthyl-2,2′-diamine (R-BINAM) is re-
ported. The one-pot conversion proceeds with good yield and
shows no racemization. The hydroxyl on the R-NOBIN product
was shown to have come from water in the reaction medium via
an H218O study. The correct value of the specific rotation of R-
NOBIN was reported.
tropisomers (axially chiral biaryls) are stereoisomers that
arise from hindered rotation of two aromatic groups
NOBIN was first synthesized as a racemic mixture by
Kocovsky et al. in 1991, using a Cu(II)Cl -mediated oxidative
A
̌
́
2
cross-coupling between 2-naphthol and 2-naphthylamine.30,31
The product mixture also included small amounts of 1,1′-
binaphthyl-2,2′-diamine (BINAM) and 1,1′-bi(2-naphthol)
(BINOL).31 An improvement of the aforementioned method
was reported by Ding et al. using a two-component molecular
crystal and Fe3+ as the oxidant in a two-phase reaction.9,32
Zhang et al. attempted a 20 g synthesis using the above-
mentioned two methods and found 40% and 58% yields for
connected by a single C−C bond. This barrier to rotation
allows for the isolation of many atropisomers in their single
enantiomer forms.1,2 The biaryl scaffold is considered a
privileged structural motif (capable of binding to multiple
receptors with high affinity) in pharmaceutical research with
demonstrated activity as antitumor, antiamebic, antifungal,
antihypertensive, anti-inflammatory, and antirheumatic agents
among other therapeutic classes.3,4 Biaryl backbones, embedded
in 4.3% of all known drugs, are of a great significance due to
their utility in biomolecular targeting and recognition.5−8
Substituted biaryls have found a myriad of uses in organic
synthesis, natural products chemistry, and material science
devices such as light-emitting diodes, solar cells, and photo-
conductors.9−11 Atropisomers such as (R)-(+)-2′-amino-1,1′-
binaphthalen-2-ol (R-NOBIN, 3) have demonstrated usefulness
as ligands and chiral auxiliaries in asymmetric catalysis leading
to a wide array of catalytic enantioselective conver-
sions.1,4,9,12−18 Kagan et al. have shown NOBIN’s usefulness
as a phase transfer catalyst.19−21 Chiral ligands made from
optically pure NOBIN by Carreira have been utilized in
numerous Ti-catalyzed aldol reactions.22−25 NOBIN-derivat-
ized ligands and catalysts have been reportedly used for Michael
addition,26 diethyl zinc addition to aldehydes, allylation of
aldehydes, allylic substitutions, 1,4-addition to α,β-unsaturated
ketones, intermolecular cyclopropanation,27 asymmetric meta-
thesis,28 aldol-type reactions, Diels−Alder and hetero-Diels−
Alder reactions, transfer hydrogenation of ketones, α-vinylation
of ketones, and Suzuki coupling reactions.9 Substituting the
binaphthyl backbone with a variety of functional groups can
alter the electronic and steric properties of the molecule that
influence its catalytic behavior.29 Such modifications of a
catalyst can help fine-tune asymmetric synthesis and steer
reactions in favor of an enantiomer of interest.29 Given the
varied utility of the atropisomer NOBIN, many attempts were
made to synthesize it.
̌
́
racemic NOBIN from Kocovsky’s and Ding’s method,
respectively.33 Zhang cited difficulties in removal of BINAM
and BINOL in the product mixture leading to lower yields of
NOBIN. With a slight modification to the Kocovsky’s method,
̌
́
Carreira et al. obtained racemic NOBIN in 65% yield (however,
in 48 h and with 10 equiv of 2-naphthylamine).4 Zhang et al.
also reported a strategy to obtain racemic NOBIN in 91% yield
from BINOL under very harsh reaction conditions (200 °C, 5
days in autoclave).33 When the same reaction was done with
enantiomerically pure BINOL, only the racemic product was
formed. Historically, NOBIN syntheses involving conversion
from BINOL as well as coupling of 2-naphthol and 2-
naphthylamine generally produced BINAM as a byproduct
preventing isolation of NOBIN in higher yields.33,34 Shortly
̌
́
after their original work, Kocovsky et al. also attempted
enantio-enrichment of binaphthyls in the presence of chiral
amines producing R-NOBIN in 42% yield with a low 46% ee.35
The utility of asymmetric synthesis of NOBIN from
enantiomerically pure BINOL, such as the one reported by
Buchwald et al., is also limited due to several required
protection and deprotection steps.36 In retrospect, attempts at
synthesizing NOBIN have faced challenges of low yields,
formation of biaryl impurities, and complex reaction procedures
(e.g., long reaction times, heavy metal catalysts).9,14,33,34,37,38
Received: November 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02663
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The Journal of Organic Chemistry
Note
The synthetic problems have resulted in the relatively high
cost of enantiomerically pure NOBIN (R-NOBIN: $928/g,
Sigma-Aldrich) and have constrained it from reaching its full
utilitarian potential despite its vast number of possible
applications.9 In this work, a novel one-step and operationally
simple conversion of R-BINAM (1) ($140/g, Sigma-Aldrich)
to R-NOBIN (3) has been reported and optimized for the gram
scale. The resulting R-NOBIN is enantiomerically pure and
eliminates the need to isolate it from a racemate via preparative
scale chiral purification, a difficult and expensive procedure.
Conversely, the starting material (R-BINAM) is relatively
straightforward to obtain in high yield and enantiomeric
purity.15,39
During a study of the racemization rates of 1, we found that 3
was produced when 1, dissolved in a mixture of 1,4-dioxane and
DI (deionized) water, was heated in the presence of an acid.
Upon further examination, it was found that a free radical
initiator also was necessary to facilitate the reaction. Benzoyl
peroxide (2), a diacyl peroxide and an efficient radical initiator,
was employed for the task (Scheme 1).40 The conversion was a
Various compositions of water-soluble organic solvents were
examined, and their effect on conversion was monitored over
the 2 h reaction time (Table 1). 1,4-Dioxane far exceeded other
organic solvents in producing a substantial amount of 3 (59−
77% conversion, entries 1−6, 9). Surprisingly, the use of THF
(entry 5) led to poor product formation (3%) despite being
structurally similar to 1,4-dioxane. Use of DMF, DMSO, and
IPA (entries 2−4) all showed drastically lower conversion to 3
compared to 1,4-dioxane. Using acetone did not show any
formation of the desired product (entry 1). The reagents were
insoluble in the acetonitrile/water mixture (entry 6). Various
ratios of 1,4-dioxane/water were also monitored (entries 7−
12). Ratios with 1,4-dioxane lower than 2 volume equivalents to
water led to partially insoluble reagents (entries 7−8). 1,4-
Dioxane in 2 volume equivalents to water provided 77%
conversion to 3 (entry 9) while higher amounts led to a
decrease in production of 3. Reaction mixtures prepared solely
in organic or aqueous solvents were unable to dissolve 1 and/or
2.
Different radical initiators also affect the reaction (Table 2).
Use of 2 mol equiv of azobis(isobutyronitrile) (AIBN), a strong
Scheme 1. Synthesis of R-NOBIN from R-BINAM
a
Table 2. Optimization of Radical Initiator
entry
initiator
1/initiator
% conversion of 1 to 3
1
AIBN
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:0.1
1:0.5
1:1
1:2
1:4
1:8
50
2
K2S2O8
17
3
2-butanone peroxide
cumene hydroperoxide
tert-butyl hydroperoxide
H2O2
8
4
5
5
37
6
3
7
lauroyal peroxide
benzoyl peroxide
benzoyl peroxide
benzoyl peroxide
benzoyl peroxide
benzoyl peroxide
benzoyl peroxide
reagents insoluble
8
10
21
75
84
44
32
9
10
11
12
13
one-pot process, and the stereochemistry was maintained
throughout the reaction with no traces of S-NOBIN observed
by chiral high performance liquid chromatography (HPLC).
The conversion was also found to be successful in converting S-
BINAM to S-NOBIN in a similar fashion with no racemization.
Optimization studies were performed on small scale (1−5 mg),
and % conversions reported in Tables 1−4 are from HPLC
analysis with 2 h reaction times, unless otherwise stated.
Unidentified side products, decomposition products, and
impurities will be referred to as impurities henceforth.41−44
a
Reaction conditions: 1 (1.67 mg, 6 mM), 2:1 1,4-dioxane/water, 2.18
M HCl overall with various radical initiators heated at 85 °C for 2 h.
radical initiator, gave a 50% conversion to 3 (Table 2, entry 1).
Subsequently, several other radical initiators were examined
(entries 2−7). Potassium persulfate and tert-butyl hydro-
peroxide led to conversions to 3 in moderate amounts of
17% and 37%, respectively (entries 2 and 5). Hydrogen
peroxide (entry 6) gave a very poor conversion to product. No
product formation was observed in the absence of a radical
initiator. Due to the faster conversion rate and easier UV
detection of derivatives of compound 2 compared to AIBN, the
former was selected for further reaction optimizations.
Experimenting with various ratios of 1:2 (entries 8−13)
showed that 2 mol equiv of 2 gave the highest conversion to 3
(entry 11). Since lower ratios drastically lowered conversion to
3 (entries 8−10), it is evident that the reaction is not catalytic
and 2 takes an active role in the reaction.40,45 Product
formation with use of AIBN as a radical initiator also indicates
that the oxygen in the hydroxyl group of the product is likely
coming from water, as AIBN does not contain oxygen moieties.
To evaluate this hypothesis, H218O was substituted for H2O in a
reaction using AIBN as a radical initiator and NOBIN with the
18O isotope was formed which was confirmed by mass
spectrometry (see Figures S6−S10 in the Supporting
a
Table 1. Optimization of Reaction Solvent
entry
organic solvent
organic/aqueous
% conversion of 1 to 3
1
acetone
2:1
2:1
2:1
2:1
2:1
2:1
1:1
3:2
2:1
3:1
4:1
5:1
0
2
DMF
5
3
DMSO
4
4
IPA
1
5
THF
3
6
ACN
reagents insoluble
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
reagents insoluble
8
reagents insoluble
9
77
65
60
59
10
11
12
a
Reaction conditions: 1 (5 mg, 17 mM), 2 (1 mol equivalent), various
water-soluble organic solvents, and 3.25 M HCl overall heated at 85
°C for 2 h.
B
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The Journal of Organic Chemistry
Note
Information). The same outcome was observed upon usage of
2 as a radical initiator as well.
The effect of eight different acids on the product formation
was examined (Table 3). Due to excessive heat formation and
to allow for thermal decomposition of 2 to form radicals.46
Similarly, temperatures higher than 90 °C are above the boiling
point of the azeotrope formed by a mixture of 2:1 1,4-dioxane/
water, contributing to the short half-life of 2.47 The half-life of 2
at 70 and 92 °C is 10 and 1 h, respectively.48,49 Consequently,
temperatures from 75 to 95 °C were further studied to
determine the optimal reaction time for the highest possible
conversion to product (Table 4). The rate of product formation
a
Table 3. Optimization of Acid
entry
acid
acetic acid
% conversion of 1 to 3
1
2
3
4
5
6
7
8
0
8
a
methanesulfonic acid
Table 4. Optimization of Time and Temperature
HBr
10
11
20
29
46
50
entry
time (h)
temp
% conversion of 1 to 3
HClO4
TFA
1
2
3
4
5
1.5
2
75 °C
80 °C
85 °C
90 °C
95 °C
94
95
98
97
97
HNO3
HCl
3
H3PO4
4.5
6.5
a
Reaction conditions: 1 (1.67 mg, 6 mM), 2 (2 equiv), 2:1 1,4-
a
dioxane/water with various acids (2.15 M overall) heated at 85 °C for
1 h.
Reaction conditions: 1 (1.67 mg, 6 mM), 2 (2 equiv), 2:1 1,4-
dioxane/1.3 M HCl (overall) heated at various temperatures.
evaporation of certain reaction mixtures, the reaction times
were limited to 1 h for this study. Use of acetic acid showed no
formation of 3 (Table 3, entry 1). When HBr, HClO4, and TFA
were used, the conversions to 3 were low (entries 3−5). Use of
H3PO4 and HCl showed the highest product formations (50%
and 46%, entries 7 and 8, respectively). Although the use of
H3PO4 did lead to a slightly higher conversion to 3 as
compared to HCl, the former also produced large amounts of
unidentified impurities (up to 40%). Consequently, HCl was
chosen for further optimization steps.
A series of experiments with varying HCl content (0.65−3.90
M) were also performed to determine the optimal concen-
tration (see Supporting Information Table S1). HCl concen-
tration of 1.30 M provided the highest conversion (94%) to 3
in a 2 h reaction time (entry 3). A steady trend of a decreasing
amount of 3 was observed with higher concentrations of acid in
the reaction mixture. A reaction mixture of 1 with 2:1 1,4-
dioxane/2.0 M HCl (overall) and 2 equiv of 2 was heated at 85
°C and decomposition of reactants and product was observed
after 3 h. It is possible that rapid decomposition of 2 after 3 h of
reaction led to this outcome.45 After heating the reaction
mixture for several days, multiple impurities were observed in
HPLC analysis, yet no traces of BINOL or S-NOBIN were
found.
A 0.5 mmol scale reaction was performed using 2 as a radical
initiator. After workup and purification, 3 was isolated in 65%
yield (see Experimental Section for details). When using the
above method with H2O2 as a radical initiator, little to no
product was formed (similar to Table 2 entry 6). A third
reaction using the original 0.5 mmol method with 2 as a radical
initiator was performed while constantly sparging O2 in the
reaction flask and no product formation was observed. Oxygen,
a known free radical scavenger, could quench the free radicals
produced by 2 and inhibit the product formation.46 A similar
outcome was observed with the addition of a radical trap
(DPPH) to the reaction mixture. This indicates the critical role
free radicals play in this reaction.
In order to determine the optimal temperature and reaction
time for forming 3, temperatures ranging from 60 to 175 °C
were evaluated. Temperatures below 75 °C showed very little
product formation while temperatures above 95 °C showed a
large amount of decomposition of reactants and product. An
adequate temperature must be provided for an appropriate time
increased in direct proportion to the increase in temperature. A
temperature of 85 °C (entry 3) was determined to be optimal
providing a balance of a high amount of product formation in a
relatively short reaction time.
With optimal parameters at hand, the reaction was scaled up
and optimized for 1 g scale. Similar to past scale-ups, the initial
attempts at 1 g scale-up resulted in product decomposition after
3 h at 85 °C. Increasing 2 from 2 to 2.7 equiv and adding it
gradually to the flask over 5 h provided 93% conversion to 3 by
HPLC analysis after a 6 h reaction time (see Supporting
Information). A slow decomposition of the product was
observed after 6 h. See the following Experimental Section
for the optimized procedure for a 1 g scale reaction. It should
be noted that the specific rotation of highly pure R-NOBIN,
[α]2D4.9 = +136 found in this work, is ∼10% higher than
previously reported.50
While the transformation is formally a Bucherer reaction,51
the requirement for free radicals would eliminate a fully ionic
mechanism. Radical-Bucherer reactions have not been
described in detail; however, it is possible that a radical
pathway leads to either the imine tautomer or oxidized
(semiquinone-like) radical imine of BINAM. These species
should undergo hydrolysis under equilibrium and rearomatiza-
tion to the 2-naphthol group by a mechanism related to the
Bucherer reaction. As an example of an oxidative trans-
formation, neutral 9,10-diaminoanthracene is almost instanta-
neously converted to anthraquinone through a similar yet
unknown oxidation/hydrolysis mechanism in air and water.52
The nonracemization of this process indicates that any redox
event, if present, must be isolated to a single naphthalenamine.
Furthermore, as no BINOL is observed as a byproduct, the
radical process in one naphthalene may be gated by the
electronic nature of its neighbor. Further experimentation is
required to elucidate this mechanism; what is included here is a
hypothetical treatment based on optimization efforts.
In this work, we have documented a successful procedure to
directly convert R-BINAM to enantiomerically pure R-NOBIN
in an operationally simple, time-efficient, and cost-effective one-
pot procedure. A yield of 70% R-NOBIN (>99% ee) was
afforded on 1 g scale after workup and purification of product.
The product structure and absolute configuration were
confirmed using X-ray crystallography among other techniques.
This conversion is first of its kind reported for the effective
C
DOI: 10.1021/acs.joc.5b02663
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The Journal of Organic Chemistry
Note
was diluted in ACN and injected in the mass spectrometer (ESI-LIT)
for analysis (see Supporting Information). In a separate reaction, 3.1
mg of AIBN (0.019 mmol) were substituted for benzoyl peroxide to
study the effect of AIBN as the radical initiator in the reaction.
synthesis procedures for stereochemically pure NOBIN
enantiomers. With optimization, it may be exploited to
potentially convert a range of BINAM derivatives into their
NOBIN counterparts.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02663.
■
EXPERIMENTAL SECTION
■
S
General. All reagents were purchased commercially and were used
without further purification. All reactions were performed under Ar.
Pressure sealed ampules were used for optimization studies. The
following abbreviations were used for NMR multiplicities: s = singlet,
d = doublet, dt = doublet of triplet, m = multiplet. For HRMS, APCI-
TOF was used. HPLC method used for % conversion analyses:
LARIHC CF7-DMP (25 cm × 0.46 cm), mobile phase = 80:20:0.1
heptane/EtOH/butylamine (v/v/v), 2 mL/min, 232 nm, temp =
ambient.53−55 HPLC method used to determine enantiomeric excess:
LARIHC CF6-P (15 cm × 0.46 cm, 2.7 μm core−shell), mobile phase
= 90:10:0.1 heptane/EtOH/butylamine (v/v/v), 1 mL/min, 232 nm,
temp = ambient (∼26 °C); tR(S‑NOBIN) = 3.83 min, tR(R‑NOBIN) = 4.07
min, tR(product) = 4.07 min; RS = 2.0, α = 1.1 (see Figure S5 in the
Supporting Information).56,57 HPLC columns were provided by
AZYP, LLC. (Arlington, TX).
CIF X-ray structure file for product (CIF)
Acid concentration optimization (Table S1), NMR
spectra, and other characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sec4dwa@uta.edu.
Notes
■
The authors declare no competing financial interest.
R-NOBIN (1 g scale). R-BINAM (1 g or 3.52 mmol) dissolved in
220 mL of 1,4-dioxane, 65 mL of DI (deionized) water, and 47 mL of
12 M HCl (1.7 M overall) was heated at 85 °C for 6 h under Ar. A 2.3
g amount of benzoyl peroxide (9.5 mmol or 2.7 mol equiv) dissolved
in 10 mL of 1,4-dioxane was added dropwise (using a syringe pump at
constant flow) to the reaction flask over 5 h. Solvents were reduced to
∼75% of the proportional amount used in optimization studies. An
increase in HCl concentration from 1.3 to 1.7 M showed a better rate
of product formation at this scale. The crude mixture was neutralized
in an ice bath using drops of saturated NaOH until the pH was ∼8. All
solvent was evaporated, the crude material was redissolved in 1:1 DI
water/EtOAc, and organic products were extracted in EtOAc. R-
NOBIN was isolated and purified using the Biotage isolera 1
automated system using a step gradient of EtOAc/hexanes and a
KP-Sil 50 g column. Product was recrystallized in DCM and washed
with hexanes for characterization. The vapor diffusion (vial-in-vial)
method with DCM as solvent and hexanes as precipitant was used to
form crystals for use in X-ray crystallography. See Supporting
Information for details. Product weight 0.7 g (70% yield), >99% ee,
ACKNOWLEDGMENTS
We thank Dr. Jonathan Smuts for assistance with character-
■
ization as well as Dr. Las
assistance with product purification. The authors acknowledge
́
zlo
́
Kurti and Craig Keene for their
̈
support of the Welch Foundation (Y-0026).
REFERENCES
■
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white solid, melting point: literature 169 °C, found 170 °C. [α]D24.9
=
1
+136 (c = 1.00, THF). H NMR (500 MHz, DMSO-d6) δ 9.29 (s,
1H), 7.88 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.74−7.71 (m,
2H), 7.36 (d, J = 8.6 Hz, 1H), 7.25 (dt, J = 6.9 Hz, 1.2 Hz, 1H), 7.19
(dt, J = 6.9, 1.2 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 7.08 (m, 2H), 6.94
(d, J = 8.0 Hz, 1H), 6.75 (dt, J = 6.9, 1.7 Hz, 1H), 4.55 (s, 2H) ppm.
13C{1H} NMR (500 MHz, DMSO-d6) δ 153.4, 144.0, 134.1, 133.7,
129.2, 128.5, 128.2, 128.1, 127.8, 127.1, 126.2, 125.7, 124.2, 123.5,
122.6, 120.8, 118.9, 118.5, 115.0, 111.3 ppm. IR (neat) 3398, 3323,
3213, 3057, 1617, 1509, 1473, 1380, 1273, 1215, 1173, 1145, 818, 752,
662, 424 cm−1. HRMS calculated for C20H15NO: 286.1226 ([M +
H]+), found 286.1220. Elemental R-NOBIN calculated: C, 84.2%; H,
5.3%; N, 4.9%. Commercial standard measured: C, 83.8%; H, 5.1%; N,
4.7%. Product measured: C, 83.1%; H, 5.0%; N, 4.8%.
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R-NOBIN (0.5 mmol Scale). R-BINAM (0.5 mmol or 142 mg), 42
mL of 1,4-dioxane, 14 mL of DI water, 6.8 mL of 12 M HCl (1.3 M
overall), and 2 mol equiv of benzoyl peroxide (1.0 mmol or 250 mg)
were heated at 85 °C for 3 h. The crude mixture was neutralized with
saturated NaHCO3 until the pH was ∼8. All solvent was evaporated,
the crude material was redissolved in 1:1 DI water/EtOAc, and organic
products were extracted in EtOAc. R-NOBIN was isolated using
preparative HPLC (column: LARIHC CF6-P 25 cm × 2.12 cm, 95/5
heptane/EtOH, 20 mL/min) to afford a 65% yield. For the reaction
with O2 sparge, O2 was bubbled in the reaction flask for the duration
of the reaction using a gas diffusion tube fitted in a rubber septum.
H218O Isotope Experiments. R-BINAM (2.5 mg or 0.0088 mmol),
benzoyl peroxide (4.3 mg or 0.018 mmol), 0.5 mL of 1,4-dioxane
(anhydrous), 0.5 mL of 4.0 M HCl in 1,4-dioxane (1.3 M overall), and
0.5 mL of H218O were heated at 85 °C for 2 h. The product mixture
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