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Synthesis of Sterically Hindered Chiral Phosphoric Acid 4hydroxy-2,6-bis(4-isopropylphenyl)dinaphthol[2, 1-d: 1’,2’-f] [1,3,2

]
dioxaphosphepine 4-oxide for Use in Bronsted Acid and Anion Phase
Transfer Catalysis
Humza A. Siddiqui*, Kevin Fong † , Courtney Haibach-Morris †
Department of Chemistry, University of California, Berkeley, 420 Latimer Hall, Berkeley, California 94704, United States
[1,1’-binaphthalene]-2,2’-diol, 2,2’-bis(ethoxymethoxy)-1,1’-binaphthalene, 2,2’-bis(ethoxymethoxy)-3,3’-diiodo-1,1-binaphthalene, 2,2’-bis(ethoxymethoxy)-3,3’-bis(4-isopropylphenyl)-1,1’-binaphthalene, 4-hydroxy-2,6-bis(4isopropylphenyl)dinaphthol[2,1-d: 1’,2’-f] [1,3,2] dioxaphosphepine 4-oxide, 1,3,5-tricyclohexyl-2-bromobenzene, Berkeley

ABSTRACT: The development of catalysts, catalytic reacI

NaH

OH
OH

O

OEt

O

OEt

n-BuLi
I2

EOM-Cl
THF

O

OEt

O

OEt

I

B
HO

OH

K3PO4
Pd(OAc)2
SPhos

12 N HCl
O

OEt

O

OEt

OH

1,4-dioxane

OH

1. POCl3, pyridine
O

2. H2O

P
O

O
OH

The development of catalysts, catalytic reactions, and kinetic enhancing methods is of primary importance in the field of
organic synthesis in its ability to address problems in the synthesis of larger, complex molecules that may, ultimately, possess interesting structural, biological, or even medicinal properties. Herein, the Dean F. Toste Group at University of California Berkeley and its associated colleagues present the synthesis of 4-hydroxy-2,6-bis(4isopropylphenyl)dinaphthol[2, 1d: 1’,2’-f] [1,3,2] dioxaphosphepine 4-oxide (6) from [1,1’binaphthalene]-2,2’-diol (1) as a means of exploring the utility
of chiral phosphoric acid ligands in catalysis as, historically,
BINOL-derived chiral phosphoric acids have served as a well
established class of catalysts that have been applied to an everincreasing number of useful transformations. The transformations include phase-transfer catalysis and other general asymmetric, enantioselective reactions in which short reaction times
and high yields are desired.

In the first scheme of the reaction, starting material [1,1’binaphthalene]-2,2’-diol (1) was obtained from our financial
backer, Aspira Scientific, and was subjected to alcohol protection by means of EOM-Cl, NaH, and THF. By protecting the
alcohol group with a relatively more non-polar ether functional group in lieu of, it is ensured that the alcohol groups will not
serve as a site of undesirable reactivity in further steps, including the subsequent bis-iodination step in which the n-BuLi
activity could potentially result in deprotonation of the alcohol
group instead
of the desired
hydrogen
NaH
atom within
OH
O
OEt
the bicyclic
OH
O
OEt
EOM-Cl
aromatic ring.
THF
The use of an
ether protection group,
consequently, also ensures that the cross-coupling by way of
4-isopropyl phenyl boronic acid is at the carbon site where

tions, and kinetic enhancing methods is of primary importance
in the field of organic synthesis. Herein, the synthesis of the
sterically hindered chiral phosphoric acid ligand (R) 4-hydroxy-2,6-bis(4isopropylphenyl)dinaphthol[2, 1-d: 1’,2’-f]
[1,3,2] dioxaphosphepine 4-oxide from [1,1’binaphthalene]-2,2’-diol is presented given the multi-step
mechanisms illustrated to the left and in the interest of exploring the functionality of chiral phosphoric acids as a class of
versatile organocatalyst alternatives in asymmetric transformations and phase-transfer catalysis. In this synthesis, a number
of reaction schemes integral to the design of catalysts are explored including alcohol protection, bis-iodination, Suzuki
coupling, Friedel-Crafts alkylation, and halogenation . A
preparation of 1,3,5-tricyclohexyl-2-bromobenzene is also
offered. 1H NMR Spectroscopy observations are presented.

iodination was desired and achieved. Comparatively, an unprotected oxygen has the potential to oxidize the Palladium catalyst back to Pd (II) instead of the necessary Pd(0) which would
render the cross-coupling ineffective if alcohol protection was
not employed. Additionally and finally, the protection also
ensures that the alcohol groups are retained for the creation of
the chiral phosphoric acid ligand in the final step by way of
pyridine, POCl3, and water. Given these consequences, it was
absolutely necessary to achieve a correct 1H NMR spectra.
The 1H NMR spectra obtained, 1H NMR (300 MHz, Chloroform-d) δ 7.91 (dd, J = 22.9, 8.6 Hz, 2H), 7.33 (ddd, J = 8.2,
6.6, 1.5 Hz, 1H), 7.28 – 7.15 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H),
5.13 (d, J = 7.0 Hz, 1H), 5.02 (d, J = 6.9 Hz, 1H), 3.36 (qq, J =
9.6, 7.0 Hz, 2H), 1.00 (t, J = 7.1 Hz, 7H), possessed peaks at
5.13 ppm, 3.336 ppm, and 1.00 ppm are respective of protons
within the ether functional group and, therefore, the 1H NMR
suggested purity and reaction completion as expected. However, as suggested by the 1H NMR spectra and the 141.646%
yield, the generated product was not entirely dry post-rotory
evaporation for bis-iodination. However, it was not expected
to hinder future schemes and the product was carried forward.
In the following scheme, approximately 8.169 g of the 14.2
grams of 2,2’-bis(ethoxymethoxy)-1,1’-binaphthalene (2)
generated is subjected to bis-iodination to ensure the employment of an aryl halide for the subsequent Suzuki Coupling
procedure. 

I

O

OEt

O

OEt

n-BuLi
I2

O

OEt

O

OEt

I

The iodination was achieved by means of a n-BuLi. An
organolithium reagent possesses a large difference in electronegativity that allows it to act as a base and nucleophile. In

this particular case, the n-BuLi removes the C3, C3’ protons to
ensure halogenation by way of the iodine and a newly generated bicyclic carbanion. Because iodine is not a very reactive
halogen, it should be removed rather easily after electrophilic
addition for the subsequent Suzuki cross coupling step and, for
this reason, it is employed herein. To ensure it does, however,
participate in electrophilic addition at the appropriate C3, C3’
sites, the ether functional groups affixed in the first scheme act
as ortho-director/activators. This makes the bicyclic compound
likely to attack the iodine at the C3, C3’ site. The reaction was
carried out successfully with a 97.429% yield of product. The
inability to generate 100% retention is likely due to inefficient
cannula transfer. The 1H NMR generated, however, does suggest reaction completion and purity as peaks generated prior to
iodination are now pushed slightly downfield. More so, a discernible difference in number of peaks generated is observed
as 2 H+ atoms are now lost. These observations suggested
carrying 2,2’-bis(ethoxymethoxy)-3,3’-diiodo-1,1-binaphthalene (3) forward for Suzuki cross coupling.

The Suzuki procedure employed requires the palladiumcatalyzed cross coupling between an aryl halide and an
organoboronic acid. Given (3) and the commercially readily
available 4-isopropyl phenyl boronic acid by Combi Blocks,
this procedure is a common, fairly advantageous method by
which to generate 2,2’-bis(ethoxymethoxy)-3,3’-bis(4-isopropylphenyl)-1,1’-binaphthalene (4).




I


B
HO
OH
O
OEt
O
OEt

O
OEt
O
OEt

K PO
Pd(OAc)

SPhos
I

3

4

2


The organophosphorus compound SPhos was employed largely in part because its palladium complex exhibits a high activity for the Suzuki cross coupling procedure. The K3PO4 was
used as a basic environment in which the Suzuki cross coupling is most effective in. Although the procedure is carried
out, generally, with relative ease, the Suzuki cross coupling
was performed twice herein as the first 1H NMR generated
was that of starting material (3). It is believed that this error is
a result of Pd(OAc)2 never actually reaching the SPhos and the
rest of the starting material within the 120 mL 4:1 dioxane:water solution. This procedure was easy to carry out again with
relatively more SPhos and Pd(OAc)2. This data is given in the
Supplemental Information. The H NMR spectra obtained (1H
NMR (300 MHz, Chloroform-d) δ 7.94 (s, 2H), 7.88 (d, J =
8.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.39 (dt, J = 8.3, 3.8 Hz,
1H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 4.3 Hz, 2H), 4.61 –
4.33 (m, 2H), 2.98 (p, J = 6.9 Hz, 1H), 2.80 – 2.62 (m, 1H),
2.43 (dq, J = 9.9, 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H), 0.40 (t,
J = 7.0 Hz, 3H)) possessed peaks at 1.31-2.98 ppm which is
respective of the isopropyl alkyl chain of the newly generated
substituent. The multiple peaks observed in the 7.0 ppm region
also suggests the presence of the desired, newly affixed functional groups’ phenyl regions. Ultimately, however, a 43.070%
yield was achieved. It is believed that this dramatic loss of
product is a result of losing starting material as a result of an
inefficient first Suzuki procedure and a column chromatography that was rushed in the interest of time.

Concurrently, during this time, some members of the Dean
F. Toste Group and associated colleagues employed a Kumada
cross coupling technique to generate other chiral phosphoric
acid ligands. A Kumada cross coupling procedure utilizes a
grignard reagent and a transition metal catalyst to couple an
aryl halide to another aryl group in a coupling mechanism not
too different from the Suzuki procedure utilized herein. To aid

some of our colleagues in their Kumada coupling procedures
and to further investigate the role of potential chiral phosphoric acid ligand catalysts, the authors of this paper also participated in a Friedel-Crafts alkylation and subsequent bromination to generate 1,3,5-tricyclohexyl-2-bromobenze. The
reaction scheme for this procedure is shown below and the
details of which are explored in the Supplemental Information.

Br

Br2

AlCl3

Br

The reaction was largely successful given the 1H NMR generated for 1,3,5-tricyclohexyl-2-bromobenzene and the product
yield generated. A singlet at 6.94 ppm respective of the 2 H+
atoms within the center benzene ring was observed. Additionally, a multiplet is observed in the 1-2 ppm region which is
highly indicative of the H+ atoms found on the cyclohexyl
groups. A peak at 3.07 ppm is also observed further suggesting
purity of product. It is possible byproduct of some sort was
created given additional, unwanted peaks (doublet at
3.78ppm), perhaps indicating that the reaction did not go entirely to completion. However, approximately, 13.043 grams
of product was achieved and the 1H NMR spectra generated
largely suggests carrying this Kumada cross coupling reagent
through for our colleagues’ subsequent mechanistic steps.

Returning to the synthesis of (6), the subsequent step after
Suzuki cross coupling was an overall de-protection of the 2,2’bis(ethoxymethoxy)-3,3’-bis(4-isopropylphenyl)-1,1’-binaphthalene (4) to generate 3,3’-bis(4-isopropylphenyl)-[1,1’-binaphthalene]-2,2’-diol (5). This step was carried out to ensure
that the proper alcohol groups are retained in generating the
final, chiral phosphoric acid ligand of interest. Notably important is the long reaction time and heat required to ensure the
ether group is removed and protons are shuffled from the long
substituent ether chain to the 1,4-dioxane. The heat and long
reaction times seem to suggest and elimination reaction. During this process, the anionic oxygens created becomes protonated, thereby regenerating the alcohol groups. A 1H NMR
was generated for (5) however it is highly imperative that this
spectra be retaken as rapid proton exchange can result in broad
peaks or the absent of peaks, the latter of which might be the
case herein. The peaks expected for the alcohol groups, according to ChemDraw Professional 15.0 by Perkin Elmer
Informatics, should be found in the 10-11 ppm region but the
spectra does not suggest this, despite appropriate peaks
everywhere else. Research online suggests that alcohol groups
are found between 1-6 ppm on 1H NMR spectra suggesting,
perhaps, that ChemDraw Program has erred in its prediction.

12 N HCl
O

OEt

O

OEt

1,4-dioxane

OH
OH

Either way, we can assume rapid proton exchange has erased
the alcohol group peaks from the spectra. Peaks at 5.4 ppm
and 3.7 ppm represent DCM and 1,4-dioxane respectively. Not
coincidentally, the 1H NMR taken for this de-protection step to

generate (5) resembles the 1H NMR taken for the final product
(6) thereby perhaps suggesting that, in fact, the appropriate
structural deviations between (5) and (6) In the 1H NMR spectra for (6), the DCM peak seems to possess a bump which
suggest the final additional proton added to (5) after the POCl3
Phosphorylation to generate (6).

Assuming (5) is generated and that the 1H NMR analysis is
correct after all, (6) was generated in the last reaction scheme.
The alcohol groups of (5) attack the POCl3 and becomes deprotonated by way of the pyridine. This process continues
until two chlorine molecules are released from the POCl. The
last chlorine anion is removed by way of the water to ensure,
at last, the chiral, phosphoric acid ligand of interest.

ASSOCIATED CONTENT
Supporting Information
Full experimental procedures, analyses, characterization data, and
NMR data. This material is available free of charge via the Internet at http://pubs.acs.org. and attached at the end of this document
as well.

AUTHOR INFORMATION
Corresponding Author
*E-mail: humzasiddiqui@berkeley.edu


Present Addresses

† Department of Chemistry, University of California, Berkeley,
420 Latimer Hall, Berkeley, California 94704, United States

Author Contributions

The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuscript.


OH
OH

1. POCl3, pyridine

O

2. H2O

P
O

O

OH




The 1H NMR spectra generated for (6) is similar to that generated for (5) thereby highlighting and remaining consistent with
respective structural changes made to the molecule (addition
of a mere single proton). A product yield of 94.667% was
achieved.

In conclusion, the multi-step synthesis of the final product,
4-hydroxy-2,6-bis(4isopropylphenyl)dinaphthol[2, 1-d: 1’,2’f] [1,3,2] dioxaphosphepine 4-oxide, was motivated by a large
desire to investigate the functionality and strength of
organocatalysts in addressing other larger, overarching problems posed in the field of organic synthesis. In particular, this
group is interested in chiral phosphoric acid ligands and their
potency in altering reaction kinetics relative to other potential
catalysts, such as the expensive metallo-catalysts. Given the
1H NMR spectra achieved during each step, it is believed that
the final product was indeed generated, even in spite of the
inconclusive nature of (5) 1H NMR. Future experiments
should do well, however, to ensure 1H NMR are sound and
correct for the product desired. Future experiments should also
seek to shorten reaction times in this multi-step synthesis and
to run experiments with the chiral phosphoric acid ligands
generated to demonstrate efficacy of catalysis.


Funding Sources

Department of Chemistry, University of California, Berkeley

Aspira Scientific

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT
We are grateful to the Department of Chemistry at University of
California, Berkeley for the research opportunity and funding to
carry out our multi-step synthesis experiments. We also thank
members of the Dean F. Toste Group, especially Ph.D candidate
Richard Thornbury, at University of California, Berkeley for
sound guidance and patience. Additionally, we thank Dante
Valdez in providing commercial reagents for use and our financial
backer Aspira Scientific for select reagents for use.

REFERENCES

[1] Shunatona, H.P., Patel, J., et. al Synthesis of Sterically Hindered
Chiral Phosphoric Acids for Use in Bronsted Acid an Anionic PhaseTransfer Catalysis; University of California, Berkeley: Berkeley, CA,
2015.
[2] Milburn, R.R., Shakil Hussain S.M., et. al 3,3’-Dipyridyl BINOL Ligands. Synthesis and Application in Enantioselective Addition
of Et2Zn to Aldehydes; Department of Chemistry, Queen’s University,
Kingston ON, Canada K7L 3N6
[3] Neel, A., Thornbury, R., Suzuki Procedure; University of California, Berkeley: Berkeley, CA, 2015.
[4] College of Chemistry - The Toste Group: Research. http://
www.cchem.berkeley.edu/toste/research.html (accessed December 10,
2015).