A new method for the synthesis of H4-BINOL

Article abstract of DOI:10.1021/jo8004556

(Chemical Equation Presented) A method amenable to the gram scale synthesis of (R)-H₄-BINOL, a derivative of (R)-BINOL and ligand of interest in asymmetric catalysis, is described. The key step is the net partial hydrogenation of (R)-BINOL made possible by prior bis-etherification of the parent BINOL.

Full text of DOI:10.1021/jo8004556

While the parent BINOL 1 works well as a ligand in a number
of catalytic asymmetric systems, several modified versions of
BINOL have been utilized in attempts to further improve such
reactions.1b One modification has been achieved by a formal
partial hydrogenation of BINOL 1 to give H4-BINOL 2 and
H8-BINOL 3.
A New Method for the Synthesis of H4-BINOL
Lars V. Heumann and Gary E. Keck*
Department of Chemistry, UniVersity of Utah, 315 South
1400 East, Room 2020, Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
ReceiVed February 26, 2008
Both the H4-BINOL 2 and H8-BINOL 3 ligands have been
shown to work well in a number of catalytic asymmetric
reactions12 including the addition of alkylzinc and alkylalumi-
num reagents to aldehydes and the hetero-Diels-Alder addition
with Danishefsky’s diene.13 In addition, the enantioselectivities
obtained with these ligands surpassed those observed for
reactions with the parent BINOL 1 as a ligand.
Recently, we were interested in examining the use of H8-
BINOL and H4-BINOL in an asymmetric vinylogous Mu-
kaiyama aldol reaction catalyzed by BINOL/Ti(OiPr)4 (BITIP).5a
While H8-BINOL is commercially available, to our knowledge,
H4-BINOL is not. Moreover, the only published method for the
preparation of H4-BINOL involves heating a mixture of Ni/Al
alloy, NaOH, H2O, iPrOH, and MOM2-BINOL to 80 °C for
24 h at a concentration of 3 µmol/L (ca. 1 L of solvent for 1 g
of substrate) followed by protective group removal, including
chromatographic purification following each operation.14 The
prospect of using the above process for a gram-to-multigram
scale synthesis of H4-BINOL 3 led us to examine the develop-
ment of an alternative procedure.
A method amenable to the gram scale synthesis of (R)-H4-
BINOL, a derivative of (R)-BINOL and ligand of interest in
asymmetric catalysis, is described. The key step is the net
partial hydrogenation of (R)-BINOL made possible by prior
bis-etherification of the parent BINOL.
A versatile ligand that has found widespread use in asym-
metric catalysis is BINOL (S)-1 and (R)-1.1 Both BINOL
enantiomers are commercially available or can be synthesized
from inexpensive starting materials in enantioenriched form
(g98:2 er), or as a racemic mixture followed by subsequent
optical resolution.1–3 The BINOL enantiomers have been
extensively used as chiral ligands in catalysis, especially in
combination with Ti(IV) salts. The BINOL/Ti(IV) system
catalyzes a number of asymmetric reactions1 including allyl and
Mukaiyama aldol additions to aldehydes,4,5 hetero-Diels-Alder
reactions,6,7 ene reactions,8 reduction of ketones and aldehydes,9,10
and oxidation of sulfides.11
H8-BINOL 3 has been accessed from BINOL 1 by using
several different hydrogenation conditions;15,16 among these, a
(4) (a) Keck, G. E.; Krishnamurthy, D.; Roush, W. R.; Reilly, M. L. Org.
Synth. 1998, 75, 12. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34,
7827. (c) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467. (d) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem.
1993, 58, 6543.
(5) (a) Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9, 4275. (b) Keck,
G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363.
(6) (a) Terada, M.; Mikami, K.; Nakai, T. Tetrahedron Lett. 1991, 32, 935.
(b) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. Tetrahedron: Asymmetry
1991, 2, 643.
(7) (a) Keck, G. E.; Krishnamurthy, D. Synth. Commun. 1996, 26, 367. (b)
Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998.
(8) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949.
(9) Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638.
(10) Imma, H.; Mori, M.; Nakai, T. Synlett 1996, 1229.
(1) (a) For a recent comprehensive review on the preparation and the use of
BINOL as a ligand, see: Brunel, J. M. Chem. ReV. 2005, 105, 857. (b) For a
recent review on modified BINOL derivatives with some information on the
parent BINOL, see: Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV. 2003, 103,
3155.
(11) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem.
1993, 58, 4529.
(12) (a) Iida, T.; Yamamoto, N.; Matsunaga, S.; Woo, H.-G.; Shibasaki, M.
Angew. Chem., Int. Ed. 1998, 37, 2223. (b) Lin, Y.-M.; Fu, I.-P.; Uang, B.-J.
Tetrahedron: Asymmetry 2001, 12, 3217. (c) Kim, J. G.; Camp, E. H.; Walsh,
P. J. Org. Lett. 2006, 8, 4413.
(2) (a) Brussee, J.; Groenendijk, J. L. G.; Koppele, J. M.; Jansen, A. C. A.
Tetrahedron 1985, 41, 3313. (b) Brussee, J.; Jansen, A. C. A. Tetrahedron Lett.
1983, 24, 3261.
(3) For oxidative coupling of 2-naphthol, see: (a) Villemin, D.; Sauvaget, F.
Synlett 1994, 435. (b) Love, B. E.; Bills, R. A. Synth. Commun. 2002, 32, 2067.
(c) Ji, S. J.; Lu, J.; Zhu, X.; Yang, J.; Lang, J. P.; Wu, L. Synth. Commun. 2002,
32, 3069. For the optical resolution of racemic BINOL, see: (d) Colonna, S.;
Re, A.; Wynberg, H. J. Chem. Soc., Perkin Trans. 1981, 1, 547. (e) Cai, D.;
Hughes, D. L.; Verhoeven, T. R.; Reider, P. Tetrahedron Lett. 1995, 36, 7991.
(13) (a) Wang, B.; Feng, X.; Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org.
Chem. 2002, 67, 2175. (b) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am.
Chem. Soc. 1997, 119, 4080. (c) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron:
Asymmetry 1997, 8, 3651. (d) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am.
Chem. Soc. 2002, 124, 10.
(14) Shen, X.; Guo, H.; Ding, K. Tetrahedron: Asymmetry 2000, 11, 4321.
10.1021/jo8004556 CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4725–4727 4725

SCHEME 1. Results with iPr-BINOL (R)-4
SCHEME 2. Synthesis of H4-BINOL (R)-2
of H8-BINOL (R)-3 could be kept low by monitoring the
reaction progress and stopping the hydrogenation at the first
appearance of iPr2-H8-BINOL. We were able to obtain yields
of up to 82% of H4-BINOL (R)-2 following this hydrogenation-
deprotection sequence (see the Experimental Section and the
Supporting Information).18 In practice, the reduction was
monitored by HPLC with use of small neutralized and filtered
aliquots of the reaction mixture, and the reaction was terminated
at 50% conversion.
Adam’s catalyst appears to be unique in its ability to catalyze
this hydrogenation.19 A number of other heterogeneous catalysts
were tested for their ability to hydrogenate iPr2-BINOL (R)-8;
however, an 8% yield of iPr2-H4-BINOL with 5% Rh/C was
found to be the best result.20
The preparation of H4-BINOL (R)-2 with use of iPr2-BINOL
(R)-8 and Adam’s catalyst represents a convenient method to
access this interesting ligand. The hydrogenation is operationally
simple and is amenable for gram-scale syntheses of H4-BINOL
(R)-2. This preparation uses a much higher substrate concentra-
tion (0.1 M vs 3 µM) than the only other available method,
and only one final chromatographic purification is required, as
opposed to two. The formation of iPr2-H8-BINOL as a byproduct
appears to be inherent to the reaction conditions; however, this
side reaction can be suppressed by stopping the hydrogenation
at the first appearance of iPr2-H8-BINOL.
straightforward procedure appeared to be the partial hydrogena-
tion of either BINOL enantiomer 1 with Adam’s catalyst
(PtO2 ·(H2O)x) in AcOH, under 3 atm of H2, which provides
enantiomerically pure H8-BINOL.17
We initially hypothesized that H4-BINOL 2 could be a
possible intermediate in the hydrogenation of BINOL 1 with
Adam’s catalyst in AcOH. Therefore, we decided to perform
this hydrogenation under only 1 atm of H2 with the intention
of intercepting H4-BINOL 2. However, in the event, only
BINOL 1 and H8-BINOL 3 could be detected by TLC or HPLC
analysis.
We next considered the use of a sterically demanding
substituent on one of the two BINOL hydroxyls.
The “iPr” group was selected as a bulky substituent and
introduced to BINOL (R)-1 with K2CO3 in dry acetone (Scheme
1). The hydrogenation was carried out in AcOH with use of
1
Adam’s catalyst and 1 atm of H2. The H NMR of the crude
product revealed that, as expected, iPr-H8-BINOL (R)-7 had
formed as a byproduct. In addition, two other isomers were
present which were later identified as compounds 5 and 6.
Deprotection of the crude mixture with BBr3 yielded H4-BINOL
(R)-2 and H8-BINOL (R)-3.17
The isolation of some H4-BINOL (R)-2 was encouraging, and
we decided to investigate the influence of a second “iPr” ether
(Scheme 2). The hydrogenation of iPr2-BINOL (R)-8 with the
same conditions was slower compared to the hydrogenation of
iPr-BINOL (R)-4. TLC analysis revealed the initial formation
of iPr2-H4-BINOL; the appearance of iPr2-H4-BINOL was
followed by the development of iPr2-H8-BINOL. The reaction
was worked up and the crude material deprotected with BBr3
yielding H4-BINOL (R)-2 as the major product together with
some H8-BINOL (R)-3. See Scheme 2.
Experimental Section
Preparation of (R)-5,6,7,8-Tetrahydro-[1,1′]binaphthalenyl-
2,2′-diol (R)-2.15 and (R)-5,6,7,8,5′,6′,7′,8′-Octahydro-[1,1′]bi-
naphthalenyl-2,2′-diol (R)-3.16,17 To a 500 mL round-bottomed
flask equipped with a stirbar at room temperature were added (R)-
iPr2-BINOL (R)-8 (1.00 g, 2.70 mmol, 1.00 equiv), glacial acetic
acid (27 mL, 0.10 M), and PtO2 ·(H2O)x (0.066 g, 0.27 mmol, 0.10
equiv). The flask was flushed with a stream of dry nitrogen and
equipped with an adapter with a valve and a balloon filled with
hydrogen. The valve was opened and the mixture exposed to a
hydrogen atmosphere (balloon, ca. 1 atm). The progress of the
reaction was closely monitored by TLC and/or HPLC since reaction
time and composition were found to be strongly dependent on the
activity of the active catalyst that was generated in situ. After 5 h
The overreduction yielding H8-BINOL (R)-3 was undesired
but appears to be inherent to this hydrogenation. The amount
(18) With use of the same batch of Adam’s catalyst, the activity of the reduced
Adam’s catalyst was found to be somewhat variable. Adam’s catalyst is a
precatalyst consisting of PtO2, and its exposure to H2 generates the active Pt(0)-
catalyst in situ. As a rule of thumb, the generation of fine black particles resulted
in a highly active catalyst whereas the reaction was found to be slow when the
particles stuck to the wall of the flask or bonded together to form small spheres.
(19) The Catalyst Technical Handbook-Be SelectiVe; Johnson Matthey
Catalysts: West Deptford, NJ, 2005.
(20) The list of catalysts examined for the hydrogenation of iPr2-BINOL
(R)-8 included 0.5% Pt/Al2O3 pellets (5% yield), 20% Pd(OH)2/C (Pearlman’s
catalyst, 4% yield), 5% Rh/Al2O3 powder (3% yield), 5% Pd/C (1% yield), 5%
Pt/C wet (2% yield), 5% Ru/C (NR), 0.5% Ru/MgO pellets (NR), 5% Pd/BaSO4
unreduced (NR), 5% Pd/BaSO4 reduced (NR), 5% Pd/C/Pb (Lindlar’s catalyst,
NR), Pd(IV) oxide (NR), Rh(IV) oxide (NR), and Pt black (NR) (yields
determined by HPLC).
(15) (a) Guo, H.; Ding, K. Tetrahedron Lett. 2000, 41, 10061. (b) Karam,
O.; Martin-Mingot, A.; Jouannetaud, M.-P.; Jacquesy, J.-C.; Cousson, A.
Tetrahedron 2004, 60, 6629. (c) Korostylev, A.; Tararov, V. I.; Fischer, C.;
Monsees, A.; Boerner, A. J. Org. Chem. 2004, 69, 3220.
(16) (a) Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J.; Domeier,
L. A.; Moreau, P.; Koga, K. M.; Mayer, J.; Chao, Y.; Siegel, M. G.; Hoffman,
D. H.; Sogah, G. D. Y. J. Org. Chem. 1978, 43, 1930. (b) McDougal, N. T.;
Trevellini, W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. AdV. Synth. Catal.
2004, 346, 1231. (c) Reetz, M.; Merk, C.; Naberfeld, G.; Rudolph, J.; Griebenow,
N.; Goddard, R. Tetrahedron Lett. 1997, 38, 5273.
(17) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 2593.
4726 J. Org. Chem. Vol. 73, No. 12, 2008

the flask was flushed with a dry stream of nitrogen and the mixture
diluted with a solution of saturated aqueous NaOH (14 mL)
followed by slow addition of saturated aqueous NaHCO3 solution
(200 mL) until evolution of gas stopped. The mixture was extracted
with 50% EtOAc/hexanes (100, 150, and 200 mL), and the organic
phase was washed with water (50 and 100 mL) and brine (50 mL),
dried over Na2SO4, then filtered and concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (50 mL) and
transferred into a 250-mL round-bottomed flask equipped with a
stirbar, rubber septum, and nitrogen inlet. Boron tribromide (2.5
mL, 27 mmol, 10.0 equiv) was added at room temperature followed
after 10 min by slow addition of aqueous NaOH solution (0.75 M,
50 mL). The organic phase was washed with saturated aqueous
NH4Cl solution (50 mL), water (50 and 100 mL), and brine (50
mL), then dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on a 3 × 21 cm silica gel column eluting with a solvent gradient
from 1% through 5% acetone/hexanes. The product-containing
fractions were concentrated to give (R)-H4-BINOL (R)-2 (0.644 g,
2.22 mmol, 82% yield) and (R)-H8-BINOL (R)-3 (127 mg, 0.431
mmol, 16% yield) as white solids. Analytical data for 2: mp 128
1H NMR (CDCl3) δ 7.90-7.83 (m, 2H), 7.42-7.23 (m, 4H), 7.12
(d, J ) 8.3 Hz, 1H), 6.89 (d, J ) 8.3 Hz, 1H), 5.23 (s, 1H), 4.54
(s, 1H), 2.84-2.72 (m, 2H), 2.33-2.05 (m, 2H), 1.79-1.55 (m,
4H), 75 MHz; 13C NMR (CDCl3) δ 152.4, 152.0, 138.5, 133.1,
131.6, 131.0, 130.4, 129.5, 128.5, 127.5, 124.1, 123.9, 117.7, 117.5,
113.4, 112.6, 29.4, 27.2, 23.1, 23.1; 75 MHz DEPT (CDCl3) δ CH2:
29.4, 27.2, 23.1 (2), CH: 131.6, 131.0, 128.6, 127.5, 124.1, 123.9,
117.7, 113.4, C: 152.4, 152.0, 138.5, 133.1, 130.4, 129.5, 117.5,
112.6; IR (neat) 3478, 3414, 3057, 2929, 2857, 1619, 1595, 1475,
1389, 1189, 1147, 817, 752 cm-1; HRMS (ESI/APCI) calcd for
C20H19O2 m/z (M + H) 291.1385, found 291.1390. Only the (R)
enantiomer was detected by HPLC analysis with use of a chiral
column (see the Supporting Information).
Acknowledgment. Financial support was provided by the
National Institutes of Health through grant GM-29861.
Supporting Information Available: General experimental
procedures, compound characterization data, and copies of 1H,
13C, and DEPT NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
°C (lit.14 mp 131-133 °C); Rf 0.23 (25% EtOAc/hexanes); [R]20
D
+40.2 (c 1.01, THF) (lit.14 [R]25D +40.4 (c 0.98, THF)); 300 MHz
JO8004556
J. Org. Chem. Vol. 73, No. 12, 2008 4727