Synthesis of 8,8′-Disubstituted 1,1′-Binaphthyls Stable to Atropisomerization: 2,2′-Dimethyl-1,1′-binaphthalene-8,8′-diol and 2,2′-Dimethyl-8,8′-bis(4-tert-butyloxazolyl)-1,1′-binaphthyl

Article abstract of DOI:10.1021/jo990968h

Axially chiral binaphthyls 3a and 3b were synthesized taking, advantage of Ullman coupling of 4a and 4b, respectively. The binaphthyls were shown to be stable to atropisomerization. Binaphthol 3b was resolved with (-)-(1S)-menthyl chloroformate (11). R-axis diastereomer of bisoxazoline 3b was used for enantioselective cyclopropanation of styrene with ethyl diazoacetate.

Full text of DOI:10.1021/jo990968h

J . Org. Chem. 1999, 64, 7921-7928
7921
Syn th esis of 8,8′-Disu bstitu ted 1,1′-Bin a p h th yls Sta ble to
Atr op isom er iza tion : 2,2′-Dim eth yl-1,1′-bin a p h th a len e-8,8′-d iol a n d
2,2′-Dim eth yl-8,8′-bis(4-ter t-bu tyloxa zolyl)-1,1′-bin a p h th yl
Sergei V. Kolotuchin and Albert I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins Colorado 80523
Received J une 17, 1999
Axially chiral binaphthyls 3a and 3b were synthesized taking, advantage of Ullman coupling of
4a and 4b, respectively. The binaphthyls were shown to be stable to atropisomerization. Binaphthol
3b was resolved with (-)-(1S)-menthyl chloroformate (11). R-axis diastereomer of bisoxazoline 3b
was used for enantioselective cyclopropanation of styrene with ethyl diazoacetate.
The axially chiral C2-symmetrical 1,1′-binaphthyl scaf-
fold has seen extensive use in organic synthesis in the
design of nonracemic ligands and chiral auxiliaries. The
most widely used compounds based on the 1,1′-binaph-
thyl framework are the chiral ligands 1,1′-bi-2-naphthol
(1a ),1 (S,S)-2,2′-bis(4-alkyloxazolyl)-1,1′-binaphthyl (1b),2
2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl (1c),3 and
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1d ).4 Bi-
naphthol 1a has also been used as a chiral auxiliary. A
common feature of 1a -d is that their functional groups
capable of chelating a metal ion attached in the 2,2′
position of the rigid binaphthyl skeleton also raise the
barrier to atropisomerization, making it slow even at
elevated temperature.5
to a tethered monocinnamate ester.6a Further uses of
binaphthol 2a as a chiral auxiliary included an enantio-
selective protonation of enolates,6b a Diels-Alder reaction,6c
and synthesis of a novel monophosphine ligand 2c.6d
Diastereomeric R-axis (a-R,S,S) and S-axis (a-S,S,S)
bisoxazoline 2b (R ) t-Bu) was accessed by Ullman
coupling. A complex of (a-R,S,S)2b (R ) t-Bu) ligated to
CuOTf was reported to catalyze an enantioselective
cyclopropanation of styrene with ethyl diazoacetate.7
A distinct feature of the 2a -c as typical examples of
8,8′-disubstituted 1,1′-binaphthyls is that they are stable
at room temperature but are prone to atropisomerization
at elevated temperature.8a For example, the barrier to
atropisomerization for 2a and 2c was reported to be 30.0
(2) (a) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2655-
2658. (b) Uozumi, Y.; Kato, K.; Hayashi, T. J . Am. Chem. Soc. 1997,
119, 5063-5064. (c) Uozumi, Y.; Kato, K.; Hayashi, T. J . Org. Chem.
1998, 63, 5071-5075. (d) Uozumi, Y.; Kyota, H.; Kishi, E.; Kitayama,
K.; Hayashi, T. Tetrahedron: Asymmetry 1996, 7, 1603-1606. (e)
Andrus, M. B.; Asgari, D.; Sclafani, J . A. J . Org. Chem. 1997, 62, 9365-
9368.
(3) (a) Uozumi, Y.; Hayashi, T. J . Am. Chem. Soc. 1991, 113, 9887-
9888. (b) Hayashi, T.; Uozumi, Y.; Pure Appl. Chem. 1992, 64, 1911-
1916. (c) Hayashi, T. Acta Chem. Scand. 1996, 50, 259-266; Chem.
Abstr. 1996, 125, 9818. (d) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J .
Am. Chem. Soc. 1998, 120, 1681-1687. (e) Hayashi, T.; Kawatsura,
M.; Uozumi, Y. Chem. Commun. (Cambridge) 1997, 561-562.
(4) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
(b) Takaya, H.; Ohta, T.; Mashima, K. Adv. Chem. Ser. 1992, 230
(Homogen. Transition Met. Catal. React.), 123-142; Chem. Abstr. 1993,
118, 21717. (c) Akutagawa, S. Appl. Catal., 1995, 128, 171-217; Chem.
Abstr. 1995, 123, 255801. (d) Kumobayashi, H.; Sayo, N.; Akutagawa,
S.; Sakaguchi, T.; Tsuruta, H. Nippon Kagaku Kaishi, 1997, 835-846;
Chem. Abstr. 1998, 128, 36303.
(5) (a) Rashidi-Ranjbar, P.; Sandstrom, J .; Schriver, G. W.; Wong,
H. N. C. Iran. J . Chem., Chem. Eng. 1996, 15, 18-22. (b) Liljefors, T.;
Carter, R. E. Tetrahedron 1978, 34, 1611-1615. (c) Kranz, M.; Clark,
T.; von Rague Schleyer, P. J . Org. Chem. 1993, 58, 3317-3325. (d) Oi,
S.; Kawagoe, K.; Miyano, S. Chem. Lett. 1993, 79-80. (e) Kyba, E. P.;
Gokel, G. W.; de J ong, F.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Kaplan,
L.; Sogah, G. D. Y.; Cram, D. J . J . Org. Chem. 1977, 42, 4173-4184.
(6) (a) Fuji, K.; Yang, X.-S.; Tanaka, K.; Asakawa, N.; Hao, X.-J .
Tetrahedron Lett. 1996, 37, 7373-7376. (b) Fuji, K.; Kawabata, T.;
Kuroda, A. J . Org. Chem. 1995, 60, 1914-1915. (c) Tanaka, K.;
Asakawa, N.; Nuruzzaman, M.; Fuji, K. Tetrahedron: Asymmetry 1997,
8, 3637-3645. (d) Fuji, K.; Sakurai, M.; Kinoshita, T.; Kawabata, T.
Tetrahedron Lett. 1998, 39, 6323-6326. (e) Fuji, K.; Sakurai, M.;
Kinoshita, T.; Tada, T.; Kuroda, A.; Kawabata, T. Chem. Pharm. Bull.
1997, 45, 1524-1526. (f) Fuji, K.; Sakurai, M.; Tohkai, N.; Kuroda,
A.; Kawabata, T.; Fukazawa, Y.; Kinoshita, T.; Tada, T. Chem.
Commun. (Cambridge) 1996, 1609-1610.
The isomeric derivatives 2a -c wherein the functional
groups are placed in the 8,8′ position of the 1,1′ binaph-
thyl scaffold have also been reported. Binaphthol 2a was
found to be a superior chiral auxiliary to binaphthol 1a
in a tandem conjugate addition of Me2CuLi and n-Bu2CuLi
(1) (a) Shibasaki, M.; Sasai, H. Pure Appl. Chem. 1996, 68, 523-
530; Chem. Abstr. 1996, 125, 85782. (b) J ohannsen, M.; Yao, S.; Graven,
A.; J orgensen, K. A. Pure Appl. Chem. 1998, 70, 1117-1122; Chem.
Abstr. 1998, 129, 216467. (c) de Lucchi, O.; Pure Appl. Chem. 1996,
68, 945-949; Chem. Abstr. 1996, 125, 142155. (d) Zimmer, R.; Suhrbier,
J . J . Prakt. Chem./ Chem.-Ztg. 1997, 339, 758-762; Chem. Abstr. 1998,
128, 3327). (e) Noyori, R. Asymmetric Catalysis in Organic Chemistry,
Wiley: New York, 1994.
(7) (a) Meyers, A. I.; McKennon, M. J . Tetrahedron Lett. 1995, 36,
5869-5872. (b) Meyers, A. I.; Price, A. J . Org. Chem. 1998, 63, 412-
413.
(8) (a) Harris, M. M.; Patel, P. K.; Korp, J . D.; Bernal, I. J . Chem.
Soc., Perkin Trans. 2 1981, 12, 1621-1628 and earlier references cited.
(b) Fuji, K. Unpublished results. Private communication and ref 6f.
10.1021/jo990968h CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

7922 J . Org. Chem., Vol. 64, No. 21, 1999
Kolotuchin and Meyers
Sch em e 1
and 30.2 kcal/mol, which translates into a half-life of 4.8
and 5.7 h at 100 °C, respectively.8b Therefore, additional
sp3 hybridized anchoring groups are needed in the 2,2′
positions of 2a -c to slow the atropisomerization of these
systems.8a The resulting dimethyl substituted axially
chiral ligand and auxiliary 3b and 3a can be used at a
temperature where their corresponding desmethyl coun-
terparts 2a and 2b would atropisomerize.8a This paper
presents a synthesis of binaphthyls 3a and 3b, their
absolute configuration, proof of their conformational
stability, and some preliminary results of enantioselective
cyclopropanation catalyzed by CuOTf ligated to 3b.
workers,12 both 1a and 2a form diastereomeric dicarbon-
ates with 11, which differ in crystallinity and can be
separated by simple crystallization from hexane. The
same result was obtained with the pair of diastereomeric
dicarbonates 12a and 12b obtained from 3a and 11.
However, on a smaller scale, the separation of 12a and
12b can also be achieved using thin-layer preparative
radial chromatography (Chromatotron) or gravity column
chromatography eluting with nonpolar system of sol-
vents. X-ray crystal analysis showed that the more
crystalline dicarbonate 12b with lower Rf had the S-
stereogenic axis.28 Removing the menthyl auxiliary from
12a ,b with lithium aluminum hydride12 afforded pure
individual enantiomers of binaphthol 3a . The optical
(9) For a review on Ullman synthesis of biaryls, see (a) Fanta P. E.
Synthesis 1974, 9-21. (b) Knight, D. W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; pp 499-505. (c) For diastereoselective Ullman coupling resulting
in biaryl bisoxazolines, see ref 2a. (d) Nelson, T. D.; Meyers, A. I.
Tetrahedron Lett. 1994, 35, 3259-3262. (e) Degnan, A. P.; Meyers, A.
I. J . Am. Chem. Soc. 1999, 121, 2762-2769.
(10) For nuclear bromination of aromatics by NBS under ionic
conditions, see (a) Lambert, F. L.; Ellis, W. D.; Parrt, R. J . J . Org.
Chem. 1965, 30, 304-306. (b) During preparation of the manuscript
use of a mixture of NBS/TFA/H2SO4 for aromatic bromination was
reported: Zhang, L. H.; Duan, J .; Xu, Y.; Dolbier, W. R., J r. Tetrahe-
dron Lett. 1998, 39, 9621-9622.
(11) (a) For a review on Bayer-Villiger oxidation, see Krow, G. R.
Org. React. 1993, 43, 251-798. (b) Franck, R. W.; Gupta, R. B. J . Org.
Chem. 1985, 50, 4632-4635.
(12) Fabbri, D.; Delogu, G.; De Lucchi, O. J . Org. Chem. 1995, 60,
6599-6601.
(13) Fiesselmann, H. Ber. 1942, 75, 881-891.
The binaphthyl core of both 3a and 3b was constructed
making use of an Ullman coupling9 of the corresponding
functionalized naphthalene bromides 4a and 4b, which
were both derived from nitrile 5 (Scheme 1). Bromination
of 5 with NBS under ionic conditions10 in a mixture of
acetic and trifluoroacetic acids catalyzed by sulfuric acid
afforded 6 in 91% yield. Reduction of 6 with DIBAL gave
the corresponding aldehyde 7 in 90% yield. Bayer-
Villiger oxidation11 of 7 was carried out with an excess
of m-CPBA to afford 8 in 85-100% yield, which partially
hydrolyzed to naphthol 9 upon aqueous workup [satu-
rated NaHCO3(aq)]. To obviate isolation and purification
of the easily oxidizable 9, formate 8 was directly con-
verted into methoxynaphthalene 4a , which was air and
shelf stable. Coupling of 4a under Ullman conditions with
copper bronze yielded racemic methoxy protected binaph-
thol 10 in 66% yield. Deprotection of 10 with boron
tribromide smoothly afforded 3a in nearly quantitative
yield.
(14) For ester cleavage via Sn2-type dealkylation, see: McMurry,
J . Org. React. 1976, 24, 187-201.
(15) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F. J . Am.
Chem. Soc. 1993, 115, 9276-9282.
(16) (a) For a review of enantioselective cyclopropanation, see Doyle,
M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946. (b) Pfaltz,
A. Acc. Chem. Res. 1993, 26, 339-345. (c) Evans, D. A.; Woerpel, K.
A.; Hinman, M. M.; Faul, M. M. J . Am. Chem. Soc. 1991, 113, 726-
728. (d) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Helv. Chim Acta 1988,
71, 1553-1565. For the use of CuOTf as a catalyst for cyclopropanation,
see Salomon, R. G.; Kochi, J . K. J . Am. Chem. Soc. 1973, 95, 3300-
3310.
(17) J ouanno, C.; LeFloc’h, Y.; Gree, R. Bull. Soc. Chim. Belg. 1995,
104, 49-53.
(18) (a) For a review on Friedel-Crafts reaction of cyclic anhydrides
with aromatic hydrocarbons, see Berliner, E. Org. React. 1949, 5, 229-
289. (b) von Limpricht, H. Ann. 1900, 312, 110-111.
(19) Huang-Minlon, J . Am. Chem. Soc. 1946, 68, 2487-2488.
(20) Todd, D. Org. React. 1948, 4, 378-422.
(21) (a) Newman, M. S.; Seshadri, S. J . Org. Chem. 1962, 27, 76-
78. (b) Koo, J . J . Am. Chem. Soc. 1953, 75, 1891-1894.
(22) (a) Gregory, G. B.; J ohnson, A. L.; Ripka, W. C. J . Org. Chem.
1990, 55, 1479-1483. (b) J acobs, S. A.; Harvey, R. G. J . Org. Chem.
1983, 48, 5134-5135.
(23) McKennon, M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568-
3571.
(24) Fuson, R. C.; Cleveland, E. A. Organic Synthesis; Wiley: New
York, 1955; Vol. III, p 339-340.
Resolution of 3a was achieved using (-)-(1S)- menthyl
chloroformate (11). As reported by De Lucchi and co-

Synthesis of 8,8′-Disubstituted 1,1′-Binaphthyls
J . Org. Chem., Vol. 64, No. 21, 1999 7923
Sch em e 2
purity of 3a was verified with chiral HPLC. As expected,
heating either of the pure enantiomers of 3a at 180 °C
in the melt for 30 min did not lead to any atropisomer-
ization as evidenced by HPLC.
about the chiral axis, the X-ray crystal structure of (a-
S,S,S)3b was determined.27
Our current rationale for the observed diastereoselec-
tivity in the Ullman coupling of 4b is based upon the
different nature of the solvents used (Figure 2). In
pyridine, the copper(I) bromide formed during the reac-
tion will be easily complexed by the huge excess of
pyridine allowing the oxazolines to position themselves
such that both the nitrogens and the tert-butyl groups
are at maximum distance from each other as shown for
copper(III) intermediate (A). This minimizes steric repul-
sion of tert-butyl groups and the lone pair repulsion of
the oxazoline nitrogens. However, in the less coordinating
DMF (B), the copper(I) ion will readily coordinate to the
two oxazoline nitrogens forming the Cu(III) intermediate
B (Figure 2), which will reductively eliminate to yield the
observed biaryl with (a-R,S,S) configuration. Thus, pyr-
idine leads mainly to the (a-S,S,S) biaryl configuration
whereas DMF allows formation of the diastereomeric (a-
R,S,S)3b. Support for this mechanistic rational can be
obtained by the fact that the bisoxazoline 3b formed in
DMF still contains the copper(I) ion complexed in the
product. The copper is removed by washing with aqueous
ammonia leaving the (a-R,S,S) diastereomer of 3b.
As an alternative approach to the formation of the
binaphthyl skeleton of 3b, we utilized Lipshutz’s condi-
tions which rely on the oxidative dimerization of higher
order cyanocuprates with molecular oxygen.15 The cy-
anocuprates are formed by transmetalation of the cor-
responding organolithium compounds with 0.5 equiv of
CuCN. A metalation study demonstrated that 4b can be
readily lithiated, and the resulting carbanion was pro-
tonated with methanol to afford 87% of 18. Following
Lipshutz protocol, lithiated 4b was treated with CuCN
and oxidized to 3b. This coupling procedure afforded 24%
of (a-S,S,S)3b, 10% of (a-R,S,S)3b, and 11% of 18. As
evidenced by 1H NMR, no incorporation of deuterium into
18 was detected when the reaction mixture was quenched
with methanol-d prior to aqueous workup. This result
suggests formation of 18 during the reaction and not
during the aqueous workup.15
For the synthesis of bisoxazoline 3b (Scheme 2), nitrile
5 was reduced with DIBAL to aldehyde 13 in 95% yield,
which was oxidized with silver(I) oxide to acid 14 in 90%
yield.13 Sulfuric-acid-catalyzed Fischer esterification of
acid 14 with methanol afforded ester 15 in 90%, which
was regioselectively brominated with NBS under ionic
conditions10 in 94% yield. It was further found that 7
could be obtained by bromination of 13 under identical
conditions. However, the 8-bromo substituent makes
aldehyde 7 less reactive than 13 possibly due to steric
hindrance. Therefore, it was not surprising that 7 could
not be oxidized with silver(I) oxide to acid 17. Likewise,
bromoester 16 is also hindered and proved to be inert to
hydrolysis (LiOH/ethanol). Ester 16 was converted to acid
17 in 82% yield with lithium chloride in refluxing DMF
taking advantage of the SN2 dealkylation.14 Acid 17 was
then converted to the oxazoline 4b under standard
conditions in 60% yield.2a Coupling of 4b, under Ullman
conditions, both in DMF and pyridine, was found to be
solvent dependent and provided both diastereomers of
3b in fair chemical yield and good diastereoselectivity
(Figure 2). Some debrominated material 18 (16-18%)
was also isolated. To assign the absolute stereochemistry
(25) For 1H NMR assignment of the phenylcyclopryl esters, see
Nakamura, A.; Konishi, A.; Tsujitani, R.; Kudo, M.-a.; Otsuka, S. J .
Am. Chem. Soc. 1978, 100, 3449-3461.
(26) Dewar, M. J . S.; Grisdale, P. J . J . Am. Chem. Soc. 1962, 84,
3541-3546.
(27) Crystal structure analysis of (a-S,S,S)3b:
C36H40N2O2, Mr
532.70, colorless prizms, 0.42 × 0.38 × 0.09 mm, monoclinic, P21, a )
11.3187(5) Å, b ) 10.1020(4) Å, c ) 13.6236(6) Å, R ) γ ) 90°, â )
106.2210(10)°, V ) 1495.71(11) Å3, Z ) 2, Fcalc) 1.183 g/cm-3, MoKR
(λ ) 0.710 73 Å), T ) 158(2) K; µ ) 0.073 mm-1. Area detector data
collected on a Siemens SMART CCD diffractomerer. A total of 9912
reflections were collected (1.56 < Θ < 28.42°); independent reflections
6030 (Rint ) 0.0188). Structure solved by direct methods (SHELXTL)
2
and refined by full-matrix least-squares on |F| . Final R indices [I >
2σ(I)]: R1 ) 0.0372, wR2 ) 0.1177. GOF ) 0.563. Residual electron
density (e Å-3) 0.193/-0.156.
(28) Crystal structure analysis of (a-S,S,S)12b: C44H54O6, Mr 678.87,
colorless prizms, 0.20 × 0.40 × 0.40 mm, orthorhombic, P212121, a )
11.52710(10) Å, b ) 17.4108(2) Å, c ) 19.16840(10) Å, R ) â ) γ )
90°, V ) 3847.02(6) Å3, Z ) 4, Fcalc) 1.172 g/cm-3, MoKR (λ ) 0.710 73
Å), T ) 158(2) K; µ ) 0.076 mm-1. Area detector data collected on a
Siemens SMART CCD diffractometer. A total of 25507 reflections were
To demonstrate high barrier to atropisomerization for
3b, its two diastereomers were heated at reflux in
mesitylene (bp 165 °C) for several hours, at which time
no atropisomerization was detected by TLC and 1H NMR.
In fact, heating the diastereomers of 3b in the melt
slightly above their melting point (>200 °C) for 5 min
did not result in atropisomerization. Because of the high
collected (1.58 < Θ < 28.29°); independent reflections 9206 (Rint
)
0.0458). Structure solved by direct methods (SHELXTL) and refined
2
by full-matrix least-squares on |F| . Final R indices [I > 2σ(I)]: R1 )
0.0568, wR2 ) 0.1044. GOF ) 1.065. Residual electron density (e Å-3
0.165/-0.205.
)

7924 J . Org. Chem., Vol. 64, No. 21, 1999
Kolotuchin and Meyers
F igu r e 1. Crystal structures of (a-S,S,S)3b and (a-S,S,S)12b, respectively. The hydrogen atoms have been omitted for clarity.
F igu r e 2. Proposed copper(III) intermediates of the Ullman coupling of 4b in pyridine (A) and DMF (B).
barrier to atropisomerization, addition of copper(I) bro-
mide to a refluxing solution of (a-S,S,S) 3b in DMF did
not promote the atropisomerization either.9d Indeed, the
reported barrier to atropisomerization of 2,2′-dimethy-
1,1′-binaphthyl is 50 kcal/mol.5a
naphthyls (3b) were prepared. Resolution of 3a was
achieved with (-)-(1S)- menthyl chloroformate (11). As
predicted, both 3a and 3b are stable to atropisomeriza-
tion. A complex of heterochiral (a-R,S,S)bisoxazoline 3b
and CuOTf catalyzed cyclopropanation of styrene with
ethyl diazoacetate with moderate enantioselectivity.
It was earlier reported from these laboratories that
only heterochiral (a-R,S,S) bisoxazoline 2b could serve
as a ligand for CuOTf to catalyze enantioselective cyclo-
propanation16 of styrene with ethyl diazoacetate.7b In-
terestingly, Hayashi and co-workers observed opposite
behavior for the corresponding homochiral and hetero-
chiral 1b.2d Therefore, a heterochiral (a-R,S,S)3b in
which nitrogen atoms can chelate a metal copper ion
without forcing the tert-butyl groups of the oxazolines into
each other was chosen as a ligand to examine this process
further. In dichloromethane, 81% ee for the trans-
cyclopropane ester 19 and 56% ee for the cis isomer 20
were achieved. It is not entirely clear what eroded the
enantioselectivity of the cyclopropanation reaction cata-
lyzed by 3b as compared to 2b.7b Perhaps less rigidity of
2b may account for subtle changes in the energy of the
diastereomeric transition states for the cyclopropanation
process.
Exp er im en ta l Section
Gen er a l. All reactions were run with magnetic stirring
under an atmosphere of dry nitrogen unless otherwise noted.
The drying agent Na2SO4 refers to anhydrous sodium sulfate.
All solvents and reagents were of reagent quality, purchased
commercially, and used without further purification, except
as noted below. Dry triethylamine, dichloromethane, and
toluene were freshly distilled from calcium hydride prior to
use. Dry THF and 2-Me-THF were freshly distilled from
sodium and benzophenone. DMF was stirred with CaH2 at 60
°C overnight, filtered, fractionally distilled, and stored over 4
Å molecular sieves. N,N,N′N′-Tetramethylethylenediamine
was distilled from and stored over strips of sodium metal. Dry
pyridine was refluxed over CaH2 overnight and distilled from
CaH2 and a small amount of lithium aluminum hydride.
Oxygen was dried by passing it through a column filled with
P2O5/Dryrite and cooled by passing it through a thin copper
tube immersed into acetone/dry ice bath. N-Bromosuccinimide
was recrystallized from water.
Analytical thin-layer chromatography (TLC) was performed
on 0.2 mm silica gel coated plastic sheets (Merck) with F254
indicator. Flash chromatography was performed on Scientific
Adsorbents Inc. 40 µm silica gel. Preparative thin-layer radial
chromatography was performed on silica gel coated plates
(silica gel 60 PF254 containing gypsum, EM Science) using a
Chromatotron (Harrison Research). HPLC was performed on
a Chiracel OJ (analysis of 3a ) and Chiracel OB (cyclopropan-
ation products) columns (l ) 25 cm, id ) 4.6 mm) at 1 mL/
min in (20% 2-propanol/hexanes) and (1% EtOAc/hexanes),
respectively, with UV detection at 264 nm. Melting points are
uncorrected.
In conclusion, C2-symmetrical axially chiral 2,2′-di-
methyl-8,8′-bi-2-naphthol (3a ) and (a-S,S,S)- and (a-
R,S,S)-2,2′ dimethyl-8,8′-bis(4-tert-butyloxazolyl)-1,1′-bi-

Synthesis of 8,8′-Disubstituted 1,1′-Binaphthyls
J . Org. Chem., Vol. 64, No. 21, 1999 7925
Nuclear magnetic resonance (NMR) spectra were recorded
in chloroform-d (CDCl3) unless otherwise stated. When chlo-
roform-d was used as a solvent chemical shifts were measured
(30% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to 5% MeOH in 30%
EtOAc/CH2Cl2) to afford 25 mg (16%) of 18 as an oil, 8.0 mg
(5%) of (a-S,S,S)3b as a tan solid and 75 mg (49%) of (a-R,S,S)-
3b as a tan solid. Analytically pure sample of (a-R,S,S)3b was
obtained by thin-layer preparative radial chromatography
(10% EtOAc/CH2Cl2 to 15% EtOAc/CH2Cl2): mp 220-221 °C;
1H NMR δ 7.97 (1H, dd, J ) 6.0, J ) 2.6), 7.87 (1H, d, J )
8.5), 7.55 (1H, d, J ) 8.4), 7.41-7.37 (2H, m), 3.64 (1H, m),
3.36 (1H, m), 2.63 (br, H2O), 2.47 (1H, m), 2.11 (3H, s), 0.66
(9H, s); 13C NMR δ 165.4, 138.0, 134.1, 133.0, 131.0, 130.4,
128.7, 128.6, 126.9, 124.0, 75.5, 68.0, 33.2, 25.8, 21.0. Anal.
Calcd for C36H40N2O2‚H2O: C, 78.51; H, 7.69; N, 5.09; O, 8.72.
Found: C, 78.50; H, 7.64; N, 5.05. [R]D ) -380° (c, 1.4, CH2-
Cl2).
(a -S,S,S)-2,2′-Dim et h yl-8.8′-b is(4-ter t-b u t yloxa zolyl)-
1,1′-bin a p h th yl (3b). Using a procedure analogous to that
for coupling of 4b in DMF, 200 mg (0.6 mmol) of 4b and 500
mg (7.8 mmol) of copper bronze in 4 mL of dry pyridine were
refluxed for 36 h to afford 10 mg (6%) of 18 as an oil, 130 mg
(85%) of (a-S,S,S)3b, and 8 mg (5%) of (a-R,S,S)3b. An
analytically pure sample of (a-S,S,S)3b was obtained by thin-
layer preparative radial chromatography (5% EtOAc/
CH2Cl2): mp 206-208 °C; 1H NMR δ 7.98 (1H, dd, J ) 7.3, J
) 2.6), 7.83 (1H, d, J ) 8.4), 7.5-7.4 (3H, m), 3.42 (1H, m),
3.15 (1H, m), 2.23 (1H, m), 1.92 (3H, s), 0.79 (9H, s); 13C NMR
δ 166.2, 138.2, 134.0, 132.6, 130.8, 130.4, 129.2, 128.5, 127.3,
123.9, 75.4, 68.2, 33.6, 25.8, 21.1 Anal. Calcd for C36H40N2O2:
C,81.17; H, 7.52; N, 5.26; O, 6.01. Found: C, 81.01; H, 7.61;
N, 5.19. [R]D ) -241°(c 1.3, CH2Cl2).
1
relative to the residual chloroform peak (7.26 ppm for H NMR)
and the center of CDCl3 multiplet (77 ppm for 13C NMR). When
dimethyl sulfoxide-d6 (DMSO-d6) was used, chemical shifts
were measured relative to the center of residual DMSO
multiplet (2.49 ppm for 1H NMR) and the center of DMSO-d6
multiplet (39.7 ppm for 13C NMR). Coupling constants are
reported in hertz (Hz). When other deuterated solvents were
used, chemical shifts were measured relative to the center of
residual solvent peaks. GS-MS was performed on a HP Gas
Chromatograph 5890 (Series II) coupled to an HP 5970 series
MSD mass selective detector. Elemental analyses were per-
formed at Atlantic Microlab, INC, Norcross, Georgia.
Nitrile 517 was synthesized by the following reaction se-
quence. Neat toluene was acylated with succinic anhydride in
the presence of anhydrous aluminum trichloride.18 The result-
ing ketoacid was reduced using Huang-Minlon modifica-
tion19,21 of the Wolf-Kishner reaction conditions20 with hy-
drazine hydrate, and the γ-p-tolylbutyric acid was cyclized in
neat polyphosphoric acid (PPA) to afford 7-methyl tetralone.21
The tetralone was treated with TMSCN using either zinc
diiodide22a or boron trifluoride etherate22b as catalysts. Aro-
matization of dihydro derivative of 5 was affected by DDQ in
refluxing 1,4-dioxane. tert-Leucinol was obtained by I2/NaBH4
reduction of commercially available tert-leucine.23 Copper
bronze used in Ullman coupling was freshly activated with
iodine/acetone/HCl (concentrated aq.).24
2,2′-Dim eth yl-8,8′-d ih yd r oxy-1,1′-bin a p h th yl (3a ). To a
clear solution of 750 mg (2.2 mmol) of 10 in 8 mL of dry CH2Cl2
cooled to 0 °C (ice/water) was added dropwise 5 mL (5 mmol)
of solution of BBr3 (1 M/CH2Cl2). The resulting brownish red
solution was stirred at room temperature for several hours
until TLC of an aliquot partitioned between CH2Cl2 and
saturated NaHCO3(aq) showed the reaction to be complete.
The brownish solution was poured into a mixture of crushed
ice, saturated aq. NaHCO3 and CH2Cl2 (CAUTION: ga s
evolu tion !). The collected organic layer was dried (Na2SO4)
and decanted. The solvent was rotoevaporated. The brown
residue was chromatographed over silica gel (40% CH2Cl2/
hexanes). The material was further purified by preparative
thin-layer radial chromatography (1% EtOAc/hexanes to 10%
EtOAc/hexanes) to afford 650 mg (95%) of 3a as an off-white
solid. Later a better elution system was found to be a gradient
of CH2Cl2 in hexanes starting with (5% CH2Cl2/hexanes). Note:
the material was loaded as a solution in minimal amount of
CH2Cl2 onto a dry plate. The lid of the Chromatotron was
removed to let the solvent evaporate followed by elution. An
analytically pure sample of 3a was obtained by recrystalliza-
tion from a small amount of peroxide-free di(iso-propyl)ether
or EtOAc in bulk hexane: mp 172-173 °C; 1H NMR δ 7.90
(1H, d, J ) 8.4), 7.49 (1H, dd, J ) 8.1, J ) 1.1), 7.46 (1H, d, J
) 8.4), 7.37 (1H, t, J ) 7.7), 6.84 (1H, dd, J ) 7.7, J ) 1.1),
5.67 (1H, s br), 2.00 (3H, s); 13C NMR δ 153.2, 135.3, 134.6,
130.5, 130.1, 128.6, 126.9, 121.6, 121.1, 112.5, 19.8. Anal. Calcd
for C22H18O2: C, 84.05; H, 5.77; O, 10.18. Found: C, 83.82; H,
5.90.
Gen er al P r ocedu r e for th e Ullm an Cou plin g. (a-R,S,S)-
2,2′-Dim et h yl-8.8′-b is(4-ter t-b u t yloxa zolyl)-1,1′-b in a p h -
th yl (3b). A mixture of 500 mg (7.8 mmol) of freshly activated
copper bronze and 200 mg (0.6 mmol) of 4b in 4 mL of dry
DMF was deoxygenated using a freeze-pump-thaw cycle
twice, and the resulting suspension was heated at ca. 100 °C
overnight. A small aliquot was withdrawn. The solvent was
removed under high vacuum. The dark residue was partitioned
between CH2Cl2 and saturated NH3(aq). The solvent from the
collected organic layer was removed under high vacuum. TLC
of the aliquot indicated the reaction to be complete. The bulk
dark suspension was cooled to room temperature, diluted with
DMF, and filtered through a plug of Celite. DMF was removed
using short-path Kugelrohr distillation. The resulting dark
residue was partitioned between CH2Cl2 and saturated NH3(aq).
The solvent from the collected organic layer was rotoevapo-
rated. The dark residue was chromatographed over silica gel
Typ ica l P r oced u r e for Lip sh u tz Cou p lin g. To a clear
solution of 692 mg (2 mmol) of 4b in 15 mL of dry 2-Me-THF
cooled to -120 °C (pentane/dry ice/L N2) was added 1.6 mL
(2.4 mmol) of tert-BuLi (1.5 M/pentane) dropwise with a
syringe. The resulting red solution was stirred for 45 min and
allowed to warm to -78 °C. To this solution was added 90 mg
(1 mmol) of dry copper cyanide with an addition funnel having
a large bore stopcock by rinsing CuCN down with 1 mL of dry
2-Me-THF followed by 1 mL of dry TMEDA. The resulting red
suspension was stirred at -40 °C for 1.5 h to give a clear olive
solution. The solution was cooled to -78 °C, and dry oxygen
precooled to -78 °C was bubbled through the solution for 1 h
at -78 °C and 1 h at room temperature. The resulting dark
solution was quenched with 3 mL of methanol, rotoevaporated,
and partitioned between CH2Cl2 and saturated NH3(aq). The
collected organic layer was washed with water, collected, dried
(Na2SO4), and decanted. The solvent was rotoevaporated, and
the dark residue was chromatographed over silica gel (30%
EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to 5% MeOH in 30%
EtOAc/CH2Cl2) to afford 60 mg (11%) of 18, 130 mg (24%) of
(a-S,S,S)3b, and 50 (10%) mg of (a-R,S,S)3b. On occasion, (a-
R,S,S 3b was further chromatographed over neutral alumina
(20% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 ).
8-Br om o-7-m eth yl-1-m eth oxy-n a p h th a len e (4a ). To a
yellowish solution of 1.83 g of 8, 2 g (62 mmol) of methanol, 5
g (35 mmol) of methyl iodide, and 68 mg of 18-crown-6 in 14
g of reagent grade acetone was added 3.18 g (23 mmol) of
potassium carbonate, and the greenish suspension was re-
fluxed overnight at which time TLC showed the reaction to
be complete. The resulting reddish suspension was cooled to
room temperature, diluted with CH2Cl2, and filtered through
a plug of Celite. The solvent was rotoevaporated and the brown
residue was chromatographed over silica gel (30% CH2Cl2/
hexanes) to afford 1.7 g (98%) of 4a as a white solid. An
analytically pure sample of 4a was obtained by recrystalliza-
tion from methanol: mp 66-68 °C; 1H NMR (benzene-d6) δ
7.37 (1H, d, J ) 8.4), 7.23 (1H, dd, J ) 8.0, J ) 1.1), 7.10 (1H,
t, J ) 8.0), 6.96 (1H, d, J ) 8.0), 6.53 (1H, d, J ) 8.0), 3.44
(3H, s), 2.45 (3H, s); 13C NMR δ 155.7, 137.5, 135.5, 129.0,
127.4, 125.5, 124.3, 121.2, 118.1, 107.9, 55.8, 25.6. MS 250,
252. Anal. Calcd for C12H11OBr: C, 57.40; H, 4.41; Br, 31.82;
O, 6.37. Found: C, 57.30; H, 4.46; Br, 31.93. In a separate
experiment the crude 4a was purified by Kugelrohr distillation
followed by recrystallization from methanol.
8-Br om o-7-m eth yl-1-(4-ter t-bu tyloxa zolin yl) n a p h th a -
len e (4b). A suspension of 14.3 g (54 mmol) of 17, 50 mL of

7926 J . Org. Chem., Vol. 64, No. 21, 1999
Kolotuchin and Meyers
neat thionyl chloride, and several drops of DMF was refluxed
for several hours until all 17 dissolved. Excess of SOCl2 was
removed by distillation at normal pressure using a still head.
Residual SOCl2 was removed by an aseotropic distillation with
250 mL of benzene. The resulting brownish residue was
pumped under high vacuum and dissolved in 50 mL of dry
CH2Cl2. The brownish solution was added to a solution of 7 g
(60 mmol) of tert-leucinol and 9 mL (70 mmol) of NEt3 in 100
mL of dry CH2Cl2 kept at 0 °C. After the addition of the acid
chloride was complete, the reaction mixture was stirred at
room temperature for several hours, washed with 5% HCl(aq),
saturated NaHCO3(aq), collected, dried (Na2SO4), and de-
canted. The solvent was rotoevaporated, and the resulting off-
white oil was pumped under high vacuum at which time it
crystallized. The solid was dissolved in 200 mL of dry CH2Cl2
and reacted with 8.6 mL (120 mmol) of neat SOCl2 which was
added dropwise. The resulting solution was stirred for 1 h at
room temperature, at which time TLC of an aliquot partitioned
between saturated NaHCO3(aq) and CH2Cl2 indicated the
reaction to be complete. The solvent from the bulk reaction
was rotoevaporated. The residue was dissolved in 150 mL of
CH2Cl2 and stirred in a 1 L beaker with excess of saturated
NaHCO3(aq) until no further gas evolution was observed and
pH(aq) ) 8 (CAUTION: ga s evolu tion !). The collected
organic layer was dried (Na2SO4) and decanted. The solvent
was rotoevaporated and the yellowish solid was chromato-
graphed over silica gel (0.5% methanol/CH2Cl2 to 2% methanol/
CH2Cl2) followed by chromatography over neutral alumina
(50% CH2Cl2/hexanes) to afford 11.3 g (60% from 17) of 4b as
an off-white solid after crystallization from hexane/several
drops EtOAc. An analytically pure sample of 4b was obtained
by thin-layer preparative radial chromatography (20% CH2-
Cl2/hexanes to CH2Cl2 to 1% EtOAc/CH2Cl2): mp 106-108 °C;
1H NMR δ 7.89 (1H, dd, J ) 8.0, J ) 1.1), 7.79-7.74 (2H, m),
7.44-7.38 (2H, m), 4.51 (1H, m), 4.34 (1H, m), 4.13 (1H, m),
2.63 (3H, s), 1.08 (9H, s); 13C NMR δ 138.9, 134.3, 131.6, 131.4,
130.7, 129.8, 128.3, 127.1, 124.6, 121.3, 76.8, 69.2, 34.3, 26.5,
25.4. MS 330, 332. Anal. Calcd for C18H20NOBr: C, 62.44; H,
5.82; N, 4.05; Br, 23.08; O, 4.62. Found: C, 62.34; H, 5.84; N,
4.01; Br, 22.97. [R]D ) -72° (c 1.5, CH2Cl2).
and the resulting yellow solid was chromatographed over silica
gel (50% CH2Cl2/hexanes to 70% CH2Cl2/hexanes) to afford 4.7
g (90%) of 7 as an off-white solid after recrystallization from
1
methanol: mp 86-88 °C; H NMR δ 11.29 (1H, s), 7.90 (1H,
dd, J ) 8.5, J ) 1.5), 7.78 (1H, dd, J ) 8.3, J ) 1.5), 7.73 (1H,
d, J ) 8.4), 7.45 (1H, m), 7.38 (1H, d, J ) 8.4), 2.58 (3H, s);
13C NMR δ 192.61, 138.9, 136.3, 134.1, 133.0, 131.4, 129.6,
129.4, 128.9, 124.9, 120.1, 24.9. MS 248, 250. Analytically pure
sample of 7 was obtained by recrystallization from methanol.
Anal. Calcd for C12H9OBr: C, 57.86; H, 3.64; Br, 32.08; O, 6.42.
Found: C, 57.72; H,3.73; Br, 32.19.
8-Br om o-7-m eth yl-1-for m yloxy-n a p h th a len e (8). To a
clear solution of 4 g (16 mmol) of 7 in 80 mL of CH2Cl2 was
added 16 g of solid m-CPBA (57-85%) at once. The clear
solution was stirred overnight, at which time it became yellow
and a white precipitate formed. TLC showed complete con-
sumption of 7. The suspension was diluted with CH2Cl2 and
filtered through a plug of Celite. The solution was washed with
saturated NaHCO3(aq), at which time the solution became
brown because of the partial deprotection of the formate ester
and oxidation of the phenol 9. The organic layer was quickly
collected and washed with 5% HCl(aq). The collected organic
layer was dried (Na2SO4) and decanted. The solvent was
rotoevaporated. The brown residue was chromatographed over
silica gel (50% CH2Cl2/hexanes to 60% CH2Cl2/hexanes) to
afford 3.7 g (87%) as a mixture of 8 (MS 264, 266) and phenol
9 (MS 236, 238) (11:2 by GC/MS) as a tan solid: mp 50-52
°C.
On a smaller scale of 0.73 g (∼3 mmol) of 7 and 2.45 g (8.5-
12 mmol) of m-CPBA (57-85%) in 10 mL of CH2Cl2 after the
reaction was complete by TLC, the yellow suspension was
diluted with 15 mL of hexanes and filtered. The filtrate was
mixed with 20 mL of silica gel and rotoevaporated. The
products, thus preloaded on silica gel, were put onto silica gel
column (50 mL of silica gel) packed in (40% CH2Cl2/hexanes)
and eluted with the same solvent mixture to afford 0.7 g (95%)
of pure 8 as a white solid: 1H NMR δ 8.46 (1H, s), 7.78 (1H,
dd, J ) 8.5, J ) 1.5), 7.75 (1H, dd, J ) 8.4), 7.45 (1H, m), 7.39
(1H, d, J ) 8.0), 7.23 (1H, dd, J ) 7.3, J ) 1.1), 2.61 (3H, s);
13C NMR δ 160.4, 144.6, 139.1, 135.4, 129.4, 127.9, 127.8,
125.1, 125.1, 121.5, 116.8, 25.2.
8-Br om o-1-cya n o-7-m et h yln a p h t h a len e (6). Using a
procedure analogous to that used for 16, 4.4 g (26.3 mmol) of
5 was reacted with 6.5 g (36.5 mmol) of NBS in a mixture of
10 mL of AcOH and 10 mL of TFA catalyzed by 5 mL of
concentrated H2SO4. The only exception was that no sodium
acetate was used during the workup. There was obtained 5.9
g (91%) of 6 as a creamy solid after recrystallization from
2,2′-Dim eth yl-8,8′-d im eth oxy-1,1′-bin a p h th yl (10). Us-
ing a procedure analogous to that for 4b, 1.10 g (4.4 mmol) of
4a was reacted with 1.16 g (18 mmol) of copper bronze in 10
mL of DMF. The wash of the residue from the reaction mixture
with saturated NH3(aq) was omitted. Instead, the solid prod-
ucts from the reaction mixture were chromatographed directly
after dilution with additional DMF, filtration, and removal of
DMF using short-path Kugelrohr distillation. Column chro-
matography of the dark residue over silica gel (30% CH2Cl2/
hexanes) was followed by thin-layer preparative radial chro-
matography (0.5% EtOAc/hexanes) to afford 497 mg (66%) of
1
ethanol: mp 102-104 °C; H NMR (benzene-d6) δ 7.48 (1H,
dd, J ) 7.3, J ) 1.5), 7.23 (1H, dd, J ) 8.0, J ) 1.1), 7.07 (1H,
d, J ) 8.2), 6.77 (1H, d, J ) 8.4), 6.63 (1H, m), 2.17 (3H, s);
13C NMR (CDCl3) δ 140.4, 138.6, 134.0, 133.6, 130.4, 130.0,
128.5, 124.4, 121.0, 120.1, 109.5, 25.2. MS 245, 247.
1
8-Br om o-7-m eth yl-1-n a p h th a len eca r boxa ld eh yd e (7).
Using a procedure analogous to that used for 16, 0.6 g (3.5
mmol) of 13 was reacted with 0.96 g (5.4 mmol) of NBS in a
mixture of 2 mL of AcOH and 2 mL of TFA catalyzed by 10
drops of concentrated H2SO4. The only exception was that no
sodium acetate was used during the workup. The product was
subjected to thin-layer preparative radial chromatography
(10% CH2Cl2/hexanes to 30% CH2Cl2/hexanes). There was
obtained 0.62 g (71%) of 7 as a creamy solid after recrystal-
lization from ethanol. There was also recovered 120 mg (20%)
of unreacted 13. The spectral characteristics and the melting
point of the material were identical to those of 7 obtained by
the reduction of 6 with DIBAL.
8-Br om o-7-m eth yl-1-n a p h th a len eca r boxa ld eh yd e (7).
Using a procedure analogous to that for 13, 5.25 g (21 mmol)
of 6 was reacted with 4.6 mL (26 mmol) of DIBAL in 40 mL of
toluene. In this case, the yellow solid resulting from the initial
reaction mixture after the quench with EtOAc and absolute
ethanol followed by removal of the solvent was partitioned
between CHCl3 and 20% HCl(aq). The resulting yellow bipha-
sic mixture was reflux for 1 h and cooled to room temperature.
The organic layer was collected, washed with water, collected,
dried (Na2SO4), and decanted. The solvent was rotoevaporated,
10 as a white solid: mp 155-157 °C; H NMR δ 7.73 (1H, d,
J ) 8.0), 7.50 (1H, dd, J ) 8.0, J ) 0.8), 7.42 (1H, d, J ) 8.0),
7.31 (1H, t, J ) 8.0), 6.67 (1H, dd, J ) 8.0, J ) 0.8), 3.11 (3H,
s), 1.96 (3H, s); 13C NMR δ 157.3, 138.4, 134.0, 131.8, 128.7,
125.7, 124.7, 124.3, 121.0, 106.0, 55.9, 20.4. MS 342. Anal.
Calcd for C24H22O2: C, 84.18; H, 6.48; O, 9.34. Found: C, 83.90;
H, 6.60. There was also obtained 180 mg (24%) of 1-methoxy-
7-methylnaphthalene: 1H NMR (benzene-d6) δ 8.33 (1H, s),
7.59 (1H, d J ) 8.0), 7.36 (1H, d, J ) 8.0), 7.19 (1H, t, J )
8.0), 7.13 (1H, d, J ) 8.0), 6.45 (1H, d, J ) 7.7), 3.44 (3H, s),
2.276 (3H, s). MS 172.
Resolu tion of 3a . A general procedure12 with several
exceptions was followed. Thus, to a solution of 0.7 g (2.3 mmol)
of racemic 3a in a mixture of 7 mL of dry CH2Cl2 and 2 mL
(14.3 mmol) of dry triethylamine cooled with an ice/water bath
was added dropwise with a syringe 1.3 mmol (6 mmol) of (-)-
(1S)-menthyl chloroformate, at which time a white precipitate
formed. The suspension was refluxed for 3 h, at which time
no starting 3a was detected by TLC. [Note: (a-S,S,S)12a has
an Rf value identical to that of starting 3a . However, once
exposed to atmospheric oxygen, the TLC spot of 3a stains
yellow while that of the dicarbonate does not.] The resulting
slightly brownish solution was cooled to room temperature,

Synthesis of 8,8′-Disubstituted 1,1′-Binaphthyls
J . Org. Chem., Vol. 64, No. 21, 1999 7927
diluted with CH2Cl2, and washed with saturated aqueous
solution of NaHCO3. The collected organic layer was dried
(NaSO4) and decanted. The solvent was rotoevaporated. The
resulting brownish oil was gravity chromatographed over 160
mL of silica gel (25% CH2Cl2/hexanes to 30% CH2Cl2/hexanes)
to afford 590 mg (39%) of (a-R,S,S)12a with a higher Rf as a
foamy white solid, 600 mg (40%) of (a-S,S,S)12b with lower
Rf as a crystalline off-white solid, and 300 mg (20%) of mixed
fractions of 12a ,b as a foamy white solid. Eluting the column
further with 10%EtOAc/CH2Cl2 afforded 280 mg of N,N-diethyl
(-)-(1R)-menthyl carbamate as a brownish oil identified by its
molecular ion (M+ 255) and 1H NMR.
A mixture of 400 mg of pure (a-R,S,S)12a and 400 mg of
pure (a-S,S,S)12b was dissolved in 20 mL of hexanes, and the
solvent was allowed to evaporate overnight to afford a mixture
of white crystals and an oil. To this mixture was added 7 mL
of hexanes, at which time all the oil dissolved. The liquid was
removed with a pipet. The crystals were rinsed with 1 mL of
hexanes and recrystallized from hexanes to afford 280 mg
(70%) of (a-S,S,S)12b (97.5% de as determined by specific
rotation).
to 0 °C (ice/water) and excess DIBAL was quenched by
dropwise addition of 10 mL of EtOAc, followed by 10 mL of
absolute ethanol (CAUTION!). The solvent from the resulting
yellow solution was rotoevaporated to as much as possible. The
yellow residue was reacted with 150 mL of water followed by
portionwise addition of 150 mL of 10% HCl(aq) and 20 mL
concentrated HCl(aq), while keeping the flask in an ice/water
cooling bath. (CAUTION! Exoth er m ic!). The canary yellow
emulsion was mixed with 300 mL of CH2Cl2 and stirred at
room temperature for 2 h. The collected organic layer was
washed with water, dried (Na2SO4), and decanted. The solvent
was rotoevaporated, and the yellowish residue was subjected
to short-path Kugelrohr distillation to afford 24 g (95%) of 13
as a colorless oil that crystallized upon standing. A more pure
sample of 13 was obtained by crystallization from hexane: mp
1
42-44 °C; H NMR δ 10.37 (1H, s), 9.08 (1H, s), 8.03 (1H, d,
J ) 8.0), 7.93 (1H, dd, J ) 7.0, J ) 1.1), 7.80 (1H, d, J ) 8.1),
7.54 (1H, t, J ) 7.2), 7.43 (1H, dd, J ) 8.4, J ) 0.8), 2.59 (3H,
s); 13C NMR δ 193.6, 139.3, 136.8, 135.0, 131.9, 130.7, 130.6,
129.0, 128.2, 123.8, 22.2. MS 170.
7-Meth yl-1-n a p h th a len eca r boxylic Acid (14). To a solu-
tion of 46 g (270 mmol) of AgNO3 in 160 mL of water was added
a solution of 23 g (575 mmol) of NaOH in 140 mL of water, at
which time a brown precipitate formed. To the mechanically
stirred suspension of Ag2O prepared as above was added a
solution of 22.3 g (131.2 mmol) of 13 in a mixture of 90 mL of
1,4-dioxane and 80 mL of ethanol. The resulting suspension
was heated to 75 °C (internal), at which time the solid changed
color from brown to gray. The suspension was stirred at 75 °C
for 30 min, diluted with 300 mL of warm water, and filtered.
The filtrate was rotoevaporated to remove ethanol and dioxane
to about a half of its original volume, diluted to 1 L with water,
and acidified to pH 1 with concentrated HCl(aq). A creamy
solid formed. The solid was filtered and recrystallized from
ethanol/water to afford 22 g (90%) of 14 as a creamy solid:
mp 146-148 °C (lit mp: 146-147).26
The mixed fractions collected at all stages of the resolution
were combined and purified by preparative thin-layer radial
chromatography (5% CH2Cl2/hexanes to 30% CH2Cl2/hexanes)
to afford 530 mg of (a-R,S,S)12a and 350 mg of (a-S,S,S)12b.
If a sample of (a-R,S,S)12a as an oil is evacuated under high
vacuum, it forms a white foamy sold. However, if a solution of
12a in hexanes is rotoevaporated and the resulting oil is
allowed to crystallize at room temperature and normal pres-
sure, it produces a crystalline off-white solid: mp 77-79 °C,
1H NMR δ 7.76 (1H, d, J ) 7.4), 7.75 (1H, d, J ) 8.4), 7.40
(1H, t, J ) 7.7), 7.37 (1H, d, J ) 8.4), 7.06 (1H, dd, J ) 7.7, J
) 1.1), 4.14 (1H, dt, J ) 10.4, J ) 4.4), 1.81 (3H, s), 1.75-0.65
(8H, series of m), 0.96 (3H, d, J ) 6.6), 0.76 (3H, d, J ) 7.0),
0.63 (3H, d, J ) 7.0), 0.56 (1H, t, J ) 11.3); 13C NMR δ 153.1,
147.5, 135.0, 134.4, 134.2, 129.6, 127.3, 126.3, 126.1, 124.4,
119.6, 78.3, 46.8, 40.1, 33.9, 31.1, 25.6, 22.9, 22.0, 20.7, 20.1,
16.0. [R]D ) +252.6 (c 1.5, CH2Cl2).
Meth yl 7-m eth yl-1-n a p h th a len eca r boxyla te (15). To 80
mL of methanol cooled to 0 °C (ice/water) was added dropwise
25 mL of concentrated H2SO4. To the resulting clear solution
was added at once 21 g (112 mmol) of the 14, and the mixture
was refluxed for 3 h, at which time TLC indicated the reaction
to be complete. The resulting yellowish emulsion was cooled
to room temperature, and the solvent was evaporated as much
as possible. The residue was partitioned between CH2Cl2 and
water. The collected organic layer was washed with saturated
NaHCO3(aq), collected, dried (Na2SO4) and decanted. The
solvent was rotoevaporated and the resulting brownish oil was
subjected to short-path Kugelrohr distillation to afford 20 g
(90%) of 15 as a yellowish oil: 1H NMR δ 8.71 (1H, s), 8.15
(1H, dd, J ) 7.3, J ) 1.5), 7.97 (1H, d, J ) 8.0), 7.78 (1H, d, J
) 8.0), 7.40 (2H, m), 4.00 (3H, s), 2.57 (3H, s). MS 200.
8-Br om o-1-ca r bom eth oxy-7-m eth yln a p h th a len e (16).
To a clear solution of 18.3 g (91.5 mmol) of 15 in a mixture of
40 mL of glacial acetic and 40 mL of trifluoroacetic acid cooled
with ice/water was added 19.5 g (110 mmol) of NBS at once.
To the resulting clear suspension was added 12 mL of
concentrated H2SO4 dropwise, at which time all NBS dissolved.
The olive solution was stirred for 30 min, and an additional 3
g (17 mmol) of NBS was added. After the olive solution was
stirred for additional 30 min, TLC indicated complete con-
sumption of 15. The olive solution was mixed with 20 g (244
mmol) of solid sodium acetate, and the resulting suspension
was partitioned between CH2Cl2 and water. The collected
organic layer was washed with saturated NaHCO3(aq) until
pH(aq) 8, and no gas evolution was observed. The collected
organic layer was dried (Na2SO4) and decanted, and the solvent
was rotoevaporated to afford an olive oil which was chromato-
graphed over silica gel (30% CH2Cl2/hexanes to 60% CH2Cl2/
hexanes). The desired 16 as a slightly olive oil was distilled
using short-path Kugelrohr distillation to afford 24 g (94%) of
16 as an off-white solid. A more pure sample of 16 was
obtained by preparative thin-layer chromatography (20%
CH2Cl2/hexanes) followed by recrystallization from heptane/
1
(a-S,S,S)12b: mp 173-175 °C, H NMR δ 7.73 (1H, d, J )
7.5), 7.69 (1H, d, J ) 8.0, J ) 1.1), 7.37 (1H, d, J ) 8.4), 7.33
(1H, t, J ) 7.5), 7.03 (1H, dd, J ) 7.5, J ) 1.1), 4.06 (1H, dt,
J ) 10.9, J ) 4.4), 1.85 (3H, s), 1.65-0.65 (8H, series of m),
0.87 (3H, d, J ) 7.0), 0.85 (3H, d, J ) 6.2), 0.70 (3H, d, J )
7.0), 0.43 (1H, ABq); 13C NMR δ 152.7, 147.7, 134.9, 134.4,
129.2, 127.0, 126.3, 125.3, 124.3, 119.2, 78.4, 46.46, 39.5, 34.0,
31.1, 25.1, 22.8, 21.9, 20.9, 20.4, 16.1. [R]D ) -166.0 (c 1.1,
CH2Cl2).
To a solution of 237 mg (0.355 mmol) of (a-R,S,S)12a in 8 g
of dry THF was added 135 mg (3.55 mmol) of LAH, and the
suspension was refluxed for 2 h, at which time TLC showed
all the starting 12a to be consumed. The gray suspension was
cooled with ice/water, and excess LAH was quenched with 2
mL of EtOAc followed by 1 mL of 10% HCl(aq). The solvent
was rotoevaporated. The residue was partitioned between 10%
HCl(aq) and CH2Cl2. The collected organic layer was washed
with saturated NaHCO3(aq), collected, dried (Na2SO4), and
decanted. The solvent was rotoevaporated. The brownish oil
was chromatographed over silica gel (25% CH2Cl2/hexanes) to
afford 96 mg (88%) of (a-R)3a as white short needles as a single
enantiomer as evidenced by chiral HPLC: mp 184-186 °C,
[R]D ) -69.2 (c 1.1, CH2Cl2).
Following analogous procedure, 200 mg (0.3 mmol) of (a-
S,S,S)12b was reacted with 80 mg (2.1 mmol) of LAH to afford
94 mg (97%) of (a-S)3a as short white needles as a single
enantiomer as evidenced by chiral HPLC: mp 184-186 °C,
[R]D ) +71.8 (c 0.94, CH2Cl2).
Gen er a l P r oced u r e for th e Red u ction of 5 a n d 6 w ith
DIBAL. 7-Meth yl-1-n a p h th a len eca r boxa ld eh yd e (13). To
a clear solution of 25.3 g (149 mmol) of 5 in 250 mL of toluene
cooled to 0 °C (ice/water) was added dropwise 30 mL (168
mmol) of neat DIBAL. After the addition of DIBAL was
complete, the resulting yellow solution was stirred for 30 min
at 0 °C and overnight at room temperature. TLC of an aliquot
partitioned between 10% HCl(aq) and CH2Cl2 indicated com-
plete consumption of 5. The bulk yellow solution was cooled
1
EtOAc: mp 70-72 °C; H NMR δ 7.89 (1H, dd, J ) 8.4, J )
1.5), 7.76 (1H, d, J ) 8.4), 7.65 (1H, dd, J ) 7.3, J ) 0.7), 7.45

7928 J . Org. Chem., Vol. 64, No. 21, 1999
Kolotuchin and Meyers
(1H, dd, J ) 7.4, J ) 0.7), 7.42 (1H, d, J ) 8.0), 4.00 (3H, s),
2.64 (3H, s); 13C NMR δ 171.5, 138.7, 134.2, 132.0, 131.1, 129.4,
128.7, 128.2, 124.5, 121.1, 52.9, 25.1. MS 278, 280.
the resulting filtered olive solution of the catalyst was added
2.7 g (26 mmol) of styrene passed through a plug of basic
alumina and 900 mg (7.9 mmol) of ethyl diazoacetate. The
brownish solution was stirred at room temperature for 4 h, at
which time TLC indicated complete consumption of ethyl
diazoacetate. The solvent was rotoevaporated. The residue was
subjected to Kugelrohr distillation with slight heating to
remove excess of styrene. (Note: the recovered styrene did not
contain any cyclopropanation products as evidenced by 1H
NMR.) The receiver was changed and all volatile products were
collected, heating the pot to higher temperature. The resulting
colorless oil was subjected to preparative thin-layer radial
chromatography (0.5% EtOAc/hexanes to 2% EtOAc/hexanes).
There were recovered 160 mg (11%) of 1R- (trans)-1-carb-
ethoxy-2-phenylcyclopropane 19 of 76% ee, 130 mg (9%) of 1R-
(cis)-1-carbethoxy-2-phenylcyclopropane 20 of 60% ee, and 150
mg (10%) of a 1:1 mixture of the two.25 The enantiomeric
excesses of the products were determined by chiral HPLC over
Chirocel OB and by specific rotation.
In a separate experiment starting with 5 g (48 mmol) of
styrene, 0.955 g (8.4 mmol) of ethyl diazoacetate, and 65 mg
(0.122 mmol) of (a-R,S,S)3b in the presence of 16 mg (0.06
mmol; 0.71mol %) of solubilized (CuOTf)2‚PhH in 4 mL of
CH2Cl2, there were recovered 320 mg of (20%) of 1R-(trans)-
1-carbethoxy-2-phenylcyclopropane 19 of 76% ee, 300 mg (19%)
of 1R-(cis)-1-carbethoxy-2-phenylcyclopropane 20 of 55% ee. In
this experiment the enantiomeric excesses were determined
by specific rotation of pure diastereomers.
8-Br om o-7-m eth yl-1-n a p h th a len eca r boxylic Acid (17).
A mixture of 18.2 g (65 mmol) of 16 and 25 g (590 mmol) of
lithium chloride in 60 mL of DMF was refluxed overnight, at
which time TLC showed the reaction to be complete. The
resulting olive solution was diluted with 80 mL of DMF,
transferred to a 1 L round-bottom flask, and the solvent was
removed by short-path Kugelrohr distillation. The resulting
greenish residue was dissolved in 500 mL of water, filtered
through a plug of Celite, and acidified to pH 1 with concen-
trated HCl(aq), at which time an off-white precipitated formed.
The solid was filtered and recrystallized from ethanol/water
to afford 14.3 g (82%) of 17 as a creamy solid: mp 162-163
°C; 1H NMR (DMSO-d6) δ 13.18 (1H, s), 8.05 (1H, dd, J ) 8.4,
J ) 1.4), 7.96 (1H, d, J ) 8.4), 7.64 (1H, dd, J ) 7.3, J ) 1.4),
7.58 (1H, d, J ) 8.4), 7.53 (1H, m), 2.58 (3H, s); 13C NMR
(DMSO-d6) δ 171.3, 138.2, 133.7, 133.4, 130.4, 129.4, 128.3,
128.0, 124.8, 120.6, 24.5.
7-Meth yl-1-(4-ter t-bu tyloxa zolin yl) Na p h th a len e (18).
To a clear solution of 200 mg (0.58 mmol) of 4b in 5 mL of dry
THF cooled to -78 °C (acetone/dry ice) was added 2 mL (3
mmol) of tert-BuLi (1.5 M/pentane) dropwise. The resulting
orange solution was stirred at 30 min and quenched by the
addition of 1 mL (26 mmol) of methanol. The resulting clear
solution was stirred at room temperature for 10 min. The
solvent was rotoevaporated. The residue was partitioned
between water and CH2Cl2. The collected organic layer was
dried (Na2SO4) and decanted. The solvent was rotoevaporated.
The residue was purified by thin-layer preparative radial
chromatography (1% EtOAc/hexanes to 2% EtOAc/hexanes) to
afford 135 mg (87%) of 18 as a colorless oil: 1H NMR δ 8.96
(1H, d, J ) 0.7), 8.06 (1H, dd, J ) 7.3, J ) 0.7), 7.93 (1H, d, J
) 8.4), 7.80 (1H, d, J ) 8.4), 7.45 (1H, m), 7.40 (1H, dd, J )
8.4, J ) 1.5), 4.5-4.2 (3H, m), 2.61 (3H, s), 1.11 (9H, s); 13C
NMR δ 163.1, 136.9, 131.4, 131.4, 131.3, 128.8, 128.2, 128.1,
125.4, 124.0, 123.6, 77.0, 67.6, 34.0, 26.0, 22.3. MS 267. [R]D
) -51 (c 2.1, CH2Cl2).
In another experiment, 240 mg (0.45 mmol) of (a-R,S,S)3b
and 80 mg (0.3 mmol; 2.3 mol %) of (CuOTf)2‚PhH solubilized
in 5 g (48 mmol) of neat styrene were diluted with 3.5 g (33.6
mmol) of styrene and allowed to react with 1.44 g (12.6 mmol)
of ethyl diazoacetate added portionwise over 6 h. The styrene
solution of the catalyst was kept in an ice/water bath. These
conditions afforded 320 mg (13.3%) of 1R-(trans)-1-carbethoxy-
2-phenylcyclopropane 19 of 81% ee, 340 mg (14.2%) of 1R-(cis)-
1-carbethoxy-2-phenylcyclopropane 20 of 56% ee, and 510 mg
(21.3%) of a 1:1 mixture of the two diastereomers as estimated
1
by H NMR.
Typ ica l P r oced u r e for Cyclop r op a n a tion of Styr en e
w ith Eth yl Dia zoa ceta te. A nylon syringe filter (0.2 µm) was
dried under high vacuum at 65 °C to constant weight and
tared. A mixture of 26 mg of (CuOTf)2‚PhH and 82 mg (0.154
mmol) of (a-R,S,S)3b was mixed in 4 mL of CH2Cl2, and the
suspension was stirred at room temperature for 2 h. The
resulting brownish suspension was filtered through the tared
nylon syringe filter into a 50 mL round-bottom flask. The nylon
filter was washed with CH2Cl2, dried under high vacuum at
65 °C to constant weight and tared. The weight increase
totaled 10 mg of solid material. Therefore, 16 mg of (CuOTf)2‚
PhH formed the catalyst (0.06 mmol of Cu; 0.75 mol %). To
Ack n ow led gm en t. We would like to thank the
National Institutes of Health for generous support of
this research program. The authors also would like to
thank Dr. Susan M. Miller at Colorado State University
for solution of the crystal structures.
Su p p or tin g In for m a tion Ava ila ble: X-ray tables for
compounds 3b and 12b. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O990968H