Crystallization-Induced Asymmetric Transformation of a Tertiary Phosphine

Article abstract of DOI:10.1021/jo991493x

An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio) undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process can also be carried out at room temperature by using iodine to catalyze the interconversion of 5 and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with retention of phosphorus configuration.

Full text of DOI:10.1021/jo991493x

J . Org. Chem. 2000, 65, 2337-2343
2337
Cr ysta lliza tion -In d u ced Asym m etr ic Tr a n sfor m a tion of a Ter tia r y
P h osp h in e
Edwin Vedejs*,† and Yariv Donde
Chemistry Department, University of Wisconsin, Madison, Wisconsin 53705
Received September 22, 1999
An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio)
undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from
refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process
can also be carried out at room temperature by using iodine to catalyze the interconversion of 5
and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of
the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive
cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio
derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with
retention of phosphorus configuration.
We have been involved in studies designed to exploit
crystallization-induced asymmetric transformation (ab-
breviated for convenience as AT) for the preparation of
molecules containing stereogenic heteroelements.1,2 This
phenomenon has long been known,3-6 but it has attracted
relatively little attention compared to other methods of
asymmetric synthesis. Nevertheless, there are a number
of intriguing applications where AT has been used to
prepare enantiomerically and diastereomerically homo-
geneous molecules on a substantial scale by the crystal-
lization of one of two equilibrating diastereomers,7 as well
as related examples where crystallization of an intercon-
verting mixture of positional isomers results in the
recovery of one of the components in an amount exceeding
that present at equilibrium.8 Phosphorus examples of AT
are also reported, including acylphosphines1 and second-
ary phosphines.9 We now report the first extension of the
AT technique to a tertiary phosphine containing three
hydrocarbon (alkyl and aryl) substituents at phosphorus.
In contrast to the acylphosphine examples, tertiary
phosphines are resistant to pyramidal inversion. Typical
inversion barriers exceed 30 kcal/mol,10 corresponding to
equilibration temperatures in excess of 100 °C. For
successful AT under thermal equilibration conditions, it
would be necessary for one of the phosphine diastereo-
mers to have a melting point that is higher than the
equilibration temperature. One way to address this
potential limitation would be to use a phosphorus sub-
stituent that promotes high crystallinity (efficient pack-
ing in the crystal lattice; high mp) and that can be
replaced by other groups when desired. Another approach
would be to use a catalyst that induces the interconver-
sion of phosphorus epimers at lower temperatures. There
are indications in the literature that this should be
possible from the reported racemization of methylphen-
ylpropylphosphine by treatment with 10 mol % of iodine
in benzene/CH3CN at 50 °C.11 If this method can be
extended to diastereomer mixtures involving stereogenic
phosphorus, then AT might be feasible with a broader
range of substrates.
Resu lts a n d Discu ssion
† Current Address: Department of Chemistry, University of Michi-
gan, Ann Arbor, MI 48109.
(1) Vedejs, E.; Donde, Y. J . Am. Chem. Soc. 1997, 119, 9293.
(2) (a) Vedejs, Edwin; Fields, Stephen C.; Schrimpf, Michael R. J .
Am. Chem. Soc. 1993, 115, 11612. (b) Vedejs, E.; Fields, S. C.; Hayashi,
R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J . Am. Chem. Soc.
1997, 119, 9293.
(3) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and
Resolutions; Krieger Publishing: Malabar, FL, 1994; Chapter 6. Secor,
R. M. Chem. Rev. 1963, 63, 297.
(4) Organometal examples: Pope, W. J .; Peachey, S. J . J . Chem.
Soc. Proc. 1900, 16, 42. Werner, A. Chem. Ber. 1912, 45, 3061.
(5) Carbohydrate examples: Hudson, C. S.; Dale, J . K. J . Am. Chem.
Soc. 1917, 39, 320. Hudson, C. S.; Yanovsky, E. J . Am. Chem. Soc.
1917, 39, 1013.
Syn t h esis of Men t h yl-Der ived Ter t ia r y P h os-
p h in es. A straightforward route to diastereomeric ter-
tiary phosphines was evaluated starting from the known
2, Scheme 1.12,13 The latter is available from (-)-menthyl
chloride 1 via the Grignard reagent and phenyldichloro-
phosphine14 as a mixture of diastereomers (2.5:1). With-
out purification, 2 was treated with organometallic
reagents including MeMgBr, i-PrMgCl, and 9-fluorenyl-
lithium at 0 °C. The resulting phosphines were evaluated
for crystallinity, and promising crystals were obtained
in the fluorenyllithium experiment. The crude phosphine
mixture was therefore complexed with BH3-THF to
furnish the phosphine boranes 3 and 4 (3:1 ratio),
corresponding to the phosphine diastereomers 5 and 6.
(6) Mills, W. H.; Bain, A. M. J . Chem. Soc. 1910, 97, 1866. Leuchs,
H.; Wutke, J . Chem. Ber. 1913, 46, 2420.
(7) Mioskowski, C.; Solladie´, G. Tetrahedron 1980, 36, 227. Reider,
P. J .; Davis, P.; Hughes, D. L.; Grabowski, E. J . J . J . Org. Chem. 1987,
52, 955. Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Fukumoto,
K.; Kametani, K. J . Chem. Soc., Perkin Trans. 1 1989, 897. Reid, J .
G.; Debiak-Krook, T. Tetrahedron Lett. 1990, 31, 3669. Wilen, S. H.;
Qi, J . Z.; Williard, P. G. J . Org. Chem. 1991, 56, 485.
(8) Noyori, R.; Uchiyama, M.; Nobori, T.; Hirose, M.; Hayakawa, Y.
Aust. J . Chem. 1992, 45, 205.
(10) Baechler, R. D.; Mislow, K. J . Am. Chem. Soc. 1970, 92, 3090.
(11) Naumann, K.; Zon, G.; Mislow, K. J . Am. Chem. Soc. 1969, 91,
7012.
(12) Boese, R.; Haegele, G.; Kueckelhaus, W.; Seega, J .; Tossing, G.
Chem.-Ztg. 1985, 109, 233-8.
(13) (a) Smith, J . G.; Wright, G. F. J . Org. Chem. 1952, 17, 1116.
(b) Glaze, W. H.; Selman, C. M. J . Org. Chem. 1968, 33, 1987-90.
(14) Tanaka, M.; Ogata, I. Bull. Chem. Soc. J pn. 1975, 48, 1094.
(9) Bader, A.; P., M.; Wild, S. B. J . Chem. Soc., Chem. Commun.
1994, 1405. Bader, A.; Pabel, M.; Willis, A. C.; Wild, S. B. Inorg. Chem.
1996, 35, 3874.
10.1021/jo991493x CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/18/2000

2338 J . Org. Chem., Vol. 65, No. 8, 2000
Vedejs and Donde
Sch em e 1
F igu r e 2. X-ray crystal structure of (Sp)-5.
individual diastereomers to 85 °C. NMR analysis after
14 h indicated that equilibrium had been reached (SP/RP
2.5:1 from either diastereomer). This temperature is well
below the melting point of 5, but initial attempts to
perform the AT experiment encountered considerable
difficulty in finding a solvent where interconversion of
diastereomers would occur under conditions that allowed
crystallization. Attention was therefore focused on the
I2-catalyzed epimerization of purified 5 in the hope that
the interconversion with 6 would be feasible at lower
temperatures and that this would facilitate the desired
crystallization process required for AT. On the basis of
earlier work,11 molecular iodine should add reversibly to
the phosphine diastereomers 5 and 6 to generate dia-
stereomeric P-iodophosphonium salts 7 and 9, which
should interconvert via the pentavalent phosphorus
intermediate 8. Indeed, treatment of 5 with 10 mol % I2
in CH3CN resulted in much faster diastereomer equili-
bration (10 min vs hours at 80 °C) compared to the
uncatalyzed thermal reaction. Subsequent cooling, evapo-
ration of CH3CN, and complexation with BH3-THF
resulted in a 1.1:1 mixture of diastereomers 3:4. Similar
results were obtained using tert-butyl methyl ether as
the solvent (interconversion of isomers within 10 min,
55 °C), but the corresponding experiment in hexane as
solvent (I2, 20 min, reflux) resulted in formation of a
yellow precipitate and very little epimerization. Appar-
ently, the phosphine-iodine adducts are insoluble in
hexane, and the catalytic cycle fails.
Initial attempts at iodine-mediated AT with crude
mixtures of 5 and 6 gave poor results. Crystals of 5 were
sometimes obtained, but the catalytic cycle that could be
demonstrated with purified 5 or 6 did not work well when
impurities were present. After much effort, it was found
that the iodine-catalyzed equilibration could be controlled
if the mixture of 3 and 4 obtained from 2 was purified
by chromatography and then was decomplexed using
diethylamine to give the mixture of relatively pure
phosphines 5 and 6. The AT experiment could then be
carried out using a procedure based on previous work in
our laboratory with substances containing equilibrating
boron diastereomers.2 In the latter study, a solution of
the diastereomeric mixture was heated to a temperature
where epimerization was relatively fast and the more
stable diastereomer was allowed to crystallize as solvent
was slowly evaporated over a time scale of hours. This
F igu r e 1. X-ray crystal structure of (Rp)-4.
The phosphine boranes were air and moisture stable and
could be separated by a combination of crystallization and
chromatography. Thus, the major fluorenyl diastereomer
3 was obtained in 32% yield by direct crystallization,
while 4 was isolated in 23% yield after careful chroma-
tography and crystallization, procedures that provided
an additional 5-10% of impure 3. Suitable crystals of
the minor diastereomer 4 were obtained for an X-ray
structure determination to establish relative stereochem-
istry and the (R)-configuration at the phosphorus ste-
reocenter (Figure 1). The major diastereomer 3 must
therefore have the (S)-configuration as shown.
Conversion of the phosphine boranes to the free phos-
phines was accomplished by treatment with excess
diethylamine (5 h, rt).15 In the case of the (SP)-diastere-
omer 3, this gave the crystalline SP-phosphine 5 (mp 140
°C) in 97% yield as a single diastereomer. The diaster-
eomeric (RP)-phosphine 6 was made in the same way from
4 and was isolated as a viscous oil. An X-ray structure
of the crystalline (SP)-isomer 5 confirmed the expected
stereochemistry, corresponding to retention of configu-
ration in the decomplexation step (Figure 2).
The melting point of (SP)-5 was sufficiently high that
thermal as well as catalyzed equilibration of phosphorus
configuration could be considered for the AT experiments.
As expected from precedent with other tertiary phos-
phines, heating a neat sample of diastereomerically pure
5 to 150 °C for 40 min resulted in a 1.3:1 (SP/RP)
diastereomeric mixture of 5 and 6. However, epimeriza-
tion also occurred upon heating CD3CN solutions of the
(15) Imamoto, T.; Oshiki,.; Onozawa, T.; Kusumoto,.T.; Sato, K. J .
Am. Chem. Soc. 1990, 112, 5244-52.

Asymmetric Transformation of a Tertiary Phosphine
J . Org. Chem., Vol. 65, No. 8, 2000 2339
Sch em e 2
procedure allows control over the rate of crystallization
by controlling the rate of solvent evaporation, and
provides the means to convert the equilibrium mixture
almost entirely to the more stable solid (the less soluble
diastereomer).
In an early experiment in the phosphorus series,
purified, noncrystalline 6 was treated with 10 mol % I2
in CH3CN followed by crystallization and slow evapora-
tion of the solvent over 4 h. The crude solid was then
in catalytic amounts, is capable of shutting down equili-
bration of diastereomers. This limitation effectively
prevented the use of crude 5 + 6, obtained directly from
the reaction of 2 with fluorenyllithium, for the AT
experiments. The resulting inefficiency stimulated a
reexamination of the thermal (uncatalyzed) AT process
where there would be no sensitive P-iodophosphonium
intermediates.
In principle, the simplest procedure for effecting AT
is by crystallization from the melt since this requires no
external reagents or solvents. Therefore, this alternative
was examined carefully. In the best experiment, a prepu-
rified mixture of 5 and 6 was melted at 150 °C and then
allowed to crystallize at 120 °C over several hours. This
resulted in an improvement of the diastereomer ratio to
19:1 5:6. However, the final diastereomer ratio obtained
using this method was also highly dependent on the
purity of the material. Even the presence of small
amounts of impurities resulted in lower ratios (<10:1).
The situation was improved by crystallization from
solution under AT conditions. High diastereomer ratios
(>20:1 5:6 by NMR assay) were obtained by crystalliza-
tion from refluxing heptane (bp 98 °C) while allowing the
solvent to evaporate over a few hours. Other solvents (n-
butanol, n-propanol/H2O, EtCN, and AcOH) gave inferior
results. This procedure was the most tolerant of the
purity of the material and even crude material from the
reaction of 2 and fluorenyllithium could be used. Under
the best conditions, the crude phosphine obtained after
simple filtration over silica gel and removal of excess
fluorene by sublimation was crystallized from a minimum
amount of heptane by allowing the solvent to evaporate
over 48 h, resulting in a final ratio of 20:1 5:6. Recrys-
tallization under nonequilibrating conditions (<65 °C)
gave pure 5 in 57% yield based on PhPCl2. This allowed
a one pot synthesis of 5 from 2 without the need to
prepare and purify the corresponding phosphine boranes
3 and 4, and 5 could be conveniently made on gram scale.
Attention was turned to reductive removal of the
fluorenyl group. This group was originally selected partly
because of its reputation for high crystallinity, and also
because it is potentially removable under reductive
conditions. A key issue was whether reductive cleavage
can be accomplished with control of phosphorus config-
uration. There is precedent for stereospecific reductive
transformations of alkoxyphosphine boranes from Ima-
moto’s work.16 Although the anionic leaving group in the
Imamoto experiments is different, the crucial intermedi-
ate 10 (Scheme 2) expected from the reductive cleavage
complexed with BH3-THF at low temperature to give a
3:1 SP/RP mixture of phosphine boranes 5 and 6. Thus,
some epimerization had occurred, but the final ratio of
diastereomers was not very different from the equilibri-
um mixture (2.5:1 5:6). Several possible reasons for the
low diastereomer ratio were considered: (1) the hydro-
lytically unstable phosphine-I2 adduct decomposes, ter-
minating the catalytic cycle; (2) undesired equilibration
of phosphorus configuration occurs when the crystalline
phosphine is dissolved prior to complexation with BH3-
THF; and (3) crystallization is too fast relative to
equilibration. After further experimentation, it was
evident that all three of these factors are important. The
hydrolytic instability of the phosphine-I2 adduct plays
a role, as evidenced by improved ratios in the presence
of powdered 3 Å molecular sieves to absorb water.
Equilibration after the initial crystallization also takes
place, apparently due to the presence of residual catalyst
in the solid. This problem could be minimized by quench-
ing the phosphine-I2 adducts derived from the catalyst
(presumably, 7-9) with H2O/K2CO3 prior to complexation
with BH3-THF. Finally, monitoring the rate of crystal-
lization as a function of temperature indicated that
iodine-catalyzed epimerization is fast enough even at
room temperature to give high diastereomer ratios
provided that crystallization (i.e., solvent evaporation) is
carried out over ca. 30 h. Under the optimized conditions,
a 3:1 diastereomer mixture of 5:6 was converted to a
1
single diastereomer (>20:1 by H and 31P NMR assay)
by crystallization from a CH3CN solution containing 4
mol % I2 while evaporating the solvent over 30 h. Pure 5
was obtained after another recrystallization (nonequili-
brating conditions; no catalyst, <65 °C) from CH3CN,
giving 5 in 83% yield based on the 3:1 mixture (51%
overall from 2).
The experiments described above were optimized using
material that had been prepurified at the stage of 3 + 4.
Application of the optimized conditions to material of
lesser purity resulted in little or no enhancement in the
final ratios. Presumably, the sensitive nature of the
phosphine-I2 adducts is the cause of these problems.
Thus, any nucleophilic impurity that has the potential
of intercepting the reactive adducts 7 or 9, both present
(16) Imamoto, T.; Oshiki,.T.; Onozawa, T.; Matsuo, M.; Hikosaka,.T.;
Yanagawa, M. Heteroat. Chem. 1992, 3, 563-75.

2340 J . Org. Chem., Vol. 65, No. 8, 2000
Vedejs and Donde
of the borane complex 3 is closely related to the inter-
mediates generated from chiral alkoxyphosphine boranes
with one electron reductants such as lithium naphtha-
lenide. Subsequent alkylation or protonation should
therefore produce phosphine boranes with high diaster-
eomeric excess if the reduction/alkylation sequence can
be performed near -78 °C. Imamoto et al. have shown
that significant pyramidal inversion at phosphorus occurs
if anionic phosphine boranes similar to 10 are warmed
above 0 °C.16
Su m m a r y
These studies demonstrate the feasibility of crystal-
lization-induced asymmetric transformation approaches
for the control of phosphorus configuration in tertiary
phosphines. The P-fluorenyl substituent functions as a
crystallization promoter that is compatible with the
conditions required for AT. After the crystallization
event, the P-fluorenyl subunit can be replaced stereospe-
cifically by other alkyl groups using a sequence of
reductive cleavage and alkylation. The thermal AT
experiment with phosphine 5 is the most efficient, but
other applications of this approach would be limited to
tertiary phosphines with melting points >100 °C. The
low-temperature iodine-catalyzed alternative is also dem-
onstrated. This procedure is complicated by the sensitive
nature of the P-iodophosphonium intermediates and by
the need to purify the mixture of phosphine diastereo-
mers. Further studies will be needed to extend the AT
approach to lower-melting tertiary phosphines.
Lithium naphthalenide proved highly effective at
reducing 3, and 11 was formed cleanly after protonation
of 10 with H2SO4/THF at -78 °C. The reaction proceeded
with essentially total stereospecificity (>99% de by HPLC
assay). Retention of configuration at phosphorus was
assigned by analogy to findings from subsequent experi-
ments (see below). Interestingly, phosphorus stereochem-
istry could be equilibrated in 11 by treatment with
t-BuOK in THF at room temperature, resulting in a 2:1
diastereomeric mixture after only 20 min. This equilibra-
tion probably involves the potassium analogue of 10.
Exp er im en ta l Section
The reductive cleavage activation procedure allowed
access to other chiral phosphines in excellent yield. Thus,
treatment of 3 with lithium naphthalenide and subse-
quent alkylation with MeI (THF -78 °C) gave the methyl
substituted derivative (13) in 90% yield. None of the
diastereomer 14 could be detected by NMR methods.
Furthermore, deprotection with diethylamine afforded a
single diastereomer of the known phosphine 1517,18
without contamination by 16 (assay by NMR in deute-
riobenzene). Likewise, a similar sequence from 2 using
benzyl bromide as the alkylating agent furnished the
corresponding benzyl-substituted phosphine 17 in 94%
Gen er a l Meth od s. Flash column chromatography was
performed using silica gel 60 (230-400 mesh). Solvents were
purified as follows: tetrahydrofuran and diethyl ether were
freshly distilled from sodium benzophenone ketyl under N2.
CH3CN was distilled from P2O5, then from anhydrous K2CO3,
and stored over 3 Å molecular sieves. Reagents were used as
received or purified as noted. All air- and/or moisture-sensitive
reactions were run under an atmosphere of N2 in flame- or
oven-dried glassware.
(-)-Men th yl Ch lor id e (1). The published procedure was
followed.13a Thus, (-)-menthol (37.9 g, 0.24 mol, Aldrich), ZnCl2
(110.1 g, 0.81 mol, Mallinckrodt), and HCl (75.0 mL, 37%, 0.90
mol, Fisher) gave (-)-menthyl chloride (37.9 g, 0.22 mmol,
92%, bp 81.0-83.0 °C/5 Torr; lit.13a 100-101.5 °C/21 Torr) as
a colorless liquid. The NMR spectrum agreed with the pub-
lished spectrum.13b
1
yield (single diastereomer, >20:1, H NMR assay).
Men th ylm a gn esiu m Ch lor id e. The published procedure
was followed with modification:14 To a suspension of Mg
turnings (1.684 g, 69.3 mmol, Fisher) in THF (10 mL) was
added dibromoethane (0.10 mL, 0.53 mmol). After the reaction
had started, the flask was placed in a 50 °C oil bath, and a
solution of (-)-menthyl chloride (6.0 mL, 32.1 mmmol) in THF
(10 mL) was added over 20 min. The oil bath was then warmed
to 60-70 °C, and the reaction mixture was stirred for 5 h. The
solids were allowed to settle, and the clear, brown solution of
menthylmagnesium chloride was removed by cannula, titrated,
and used immediately.
Men th yl(1-n a p h th yl)p h en ylp h osp h in e Bor a n e. A solu-
tion of menthylmagnesium chloride (12.8 mL, 0.59 M in THF,
7.5 mmol) was added dropwise, over 1.5 h, to a cooled (bath
temperature ) -45 °C) solution of PhPCl2 (1.0 mL, 7.4 mmol,
distilled, Aldrich) in THF (10 mL). The resulting cloudy
mixture was allowed to warm to room temperature and stirred
for 22 h.
To another flask, containing a solution of 1-naphthyl
bromide (1.1 mL, 7.9 mmol, Aldrich) in THF (10 mL), was
added t-BuLi (8.8 mL, 1.8 M/pentane, 15.8 mmol) at -78 °C,
and the yellow suspension was stirred for 20 min. At this time,
the chlorophosphine solution was diluted with 9 mL of THF
to dissolve solids and was added to the 1-naphthyllithium
mixture by cannula over 15 min. The original flask was rinsed
with THF (4 mL), and the yellow reaction mixture was allowed
to warm to room temperature.
1
Comparison with the published H NMR data (CDCl3)
for the diastereomers 15 and 16 allowed correlation of
the relative configuration at phosphorus and demon-
strated that the original fluorenyl cleavage from 3
proceeds with retention of configuration. By analogy,
overall retention of configuration was also assigned for
11 and 17. Similar findings were reported by Imamoto
et al. starting from chiral alkoxyphosphines.16
(17) (a) Valentine, D. J r.; Blount, J . F.; Toth, K. J . Org. Chem. 1980,
45, 3691. (b) Fisher, C.; Mosher, H. S. Tetrahedron Lett. 1977, 18, 2487.
(18) In the course of the correlation experiments, it was observed
that diastereomerically pure 15 equilibrates with 16 in CDCl3 (deoxy-
genated and filtered through K2CO3), resulting in a 1.2: 1 diastereomer
mixture after 2.5 h at room temperature. The configurational instabil-
ity of electron rich P-chiral phosphines in CDCl3 has been recently
noted19 and may be related mechanistically to the iodine-mediated
equilibration discussed earlier if CDCl3 acts as a positive chlorine
source.
After 18 h at room temperature, the clear yellow solution
was cooled to 0 °C, and BH3-THF (11.0 mL, 1 M/THF, 11.0
mmol, Aldrich) was added. The solution was stirred for 3 h,
and the reaction was quenched with 10 mL 1 M HCl. The
mixture was extracted with ether, and the combined ether
extracts were dried (MgSO4), filtered, and evaporated (aspira-

Asymmetric Transformation of a Tertiary Phosphine
J . Org. Chem., Vol. 65, No. 8, 2000 2341
tor) to leave an oil. The crude oil was purified by flash
chromatography on silica gel (12 × 5 cm) 1:9 acetone/hexane
eluent to give menthyl(1-naphthyl)phenylphosphine borane
(1.36 g, 48% yield) as a 1:1 mixture of diastereomers. A pure
diastereomer was obtained by crystallization of the foam from
cold hexane (-20 °C) and further recrystallization of the
resulting solid from hot benzene/hexane to give colorless
crystals: mp 147.0 °C, dec; analytical TLC on silica gel, 1:9
acetone/hexane, Rf ) 0.50; no parent ion for C26H34BP; M - 14
(BH3), 374.2160, error ) 1 ppm; IR (CDCl3, cm-1) 2394 (BH);
500 MHz NMR (C6D6, ppm) δ 8.7-8.6 (2H, m), 8.06-8.01 (2H,
m), 7.47-6.89 (8H, overlapping m), 3.10-3.02 (1H, m), 2.5-
1.7 (3H, broad m), 2.2-2.1 (2H, m), 1.68-1.51 (3H, overlapping
m), 1.41-1.33 (1H, m), 1.19-1.13 (1H, broad m), 1.1-1.0 (1H,
m), 0.92 (3H, d, J ) 6.7 Hz), 0.8-0.7 (1H, m), 0.69 (3H, d, J )
6.4 Hz), 0.46 (3H, d, J ) 6.3 Hz).
(SP )/(RP )-(9-F lu or en yl)m en th ylp h en ylp h osp h in e Bo-
r a n e (3, 4). A solution of menthylmagnesium chloride (35.5
mL, 1.03 M/THF, 36.6 mmol) was added dropwise to a cooled
(bath temperature -49 °C) solution of PhPCl2 (5.0 mL, 36.8
mmol, distilled) in THF (50 mL) over 1.25 h. The cloudy
mixture was brought to room temperature and allowed to stir
for 17 h.
In another flask, 9-fluorenyllithium was prepared by addi-
tion of n-BuLi (23.3 mL, 1.59 M/hexanes, 37.0 mmol) to an
ice-cold solution of fluorene (6.166 g, 37.0 mmol, recrystallized
from hexanes) in 40 mL of THF over 15 min. THF, 15 mL,
was added to dissolve some solids and the resulting orange
solution stirred for 20 min at 0 °C.
At this time, the fluorenyllithium solution was added by
cannula to an ice-cold solution of the chlorophosphine over 30
min (rinsing with 10 mL THF). The clear orange solution was
stirred for 23 h at room temperature and then heated (bath
temp 55-60 °C) for 2.5 h. The reaction was cooled in an ice
bath and treated with BH3-THF (50.0 mL, 1 M/THF, 50.0
mmol, Aldrich) and the solution stirred for 1 h at 0 °C and 0.5
h at room temperature.
The reaction was quenched by cautious addition of 100 mL
of 1 M HCl and extracted with ethyl acetate. The combined
extracts were dried (MgSO4), filtered, and evaporated (aspira-
tor) to leave a thick, cloudy yellow oil. The oil was filtered
through silica gel (10 × 4 cm) eluting with CH2Cl2 to leave a
yellow foam after solvent removal (aspirator). Proton NMR
analysis (comparing the fluorenyl doublets: δ 4.73 ppm for
(SP)-3 and 4.58 ppm for (RP)-4) showed SP/RP 3:1.
The crude product was triturated with hexanes (30 mL), and
a white solid slowly formed. The solid (6.88 g) was collected
by vacuum filtration and washed with hexanes. Recrystalli-
zation from acetonitrile (ca. 55 mL) gave two crops of white
crystals. Crop 1 (4.961 g, 11.6 mmol, 32%) was pure (SP)-(9-
fluorenyl)menthylphenylphosphine borane (3) by NMR, while
crop 2 (0.723 g, 1.7 mmol, 5%) was a 10:1 SP/RP mixture.
Characterization data for the pure diastereomer: mp 162.0
°C, dec; analytical TLC on silica gel, 1:1 dichloromethane/
hexane, Rf ) 0.40; M - 14 (BH3), 412.2310, error ) 3 ppm;
base peak 165 amu; IR (CDCl3, cm-1) 2391 (BH), 1067; 200
MHz NMR (C6D6, ppm) δ 8.01 (1H, d, J ) 6.9 Hz), 7.44-6.74
(12H, m), 4.73 (1H, d, J ) 11.8 Hz), 2.84-2.59 (2H, m), 1.90-
0.62 (11H, overlapping m), 0.96 (3H, d, J ) 6.9 Hz), 0.93 (3H,
d, J ) 6.9 Hz), 0.70 (3H, d, J ) 5.6 Hz).
The supernatant from the hexane trituration and the
mother liquor from the recrystallization were combined and
purified by flash chromatography on silica gel (15 × 9 cm; 50
mL fractions; gradient elution of hexanes, 1:4 CH2Cl2/hexanes,
1:1 CH2Cl2/hexane) to give 3.67 g (8.6 mmol, 23%) of (RP)-(9-
fluorenyl)menthylphenylphosphine borane (4) and impure
(SP)-3 (0.923 g, 2.2 mmol, 6%, after further purification by
recrystallization from CH3CN). X-ray quality crystals of (RP)-4
were obtained by recrystallization from acetonitrile, confirming
the relative stereochemistry at the phosphorus center as (R):
mp 168.0 °C, dec; analytical TLC on silica gel 1:1 dichlo-
romethane/hexane, Rf ) 0.50; HRMS, M - 14 (BH3), 412.2269,
base peak ) 165 amu; IR (CDCl3, cm-1) 2387 (BH), 1067; 270
MHz NMR (C6D6, ppm) δ 8.41 (1H, d, J ) 7.7 Hz), 7.61-7.56
(1H, m), 7.34-6.49 (11H, m), 4.58 (1H, d, J ) 10.3 Hz), 2.67-
1.43 (11H, overlapping m), 1.02-0.68 (2H, overlapping m), 1.00
(3H, d, J ) 6.9 Hz), 0.73 (3H, d, J ) 6.9 Hz), 0.10 (3H, d, 6.7
Hz).
(SP )-(9-F lu or en yl)m en th ylp h osp h in e (5). The phosphine
borane (SP)-3 (0.152 g, 3.6 mmol) was dissolved in deoxygen-
ated Et2NH (5 mL, distilled, Aldrich), and the clear, colorless
solution was stirred for 16 h at room temperature. The Et2-
NH was removed under an N2 stream, and the residue was
taken up in deoxygenated benzene and filtered through a pad
of silica gel under N2. The benzene was removed under vacuum
to give (SP)-(9-fluorenyl)menthylphenylphosphine (5) as a
white crystalline solid (0.145 g, 3.5 mmol, 97%). Pure material
was obtained by recrystallization from deoxygenated acetoni-
trile, mp 140.2-142.0 °C (sealed capillary), colorless prisms.
X-ray analysis confirmed the stereochemistry as SP: analytical
TLC on silica gel, 1:9 EtOAc/hexane, Rf ) 0.36; molecular ion
calcd for C29H33P 412.23206, found m/e ) 412.2337, error ) 4
ppm; base peak ) 165 amu; 270 MHz NMR (C6D6, ppm) δ 7.7-
7.6 (5H, m), 7.3-7.1 (6H, overlapping m), 6.92-6.85 (2H, m),
4.82 (1H, s), 2.84-2.78 (1H, m), 2.35 (1H, d, J ) 12.2 Hz),
2.19-2.16 (1H, m), 1.6-1.4 (3H, m), 1.2-0.5 (4H, overlapping
m), 0.95 (3H, d, J ) 6.6 Hz), 0.77 (3H, d, J ) 6.9 Hz), 0.63
(3H, d, J ) 6.6 Hz); 31P NMR (202 MHz, {1H}, C6D6, ppm) δ
-0.4.
(RP )-(9-flu or en yl)m en t h ylp h en ylp h osp h in e (6). Ob-
tained as a viscous oil in >98% yield using the same proce-
dure: 1H NMR 200 MHz (C6D6, ppm) δ 7.84 (1H, d, J ) 7.2
Hz), 7.68 (1H, d, 6.9 Hz), 7.4-6.6 (11H, m), 4.62 (1H, d, J )
3.6 Hz), 2.43-2.34 (2H, m), 1.9-0.8 (11H, overlapping m), 0.95
(3H, d, J ) 6.4 Hz), 0.73 (3H, d, J ) 6.7 Hz), 0.36 (3H, d, J )
6.7 Hz); 31P NMR (121 MHz, {1H}, C6D6, ppm) δ 13.2.
Op tim ized I2-Med ia ted AT for 5. To a three-neck round-
bottom flask, equipped with magnetic stirring and a coarse
fritted funnel, was added powdered 3 Å molecular sieves (0.54
g), and the apparatus was flame dried under N2. The phos-
phine (0.436 g, 1.06 mmol, SP/RP 3:1) was added, and then a
solution of I2 (9.7 mg, 0.04 mmol, Mallinckrodt) in deoxygen-
ated CH3CN (3.5 mL) was added by cannula. The resulting
yellow mixture was heated in an oil bath (bath temperature
55 °C) for 10 min, at which time all but a few crystals had
dissolved. The mixture was allowed to cool to room tempera-
ture, crystallization began, and the solvent was removed over
30 h with a gentle N2 stream to leave a solid mass.
To the solid mass was added K2CO3 (16 mg, 0.11 mmol) in
deoxygenated H2O (0.5 mL). The mixture was too thick, so
more H2O was added until the mass could be stirred and
broken up (a total of 0.75 mL was added). Deoxygenated CH3-
CN (0.25 mL) was added, and the creamy tan mixture was
stirred further. At this time, the mixture was taken into
deoxygenated THF, dried (MgSO4), and filtered through the
glass frit under N2. Evaporation of the solvent and 1H NMR
analysis indicated SP/RP > 20:1. The crude solid was recrystal-
lized from hot deoxygenated CH3CN under N2 to give pure
(SP)-5 (0.364 g, 0.88 mmol, 83%).
(SP )-5 by Th er m a l AT (On e-P ot P r oced u r e fr om P h -
P Cl2). Menthylmagnesium chloride (4.0 mL, 4.0 mmol, 1.0
M/THF) was diluted with 6.8 mL of THF and added to a
solution of PhPCl2 (0.51 mL, 3.76 mmol, Aldrich, distilled) in
THF (6.4 mL), cooled to -48 °C, over 40 min by cannula with
magnetic stirring. The Grignard flask was rinsed with THF
(1 mL) and the resulting off-white suspension allowed to warm
to room temperature. The clear, slightly yellow solution was
stirred for 17 h at room temperature and then cooled to -75
°C.
In another flask, an ice-cold solution of fluorene (0.656 g,
3.95 mmol, Aldrich, recrystallized from hexanes) in 20 mL of
THF was treated with n-BuLi (2.5 mL, 1.6 M/hexanes) with
magnetic stirring. The clear, orange solution was stirred for
30 min and then cooled to -48 °C.
At this time, the fluorenyllithium solution was added to the
cold chlorophosphine solution over 55 min by cannula. The
orange mixture was stirred for 1 h and then allowed to warm
to room temperature. After 3 h at room temperature, the clear,
yellow solution was quenched by addition of CF3CO2H (0.20
mL, 2.6 mmol, distilled from P2O5). After 20 min, Et3N (0.60
mL, 4.3 mmol, distilled from CaH2) was added and a white

2342 J . Org. Chem., Vol. 65, No. 8, 2000
Vedejs and Donde
precipitate formed. After 10 min, the volatiles were removed
in vacuo. The crude foam was taken into deoxygenated benzene
and filtered through a pad of silica gel under N2. The excess
fluorene was removed by sublimation at 65-70 °C/0.08-0.04
Torr for 19 h with occasional agitation to leave a slightly yellow
solid (1.26 g). The original ratio of 5:1 had increased to 8.5:1
during this process, presumably by AT. The crude product was
transferred to a one-piece 25 mL flask-condenser apparatus.
Deoxygenated heptane (0.8 mL, Fisher) was added and the
mixture placed in an 85 °C oil bath (some solid still remained).
A gentle N2 stream was applied to slowly evaporate the
heptane. After 24 h, the mixture appeared as a thick oil, the
N2 stream was increased, and this was accompanied by more
crystallization. After another 24 h, the solid was allowed to
cool to room temperature. NMR (1H,31P) analysis indicated SP/
RP 20:1. Recrystallization from deoxygenated CH3CN (+65 to
-20 °C) gave SP-5 (0.890 g, 2.16 mmol, 57% based on PhPCl2)
as colorless prisms.
(SP )-(L-Men th yl)p h en ylp h osp h in e Bor a n e (11). Lithium
naphthalenide was prepared according to the procedure of
Rieke:20 To a 50 mL round-bottom flask were added naphtha-
lene (0.493 g, 3.8 mmol, crystallized from ether), lithium (50
mg, 7.2 mmol, Aldrich), and THF (12 mL) under N2. After
being stirred for 3 h, the black solution was cannula trans-
ferred to another 50 mL round-bottom flask, rinsed with THF
(2 × 1 mL), and cooled to -78 °C.
lithium (47 mg, 7.2 mmol, Aldrich). The dry mixture was
stirred under N2 for 20 min, THF (10 mL) was added, and the
dark solution was stirred further for 3 h. The black solution
was then cannula transferred to a 50 mL round-bottom flask
(rinsing with THF, 2 × 1 mL) and cooled to -78 °C.
To the cold lithium naphthalenide solution was added a
precooled (-78 °C) solution of (SP)-(9-fluorenyl)menthylphen-
ylphosphine borane 3 (0.359 g, 0.84 mmol) in THF (8 mL) by
cannula over 5 min (rinsing with cold THF, 2 × 1 mL). After
45 min, a precooled (-78 °C) solution of CH3I (0.52 mL, 8.35
mmol, Aldrich, filtered through basic alumina) in THF (4 mL)
was added by cannula over 5 min. The resulting orange
solution was stirred for 30 min and then allowed to warm to
room temperature. After another 30 min, 20 mL of H2O was
added. The mixture was extracted with ether, and the com-
bined ether extracts were dried (MgSO4), filtered, and evapo-
rated (aspirator) to leave an oily yellow solid. 1H NMR analysis
indicated a single diastereomer (>20:1). The product was
purified by flash chromatography on silica gel (5 × 2.5 cm)
using a gradient from hexane to 1:1 hexane/CH2Cl2 to give a
white crystalline solid (0.209 g, 0.76 mmol, 90%); analytical
TLC on silica gel, 1:1 dichloromethane/hexane, Rf ) 0.40. Pure
material was obtained by crystallization from hexane (-20
°C): mp 85.5-86.3 °C, colorless crystals; HRMS, M - 14 (BH3),
262.1814; base peak ) 262 amu; IR (KBr, cm-1) 2386, BH; 300
MHz 1H NMR (C6D6, ppm) δ 7.64-7.57 (2H, m), 7.10-7.07
(3H, m), 2.3-2.2 (1H, m), 2.2-1.2 (11H, overlapping m), 1.0-
0.6 (13H, overlapping); the P-methyl doublet and the doublets
of the menthyl group could not be integrated accurately but
appear at 1.28 (J ) 9.3 Hz), 0.88 (J ) 7.0 Hz), 0.69 (J ) 7.0
Hz), 0.63 (J ) 5.8 Hz), respectively; 31P NMR (202 MHz,{1H},
C6D6, ppm) δ 17.2-15.6 (broad m). Anal. Calcd: C, 73.91; H,
10.97. Found: C, 73.31; H, 10.44.
The lithium naphthalenide solution was cooled to -78 °C,
and a precooled (-78 °C) solution of (SP)-(9-fluorenyl)menth-
ylphenylphosphine borane 5 (0.418 g, 0.98 mmol) in THF (6
mL) was added by cannula over 11 min. After 30 min, a
precooled (-78 °C) solution of H2SO4 (0.50 mL, 9.0 mmol, EM,
95-98%) in THF (5 mL) was added by cannula over 5 min.
The resulting colorless solution was allowed to warm to room
temperature by removing the bath. After 1 h, the cloudy, white
mixture was evaporated and partitioned between 10 mL of
H2O and 20 mL of CH2Cl2. An emulsion formed, so 10 mL of
saturated NH4Cl solution was added. The aqueous layer was
extracted further with CH2Cl2, and the combined CH2Cl2
extracts were dried (MgSO4), filtered, and evaporated (aspira-
tor) to leave a white solid. The crude product was filtered
through a plug of silica gel (2.5 × 2.5 cm; CH2Cl2 eluent).
The diastereomeric purity of 11 was assayed by HPLC
(Gilson silica gel column, 0.46 × 25 cm, hexanes eluent, UV
detection at 240 nm). A sample containing both diastereomers
(SP/RP 1.9:1 by 1H NMR) was prepared starting from SP-11 by
treatment with t-BuOK (0.3 equiv in THF, rt 20 min). The
HPLC trace of this mixture gave two peaks at 14.6 and 16.7
min in a ratio of 1.0:1.1. The HPLC trace of the crude reaction
mixture gave the same two peaks in a ratio of 104:1, indicating
that the peak at 14.6 min is due to (S)P-11, the peak at 16.7 is
due to (RP)-12, and the response factor is 2.1. Thus, these
results indicate a diastereomer ratio of SP/RP 218:1 in the
present reaction. The product was purified by flash chroma-
tography on silica gel (10 × 3 cm), 20% CH2Cl2/hexanes eluent,
taking 5-10 mL fractions, to give a white crystalline solid
(0.235 g, 0.90 mmol, 92%). Analytical TLC on silica gel, 1:1
dichloromethane/hexane, Rf ) 0.49. Pure material was ob-
tained by crystallization from hexane (-20 °C): mp 97.3-99.0
°C, fine, white needles; HRMS, M - 14 (BH3), 248.1675, error
) 8 ppm; IR (KBr, cm-1) 2384, BH; 300 MHz NMR (C6D6, ppm)
δ 7.6-7.5 (2H, m), 7.1-7.0 (3H, m), 5.36 (1H, dqd, J ) 365.0,
7.0, 2.7 Hz), 2.1-1.0 (9H, overlapping m), 0.9-0.6 (13H,
overlapping m); the methyl doublets of the menthyl group
could not be integrated accurately because of overlapping
peaks but appear at 0.90 (J ) 7.0 Hz) 0.73 (J ) 6.6 Hz), and
0.58 (J ) 6.6 Hz); 31P NMR (202 MHz, {1H}, C6D6, ppm) δ -3.7
to -4.2 (broad m). Anal. Calcd: C, 73.28; H, 10.78. Found: C,
73.21; H, 10.52.
(RP )-Ben zyl(L-m en th yl)p h en ylp h osp h in e Bor a n e (17).
Lithium naphthalenide was prepared according to the proce-
dure of Rieke:20 To a 50 mL round-bottom flask were added
naphthalene (0.491 g, 3.8 mmol, crystallized from ether),
lithium (39.7 mg, 5.7 mmol, Aldrich), and THF (6 mL) under
N2. The lithium was cut under the solvent, and the resulting
dark green solution was magnetically stirred for 3.5 h. The
lithium naphthalenide solution was cannula transferred to a
100 mL round-bottom flask, rinsing with THF (2 × 2 mL) and
cooled to -78 °C.
To the cold lithium naphthalenide solution was added a
precooled (-78 °C) solution of (SP)-(9-fluorenyl)menthylphen-
ylphosphine borane 3 (0.410 g, 0.96 mmol) in THF (6 mL) by
cannula over 12 min. The phosphine borane flask was rinsed
with THF (2 × 2 mL), and the rinses were added to the
reaction mixture. After 30 min, a precooled (-78 °C) solution
of benzyl bromide (1.2 mL, 10.1 mmol, Aldrich, filtered through
basic alumina) in THF (5 mL) was added by cannula over 5
min. The resulting orange solution was stirred for 15 min at
-78 °C and then allowed to warm to room temperature by
removal of the bath. After 1.5 h, the colorless reaction mixture
was quenched by addition of 1 M HCl (15 mL).
The mixture was extracted with ethyl acetate (1 × 25 mL,
2 × 15 mL), and the combined extracts were dried (MgSO4),
filtered, and evaporated (aspirator). The residue was purified
by radial chromatography on silica gel PF254 (4 mm) in two
passes, 1:4 dichloromethane/hexane eluent to give 17 (0.315
g, 0.90 mmol, 94%); analytical TLC on silica gel, 1:1 dichloro-
methane/hexane, Rf ) 0.43. Pure material was obtained by
crystallization from hexane: mp 149 °C, dec, fine white
needles; molecular ion calcd for C23H34BP 352.24914, found
m/e ) 352.2496, error ) 1 ppm; IR (KBr, cm-1) 2393, BH; 300
MHz NMR (C6D6, ppm) δ 7.54-7.47 (2H, m), 7.01-6.85 (8H,
m), 3.41 (1H, dd, J ) 13.8, 6.8 Hz), 3.11 (1H, dd, J ) 13.8,
13.8 Hz), 2.59-2.55 (1H, m), 2.05-0.60 (21H, m); the methyl
doublets of the menthyl group could not be integrated ac-
curately due to overlapping peaks but appear at 0.98 (J ) 7.0
Hz), 0.83 (J ) 6.6 Hz), 0.61 (J ) 6.2 Hz); 31P NMR (202 MHz,
C6D6, {1H}, ppm) δ 28.5-26.4 (broad m). Anal. Calcd: C, 78.40;
H, 9.75. Found: C, 78.49; H, 9.43.
(RP )-(L-Men th yl)m eth ylp h en ylp h osp h in e Bor a n e (13).
Lithium naphthalenide was prepared according to the proce-
dure of Rieke:20 To a 25 mL round-bottom flask were added
naphthalene (0.427 g, 3.3 mmol, crystallized from ether) and
(RP )-(L-Men th yl)m eth ylp h en ylp h osp h in e (15). Phos-
phine borane 13 (0.056 g, 0.20 mmol) was dissolved in Et2NH
(1 mL, distilled from NaOH) and the solution brought to reflux
(19) Muci, A. R.; Campos, K. R.; Evans, D. A. J . Am. Chem. Soc.
1995, 117, 9075.
(20) Ebert, G. W.; Rieke, R. D. J . Org. Chem. 1988, 53, 4282-8.

Asymmetric Transformation of a Tertiary Phosphine
J . Org. Chem., Vol. 65, No. 8, 2000 2343
under N2 (bath temperature 60-65 °C). After 4 h, the solution
was allowed to cool to room temperature and directly analyzed
by 31P NMR, which showed a single peak at -34.4 ppm. The
NMR sample was rinsed back into the flask with deoxygenated
(N2 purge) benzene, and the volatiles were evaporated (N2
stream). The residue was filtered through a plug of silica gel
(3 × 1 cm) eluting with deoxygenated (N2 purge) benzene and
the benzene evaporated (N2 stream, vacuum pump) to leave a
colorless oil (0.053 g, 0.20 mmol, 100%). The oil was dissolved
in deoxygenated CDCl3 (N2 purge; filtered through K2CO3), and
the 1H and 31P NMR spectra were recorded. The diastereomeric
purity was 1:15 SP/RP, which decayed to 1:1.2 after 2.5 h: 1H
NMR for the (RP) diastereomer (300 MHz, CDCl3, ppm) δ 7.4-
7.3 (5H, m), 2.85-2.77 (1H, m), 1.7-0.6 (20H, overlapping m),
0.4-0.25 (1H, m). The P-Me doublet could not be integrated
accurately but appeared at 1.34 ppm (J ) 4.8 Hz). Key signals
for the (SP) diastereomer: 2.60-2.53 (1H, m) and the P-Me at
1.21 (J ) 3.7 Hz). These signals were used to compare with
those reported in the literature17a for both diastereomers and
allowed for assignment of 12 as the (RP) diastereomer: 31P
NMR (not reported in ref 17a) (121 MHz, CDCl3, ppm) (RP)-
15 δ -33.1; (SP)-16 -30.3; in Et2NH: δ -31.3 ppm (SP), -34.3
ppm (RP).
Following the same procedure on 10 mg of 13 resulted in
67% yield of the free phosphine. 1H NMR analysis indicated a
single diastereomer (>20:1) based on only one set of signals:
(300 MHz, C6D6, ppm) δ 7.45-7.35 (2H, m), 7.2-7.05 (3H, m),
3.15-3.0 (1H, m), 1.7-0.7 (19H, overlapping m), 0.65-0.45
(2H, m). The characteristic P-Me doublet was observed at δ
1.18 (J ) 5.5 Hz).
Ack n ow led gm en t. This work was supported by the
National Science Foundation and by a fellowship to Y.D.
from the Eastman Kodak Co.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
substances; X-ray data tables for the more stable phosphine 5
and for the borane complex 4, corresponding to the less stable
phosphine diastereomer. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O991493X