A practical synthesis of trans-dichlororuthenium ((S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)-pyridine)(ethylene) amenable to large-scale preparation

Full text of DOI:10.1021/jo005652k

J . Org. Chem. 2001, 66, 1057-1060
1057
reported by Davies et al.10 The disadvantages of this
process on scale are the use of the Lewis acid as the
solvent and high reaction temperature (120 °C). Nish-
iyama published a four-step procedure starting from a
commercially available 2,6-pyridinedicarboxylic acid that
afforded the desired Pybox ligand in a good overall yield
A P r a ctica l Syn th esis of
tr a n s-Dich lor or u th en iu m
(S,S)-2,6-Bis(4-isop r op yl-2-oxa zolin -2-yl)-
p yr id in e)(eth ylen e) Am en a ble to
La r ge-Sca le P r ep a r a tion
(
4
(
2
64%). However, the use of SOCl (in the first step as the
Michael J . Totleben,* J . Siva Prasad,
solvent) in two steps, 95% NaH in the oxazoline cycliza-
tion step, and silica gel chromatography of an intermedi-
ate in this process were not desirable for scale-up in a
manufacturing environment.
We were able to modify Nishiyama’s procedure for use
in our pilot facility to produce the Pybox ligand in multi-
kilogram quantities (Scheme 1). 2,6-Pyridinedicarbonyl
chloride, 2, was prepared by treatment of less-expensive
J ames H. Simpson, Steven H. Chan, Dale J . Vanyo,
Daniel E. Kuehner, Rajendra Deshpande, and
Gus A. Kodersha
Process Research and Development, Bristol-Myers Squibb
Pharmaceutical Research Institute, One Squibb Dr.,
P.O. Box 191, New Brunswick, New J ersey 08903-0191
michael.totleben@bms.com
Received September 18, 2000
2
,6-pyridinedicarboxylic acid11 with excess Vilsmeier
reagent in CH Cl , affording 2 in yields of >94% as
2 2
12
determined by in-process quantitation. The dicarbonyl
chloride 2 was coupled with L-valinol (96%, 97% ee) under
Schotten-Baumann conditions. The coupled product 3
The enantioselectivity achieved using transition metal
catalysts can be strongly influenced by chiral bisoxazoline
ligands.1 Catalysts such as 1, which utilize pyridine
bisoxazoline (Pybox) ligands, have garnered much atten-
tion. Pybox ligands have been employed in the prepara-
tion of chiral catalysts for asymmetric transformations
2 2
precipitated out at the CH Cl /aqueous interface and was
collected by vacuum filtration in yields of 70 to 80%.
Decantation of a portion of the top aqueous phase was
necessary to reduce the filtration time.13 Experiments
using higher concentrations of NaOH (having smaller
aqueous volumes and, thus, shorter filtration times) gave
lower yields of 3 and increased amounts of recovered 2,6-
pyridinedicarboxylic acid from hydrolysis of 2.
A THF slurry of 3 was added to Vilsmeier reagent in
THF at 20 to 25 °C. Analysis by HPLC indicated that all
of 3 was consumed in approximately 4 h, and that in 10
to 12 h, the dichloride 4 was the major product observed.
The reaction was treated with a TEA/THF solution at
2
3,4
aldol,5 Diels-
such as Kharasch, hydrosilylation,
Alder,6 and cyclopropanation8,9 reactions. Given the
utility of the Pybox ligands, it is desirable to have a safe,
cost-effective process for the preparation of the necessary
Pybox ligand, and the appropriate catalyst, on larger
scale (g1 kg), with reproducible yields and quality.
,7
-10 to 0 °C. The TEA/THF solution was added at such a
rate as to maintain the -10 to 0 °C temperature range.
The resultant mixture was heated to 50 °C for 1 to 1.5 h
and then exchanged into toluene following aqueous
workup to remove TEA‚HCl. The toluene solution of 4
was treated with aqueous 40 wt % tetra-n-butylammo-
nium hydroxide and 10% KI. After stirring the mixture
at 30 to 35 °C for 10-12 h, Pybox 5 was obtained in yields
of 71-80% after workup and crystallization. The optical
Several procedures for the synthesis of Pybox ligands
are reported in the literature. Singh and co-workers used
a methanesulfonic acid promoted dehydrative cyclization
to form the oxazoline rings. However, this method
requires conditions (e.g., larger solvent volumes) that
may not be desirable for manufacturing. Another dehy-
2
1
4
2 2
rotations ranged from -110 to -117° (c ) 0.7, CH Cl ),
and the overall yields from 2,6-pyridinedicarboxylic acid
were 53-63%. (Results of laboratory and pilot facility
runs are summarized in Table 1).
drative cyclization approach employing BF
3
2
‚OEt was
Alternative routes for the synthesis of 5 were explored.
Treatment of 3 with methanesulfonyl chloride and a
variety of amine bases produced mixtures containing a
(
(
1) Bolm, C. Angew. Chem., Int. Ed. Engl. 1991, 30, 542.
2) Sekar, G.; DattaGupta, A.; Singh, V. K. J . Org. Chem. 1998, 63,
2
961.
3) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
(
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846. (b) Nishiyama, H.;
Kondo, M.; Nakamura, T.; Itoh, K. Organometallics 1991, 10, 500.
(10) Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J . J .
Org. Chem. 1996, 61, 9629.
(11) , 6-Pyridinedicarbonyl chloride is commercially available at ca.
$4000/kg, whereas 2, 6-pyridinedicarboxylic acid is priced at $320/kg
(both from Sigma-Aldrich-Fluka).
(12) A 50 µL aliquot of the reaction mixture was quenched in
acetonitrile containing 1 mL of diethylamine and diluted to 10 mL.
The amount of 2,6-pyridinedicarboxamide was measured by HPLC.
The acid chloride preparation was deemed complete when the yield of
the dicarboxamide was >90 M% (typically, it was >94 M%).
(13) Addition of seed crystals of 3 to the mixture of L-valinol, NaOH,
(
4) Nishiyama, H.; Yamaguchi, S.; Kondo, M.; Itoh, K. J . Org. Chem.
992, 57, 4306.
5) Evans, D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem. Soc.
996, 118, 5814.
6) Evans, D. A.; Murry, J . A.; von Matt, P.; Norcross, R. D.; Miller,
S. J . Angew. Chem., Int. Ed. Engl. 1995, 34, 798.
7) (a) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven,
1
1
(
(
(
T. R.; Reider, P. J . Tetrahedron Lett. 1996, 37, 1725. (b) Davies, I. W.;
Gerena, L.; Castonquay, L.; Senanayake, C. H.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . J . Chem. Soc., Chem. Commun. 1996,
1
753
2 2
and CH Cl prior to acid chloride charge helps produce larger crystals
of 3, and increases the overall filtration rate.
(8) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron. 1994,
5
0, 13725.
(
9) (a) Park., S.-B.; Murata, K.; Matsumoto, H.; Nishiyama, H.;
Tetrahedron Asymmetry 1995, 6, 2487. (b) Nishiyama, H.; Itoh, Y.;
Matsumoto, H.; Park, S.-B. J . Am. Chem. Soc. 1994, 116, 2223.
1
0.1021/jo005652k CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/10/2001

1
058 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
Sch em e 1
Ta ble 1. Yield s of Ch ir a l Diol 3 a n d P ybox Liga n d 5a
Sch em e 2
pyridine-
dicarboxylic
acid (kg)
yield
of 3
(kg)
%
yield
of 5
(kg)
%
yield input 3
yield overall
run
of 3
(kg)
of 5 yield (%)
1
2
3
0.02
6.71
6.71
0.0321 76.5
0.02 0.0144 80.6
61.7
53.7
62.4
10.10
10.72
72.4
79.0
10.10 6.70
10.10 7.12
74.2
79.0
a
Yields are corrected for water content.
number of unidentified impurities and low amounts of
. p-Toluenesulfonyl chloride with NMM as the base
Ta ble 2. Yield s of Ru ‚P ybox-ip Ca ta lyst 1a
5
performed better, giving much cleaner reaction mixtures
at 20 to 25 °C. However, after 8 days at this temperature,
the conversion of 3 to 5 was not complete. Analysis of
the crude reaction mixture revealed the presence of a
minute quantity of 3 and a significant amount of a
monooxazoline intermediate (both unquantified). Experi-
ments run at higher temperatures proceeded at a much
faster rate, but afforded only moderate yields of 5 that
required treatment with activated charcoal to remove
discoloration. The results of the methane and p-toluene-
sulfonyl chloride experiments question the stability of the
mesylate and tosylate intermediates formed in these
reactions. Attempts to form the bisoxazoline ligand by
treatment of 3 with p-toluenesulfonic acid and azeotropic
removal of water (Dean-Stark trap) yielded moderate
amounts of 5 mixed with small amounts of 3, and minute
amounts of other impurities. The NMR spectrum of 5
from this method was not clean, and the mass balance
was poor.
run
input ligand 5 (kg)
yield of 1 (kg)
% yield of 1
1
2
3
0.05
0.75
0.80
0.0694
1.06
1.16
83.4
84.8
85.9
a
Yields are corrected for water content.
usually seen in 5-10 M% (this did not appear to
adversely affect the activity or selectivity of the catalyst
in our hands). Yields corrected for residual 5 are provided
in Table 2. The main advantage in this process is the
replacement of silica gel chromatography of 1 by a
crystallization. The chromatography of 1 was cumber-
some, even on a few grams scale. Also, the catalyst
adhered to the walls of the flask on concentration,
making transfer difficult. By contrast, our isolation
method affords 1 as a free-flowing slurry that filters
easily. The burgundy-colored catalyst is air-stable and
can be stored in amber bottles at ambient temperatures
for extended periods of time.
The Ru‚Pybox catalyst 1 was prepared according to the
literature procedure.9
b,15
One caveat on the amount of 5 used in the preparation
of 1 should be noted. When the input of 5 was over 800
g in one trial, impurities were observed in 1 that were
difficult to completely purge. The reason for this is not
known, and further examination is in progress.
The reaction is shown in Scheme
2
. Dichlororuthenium(II) (p-cymene) dimer and 5 were
2 2
dissolved in CH Cl at 20 to 25 °C. Ethylene gas was
bubbled in16 until the reaction was complete, typically
in 30 min, by NMR.17 The catalyst was crystallized by
addition of the reaction mixture to heptane. The yield of
1
after drying was 87-91% based on the input of 5. The
(17) When the NMR shows <10% of 5, the reaction is deemed
complete. For an NMR sample: 100-200 µL of reaction mixture was
yields are uncorrected for residual ligand, which was
removed and blown to dryness with N
CDCl
2
. The residue was dissolved in
3
, and its proton spectrum was recorded. The areas under the
(
15) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki,
K.; Itoh, K. Bull. Chem. Soc. J pn. 1995, 68, 1247.
16) For small scale reactions, headspace ethylene can be used
without any loss of yield or quality.
multiplet at 1.85 ppm (isopropyl methine for the ligand) and 2.5 ppm
(isopropyl methine for the catalyst) were integrated and used in the
calculation for determining the amount of 5 remaining in the reaction
mixture. Normally, 5-10% of free 5 is observed.
(

Notes
In summary, we have defined a process which allows
the preparation of the chiral Pybox ligand 5 reproducibly
on a >1 kg scale. The procedure circumvents processing
obstacles that restrict the usage of existing methods.
Although Vilsmeier reagent and tetra-n-butylammonium
J . Org. Chem., Vol. 66, No. 3, 2001 1059
addition is exothermic), and gradually increasing the rate of
stirring as 2 is added. Stir the reaction at 0-10 °C for 10 min
and then at 20-25 °C for 10-12 h. Cool the mixture down to
0
-10 °C and hold there for 1 h. Stop the stirring, and allow the
phases to separate (3 will precipitate and reside at the aqueous/
organic interface). Carefully siphon off ∼500 mL of the top
aqueous layer (this reduces filtration time. See ref 13). Collect
the product by vacuum filtration of the cold mixture. Wash the
2
hydroxide are more expensive than SOCl and NaH used
4
in Nishiyama’s procedure, they offer improved and safer
handling on kilogram scale. The chiral catalyst 1 was
prepared on near kilogram scale reproducibly with good
quality. Efforts to streamline this process further are
underway.
2 2
filter cake with cold water (50 mL) and cold CH Cl (50 mL).
Dry the wet cake at 45 to 55 °C under reduced pressure for 18
to 20 h (or until the moisture content is <1% w/w) to afford 32.1
g (76.5 M%) of 3 as a white solid. mp ) 118-120 °C; moisture
1
content ) 0.8% w/w; H NMR (d -MeOH) δ: 8.18 (d, J ) 8.07
4
Hz, 2H), 8.05 (dd, J ) 7.39. 8.79, 15.46 Hz, 2H), 3.81 (m, 2H),
3
6
.66 (d, J ) 5.13 Hz, 4H), 1.93 (m, 2H), 0.93 (d, J ) 6.66 Hz,
-MeOH) δ: 165.97,
Exp er im en ta l Section
H), 0.88 (d, J ) 6.70 Hz, 6H); 13C NMR (d
4
Gen er a l. 2,6-Pyridinedicarboxylic acid, Vilsmeier reagent,
L-valinol, 40 wt % tetra-n-butylammonium hydroxide, and
potassium iodide were commercially available and used as is.
150.50, 140.33, 125.98, 63.08, 58.76, 30.23, 20.19, 19.50. Anal.
Calcd 60.51% C, 8.07% H, and 12.45% N for C17H27N O .
3
4
Found: 60.25% C, 7.78% H, 12.37% N.
Toluene, THF, and CH
2
Cl
2
were used without any further
(S,S)-2,6-Bis(4-isop r op yl-2-oxa zolin -2-yl)p yr id in e (5). A
1 L, three-neck flask was equipped with a mechanical stirrer,
an addition funnel, and a Claisen adapter fitted with a thermo-
couple probe and N inlet. The flask was flushed with N for at
purification or drying. THF was checked for peroxides prior to
use with indicator strips. The moisture content of THF should
be e0.05% w/w, and e 0.01% w/w for CH Cl . Moisture content
2 2
2
2
was determined by coulometric titration on a Mitsubishi CA-06
moisture meter on a weight/weight basis. Melting points were
obtained using a Thomas-Hoover melting point apparatus and
are uncorrected. Proton and carbon NMR were run on a Bruker
AC-300 spectrometer at 300 MHz for proton and 75 MHz for
least 15 min. Charge the flask with Vilsmeier reagent (19.82 g,
154.8 mmol, 2.6 equiv) and dry THF (100 mL). Stir the mixture
vigorously at 20 to 25 °C. Charge a slurry of 3 (20.00 g, 59.3
mmol, 1 equiv) in dry THF (100 mL) in one portion at 20 to 25
°C (an exotherm of 10 °C was observed, but quickly drops off).
Stir the reaction at 20 to 25 °C for 10 to 12 h to afford the
dichloride 4.20 Cool the reaction to -10 to -5 °C and charge the
addition funnel with TEA (50 mL, 358.7 mmol, 6 equiv) and dry
1
3
4 3
C in d -MeOH or CDCl . High-pressure liquid chromatography
was run under the following conditions: column ) YMC
ODS-A, 5 µm, 150 × 4.6 mm; flow rate ) 1 mL/min; detector )
2
1
2
50 nm; injection volume ) 10 µL; column temperature ) 25
THF (50 mL). Add the TEA/THF solution subsurface over 15
min, maintaining the temperature at -10 to 0 °C. Replace the
addition funnel with a reflux condenser and heat the reaction
°
3 2
C; mobile phase ) CH CN/H O (w/ 0.1% v/v TFA) according to
the timetable below:
2
2
to 50 ( 2 °C for 1-1.5 h. Cool the reaction to 20 to 25 °C and
add deionized H O (50 mL) to dissolve TEA‚HCl. Stir for 10 min,
2
time (min)
0
% CH3CN
% H2O
and then separate the two phases. Extract the aqueous phase
with toluene (50 mL), and combine the organics. The rich organic
can be held at 20-25 °C for up to 64 h without any loss in quality
or yield.
30
30
70
70
30
30
70
70
30
30
70
70
1
2
3
3
4
0
0
0
5
0
Charge the rich organic to a calibrated 1 L, three-neck flask
equipped with a mechanical stirrer, concentrator condenser, and
a thermocouple probe. Concentrate the rich organic to 25-35%
of the starting volume (final volume of ∼150 mL in this case)
with moderate stirring at 40-50 °C under reduced pressure (15-
The retention time is 3.8 min for 3, 7.8 min for 5, 20 min for
toluene, and 21.4 min for 4. Gas chromatography was done under
the following conditions: column ) Restek Rt-X1, 30 m, i.d. 0.32
2
0 inHg of vacuum). It is advisable to put a small amount of
BHT in the receiver flask to retard peroxide formation. Cool the
concentrate to 20-25 °C, and then add solid KI (0.98 g, 5.9
mm; T
T ) 10 °C/min. The retention time is 2.4 min for CH
min for THF, 4.8 min for TEA, 6.3 min for toluene. Compounds
i
) 50 °C (hold for 2 min); T
f
) 200 °C (hold for 10 min);
mmol) and a 40 wt % solution of tetra-n-butylammonium
∆
3
CN, 3.7
hydroxide in water (115.5 g of solution, 178 mmol).2
3,24
Heat the
1
5a
3b
biphasic mixture at 30 ( 2 °C with vigorous stirring for 10-12
h. (If the reaction stalls, an additonal charge of the base can be
made to push the reaction to completion. The reaction can be
left to run for up to 24 h without any loss in yield or quality).
1
and 5 have been reported in the literature.
S,S)-2,6-Bis(N,N′-3-h yd r oxy-2-isop r op yl)p yr id in ed ica r -
(
boxa m id e (3). A 500 mL, three-neck flask was equipped with
a mechanical stirrer, thermocouple probe, reflux condenser, and
N inlet. The flask was flushed with N for at least 15 min.
2 2
2
Dilute the reaction with H O (50 mL) and toluene (100 mL). Stir
the mixture for 10 min, and then separate the phases. Extract
the aqueous phase with toluene (100 mL), and combine the
organic phases. Wash the rich organic with 5% NaCl (100 mL).
Transfer the rich organic (total volume ∼600 mL) to a calibrated
Charge the flask with (chloromethylene)dimethylammonium
chloride (Vilsmeier reagent; 40.88 g, 319.4 mmol, 2.6 equiv) and
CH
and then add solid 2,6-pyridinedicarboxylic acid (20.41 g, 122.1
mmol) in one portion under a gentle stream of N (no exotherm
observed). Stir the resulting yellow solution at 30 to 40 °C for
2 2
Cl (200 mL). Stir the thick slurry efficiently at 20 to 25 °C,
2
L, three-neck flask equipped with a mechanical stirrer,
2
1
8
thermocouple probe, and concentrator condenser. Concentrate
1
2,19
5
-6 h under an atmosphere of N
2
.
Hold the solution of 2 for
the coupling reaction (the acid chloride solution is stable enough
at 20 to 25 °C to be held for 25 h without loss of potency).
A 2 L, three-neck flask was equipped with a mechanical
stirrer, addition funnel, and a Claisen adapter fitted with a
(20) HPLC indicates that all of 3 is consumed within 4 h. The
dichloride formation is complete when intermediate peaks at retention
times 15.3 and 15.8 min are <0.1 area % each. The retention time for
4
is 21.5 min.
(
21) Subsurface addition greatly reduces the amount of airborne
thermocouple probe and N
for 10 min. Charge the flask with L-valinol (30.56 g, 296.2
mmol, 2.4 equiv), CH Cl (32 mL), and 1 M NaOH (733 mL, 733
2
inlet. The flask was flushed with
TEA‚HCl and fogging in the pot. This was accomplished by attaching
a piece of Teflon tubing to the tip of the addition funnel.
N
2
2
2
(22) The reaction is deemed complete when HPLC analysis gives 4
+
mmol, 6 equiv). Cool the mixture to 0-5 °C. Charge the addition
funnel with the acid chloride 2. Add the solution of 2 subsurface
over 30 to 40 min, maintaining the temperature at 0-10 °C (the
at g94 area %. LCMS (ESI) m/z (%): 373.8 (MH , 100), 375 (MH + 2,
3
1
7%), 377 (MH + 4, 17%). Note that the LCMS used was calibrated at
Da off.
(23) The amounts of tetra-n-butylammonium hydroxide and KI are
based on the input of 3.
(
18) Alternatively, the dicarboxylic acid can be added as a slurry in
a portion of the CH Cl
19) If the reaction stalls, fresh charges of Vilsmeier reagent can be
made.
(24) wt % Tetra-n-butylammonium hydroxide tends to solidify at
<30 °C, and usually requires warming before use to liquify it. A 55 wt
% solution is available that reportedly does not solidify at ambient
temperatures.
2
2
.
(

1
060 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
the rich organic to approximately 25% of the starting volume
150 mL) at 40-50 °C under reduced pressure (15-20 inHg
addition of ethylene is exothermic, and the temperature should
be maintained at 20 ( 10 °C. Upon completion, displace the
2
ethylene gas with N or argon, and filter the solution through
(
vacuum). Add toluene (50 mL) at 40-50 °C. Gradually add
n-heptane (300 mL, 1.5: 1 ratio with pot volume) at 40-50 °C
with good stirring. Heat the resulting slurry to 75 to 80 °C to
afford a clear solution, and hold at this temperature range for
Whatman 4 paper. Equip a 10 L, three-neck flask with a
mechanical stirrer, thermocouple probe, and N inlet. Charge
2
the flask with n-heptane (5.5 L). Add the reaction mixture to
n-heptane over 30 min with good stirring to allow for rapid
dispersion of the solution into the n-heptane. After the addition
is complete, stir the slurry for 1 h. Filter the slurry on Whatman
4 paper under vacuum, using portions of the mother liquor to
rinse out the crystallizing flask as needed. Wash the filter cake
with with n-heptane (600 mL), and deliquor. Dry the product
at 35 to 45 °C under 25-30 inHg vacuum to give 1 in a yield of
69.4 g (83.4 M%). The yield is corrected for 4.9% leftover 5. mp
2
5
1
0 min. Allow the solution to cool to 20-25 °C (5 begins to
precipitate at <60 °C). When the internal temperature reaches
0-25 °C, cool to 0-5 °C, and stir for 1 h. Filter the slurry cold
2
under vacuum, rinsing the flask with mother liquor as needed.
Wash the filter cake with n-heptane (100 mL). The product was
deliquored and then dried at 45-50 °C under 25-30 inHg
vacuum for 8 h (or until the loss on drying is <1%) to give 14.4
2
0
g (81 M%) of 5 as fine, colorless rods. mp ) 151-154 °C; [R]
D
1
4 1
) 210-225 °C; 1H NMR (CDCl
)
-110° (c 0.70, CH
2
Cl
2
);
H NMR (CDCl
3
) δ: 8.21 (d, J )
3
) δ: 7.89 (s, 3H, pyridine
7
9
6
1
.66 Hz, 2H), 7.86 (t, J ) 7.89, 15.57 Hz, 1H), 4.53 (q, J ) 8.15,
.47, 17.63 Hz, 2H), 4.17 (m, 4H), 1.87 (m, 2H), 1, 05 (d, J )
protons), 5.25 (m, 2H, ethylene), 4.78-4.97 (m, 2H, 2 x OCH
2
and ethylene), 4.43 (m, 2H, NCH), 2.48 (m, 2H, isopropyl
methines), 1.00 (d, J ) 7.2 Hz, 6H, isopropyl methyls), 0.78 (d,
.68 Hz, 6H), 0.94 (d, J ) 6.71 Hz, 6H); 13C NMR (CDCl
) δ:
3
61.84, 146.56, 140.19, 136.82, 125.38, 72.55, 70.61, 32.50; IR
J ) 7.2 Hz, 6H, isopropyl methyls); 13C NMR (CDCl
3
) δ: 163.70,
-
1
(
KBr): 1643 cm . Anal. Calcd 67.75% C, 7.69% H, 13.94% N
145.90, 133.46, 123.30, 71.70, 70.90, 70.50, 19.10, 14.30; IR
-
1
for C17 . Found: 67.76% C, 7.66% H, 13.90% N.
H
23
N
3
O
2
(KBr): 2960, 1598, 1501, 1403, 1388, 1342, 1250, 968 cm
.
tr a n s-Dich lor or u th en iu m ((S,S)-2,6-Bis(4-isop r op yl-2-
oxa zolin -2-yl)p yr id in e)(eth ylen e) (Ru P ybox-ip ), 1. Equip
a 1 L, three-neck flask with a mechanical stirrer, thermocouple
probe, condenser, and N inlet/outlet connected to a mineral oil
2
bubbler. A bath for cooling is placed under the flask. Charge
Ack n ow led gm en t. The authors thank The Bristol-
Myers Squibb Pharmaceutical Research Institute for
supporting this work, Dr. B. Karcher for assistance with
the LCMS, Mr. J . Garcia and Ms. E. Khattak for
technical support, and Dr. T. Vu for reviewing this
manuscript.
ligand 5 (50.0 g, 165.8 mmol) and dichloro(p-cymene)ruthenium-
(II) dimer (49.1 g, 80.17 mmol) to the flask. Flush the flask with
N
2
or argon for at least 15 min. Charge in HPLC grade CH Cl
2
2
(
550 mL), and stir the mixture for 5-10 min to afford a solution
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for 3. This material is available free of charge via the Internet
at http://pubs.acs.org.
(a 5 °C exotherm is observed). Bubble ethylene gas through the
1
7
solution at a moderate rate until the reaction is complete. The
(25) 5 is stable in toluene at 100 °C for up to 48 h.
J O005652K