An efficient method for removal of ruthenium byproducts from olefin metathesis reactions

Article abstract of DOI:10.1021/ol027423l

(Matrix presented) Sequential treatment of the ring-closing metathesis reaction products with silica gel, activated carbon (50 equiv wt relative to the crude products), and column chromatography on silica gel efficiently removed dark brown ruthenium bypro

Full text of DOI:10.1021/ol027423l

ORGANIC
LETTERS
2
003
Vol. 5, No. 4
31-533
An Efficient Method for Removal of
Ruthenium Byproducts from Olefin
Metathesis Reactions
5
Jong Hyun Cho and B. Moon Kim*
School of Chemistry and Center for Molecular Catalysis, College of Natural Sciences,
Seoul National UniVersity, Seoul 151-742, Korea
kimbm@snu.ac.kr
Received December 7, 2002
ABSTRACT
Sequential treatment of the ring-closing metathesis reaction products with silica gel, activated carbon (50 equiv wt relative to the crude
products), and column chromatography on silica gel efficiently removed dark brown ruthenium byproducts from the reaction mixture. After
this treatment, colorless compounds could be obtained with a ruthenium level of 0.06−0.53 µg per 5 mg of product.
Olefin metathesis has emerged as a powerful tool in the
preparation of cyclic organic compounds. Ruthenium cata-
lysts 1, 2, and 3 have been widely used for ring-closing olefin
the ruthenium byproducts completely from the desired
product(s) even after purification on silica gel column
chromatography several times. The metal complex remaining
in the product(s) may cause isomerization or decomposition
1
metathesis (RCM), ring-opening metathesis polymerization
ROMP), and acyclic cross metathesis.2-4
during the purification of the product(s). We have been
5
(
involved in the synthesis of cyclic peptide analogues using
6
the RCM and we were particularly alarmed by the fact that
a large amount of the ruthenium catalyst (30-50 mol %
relative to substrates) was required for the optimal yields of
cyclic peptide analogues. In the case where a large amount
of the ruthenium catalyst was employed, a considerable
portion of the ruthenium byproducts remained in the product,
6
culminating in toxicity during bioassays. This prompted us
One major concern in the use of olefin metathesis reactions
especially in connection with the synthesis of biologically
active compounds is the generation of colored, toxic ruthe-
nium metal byproducts. It is extremely difficult to remove
(
3) (a) Nguyen, S. T.; Jonson. L. K.; Grubbs, R. H. J. Am. Chem. Soc.
1992, 114, 3974-3975. (b) Nguyen, S. T.; Grubbs. R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1993, 115, 9858-9859. (c) Fu, G. C.; Nguyen, S. T.;
Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856-9857. (d) Miller, S. J.;
Kim, S. H.; Chen, Z. R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108-
2109 (e) Randall, M. R.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem.
Soc. 1995, 117, 9610-9611. (f) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1995, 117, 5503-5511. (g) Dias, E. L.;
Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897. (h) Clark, T. D.;
Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364-12365.
(4) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Itoh, T.; Mitsukura, K.; Ishida, N.; Uneyama, K. Org. Lett.
2000, 2, 1413-1434. (c) Lera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765-
2786. (d) Smith, A. B., III; Kozmin, S. A.; Adams, C. M.; Paone, D. V. J.
Am. Chem. Soc. 2000, 122, 4984-4985.
(1) For a review see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc.
Chem. Res. 1995, 28, 446-452. (b) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2037-2056. (c) Amstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371-388. (d) Grubbs, R. H.; Chang, S. B.
Tetrahedron 1998, 54, 4413-4450. (e) F u¨ rstner, A. Angew. Chem., Int.
Ed. Engl. 2000, 39, 3012-3043. (f) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29.
(2) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c) Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606-9614.
(5) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137-
4140.
(6) Unpublished results from this laboratory.
(
3
d) Blackwell, H. E.; Grubbs, R. H. Angew. Chem., Int. Ed. 1998, 37, 3281-
284.
1
0.1021/ol027423l CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003

to look for an efficient method for the removal of the
ruthenium byproducts.
Several groups including Grubbs, Paquette, and Georg
Table 1. Ruthenium Levels in 6 (µg/5 mg) after the
5
7
8
Purification by Method A or Ba
have recently reported methods for removing ruthenium
byproducts formed from the Grubbs reagent. The Grubbs’
method involves conversion of the ruthenium byproducts into
water-soluble ruthenium phosphine complexes, using quite
expensive tris(hydroxymethyl)phosphine, and the Paquette
group utilized oxidation of the ruthenium species with
activated carbon
(equiv wt)
ruthenium
method
entry
(µg/5 mg)
(yield %)
1
2
3
4
5
6
7
8
9
-
-
100
10
20
50
100
50
71.58 ( 0.33
9.56 ( 0.05
2.89 ( 0.01
5.23 ( 0.03
5.08 ( 0.02
1.72 ( 0.02
1.52 ( 0.02
0.36 ( 0.01
0.30 ( 0.01
- (95)
- (95)
- (93)
A (92)
A (90)
A (92)
A (90)
B (94)
B (91)
4
Pb(OAc) . Both methods are associated with some significant
drawbacks resulting from the introduction of expensive or
toxic reagents to remove the ruthenium species. Georg and
co-workers dealt with the ruthenium metal species by
100
3
treatment with Ph PO or DMSO. Also Dixneuf used carbon
black to clean up ionic liquid after RCM reaction for the
purpose of recycling the ionic liquid. Optimized conditions
of these methods allowed for the reduction of the ruthenium
levels down to approximately 1-2 µg per 5 mg of product-
a
Method A: Treatment of crude product with activated carbon (equiv
9
wt of catalyst 1) followed by column chromatography on silica gel. Method
B: Adsorption on silica gel followed by filtration and treatment with
activated carbon (equiv wt of the crude product 5), then silica gel column
chromatography.
(
s).
During the study on the synthesis of natural cyclic
pentapeptide analogues such as {cyclo(Phe-Leu-Pro-Ala-
2
0, 50, and 100 equiv wt relative to catalyst 1). The
10
ruthenium levels in 5 mg of purified cyclic compound 6 were
measured by inductively coupled plasma mass spectrometry
Ala)} using Grubbs catalyst 1, we were in search of a more
effective and environment-friendly method for removal of
the ruthenium byproducts. Here we wish to report such a
method through a sequence involving adsorption and filtra-
1
2
(ICP-MS). We found that the amount of ruthenium in the
crude product 5 was 71.58 µg/5 mg without any purification
(entry 1), and 9.56 µg/ 5 mg after column chromatography
on silica gel only (entry 2). The number went down to 2.89
µg/5 mg after treatment of crude 5 with 100 equiv of
activated carbon for 12 h (entry 3). However, when the
activated carbon treatment was followed by silica gel column
chromatography, the ruthenium levels decreased from 5.23
µg to 1.52 µg per 5 mg of the products after treatment with
increasing amounts of activated carbon (Table 1, entries
11
tion on silica gel/activated carbon /column chromatography
on silica gel. This sequence was extremely efficient in
reducing the ruthenium level below 1 µg per 5 mg of the
reaction products.
We used diethyl diallylmalonate as a control substrate and
8
followed the reported procedure of RCM as shown in
Scheme 1. The RCM of 4 was carried out by using 10 mol
4
-7). The yields of the products were uniformly high after
treatment with activated carbon and silica gel.
Scheme 1
Even though the ruthenium level in entry 7 of Table 1
was comparable to the best method available in the litera-
5,7,8
ture,
we continued our search for the conditions, aspiring
toward further minimization of the ruthenium level. Indeed,
insertion of one more step before the activated carbon
treatment brought the ruthenium level further down. Thus
after RCM the crude product 5 was adsorbed on silica gel
and passed through a silica gel pad, and the filtrate was
treated with activated carbon for 12 h at room temperature.
The residue was purified via silica gel column chromatog-
raphy to yield colorless 6 (Method B). Under these
conditions, the residual ruthenium level was reduced to 0.36
and 0.30 µg in 5.0 mg of 6 with use of 50 and 100 equiv of
%
of ruthenium catalyst 1 to provide dark brown crude
reaction product 5. At first the crude product was directly
treated with activated carbon for 12 h. After filtration of the
activated carbon, the filtrate was purified with column
chromatography on silica gel to give colorless compound 6
1
3
(Method A). As summarized in Table 1, we examined the
residual ruthenium levels of the purified products upon
treatment with increasing amounts of activated carbon (10,
(
12) Reference 8 describes in detail the sampling procedure for deter-
mination of the levels of residual ruthenium in the RCM products.
13) Procedure for RCM of 4 and purification of crude product 5 with
(
(
7) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.;
Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259-1261.
8) Ahn, Y. M.; Yang, K. L.; Georg, G. I. Org. Lett. 2001, 3, 1411-
413.
9) S e´ meril, D.; Olivier-Bourbigou, H.; Bruneau, C.; Dixneuf, P. H.
silica gel and activated carbon (method B): To a stirred solution of 300
mg of diethyl diallylmalonate (4, 1.25 mmol) in degassed dichloromethane
(500 mL) was added catalyst 1 (100 mg, 10 mol %) under argon atmosphere
at room temperature. After the reaction mixture was stirred for 2 h, the
dark solution was adsorbed on silica gel (1.0 g, 10 equiv wt, relative to
catalyst 1) and passed through a pad of silica gel (hexane:EtOAc ratio 6:1
to 2:1). The filtered solution was stirred with activated charcoal (12.0 g,
50 equiv wt of 5) for 12 h. After the carbon was filtered, the filtrate was
concentrated in vacuo and purified on a silica gel chromatographic column
(hexane:EtOAc ratio 5:1) to provide product 6 as a colorless oil in 90%
yield.
(
1
(
Chem. Commun. 2002, 164-147.
(
10) Schmidt, U.; Langner, J. J. Peptide Res. 1997, 49, 67-73.
(11) (a) The Merck Index; Budavari, S., Ed.; Merk: Rahway, NJ, 1989;
p 1814. Activated carbon was used chiefly for clarifying, deodorizing,
decolorizing. and filtering. (b) Activated carbon used in this study was from
Aldrich Chemical Co. Inc. Darco G-60, -100 mesh, powder.
532
Org. Lett., Vol. 5, No. 4, 2003

activated carbon, respectively (Table 1, entries 8 and 9). This
result showed that Method B was slightly more effective than
Method A. It is of particular note that this protocol is superior
for the removal of ruthenium byproducts compared to
previously reported methods5,7,8 (ca. 1.03-1.55 µg in 5.0 mg
of the product) with about a 3- to 5-fold decrease in
ruthenium levels as shown in Table 2.
Table 4. Amount of Remaining Ruthenium Species (µg/5 mg
of Product) Following Method B
Table 2. Comparison of Our Method with Others’ Best Results
on Remaining Ruthenium Levels in RCM Products (µg/5 mg)
ruthenium
entry
methodsa
equivb
time
(µg/5 mg)
1
2
3
4
5
6
P(CH2OH)3
Pb(OAc)4
DMSO
Ph3PO
Method A
Method B
86
1.50
100
50
100c
100c
20 min
overnight
12 h
24 h
12 h
1.03 ( 0.04
1.55 ( 0.04d
1.34 ( 0.02
1.27 ( 0.01
1.52 ( 0.01
0.30 ( 0.01
12 h
a
Three methods are Grubbs (entry 1), Paquette (entry 2), and Georg
b
(
entries 3 and 4), respectively. Equivalent of P(CH2OH)3, Pb(OAc)4,
DMSO, Ph3PO, and carbon related to Grubbs catalyst. Equivalent of carbon
related to crude mixture (5). The value was prorated to fit the scale with
c
d
other data.
To monitor optimal activated carbon treatment time for
Method B, each reaction mixture was treated with 50 equiv
wt of activated carbon relative to the crude filtrates at a given
time period and the remaining ruthenium in the purified RCM
and 93% yields, with ruthenium levels at 0.53 and 0.30 µg/5
mg, respectively (entry 1, Table 4). In the case of N,N-diallyl
p-toluenesulfonamide 7 with 10 mol % of catalyst 1, the
ruthenium level was 0.47 µg/5 mg (entry 2). When RCM of
various amino acid or peptide derivatives 9, 11, and 13 were
carried out in the presence of 50 mol % of catalyst 1,
ruthenium levels of 0.18, 0.23, and 0.06 µg in 5.0 mg of 10,
1
2
products was analyzed by ICP-MS as outlined in Table 3.
Table 3. Ruthenium Levels of 6 (µg/5 mg) According to
Method B Depending upon Treatment Time of Activated
Carbon (50 equiv wt to 5)
1
2, and 14, respectively, were obtained (entries 3-5, Table
treatment
time (h)
ruthenium
yield
(%)
4
). The ruthenium species in entry 5 (0.06 µg/5 mg of
entry
(µg/ 5 mg)
product) is by far the lowest reported level.
1
2
3
4
5
1
3
6
12
24
7.00 ( 0.20
1.62 ( 0.02
0.82 ( 0.01
0.36 ( 0.01
0.34 ( 0.01
95
94
90
92
90
In summary, a most efficient protocol has been developed
for removal of ruthenium byproducts generated from Grubbs
catalyst 1 during RCM reaction, using a sequence of
adsorption and filtration on silica gel, treatment with activated
carbon, and column chromatography on silica gel. This
methodology was successfully applied to the RCM with use
of 10, 30, and 50 mol % of catalyst 1 on various substrates.
By using the optimal conditions, the residual ruthenium levels
in the RCM products were reduced to 0.06-0.53 µg/5 mg
of products without detectable loss of the products. Another
advantage of this protocol is that activated carbon can be
easily handled and conveniently removed from the RCM
products through filtration.
We found that the best result was obtained from the 24 h
treatment (entry 5), although treatment for 12 h gave an
almost equivalent result (entry 4). A ruthenium level close
to that obtained via previously reported methods was
achieved after a 3 h treatment (entry 2). In all cases yields
of the purified product were over 90%.
With this efficient protocol for removal of the residual
ruthenium in the RCM product in hand, we screened this
method against conditions using an excessiVe amount of
catalyst 1 with various substrates. When RCM of diethyl
Acknowledgment. The authors thank the Korea Science
and Engineering Foundation through the Center for Molec-
ular Catalysis at Seoul National University and the Brain
Korea 21 Program of the Ministry of Education, Korea for
the BK21 postdoctoral fellowship to J.H.C.
2
2
,2-diallylmalonate was carried out at room temperature for
h with 30 and 50 mol % of catalyst 1 and the crude product
was cleaned up with 50 equiv wt of activated carbon at room
temperature for 12 h, a colorless oil 6 was obtained in 94%
OL027423L
Org. Lett., Vol. 5, No. 4, 2003
533