Efficient ruthenium carbenoid-catalyzed cross-metathesis of allyl halides with olefins

Article abstract of DOI:10.1021/ol026235s

(Matrix presented) Cross-metatheses of allyl halides and terminal olefins mediated by catalyst 2 are reported and showed good yield and excellent E/Z selectivity. The application of these compounds as alkylating reagents is also demonstrated.

Full text of DOI:10.1021/ol026235s

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2723-2726
Efficient Ruthenium Carbenoid-Catalyzed
Cross-Metathesis of Allyl Halides with
Olefins
Bingcan Liu, Sanjoy K. Das, and Rene´ Roy*
Department of Chemistry, Center for Research in Biopharmaceuticals,
UniVersity of Ottawa, Ottawa, ON K1N 6N5, Canada
rroy@science.uottawa.ca
Received May 23, 2002
ABSTRACT
Cross-metatheses of allyl halides and terminal olefins mediated by catalyst 2 are reported and showed good yield and excellent E/Z selectivity.
The application of these compounds as alkylating reagents is also demonstrated.
Functionalized allyl halides are valuable synthetic synthons.
They are widely used as N-, O-, S-, and C-alkylating reagents
in organic synthesis and the chemistry industry.1 How-
ever, the synthesis of these simple building blocks is not
straightforward and may suffer from harsh conditions, long
synthetic sequences, and low overall yields.2 Thus, it is
necessary to develop more efficient methods for their
preparation.
The past decade has witnessed a great development in
olefin metathesis. The discovery of ruthenium-carbene
catalysts 1 and 2 has attracted a great deal of attention.3
In particular, catalyst 2, with its high stability, broad
functional group tolerance, and excellent stereoselectivity,
has gained widespread application.4 Thus, one can readily
foresee that cross-metathesis (Scheme 1) of allyl halides
with alkenes would provide a promising method for the
preparation of substituted allyl halides, which could serve
as a handle for further functionalization. So far, only a
few examples of cross-metathesis involving allyl halides have
(1) (a) Nystro¨m, J.-E.; Ba¨ckvall, J.-E. J. Org. Chem. 1983, 48, 3947-
3950. (b) Sheffy, F. K.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 7171-
7175. (c) Sheffy, F. K.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 4833-
4840. (d) Shigeo, K.; Shinya, F.; Sachihiko, I. Tetrahedron Lett. 1988, 29,
1173-1176. (e) Baruah, M.; Baruah, A.; Prajapati, D.; Sandhu, J. S. Synlett
1998, 10, 1083-1084. (f) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55,
3917-3922. (g) Fakajima, M.; Saito, M.; Hashimoto, S. Chem. Pharm.
Bull. 2000, 48, 306-307.
(2) (a) Gershon, H.; Shanks, L.; Gawiak, D. E. J. Med. Chem. 1976, 19,
1069-72. (b) Sotter, P. L.; Hill, K. A. Tetrahedron Lett. 1975, 21, 1679-
1682. (c) Mornet, R.; Gouin, L. Synthesis 1977, 11, 786-787. (d) Heasley,
G. E.; McCully, V. M.; Wiegman, R. T.; Heasley, V. L.; Skidgel, R. A. J.
Org. Chem. 1976, 41, 644-648. (e) Hedge, S. G.; Vogel, M. K.; Saddle;
J.; Hringo, T.; Rockwell, N.; Haynes, R.; Oliver, M.; Wolinsky, J.
Tetrahedron Lett. 1980, 21, 441-444. (f) Cooper, R. D. G. Tetrahedron
Lett. 1980, 21, 781-784. (g) Dauben, W. G.; Kohler, B.; Roesle, A. J.
Org. Chem. 1985, 50, 2007-2010. (h) Schmid, G. H.; Wolkoff, A. W. J.
Org. Chem. 1967, 32, 254-254.
(3) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b)
Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153-3155. (c) Chatterjee,
A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. (d) Diver, S. T.;
Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 5106-5109. (e) Roy, R.;
Dominique, R.; Das, S. K. J. Org. Chem. 1999, 64, 5408-5412. (f) Roy,
R.; Das, S. K. Chem. Commun. 2000, 519-529. (g) Dominique, R.; Liu,
B.; Das, S. K.; Roy, R. Synthesis 2000, 6, 862-868.
(4) (a) Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int.
Ed. 2001, 40, 1277-1279. (b) Chatterjee, A. K.; Morgan, P. J.; Scholl, M.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783-3784. (c) Lee, C. W.;
Choi, T. L.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 124, 3224-3225. (d)
Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 807-
810.
10.1021/ol026235s CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002

Scheme 1
Table 1. Results of Cross-Metathesis of Allyl Halides with
Terminal Alkenes
entry olefin allyl halide conditionsa product
yield (E/Z)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4b
4c
4d
3a
3b
3c
3a
3b
3d
3a
3a
3a
B
B
B
A
A
A
B
B
B
5
75% (>20:1)
56% (>20:1)
25% (ND)b
51% (4:1)
6
7
5
6
20% (4:1)b
7a
8
64% (∼5:1)b,c
65% (17:1)
55% (15:1)
72% (>20:1)
9
10
a Method A: N2, CH2Cl2, 20 mol % 1, reflux, 6 h. Method B: N2,
CH2Cl2, 10 mol % 2, reflux, 6 h. b Yields estimated on the basis of
1H NMR data of crude reaction mixtures. c Prepared from 5-iodo-1-
pentene.
been reported.4d,5 Unfortunately, the reactions using catalyst
15 could not be reproduced in our hands. Herein we report
catalyst 2-mediated efficient cross-metathesis reactions of
olefin-containing sugars, unnatural amino acids, and precur-
sors thereof.
the E isomer showed a medium to strong absorption band at
968 cm-1 and the Z isomer did not show absorption in this
range.2b The yields from allyl chloride to allyl iodide
decreased dramatically (entries 1-5), presumably due to the
increased coordinating ability of iodide toward ruthenium
or else by oxidative insertion.
It has been widely reported that catalyst 2 has demon-
strated much higher E/Z selectivity compared to 1. To
investigate the suitability of catalyst 2 for cross-metathesis
of allyl halides, the known perbenzylated O-allyl galacto-
pyranoside 4a6,7 was subjected to reaction with different allyl
halides under varying conditions (Scheme 2). First, the cross-
This chelating effect was also hypothesized by Grubbs et
al.4a with neighboring carbonyl groups. However, catalyst 2
greatly dampened this chelating effect with improved yield
and E/Z selectivity compared to catalyst 1. Interestingly,
when the iodide positioning was moved away, such as in
entry 6 with 5-iodo-1-pentene, cross-metathesis provided 7a
in 64% yield even when catalyst 1 was used. Attempts to
vary the reaction conditions with allyl iodide 3c provided
no improvement in the reaction yields (<10%) when the
catalysts were added in portions or the reactions run at room
temperature.
Scheme 2
Cross-metathesis of galactosides 4b,7 4c,9 and 4d10 (Table
1) gave similar yields and stereoselectivities. These results
indicated that the nature of the sugar protecting groups
together with the anomeric configurations did not play a
significant role in terms of stereo and electronic effects. In
all the cases using catalyst 2, less than 5% of homodimers
were observed that could be recycled if desired.
It is worth mentioning that C-linked galactoside 10,
obtained from cross-metathesis of 4d and allyl chloride, is a
very useful alkylating agent that could not be prepared easily
through other routes. Presently, C-linked glycosides have
gained tremendous attention because of their biological
stability. Thus 10 can easily be further functionalized to other
C-linked glycomimetics.11
metathesis of 4a with allyl chloride in CH2Cl2 was performed
under N2 at reflux for 6 h to give compound 5 in 75% yield
(Table 1) with a greater than 20:1 E/Z ratio. Since the NMR
signals for the vinyl protons were obscured, the E/Z identity
was determined on the basis of 13C NMR. For the E isomer,
the allylic chloride-substituted carbon appeared at around δ
44 ppm, while the Z isomer appeared upfield by about 5
ppm (δ 38 ppm) due to the γ effect.3d,8 From the IR spectrum,
(8) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy. High-
Resolution Methods and Applications in Organic Chemistry and Biochem-
istry; VCH: New York, 1987; p 192.
(9) Winnik, F. M.; Carver, J. P.; Krepiinski, J. J. J. Org. Chem. 1982,
47, 2701-2107.
(5) Blanko, O. M.; Castedo, L. Synlett 1999, 5, 557-558.
(6) Takano, T.; Nakatsubo, F.; Murakami, K. Carbohydr. Res. 1990, 203,
(10) Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479-
1482.
341-342.
(7) Mereyala, H. B.; Guntha, S. Tetrahedron Lett. 1993, 34, 6929-
(11) Du, Y.; Linhardt, R. J.; Vlahou, I. R. Tetrahedron 1998, 54,
9913.
6930.
2724
Org. Lett., Vol. 4, No. 16, 2002

Table 2. Cross-Metathesis with Allyl Chloride (3a)a
Scheme 4
a Conditions: 10 mol % 2, CH2Cl2, N2, reflux, 6 h.
temperature. The monodecarboxylation of 17 proved to be
problematic. Due to the presence of the carbohydrate moiety,
common procedures involving DMSO at high temperatures
failed.12,13 Eventually, ester 17 was hydrolyzed first by
refluxing in 2 M KOH/MeOH for 1 day and then decar-
boxylated in acetonitrile.14 Interestingly, the acetonitrile had
to be degassed and the catalyst CuCl could not be used in
more than 25 mol %.15 Finally, hydrogenolysis provided 18
in a good yield. This fully deprotected 18 can be a useful
building block for the synthesis of high-order glycodendrim-
ers.16
To further investigate the scope of this procedure, three
noncarbohydrate substrates were chosen for this pur-
pose (Table 2). Under the above conditions with catalyst 2,
compound 11a reacted with allyl chloride to generate product
12a in good yield and with excellent stereoselectivity.
The second entry is an interesting one, since both the
electron-deficient tert-butyl acrylate (11b) and allyl chloride
(3a) were poor reacting partners toward catalyst 1. How-
ever, with catalyst 2, the reaction provided a reasonable
yield and remarkable stereoselectivity with the trans isomer
being the only detectable stereoisomer observed. Compound
12c, a cross-metathesis product from allyl chloride and
allylglycine, is an interesting compound, which can be further
functionalized for the synthesis of peptidomimetics.
In conclusion, cross-metathesis of allyl halides and mono-
substituted olefins mediated by catalyst 2 has been studied
Scheme 5a
To provide an application of these allyl halides, compound
5 was selected for O-alkylation (Scheme 4). In this case,
1,4-dihydroxymethyl benzene 13 was treated with NaH in
DMF and then reacted with 5 to provide 14 in 55% yield at
room temperature.
In the second case, the C-alkylating utility of 5 was tested
(Scheme 5). After treatment with NaH in dry THF, diethyl
malonate 16 reacted smoothly with 5 to provide the double-
alkylated malonate ester 17 in an excellent yield at room
Scheme 3
a Conditions: (a) THF, NaH, rt, 4 h, 90%; (b) 2 M KOH, MeOH,
reflux, 1 day, N2, 85%; (c) 20 mol % CuCl, 24 h, CH3CN, N2,
82%; (d) 10% Pd-C, ethanol, 24 h, 95%.
Org. Lett., Vol. 4, No. 16, 2002
2725

and was shown to occur in moderate to good yields and with
excellent E/Z selectivity. The utility of these compounds has
also been explored.
Acknowledgment. We thank NSERC for financial sup-
port. B.L. thanks OGSST for a graduate scholarship. We are
also thankful to Strem Chemicals (MA) for a generous supply
of catalyst 2.
(12) March, J. AdVanced Organic Chemistry, 3rd ed.; Wiley-Inter-
science: New York, 1985; p 653f and literature cited therein.
(13) Langlois, P.; Soucy, P.; Dory, Y. L.; Deslongchamps, P. Can J.
Chem. 1996, 74, 129-143.
Supporting Information Available: Experimental pro-
cedures with spectroscopic data for compounds 5-7a, 8-10,
12a-c, 14, 17, and 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Kende, A. S.; Dong, H.; Mazur, A. W.; Ebetino, F. H. Tetrahedron
Lett. 2001, 42, 6015-6018.
(15) Graham, S. L.; Scholz, T. H. Chem. Commun. 1986, 1029-
1031.
(16) Roy, R. Curr. Opin. Struct. Biol. 1996, 6, 692-702.
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