Rhodium-catalyzed direct C - H addition of 4,4-dimethyl-2-oxazoline to alkenes

Article abstract of DOI:10.1021/ol049417q

A new method for the preparation of 2-substituted oxazolines by rhodium-catalyzed coupling of alkenes with 4,4-dimethyl-2-oxazoline is reported. The oxazoline products are obtained in good yield with excellent selectivity for the linear product. A variety of alkene substitution patterns and functional groups are tolerated. This procedure represents an attractive alternative to hydroesterification because it does not involve the manipulation of CO gas.

Full text of DOI:10.1021/ol049417q

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1685-1687
Rhodium-Catalyzed Direct C−H Addition
of 4,4-Dimethyl-2-oxazoline to Alkenes
Sean H. Wiedemann, Robert G. Bergman,* and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California and DiVision of Chemical Sciences, Lawrence Berkeley
National Laboratory, Berkeley, California 94720
bergman@cchem.berkeley.edu
Received March 29, 2004
ABSTRACT
A new method for the preparation of 2-substituted oxazolines by rhodium-catalyzed coupling of alkenes with 4,4-dimethyl-2-oxazoline is reported.
The oxazoline products are obtained in good yield with excellent selectivity for the linear product. A variety of alkene substitution patterns
and functional groups are tolerated. This procedure represents an attractive alternative to hydroesterification because it does not involve the
manipulation of CO gas.
New methods for the one-carbon elongation of alkenes
employing a synthon other than toxic CO gas, would be
broadly useful in synthetic chemistry.1 Known examples
make use of formic acid,2,3 formates4-7 and formamides6,8
(eq 1). Early work was limited to ethylene3,4 because of poor
However, most of these are limited to activated alkenes5,6
or substrates bearing a pendant directing group.7,8 A currently
unexplored strategy for addressing this reaction manifold
involves the use of a formate derivative with a C-N double
bond. A C1 fragment without a C-O double bond cannot
undergo decarbonylation, which is otherwise a significant
pathway for reagent decomposition.9 Oxazolines were chosen
for this work because they are a well-studied class of
heterocycles used as synthetic intermediates,10 protecting
groups,11 and chiral ligands.12 We now wish to report a
general and efficient method for the functionalization of
simple alkenes that operates by the metal-catalyzed C-H
reactivity or side reactions, but more recent methods have
provided significant improvements in yield and selectivity.2
(1) Wang, L.; Floreancig, P. Org. Lett. 2004, 6, 569-572.
(5) Nahmed, E. M.; Jenner, G. J. Mol. Catal. 1990, 59, L15-L19. Suzuki,
Y.; Katoh, H.; Ishii, Y.; Hidai, M. J. Mol. Catal. A: Chem. 1995, 95, 129-
133.
(6) Kondo, T.; Okada, T.; Mitsudo, T. Organometallics 1999, 18, 4123-
4127.
(7) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750-751.
(8) Ko, S.; Han, H.; Chang, S. Org. Lett. 2003, 5, 2687-2690.
(9) Jenner, G. Appl. Catal., A 1995, 121, 25-44.
(10) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. Engl. 1976,
15, 270-281; Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837-
860.
(11) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.
Meyers, A. I.; Temple, D. L.; Haidukew, D.; Mihelich, E. D. J. Org. Chem.
1974, 39, 2787-2793.
(12) Ghosh, A. K.; Packiarajan, M.; Cappiello, J. Tetrahedron: Asym-
metry 1998, 9, 1-45. Gomez, M.; Muller, G.; Rocamora, M. Coord. Chem.
ReV. 1999, 195, 769-835.
(2) Simonato, J. P.; Walter, T.; Metivier, P. World Patent 0105737, 2001.
Simonato, J. P.; Walter, T.; Metivier, P. World Patent 0105738, 2001.
Simonato, J. P.; Walter, T.; Metivier, P. J. Mol. Catal. A: Chem. 2001,
171, 91-94. Simonato, J. P. J. Mol. Catal. A: Chem. 2003, 197, 61-64.
(3) Burk, P. L.; Pruett, R. L. Euro. Patent 0092350, 1983.
(4) Ueda, W.; Yokoyama, T.; Morikawa, Y.; Morooka, Y.; Ikawa, T. J.
Mol. Catal. 1988, 44, 197-200. Keim, W.; Becker, J. J. Mol. Catal. 1989,
54, 95-101. Lavigne, G.; Lugan, N.; Kalck, P.; Soulie, J. M.; Lerouge,
O.; Saillard, J. Y.; Halet, J. F. J. Am. Chem. Soc. 1992, 114, 10669-10670.
Castanet, Y.; Mortreux, A.; Petit, F.; Legrand, C. Euro. Patent 449693, 1993.
Legrand, C.; Castanet, Y.; Mortreux, A.; Petit, F. J. Chem. Soc., Chem.
Commun. 1994, 1173-1174. Grevin, J.; Kalck, P. J. Organomet. Chem.
1994, 476, C23-C24. Lugan, N.; Lavigne, G.; Soulie, J. M.; Fabre, S.;
Kalck, P.; Saillard, J. Y.; Halet, J. F. Organometallics 1995, 14, 1712-
1731. Fabre, S.; Kalck, P.; Lavigne, G. Angew. Chem., Int. Ed. Engl. 1997,
36, 1092-1095.
10.1021/ol049417q CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/15/2004

activation and addition of oxazolines across a carbon-carbon
double bond.
Table 2. Alkene Generalitya
Our interest in this area arose from research on the Rh(I)-
catalyzed C-H functionalization of imidazole and related
N-heterocycles.13-16 Previous studies have shown that the
C-H bond at the 2 position of such heterocycles can be
efficiently added across alkene π-bonds both inter-13 and
intramolecularly.14,15 Mechanistic data from the reaction of
one benzimidazole derivative revealed the intermediacy of
a Rh complex with substrate bound as a N-heterocyclic
carbene (NHC).16 Because some saturated N-heterocycles are
known to be good NHC ligands,17,18 we decided to attempt
extension of the C-H activation reaction to azolines.19 When
4,4-dimethyl-2-oxazoline (1) and 4,4-dimethyl-2-imidazoline
1
were reacted with 10 mol % /2[RhCl(coe)2]2, 7.5 mol %
PCy3‚HCl, 7.5 mol % PCy3, and 4 equiv of 3,3-dimethyl-
butene in THF-d8 at 135 °C (conditions found to be
appropriate for azole activation),14 the desired products were
obtained in 50% and 35% yield, respectively, by NMR (eq
2).20
The reaction conditions for the coupling of 1 were quickly
improved by dropping the reaction temperature to 45 °C and
increasing the reaction time to 18 h. Prolonged heating of
the reaction mixture did not result in increased yield.
To optimize the reaction conditions further, a number of
phosphine hydrochloride salts were prepared and tested in
the addition of 1 to 1-hexene to give 2-hexyl-4,4-dimethyl-
2-oxazoline (2) (Table 1). Aryl phosphines (Table 1, entries
a Reactions run with 5 equiv of alkene, 5 mol % 1/2[RhCl(coe)2]2, 5 mol
% PCy3‚HCl, and 2.5 mol % PCy3 in THF for 18 h. b Only the linear product
was isolable in all cases. c Reaction run with 1 equiv of alkene. d Reaction
run with 10 mol % 1/2[RhCl(coe)2]2, 10 mol % PCy3‚HCl, and 5 mol %
PCy3.
Table 1. Survey of Phosphine Effects on Coupling with 1a
entry
phosphonium salt
1 (%)
2 (%)
1
2
3
4
5
6
7
8
9
noneb
PCy3‚HCl
56
21
29
43
50
37
46
34
45
0
64
49
12
4
31
9
32
0
P(i-Pr)3‚HCl
PCy2Ph‚HCl
PCy2(o-biPh)‚HCl
PCy2Et‚HCl
P(t-Bu)2Me‚HCl
P(t-Bu)2Et‚HCl
P(t-Bu)3‚HCl
by varying the extent of R-branching (Table 1, entries 6-9),
PCy3‚HCl continued to give the most effective catalysis.
When PCy3 was used instead of a phosphonium salt (Table
1, entry 1), no desired reactivity was observed. This result
is consistent with the intermolecular alkene coupling of
benzimidazole, for which an acid additive was also neces-
sary.13
a Reactions run with 5 equiv of 1-hexene, 5 mol % 1/2[RhCl(coe)2]2,
and 7.5 mol % phosphonium salt in THF at 45 °C for 18 h; yields determined
by GC analysis. b Reaction run with 7.5 mol % PCy3.
Following optimization efforts, standard conditions of 5
mol % 1/2[RhCl(coe)2]2, 5 mol % PCy3‚HCl, 2.5 mol % PCy3,
(14) Tan, K. L.; Vasudevan, A.; Bergman, R. G.; Ellman, J. A.; Souers,
A. J. Org. Lett. 2003, 5, 2131-2134.
4 and 5), regardless of cone angle, were ineffective. The
reaction requires a bulky, electron-rich phosphine. Despite
efforts to obtain a trialkylphosphine with superior properties
(15) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685-2686.
(16) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202-3203.
(17) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(18) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 2163-2187.
(13) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 13964-13965.
1686
Org. Lett., Vol. 6, No. 10, 2004

and 5 equiv of alkene in THF at 45 °C were adopted. This
reaction temperature is significantly lower than that used in
the coupling of aromatic azoles. The increased catalyst
activity is consistent with trends observed for other transition-
metal-catalyzed processes, which become more efficient
when unsaturated NHC ligands are replaced by saturated
analogues.17 This trend is, however, difficult to rationalize
because aromaticity in NHC ligands has been found to exert
very little influence on basicity.21 Attempts to isolate an NHC
complex by stoichiometric reaction of 1 with the rhodium/
phosphine catalyst mixture were unsuccessful, suggesting that
such an intermediate may exist only transiently under the
conditions investigated.
Using the standard reaction conditions, a study of alkene
scope was undertaken. 1-Hexene proved to be a competent
substrate (Table 2, entry 2), giving solely the linear product
despite the ability of Rh(I) to isomerize olefinic double
bonds. More highly substituted hydrocarbon substrates were
also active. Cyclohexene underwent coupling with moderate
yield (Table 2, entry 6) whereas the linear 1,2-disubstituted
alkenes tested, cis- and trans-4-octene, gave only trace
amounts of coupling product under the standard conditions.
A 1,1-disubstituted alkene (Table 2, entry 4) demonstrated
reactivity similar to that of terminal alkenes. In contrast,
R-methylstyrene, which can form a new stereocenter upon
coupling, exhibited severely attenuated activity (Table 2,
entry 5). The low yields associated with aryl-substituted
alkenes (Table 2, entries 3 and 5) are difficult to rationalize
at present. Finally, a trisubstituted alkene, 1-methylcyclo-
hexene, was evidently too highly substituted to couple
effectively.
Another set of alkene substrates was tested in order to
assay the functional group tolerance of the addition reaction
(Table 2, entries 7-11). Alkenes with heteroatom substitu-
ents performed best at elevated temperatures. We demon-
strated that protected aldehyde, acid, alcohol, and amine
functionality can be incorporated into substituted oxazoline
products.
In summary, we report a new method for the rhodium-
catalyzed coupling of commercially available 1 with alkenes
to give linear products with excellent selectivities and good
yields. The products of this reaction are well suited to further
elaboration or direct hydrolysis to esters or acids. A number
of substitution patterns and functional groups are tolerated.
The present method uses significantly milder reaction condi-
tions than those reported for related hydroesterifications and
does not require handling of CO or the use of high-pressure
equipment, making this reaction an attractive tool for the
synthetic chemist.
Efforts aimed at improving this reaction are underway.
By varying the cyclic imidate component we hope to lower
the alkene loading while maintaining reaction efficiency. In
addition, chiral catalysts or chiral oxazolines derived from
natural amino acids could permit selective formation of new
stereocenters in reactions of unsymmetrical methylene
compounds.
Acknowledgment. This work was supported by NIH
Grant GM069559 (to J.A.E.) and by the Director, Office of
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under
Contract DE-AC03-76SF00098 (to R.G.B). The Center for
New Directions in Organic Synthesis is supported by Bristol-
Myers Squibb as a sponsoring member and Novartis as a
supporting member.
(19) Acyclic amidines and imidates were found to be unreactive toward
alkene addition. Presumably this is because in the thermodynamically
favored isomer the nitrogen lone pair and the C-H bond to which the metal
must be directed are in a trans relationship to one another.
(20) This result complements previously published Rh-catalyzed arylation
of 1 with iodobenzene, which also proceeds under the conditions effective
for benzimidazole coupling. Lewis, J. C.; Wiedemann, S. H.; Bergman, R.
G.; Ellman, J. A. Org. Lett. 2004, 6, 35-38.
(21) Lee, M.-T.; Hu, C.-H. Organometallics 2004, 23, 976-983. Hillier,
A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo, L.; Nolan, S.
P. Organometallics 2003, 22, 4322-4326.
Supporting Information Available: Experimental de-
tails, including analytical data for all compounds described.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL049417Q
Org. Lett., Vol. 6, No. 10, 2004
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