Direct, stereoselective substitution in [Rh(CO)2Cl] 2-catalyzed allylic alkylations of unsymmetrical substrates

Article abstract of DOI:10.1021/ol0496529

[Rh(CO)₂Cl]₂ has been found to possess the unusual property of catalyzing allylic alkylations of unsymmetrical allylic carbonates with high levels of regioselectivity to provide products arising from substitution at the carbon atom b

Full text of DOI:10.1021/ol0496529

ORGANIC
LETTERS
2
004
Vol. 6, No. 8
321-1324
Direct, Stereoselective Substitution in
Rh(CO) Cl] -Catalyzed Allylic
1
[
2
2
Alkylations of Unsymmetrical Substrates
Brandon L. Ashfeld, Kenneth A. Miller, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received February 26, 2004
ABSTRACT
2 2
[Rh(CO) Cl] has been found to possess the unusual property of catalyzing allylic alkylations of unsymmetrical allylic carbonates with high
levels of regioselectivity to provide products arising from substitution at the carbon atom bearing the leaving group, irrespective of the
structure of the starting carbonate. The substitution reaction occurs with retention of stereochemistry at the reacting center, and the carbon−
carbon double-bond stereochemistry of primary (Z)-allylic carbonates is maintained.
Transition metal-catalyzed allylic alkylations constitute one
of the more widely utilized classes of reactions in modern
synthetic organic chemistry.1,2 The focus of many recent
efforts in this area has been in developing catalysts that
enable high regio- and stereochemical control in the substitu-
tion reaction of symmetrical and unsymmetrical substrates.
Irrespective of the structure of the starting materials (e.g., 1
or 2), palladium-catalyzed processes typically favor nucleo-
philic substitution at the sterically less hindered allylic
more encumbered allylic terminus (Figure 1).2,10,11 These
reactions are generally believed to proceed via a transition
metal-stabilized allyl intermediate that may range in structure
1
3
from an unsymmetrical η -complex to a symmetrical η -allyl
complex. The regioselectivity of the ensuing nucleophilic
attack is then dictated by a combination of steric and
electronic factors that vary with the intermediate complex
1
2
and the nucleophile.
Given the various catalysts capable of promoting allylic
alkylations, it is generally possible to prepare either 3 or 4
through judicious selection of catalyst and allylic substrate
3
4
5
6,7
8
9
terminus to give 3, whereas Ru, Mo, Rh, Ir, and W
preferentially deliver products 4 arising from attack at the
1
or 2. However, that there may not be a direct correlation
(
1) For reviews on transition metal-catalyzed allylic alkylations, see: (a)
between the structure of 1 or 2 and the major product may
sometimes be a disadvantage. Indeed, it is perhaps somewhat
Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; Wiley: New York, 1996. (b) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921.
(2) For leading references on other transition metal-catalyzed allylic
alkylations, see: (a) Tsuji, J. Organic Synthesis with Palladium Compounds;
Springer-Verlag: Heidelberg, 1980. (b) Blacker, A. J.; Clarke, M. L.; Loft,
M. S.; Mahon, M. F.; Humphries, M. E.; Williams, J. M. J. Chem. Eur. J.
(5) Trost, B. M.; Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska,
S. W.; Reamer, R. A.; Palucki, M.; Yasuda, N.; Reider, P. J. Angew. Chem.,
Int. Ed. 2002, 41, 1929.
(6) (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 5157.
(b) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003, 5,
1713.
(7) (a) Takeuchi, R.; Kitamura, N. New J. Chem. 1998, 22, 659. (b)
Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725.
(8) Takeuchi, R. Synlett 2002, 1954.
2
1
8
4
2
000, 6, 353. (c) Trost, B. M.; Andersen, N. G. J. Am. Chem. Soc. 2002,
24, 14320. (d) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125,
974. (e) Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
690. (f) Bartels, B.; Garcia-Yebra, C.; Helmchen, G. Eur. J. Org. Chem.
003, 1097. (g) Trost, B. M.; Jiang, C. Org. Lett. 2003, 5, 1563.
(3) Trost, B. M. Tetrahedron 1977, 33, 2615
(
4) (a) Ono, H.; Satake, N.; Watanabe, Y. Organometallics 1995, 14,
(9) Trost, B. M.; Hung, M.-H. J. Am. Chem. Soc. 1983, 105, 7757.
(10) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647.
(11) Evans, P. A.; Nelson J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(12) Trost, B. M.; Hung, M.-H. J. Am. Chem. Soc. 1984, 106, 6837.
1
4
4
945. (b) Morisaki, Y.; Kondo T.; Mitsudo T. Organometallics 1999, 18,
742. (c) Trost, B. M.; Fraisse, P.; Ball, Z. Angew. Chem., Int. Ed. 2002,
1, 1059.
1
0.1021/ol0496529 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/12/2004

Table 1. Regioselectivity in the [Rh(CO)
2
2
Cl] -Catalyzed
Allylic Alkylation Reactions13
Figure 1. Regiochemical trends in transition metal-catalyzed allylic
alkylations.
surprising that no single catalyst has yet been identified that
enables direct, stereoselective allylic substitution at the
carbon atom bearing the leaving group. Moreover, if such a
catalyst were capable of promoting subsequent transforma-
tions, there exists the potential of developing a number of
synthetically useful cascade sequences.
In the aforementioned contexts, it is noteworthy that we
recently discovered that [Rh(CO)
allylic alkylation of pentenyl carbonate 5a (R ) Et, R -R
H) with the sodium salt of dimethyl malonate at room
2 2
Cl] catalyzed the rapid
1
2
4
)
1
2
4
temperature to provide 6a (R ) Et, R -R ) H) with a
high degree of regioselectivity (6a/7a ) 97:3) (Figure 2).
2 2
Figure 2. Direct substitution in [Rh(CO) Cl] -catalyzed allylic
alkylations.
This unexpected result immediately captured our attention
because the regiochemical outcome was opposite that
observed by Evans for allylic alkylations catalyzed by RhCl-
1
1
(
(
PPh
CO)
3
)
3
/P(OMe)
3
. We therefore explored the scope of [Rh-
2
Cl] -catalyzed allylic alkylations, and some of our
preliminary findings are summarized in Table 1.
2
13
(
13) Representative Experimental Procedure. The allylic substrate 5
(
1.0 mmol) was added to a solution of [Rh(CO)2Cl]2 (19 mg, 0.05 mmol)
a
Isolated yields. b Ratios determined by GLC. THF, rt. d THF, 0 °C.
c
in THF (5 mL), and the solution was stirred for 30 min at room temperature.
In a separate flask, dimethyl malonate (0.29 mL, 2.5 mmol) was added to
a slurry of NaH (60% w/w in mineral oil, 40 mg, 2.0 mmol) in THF (5
mL) at room temperature, and the mixture was stirred for 20 min. The
resulting sodium enolate was added via syringe to the solution of 5 and
e
i
DMF, rt. DMF, -20 °C. DMF, 0 °C. h Ratio of cis/trans isomers.
Corresponding carbonate was unstable.
f
g
[
Rh(CO)2Cl]2 at room temperature. The mixture was then sealed in a screw
cap vial under an atmosphere of argon, and stirring was continued at room
temperature until the starting material was consumed (as indicated by TLC).
The reaction was then filtered through a short plug of silica gel eluting
with Et2O (50 mL), and the filtrate was concentrated under reduced pressure.
The crude residue was purified by flash chromatography, eluting with
pentane/Et2O (5:1 or 10:1) to furnish the products 6 and 7. All new
compounds were purified (>95%) by flash chromatography and were
Examination of the entries in Table 1 reveals that [Rh-
CO) Cl] catalyzed the facile and regioselective alkylations
2 2
of a variety of allylic carbonates 5a-l to provide the
corresponding malonates 6a-l as the major products in every
case. The reactions typically proceeded with excellent
regiocontrol that favored substitution at the carbon atom
(
1
13
characterized by H and C NMR, IR, and HRMS.
1322
Org. Lett., Vol. 6, No. 8, 2004

bearing the leaving group. A number of general trends and
notable features merit additional discussion.
Primary allylic carbonates having internal disubstituted
carbon-carbon double bonds selectively provided the linear
alkylation products (entries 1-6). This mode of regioselec-
tivity corresponds to that expected of palladium catalysts but
is opposite to that typically observed for ruthenium, molyb-
1,14
denum, rhodium, and iridium catalysts. The (Z)-carbonate
b (entry 2) underwent substitution to give the less stable
Z)-product with little isomerization to the (E)-isomer. This
5
(
2 2
Figure 3. Retention of configuration in the [Rh(CO) Cl] -catalyzed
result is significant because (Z)-allylic substrates generally
suffer extensive ZfΕ isomerization with other transition
metal catalysts, although there are scattered reports of
Z-selective allylic substititutions of (Z)-substrates catalyzed
allylic substitution.
from those previously studied because the termini of the
allylic moieties are unequally substituted. Mechanistic studies
are underway to understand the origin of the regiochemistry
by iridium,10 palladium, and tungsten. Alkylation of 5e
illustrates that enol ethers conjugated with the allylic subunit
do not adversely affect the regiochemistry or efficiency of
the reaction (entry 5). That 5f underwent (entry 6) any
alkylation is noteworthy because 2,3,3-trisubstituted allylic
carbonates are inert to the modified Wilkinson’s catalyst
reported by Evans and typically require forcing conditions
with other transition metal catalysts.1 The isomeric tertiary
allylic carbonate 5g underwent facile alkylation to provide
the product of direct substitution, even though a quaternary
center was generated in the process (entry 7).
15
16
2 2
in [Rh(CO) Cl] -catalyzed allylic alkylations and why it
differs from such reactions promoted by other transition metal
catalysts. Of particular interest is determining whether the
rhodium-stabilized allyl intermediate resembles a (σ + π)
enyl complex as suggested by Evans or some other π-allyl
1,17
1
1
variant.
To determine the stereochemical outcome of [Rh(CO)
catalyzed allylic substitutions, the allylic carbonate (+)-8 was
synthesized in g99% ee in two steps from the correspond-
ing racemic alcohol via Sharpless kinetic resolution (Figure
2
2
Cl] -
20
Preliminary results with secondary allylic carbonates and
acetates 5h-k (entries 8-11) underscore the differences
between the reactivity of [Rh(CO) Cl] and other catalysts
2 2
capable of promoting allylic substitutions. In each of these
cases, direct displacement of the leaving group is the
dominant reaction pathway. This appears to be true even
when the substituents at both ends of the allylic moiety are
sterically and electronically similar (entry 10) or when
conjugation would favor substitution at the opposite allylic
3
). When (+)-8 was allowed to react with the sodium salt
of dimethyl malonate in the presence of [Rh(CO) Cl] , (+)-9
was obtained in 93% yield and 98% ee (regioselectivity )
2
2
20
10
1
4
21
11
9
3:7). Like Pd, Ru, Mo, Rh, and Ir catalysts, [Rh(CO)
Cl] thus appears to catalyze substitutions of secondary allylic
carbonates with net retention of configuration.
We have thus demonstrated that [Rh(CO) Cl]
2
-
2
2
2
has the
remarkable propensity to catalyze allylic substitutions at the
carbon atom bearing the leaving group on substrates with a
variety of substitution patterns. The following question now
arises: How can this unusual reactivity be exploited in
synthesis? We are currently pursuing this query on a number
of fronts. For example, that allylic substitutions of (Z)-alkenes
proceed with retention of double-bond geometry suggests
2 2
terminus (entry 11). Finally, [Rh(CO) Cl] may be used
effectively to catalyze the alkylation of propargylic carbon-
ates to give substituted alkynes with none of the allenic
product being observed (entry 12).
2 2
That [Rh(CO) Cl] catalyzes the allylic alkylations of
unsymmetrical substrates to give products in which substitu-
tion occurs at the carbon atom bearing the leaving group
may be regarded as a memory effect. Such phenomena have
been examined in palladium-catalyzed allylic alkylations of
enantioenriched and racemic secondary allylic substrates
having the same number of substituents on the allyl
2 2
that [Rh(CO) Cl] might be used to catalyze cyclizations to
give medium and large rings containing (Z)-olefins. The
synthesis of rings by transition metal-catalyzed cyclizations
has received considerable attention since the early 1980s.22
Inasmuch as the synthesis of eight-membered rings is
particularly demanding, we first examined whether eight-
1
8,19
moiety.
The nature of the memory effect observed in
Cl] -catalyzed allylic alkylations thus differs
these [Rh(CO)
2
2
membered lactones might be formed by [Rh(CO)
catalyzed cyclizations. In the event, treating the â-ketoester
10 with [Rh(CO) Cl] in DMF at 0 °C provided lactone 11
2 2
Cl] -
(
(
14) Bhatia, B.; Reddy, M. M.; Iqbal, J. Tetrahedron Lett. 1993, 34, 6301.
15) (a) Huntzinger, M. W.; Oehlschlager, A. C. J. Org. Chem. 1991,
2
2
5
1
2
6, 2918. (b) Sjogren, M. P. T.; Hansson, S.; Akermark, B. Organometallics
994, 13, 1963. (c) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed.
000, 39, 802.
in 68% yield (Figure 4); none of the corresponding six-
membered lactone was observed. To the best of our
knowledge, this represents the first example of forming an
(16) Frisell, H.; Akermark, B. Organometallics 1995, 14, 561.
(17) (a) Takahashi, T.; Nemoto, H.; Tsuji, J. Tetrahedron Lett. 1983,
2
4, 2005. (b) Trost, B. M.; Lautens, M.; Chan, C.; Jebaratnam, J.; Mueller,
T. J. Am. Chem. Soc. 1991, 113, 636.
(20) Enantiomeric excess was determined by HPLC analysis with a chiral
stationary phase column [Chiracel OD or AD].
(21) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1987, 109, 1469.
(22) (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102,
4743. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. (c)
Trost, B. M.; Vos, B. A.; Brzezowski, C. M.; Martina, D. P. Tetrahedron
Lett. 1992, 33, 717.
(18) Poli, G.; Scolastico, C. Chemtracts: Org. Chem. 1999, 12, 837.
19) (a) Fiaud, J. C.; Malleron, J. L. Tetrahedron Lett. 1981, 22, 1399.
(
(b) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1996, 118, 235. (c) Lloyd-
Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocil, S.;
Kocovsky, P. Chem. Eur. J. 2000, 6, 4348. (d) Fairlamb, I. J. S.; Lloyd-
Jones, G. C.; Vyskocil, S.; Kocovsky, P. Chem. Eur. J. 2002, 8, 4443.
Org. Lett., Vol. 6, No. 8, 2004
1323

retention of double-bond geometry and tetrahedral chirality.
The potential utility of [Rh(CO) Cl] as a catalyst for
2
2
promoting allylic alkylations is illustrated by the cyclization
of 10 to deliver the eight-membered lactone 11. Because
2 2
[Rh(CO) Cl] is known to catalyze other transformations, a
number of synthetic applications may be envisaged in which
allylic alkylations are combined with other transformations,
resulting in cascade processes to rapidly assemble complex
structures. Experiments to elucidate the mechanistic details,
2 2
Figure 4. Intramolecular [Rh(CO) Cl] -catalyzed allylic alkylation.
2 2
scope, and utility of [Rh(CO) Cl] -catalyzed allylic substitu-
tions, especially in tandem reactions, are in progress and will
be reported in due course.
eight-membered lactone by an intramolecular, transition
metal-catalyzed allylic alkylation of a â-ketoester. When this
same reaction was conducted using Pd(PPh ) as the catalyst,
3 4
a mixture (60:40) of eight- and six-membered lactones was
obtained.
In summary, we have discovered that [Rh(CO) Cl] , a
2 2
commercially available catalyst that may be easily used
without special precautions to exclude oxygen, catalyzes
allylic alkylations under mild and ligandless conditions.
Reactions involving unsymmetrical substrates, including
those with internal double bonds, proceed efficiently, rapidly,
and regioselectively at the carbon atom bearing the leaving
group. The substitution also proceeds stereoselectively with
Acknowledgment. We are grateful to the National Insti-
tute of General Medical Sciences (GM 31077), the Robert
A. Welch Foundation, Pfizer, Inc., and Merck Research
Laboratories for their generous support of this research.
1
Supporting Information Available: Copies of H NMR
spectra are provided for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0496529
1324
Org. Lett., Vol. 6, No. 8, 2004