Catalytic asymmetric claisen rearrangement of unactivated allyl vinyl ethers

Article abstract of DOI:10.1021/ja1039314

Nearly a century after their original discovery, catalyzed enantioselective variants of the venerable Claisen rearrangement remain relatively rare. We have discovered a cooperative transition metal-Lewis acid cocatalyst system that affects highly enantio- and diastereoselective examples of archetypical Claisen rearrangements. The catalyzed rearrangements proceed using an easily prepared enantioenriched transition metal catalyst and a commercially available Lewis acid cocatalyst at ambient temperature in common solvents.

Full text of DOI:10.1021/ja1039314

Published on Web 08/05/2010
Catalytic Asymmetric Claisen Rearrangement of Unactivated Allyl Vinyl
Ethers
Maryll E. Geherty, Robert D. Dura, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received May 19, 2010; E-mail: sgnelson@pitt.edu
initial Claisen catalyst designs.5 Moreover, the activation of allylic
Abstract: Nearly a century after their original discovery, catalyzed
enantioselective variants of the venerable Claisen rearrangement
remain relatively rare. We have discovered a cooperative transi-
tion metal-Lewis acid cocatalyst system that affects highly
enantio- and diastereoselective examples of archetypical Claisen
rearrangements. The catalyzed rearrangements proceed using
an easily prepared enantioenriched transition metal catalyst and
a commercially available Lewis acid cocatalyst at ambient tem-
perature in common solvents.
ethers toward nucleophilic substitution by the [CpRu(quinaldic
acid)]+ complex, ostensibly with assistance by an intramolecular
H-bond to the departing ether oxygen, was also instrumental in
preliminary catalyst design.6
Based on the preceding analysis, the Ru(II) complexes obtained
by reacting [CpRu(CH3CN)3]PF6 (1) with ligands 2-4 were
Pericyclic reactions, including [3,3] sigmatropic rearrangements,
examined as catalysts for the asymmetric Claisen rearrangements
enjoy unparalleled value for the synthesis of complex organic
of 1,6-disubstituted allyl vinyl ethers (e.g., 5). The picolinamide
ligands 2 and 3 were designed as enantioenriched surrogates for
structures.1 As a result, the growing emphasis on catalytic asym-
metric transformations in academic, medicinal, and process chemistry-
quinaldic acid based on similarities in metal chelate size and pendent
related synthesis activities has inspired the development of an
H-bond donor shared by these two ligand types (eq 2). As
extensive array of catalyzed enantioselective reaction variants.
constituted, however, the derived Ru(II) complexes were not
competent catalysts, as reacting allyl vinyl ether 5 with varying
amounts (5-10 mol %) of Ru(II) salt 1 combined with 2 or 3 (1
equiv relative to 1) elicited no detectable rearrangement (Table 1).
However, catalyzed variants of the [3,3] sigmatropic rearrangement
family of pericyclic reactions proceeding with high enantioselec-
tivity continue to be relatively rare.2 Among the highly successful
catalytic asymmetric [3,3] rearrangements that have been developed,
reaction variants successfully harnessing these transformation’s
potential for establishing vicinal stereocenter relationships are
especially unique.3 As a complementary solution to the development
of enantioselective [3,3] sigmatropic rearrangements controlling
both absolute and relative stereochemistry, we describe herein the
Ru(II)-catalyzed Claisen rearrangement of unactivated allyl vinyl
ethers (Figure 1).
Table 1. Survey of Catalyst Composition and Reaction Conditions
(eq 2)
% ee 6
(anti:syn)
entry
Ligand
Additive(s)
% Conv 5a
a
b
c
d
2 or 3
-
0b
63
63
93
-
2
3
3
5 mol % B(OPh)3
81 (2:1)
5 mol % B(OPh)3
5 mol % B(OPh)3,
100 wt % 4 Å MS
5 mol % B(OPh)3, 4 Å
MS, 20 mol % CH3CN
5 mol % B(OPh)3, 4 Å
MS, 20 mol % CH3CN
89 (10:1)
89 (16:1)
Figure 1. Enatioselective Ru(II)-catalyzed Claisen rearrangements.
e
f
3
4
100 (91%
yield 6+7)
45
93 (20:1)c
24 (2:1)
The homology existing between concerted, but nonsynchronous,
Claisen rearrangements and intramolecular SN′ reactions implicates
C-O bond scission and ensuing enolate-allyl cation recombination
as one mechanism for Claisen catalyst design (eq 1).4 However,
lacking the intrinsic regiochemical bias present in the concerted
processes, rearrangements initiated by C-O bond cleavage require
a mechanism for rendering the formal [3,3] sigmatropic process
preferred relative to the competing [1,3] rearrangement. The
proficiency of [Cp*Ru(2,2′-bipyridine)]+ complexes as catalysts for
allylic alkylation reactions exhibiting a strong bias for generating
branched substitution products, therefore, provided one model for
a Reactions performed in THF at 23 °C. b Up to 10 mol % each of
[CpRu(CH3CN)3]PF6 and ligand (2 or 3) were used. c 28% ee for
compound 7.
Based on the supposition that the ligand-modified Ru(II)
complexes had failed to achieve the necessary C-O oxidative
insertion, the capacity of Lewis acid cocatalysts to assist oxidative
insertion through Lewis acid-base association with the ether
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10.1021/ja1039314  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 11875–11877 11875

C O M M U N I C A T I O N S
Table 2. Catalyzed [3,3] Rearrangement of C6-Aryl Allyl Vinyl
oxygen was evaluated. The impact of the putative Ru(II)-main group
Lewis acid cocatalyst system was dramatically apparent upon
reacting allyl vinyl ether 5 with [CpRu(CH3CN)3]PF6 and 2 (5 mol
% each) and B(OPh)3 (5 mol %, THF, 23 °C). Under these
conditions, substrate conversion to a mixture of rearrangement
adducts 6 and 7 improved to 63% with good enantioselectivity for
the formal [3,3] adduct 6 (86% ee), albeit with only moderate
diastereoselectivity (6anti:6syn ) 6:1) (Table 1, entries b, c). The
Ru(II) catalyst obtained from the 4-(dimethylamino)pyridine-2-
carboxamide ligand 3 delivered the anti 2,3-disubstituted pentenal
6 from allyl vinyl ether 5 with similar enantioselectivity and
considerably improved diastereoselectivity (89% ee, 6anti/6syn ) 10:
1). Supporting control experiments confirmed that B(OPh)3, alone
or in combination with the ligands 2 or 3, elicited no detectable
rearrangement.7
Ethers
% ee 9
(anti:syn)
% yield
(9+10)a b
,
entry
Allyl vinyl ether (8)
9:10
a
R1 ) Et,
>99 (6.3:1)
90 (18:1)
92 (17:1)
92 (25:1)
78 (11:1)
93 (25:1)
96 (17:1)
96 (10:1)
96 (10:1)
26 (10j)
3.6:1
89
86
90
92
89
80
78
63
90
70
R2 ) Ph (8a)
b
c
d
e
f
R1 ) Me,
14:1
7.6:1
4.7:1
4.4:1
6.5:1
4.6:1
18:1
3:1
R2 ) 4-MeOC6H4 (8b)
R1 ) Me,
R2 ) 4-MeC6H4 (8c)
R1 ) Me,
R2 ) 4-BrC6H4 (8d)
R1 ) Me,
R2 ) 2-MeOC6H4 (8e)
R1 ) Me,
Further improvements in substrate conversion were realized by
incorporating 4 Å molecular sieves (MS) to the previously
optimized reaction conditions. Catalyzed rearrangement of allyl
vinyl ether 5 (5 mol % 1, 5 mol % 3, 5 mol % B(OPh)3, THF, 23
°C) in the presence of 4 Å MS (100 wt %) provided 93% conversion
with a commensurate, and unanticipated, improvement in both
diastereo- and regioselectivity (6anti:6syn ) 16:1, 6:7 ) 4.6:1).
R2 ) 3-MeOC6H4 (8f)
R1 ) Me,
g
h
i
R2 ) 3-ClC6H4 (8g)
R1 ) Me,
R2 ) 2-Furyl (8h)
R1 ) Me,
R2 ) 1-Naphthyl (8i)
R1 ) Me,
jc
0:100
c
R2 ) C6H11 (8j)
Added acetonitrile was also found to have a beneficial effect on
the catalyzed rearrangements. Control experiments revealed that
the Ru(II)-catalyzed Claisen rearrangements were subject to product
inhibition; added acetonitrile was expected to disrupt the putative
Ru(II)-pentenal chelate emerging from the rearrangement event.
Thus, 20 mol % added CH3CN resulted in full substrate conversion
(91% yield 6 + 7) while simultaneously yielding enhancements in
enantio-, diastereo-, and regioselectivity for the [3,3] adduct (93%
ee 6anti, 6anti:6syn ) 20:1, 6:7 ) 5.3:1) (Table 1, entry e). Similarly
high levels of enantioselectivity were not observed in the minor
[1,3] product 7 (28% ee).
a Reaction conditions: CH3CN (20 mol %), 4 Å MS (100 wt %),
and 10 are inseparable by routine
THF, 23 °C. b Compounds
9
chromatography; methods for separating 9 and 10 are provided in the
c
Supporting Information. B(OpC6H4F) (10 mol %) was used as
cocatalyst.
In accord with our original catalyst design, catalyst competency
proved to be critically dependent on the presence of the free alcohol
function in the ligand 3. The CpRu(II) complex obtained from
picolinamide ligand 4 in which a methyl ether replaces this alcohol
function provided a dramatically inferior catalyst for the rearrange-
ment of ether 5, affording substantially eroded substrate conversion
and stereoselectivity compared to reactions employing catalyst
complexes derived from 3 (Table 1, entry f).
Using the present catalyst system, the regiochemical bias
exhibited by rearrangements of C6-aryl substrates does not extend
to the corresponding C6-alkyl substrates. Catalyzed rearrangement
of the C6-alkyl substrate 8j afforded only the [1,3] adduct 10j with
modest enantioselectivity (26% ee) (Table 2, entry j). The attenuated
reactivity of these substrates relative to the C6-aryl derivatives
required higher catalyst loadings (10 mol % 1 + 3) and
B(OpC6H4F)3 (10 mol %), in place of B(OPh)3, as the Lewis acid
cocatalyst to achieve satisfactory efficiency.
Under these fully optimized reaction conditions (5 mol % 1, 5
mol % 3, 5 mol % B(OPh)3, 20 mol % CH3CN, 100 wt % 4 Å
MS, THF, 23 °C), various C1 alkyl-C6 aryl or heteroaryl allyl vinyl
ethers 8a-i afforded Claisen rearrangement adducts 9a-i possess-
ing generally high enantioselectivity and consistently high anti
diastereoselectivity, an outcome directly complementary to the syn
diastereoselection characterizing thermal [3,3] rearrangements of
similar E,E-allyl vinyl ethers (Table 2). Unlike enantio- and
diastereoselectivity, however, regioselectivity exhibited considerable
variability over the range of C6-aryl substrates examined (9:10 )
18:1-3:1). Rearrangement stereo- and regioselectivity was also
strongly dependent on substrate olefin geometry. As anticipated,
inverting the geometry of either olefin present in the Claisen
substrate produced a turnover in diastereoselectivity; Z vinyl ether
11 (eq 3) and Z allyl ether 12 (eq 4) each afforded the syn [3,3]
adduct 6 as the major rearrangement stereoisomer (93% ee);
however, diastereoselectivity and, in the case of 11, regioselectivity
were eroded relative to those obtained from the E,E ally vinyl ethers.
These investigations have identified a unique catalyst system for
affecting highly enantio- and diastereoselective Claisen rearrange-
ments. The reactions employ easily obtained catalysts and ligands
and proceed in common solvents at ambient temperature. While
effective [3,3] rearrangements are currently limited to C6-aryl
substrates, we anticipate that current efforts to elucidate both the
reaction mechanism and catalyst structure will expand the structural
diversity available from these reactions.
Acknowledgment. Support from the National Science Founda-
tion (CHE 0718467) is gratefully acknowledged.
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C O M M U N I C A T I O N S
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Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162.
(3) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem., Int. Ed.
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Supporting Information Available: Experimental procedures and
1H and 13C spectra (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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