Palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethane with imines

Article abstract of DOI:10.1021/ja0753389

The transition metal-catalyzed trimethylenemethane [3+2] cycloaddition provides a direct route to functionalized heterocycles. Herein, we describe a catalytic, asymmetric protocol for the reaction between 3-acetoxy-2-trimethylsilylmethyl-1-propene and var

Full text of DOI:10.1021/ja0753389

Published on Web 09/21/2007
Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of Trimethylenemethane
with Imines
Barry M. Trost,* Steven M. Silverman, and James P. Stambuli
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 17, 2007; E-mail: bmtrost@stanford.edu
Table 1. Imine Optimization Study
Pyrrolidines are ubiquitous structural units in the chemical
literature, with numerous applications seen throughout the phar-
maceutical industry as well as among natural products.1 As such,
much attention has been devoted toward their synthesis. While
cycloaddition strategies to form pyrrolidines are well documented,
they are largely based on the reaction of azomethine ylides with
two carbon units.2 Complementary strategies involving the addition
of imines to suitable three carbon units have received less attention.
The transition metal-catalyzed [3+2] trimethylenemethane (TMM)
cycloaddition is a highly efficient process that provides a direct
route to five-, seven-, and nine-membered ring systems.3 Though
this venerable reaction has been primarily studied in the construction
of carbocycles, there have been few accounts detailing TMM
cycloaddition reactions of imines to form pyrrolidines.4 Further,
asymmetric syntheses of this moiety are highly desirable. Our recent
disclosure of an asymmetric variant of the TMM reaction between
3-acetoxy-2-trimethylsilylmethyl-1-propene and olefins5 prompted
us to investigate the enantioselective synthesis of pyrrolidines using
this methodology.
a Conversion. b ND ) Not determined.
Table 2. Palladium-Catalyzed [3+2] Reactions of N-Aryl Imines
Initial studies focused on the reaction of benzylidene aniline
under the previously developed conditions (5 mol % Pd(dba)2,
10 mol % ligand, 1.6 equiv TMS propenyl acetate) at 45 °C
(Scheme 1). Ligand L16 gave only 3% ee at 71% conversion. On
the basis of a report detailing the beneficial effects that minor
alterations of phosphoramidite ligands have on the selectivity of
iridium-catalyzed AAA reactions,7 we tested L2 and L3. Unfor-
tunately, enantiomeric excesses remained low, though increased
conversion was observed. Further variations of this segment that
may affect conformation such as inverting the stereochemistry of
the methyl group (L4) increased the ee, but removal of a methyl
Scheme 1
a Isolated yields. b Reaction performed with 2.5 equiv propenyl acetate.
group (L5) provided an inactive catalyst. The previously utilized
asymmetric palladium catalyst for the TMM reaction of olefins
(L6)5,8 provided the desired product in only 35% ee and 73%
conversion. Adjusting the nature of the chiral space by increasing
the size of the aryl groups led initially to replacement of one phenyl
group with a 2-naphthyl group (L7), which did increase the ee.
Substitution with 4-biphenyl groups (L8) or even better, the bis-
1-naphthyl ligand (L9) boosted the ee. Bis-2-naphthyl ligand L10
gave the best results with a 76% conversion and 84% ee. To
examine the effects of ring size, we turned to azetidine ligand L11,
which gave significantly lower ee.
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10.1021/ja0753389 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Palladium-Catalyzed [3+2] Reactions of N-Boc Imines
Figure 1. ORTEP illustration of (R)-tert-butyl 2-(4-chlorophenyl)-4-
methylenepyrrolidine-1-carboxylate (Table 3, entry 6) with thermal ellipsoids
drawn at the 50% probability level.
anilines. The temperature could be reduced considerably, as low
as -15 °C in some cases (entries 3, 7, 9, 12), and conversion
remained high with moderate increases in enantioselectivity ob-
served. Unfortunately, further reduction to -25 °C failed to provide
desired product in any case studied. The reaction proved insensitive
to the nature of the aromatic substituent with similar results obtained
regardless of substitution pattern (entries 2-4) or electronic nature
of the substituent. Heterocycles presented no problems (entries 10-
12) with ee values remaining high, though slightly reduced yield
was observed. While the standard conditions utilized 5 mol % Pd
and 10 mol % ligand to ensure complete conversion, catalyst loading
could often be lowered (entry 8) with little change in results. The
absolute configuration was determined by X-ray crystallographic
analysis, as shown in Figure 1.
In summary, we have reported a new phosphoramidite ligand
that effects the palladium-catalyzed asymmetric TMM reaction of
imines to form substituted pyrrolidines in high ee. Investigations
into the scope of this reaction, as well as the use of substituted
TMM donors are currently underway and will be reported in due
course.
Acknowledgment. We thank the NSF and the NIH (Grant
GM13598) for their generous support of our programs. Palladium
salts were a generous gift from Johnson-Matthey. We thank Dr.
V. G. Young, Jr. from the University of Minnesota for the X-ray
crystal structures.
a Isolated yields. b Reaction performed with 2.5% Pd(dba)2 and 5% L10.
Using the optimized ligand L10, we next determined the best
class of imine for this reaction (Table 1). Ideally, we wanted a
group that would not only provide high enantiomeric excess, but
could also be easily removed. While the use of a tosyl group (entry
2) provided a good yield, the ee was low. No reaction was observed
with benzyl or phosphonyl imines (entries 3-4) and complex
mixtures were obtained with Fmoc and Cbz imines (entries 6-7).
However, the use of the N-Boc imine (entry 5) gave excellent results
with the protected pyrrolidine being obtained in 98% yield and 87%
ee.
The reaction using both N-Boc and N-aryl imines was examined.
A short assessment of substituted benzylidene anilines is shown in
Table 2.8 The reaction worked well when the N-bound aryl ring
bore electron donating groups (entries 2-3) or withdrawing groups
(entry 4). On the C-bound ring, electron withdrawing groups
significantly enhanced reactivity as reflected in reduced amounts
of silyl acetate needed to reach full conversion (2.5 equiv in entry
1 versus 1.6 equiv in entries 2-4) and lower temperature required
(entry 4).
Supporting Information Available: Experimental details and
spectral data for all unknown compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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(9) Our initial studies of TMM reactions of aliphatic N-aryl imines afforded
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The use of Boc-imines provided a broader reaction scope (Table
3). This class proved more reactive than the substituted benzylidene
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