Asymmetric synthesis of bicyclic amidines via rhodium-catalyzed [2+2+2] cycloaddition of carbodiimides

Article abstract of DOI:10.1021/ja710065h

A highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkynes and alkenyl carbodiimides has been developed. This reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles and provides a new class of chiral bicyclic amidines as the major products. An isonitrile migration process responsible for the formation of the minor cycloadduct can be observed and is highly sensitive to the electronics of alkynyl substrates. Copyright

Full text of DOI:10.1021/ja710065h

Published on Web 02/27/2008
Asymmetric Synthesis of Bicyclic Amidines via Rhodium-Catalyzed [2+2+2]
Cycloaddition of Carbodiimides
Robert T. Yu and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received November 6, 2007; E-mail: rovis@lamar.colostate.edu
Table 1. Ligand Screen
Recent advances in the field of transition metal-catalyzed
cycloadditions have made them among the most efficient methods
to assemble polycyclic carbocycles and heterocycles.1 Cycloaddi-
tions employing carbodiimides are surprisingly scarce in the
literature.2 An intramolecular Pauson-Khand-type reaction of
alkynyl carbodiimides has recently been described,3 while [2+2+2]
cycloadditions of diynes and carbodiimides have been documented
to provide mostly inseparable mixtures.4,5 To the best of our
knowledge, there have been no reports of successful enantioselective
[m+n+o]-type cycloadditions involving carbodiimides as a 2π
component.
a Conditions: 1 (2 equiv), 2 (0.16 mmol), Rh catalyst, L in PhMe at
110 °C. b Product selectivity (3:4) is determined by 1H NMR of the
unpurified reaction mixture. c Isolated yield. d Determined by HPLC analysis
using a chiral stationary phase.
We previously described an unusual cycloaddition between
phenyl acetylene 1a and isocyanate 2 (X ) O, eq 1), where the
major pathway proceeds via metalacycles I and II, involving a CO
migration process.6 The resulting cycloaddition affords product 4
(X ) O) in good efficiency, while cycloadduct 3 can only be formed
as the minor component (3:4 ) 1:7, Ar ) Ph). In an effort to
selectively access products of type 3, we envisioned that a
cycloaddition employing carbodiimides (2, X ) NAr) should favor
the formation of metalacycle III by placing the bulky imido moiety
farther away from the rhodium center (I vs III). Herein, we report
the successful application of this strategy, providing a selectivity
complementary to that of the cycloaddition previously described
using isocyanates.7 Further, this reaction offers a novel entry into
the asymmetric synthesis of bicyclic amidines (3, X ) NAr).8
Our investigations began with the cycloaddition of phenyl
acetylene 1a and the phenyl-substituted pentenyl carbodiimide 2a,
employing our previously developed reaction conditions (entries
1, 2, Table 1).6b These conditions afford the desired bicyclic amidine
3 in moderate yields, with the ligand L2 providing the highest
enantioselectivity. The p-tol-TADDOL-derived ligand L3 provides
a very efficient reaction with half the catalyst loading and shorter
reaction times (entry 3). Further optimization led to the identification
of m-xylyl-TADDOL derivative L4 as the best ligand, affording
the bicyclic amidine with good chemical yield and excellent
enantioselectivity (entry 4). The amino group on the ligand proves
to have a significant effect on the reaction; replacing the pyrrolidinyl
moiety with the piperidine can further improve the product
selectivity for 3, although the enantioselectivity decreases (entry
5). It is significant to note that the type 4 product resulting from a
rare isocyanide (CNR) migration9 can be observed in the reaction
mixture as the minor component.
Table 2. Carbodiimide Scope
a-d See Table 1. e 0.8 mmol scale of 2c, 1 mol % Rh catalyst, and 2 mol
% L4. f 5 mol % Rh catalyst and 10 mol % L4.
substituted carbodiimides. The reaction tolerates both electron-rich
and electron-poor substituents at various positions to afford bicyclic
amidines 3 in good yields and excellent enantioselectivity (entries
1-5). Aryl carbodiimides with strong electron-withdrawing groups
provide much greater product selectivity (entries 4, 5). For larger
scale reactions, the catalyst loading may be reduced to 1 mol %
[Rh(C2H4)2Cl]2 with virtually identical yield and enantioselectivity.
For further substrate development, we chose o-anisidine-derived
carbodiimide as the standard cycloaddition partner. This selection
was based on the optimal enantioselectivity obtained and the
potential role of this functionality as an oxidatively cleavable
protecting group of the resulting cycloadducts.10
The asymmetric synthesis of amidine 6a, possessing a nitrogen-
substituted quaternary center, can be achieved in high efficiency
from the corresponding disubstituted alkenyl carbodiimide (eq 2).6c
Although a much more sluggish reaction, cycloaddition of carbo-
Table 2 summarizes the scope of the enantioselective [2+2+2]
cycloaddition of phenyl acetylene 1a and a variety of aryl-
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10.1021/ja710065h CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Terminal Alkyne Scope
The resulting bicyclic amidines 3 are potentially useful chiral
building blocks. Under appropriate conditions, the olefin and the
amidine moiety can each be selectively reduced while leaving the
other functionality untouched for further transformation (eq 4).
In summary, we have developed the first enantioselective
[2+2+2] cycloaddition utilizing carbodiimides to give bicyclic
amidines with excellent enantiocontrol. Observation of the isocya-
nide migration process during the cycloaddition is notable. Studies
to explore the synthetic utility of bicyclic amidines 3 are ongoing.
Acknowledgment. This paper is dedicated with deep respect
to the memory of our friend and colleague Prof. Albert I. Meyers.
We thank NIGMS (GM080442), Eli Lilly, Boehringer Ingelheim,
and Johnson & Johnson for support. T.R. is a fellow of the Alfred
P. Sloan Foundation and thanks the Monfort Family Foundation
for a Monfort Professorship.
Supporting Information Available: Experimental procedures,
characterization, 1H and 13C NMR spectra; CIF file for 3bc. This
material is available free of charge via the Internet at http://pubs.acs.org.
a-d See Table 1. e Absolute configuration assigned by analogy to (S)-
3bc (established by X-ray analysis). f 5 mol % Rh catalyst and 10 mol %
L4. g Isolated yield of 4 (a 2:1 mixture of imine isomers).
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