Iridium(I)-catalyzed regio- and enantioselective decarboxylative allylic amidation of substituted allyl benzyl imidodicarbonates

Article abstract of DOI:10.1021/ja067966g

The first Ir(I)-catalyzed decarboxylative allylic amidation of allyl benzyl imidodicarbonates is described. The reaction requires Ir(I), chiral phosphoramidite ligand, and DBU as well as proton sponge, and proceeds with excellent regio- and enantioselectivities to afford the branched 1-(aryl/alkyl)-1-benzyloxycarbonylaminoprop-2-ene in good to excellent yields. The scope, mechanism, and synthetic applications of the developed catalytic reaction are discussed. Copyright

Full text of DOI:10.1021/ja067966g

Published on Web 01/06/2007
Iridium(I)-Catalyzed Regio- and Enantioselective Decarboxylative Allylic
Amidation of Substituted Allyl Benzyl Imidodicarbonates
Om V. Singh and Hyunsoo Han*
Department of Chemistry, The UniVersity of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698
Received November 10, 2006; E-mail: hyunsoo.han@utsa.edu
Table 1. Decarboxylative Allylic Amidation of 2-Pentenyl- and
Transition-metal-catalyzed stereoselective allylic substitution has
provided an important and convenient tool for carbon-carbon and
carbon-heteroatom bond formation in organic synthesis1 and is
still evolving to include more diverse allylic electrophiles, nucleo-
philes, and catalysts. Of particular interest is the recent development
of transition-metal-catalyzed decarboxylatiVe allylic substitution
reactions.2 Ru and, particularly, Pd metals have been employed,
and synthetically useful levels of regio- and enantioselectivities have
been achieved in the decarboxylative allylation reaction of allyl
â-ketoacetate derivatives (X ) -CH2- in eq 1). However, given
the well-known fact that carbamic acids can undergo facile
decarboxylation, it is rather surprising that the analogous decar-
boxylative allylic amidation (X ) -NH- in eq 1) has never been
realized. To the best of our knowledge, there has been only one
report for the decarboxylative carbon-nitrogen bond formation,
where Tunge et al. described Pd-catalyzed decarboxylative allylic
amination, albeit reaction stereochemistry was not an issue.3 Herein,
we describe the first iridium(I)-catalyzed highly regio- and enan-
tioselective decarboxylative allylic amidation reaction of substituted
allyl benzyl imidodicarbonates (X ) -NH- in eq 1).
Cinnamyl Benzyl Imidodicarbonatesa
base(s)
(mol %)
conversionb (%),
reacn time (h)
ee of 2
entry substrate
solvent ligand
2/3b
(%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
DBN (100) THF
DBU (100) THF
L3
L3
L3
L3
L3
L1
L2
L3
L3
L3
L3
100, 1
100, 1
100, 1
100, 1
100, 2
98, 16
100, 1
98, 24
94, 24
<20, 24
100, 1
98:02
98:02
95:05
96:04
95:05
93:07
95:05
94:06
89:11
ND
DBU (10)
DBU (50)
THF
THF
DBU (500) THF
DBU (100) THF
DBU (100) THF
DBU (100) Et2O
DBU (100) EtOH
DBU (100) THF
DBU (100) THF
PS (100)
10
11
>99:1 >99
a 0.2 mmol scale with [Ir(COD)Cl]2 (2 mol %) and L (4 mol %) in THF
(0.5 mL) at room temperature. b Based upon 1H NMR of the crude reaction
mixture.
salts (LiCl, LiBr, CuI, ZnBr2, etc.) did not help.9 However,
surprisingly, proton sponge (PS) increased the reaction rate by
>100-fold, and excellent regio- and enantioselectivities were
obtained (entry 11). Both DBU and PS were found to be necessary
for the reaction, since the reaction did not proceed to completion
in the absence of either.
The scope of the iridium(I)-catalyzed regio- and enantioselective
decarboxylative allylic amidation was examined with a variety of
substituted allyl benzyl imidodicarbonates, and the results were
shown in Table 2. The decarboxylative allylic amidation appears
to be quite general accommodating a wide range of substituents
such as linear and branched alkyl (entries 1-4), conjugated alkenyl
(entry 5), aryl (entry 6), heteroaryl (entry 7), heteroatom-function-
alized alkyl (entries 8 and 9), and isolated alkenyl groups (entries
10 and 11). For the sterically more hindered (entries 3 and 4) and/
or slow substrate (entry 9), higher catalyst load (4 mol %) and
temperature (55 °C) were necessary to ensure good reaction yields
as well as high regio- and enantioselectivities.
To probe the reaction mechanism, a crossover experiment was
conducted with a 1:1 mixture of 4 and 5 to determine the intra- vs
intermolecular nature of the reaction. Crossover products 7 and 8
formed along with usual products 6 and 9 in almost equal amounts
(eq 2). This result is more consistent with the reaction mechanisms
involving the Ir-π-allylic intermediate over intramolecular [3,3]-
rearrangement (eq 3). Combined with the fact that the stereochem-
ical outcome of the allylic amidation is the same as that of the
allylic amination by L,6,7 the results of the crossover experiment
further suggest that the actual nucleophile in the reaction may be
Literature analysis on regio- and enantioselective allylic
amination4-7 revealed that reaction conditions involving [Ir(COD)-
Cl]2, a phosphoramidite ligand such as L1-L3, and THF solvent
could be a good starting point for the decarboxylative allylic
amidation, and a base was required to generate the active catalyst.8
This led us to examine the effectiveness of various tertiary amines
like TEA, DIPEA, DMAP, DABCO, DBU, and DBN in the
decarboxylative allylic amidation reaction of 2-pentenyl benzyl
imidodicarbonate (1a) by [Ir(COD)Cl]2 and chiral phosphoramidite
L3 in THF. As shown in entries 1 and 2 of Table 1, respectively,
only with DBN and DBU the reaction proceeded to give the
decarboxylative allylation products 2a and 3a in a good yield and
with an excellent regioselectivity, while the other amines either
failed to react or gave only a trace amount of products (<5%).
DBU was further investigated, and 1 equiv of DBU was found to
be optimal in terms of both reaction time and regioselectivity
(entries 2-5 in Table 1). Next, the effects of different ligands (L1,
L2, and L3) and solvents (THF, Et2O, EtOH, CH2Cl2, and DMF)
were studied, and a combination of L3 and THF resulted in the
fastest reaction and highest regioselectivity (entries 2 and 6-9).
As an initial attempt to validate the generality of the found
reaction conditions, cinnamyl benzyl imidodicarbonate (1b) was
tested, but disappointingly branched product 2b was obtained only
in 20% yield after 24 h (entry 10 of Table 1). Therefore, we sought
additives to improve reaction time and yield. The addition of metal
9
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J. AM. CHEM. SOC. 2007, 129, 774-775
10.1021/ja067966g CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ir-Catalyzed Enantioselective Decarboxylative Allylic
Scheme 1
Amidation of Substituted Allylic Benzyl Imidodicarbonates
respectively; analytical data of which matched with those of the
corresponding known compounds (Scheme 1). Compound 10 was
N-alkylated by KH and allyl bromide to give diene 11, which upon
ring closing metathesis (RCM) by Grubbs second generation
catalyst10 transformed to 12.11 The intramolecular amidomercuration
reaction of 13 with Hg(TFA)2 in nitromethane afforded 14, which
was previously used as a synthetic precursor for the stereoselective
synthesis of (+)-isosolenopsin A.12
In conclusion, we have successfully developed the iridium(I)-
catalyzed highly regio- and enantioselective decarboxylative allylic
amidation reaction, which is quite general and proceeds under mild
reaction conditions. This, combined with the synthetic utility of
optically pure Cbz-protected allylic amines, should make the
developed decarboxylative allylic amidation of particular value in
organic synthesis.
a Reaction condition A: substrate (0.2 mmol), [Ir(COD)Cl]2 (2 mol %),
L3 (4 mol %), DBU (1 equiv), PS (1 equiv), THF (0.5 mL) at room
temperature. Reaction condition B: same as the condition A except
[Ir(COD)Cl]2 (4 mol %) and L3 (8 mol %) at 55 °C. b Isolated yield of b
and l. c Ratio of regioisomers determined by 1H NMR of the crude reaction
mixture. d Enantiomeric excess determined by chiral HPLC.
Acknowledgment. Financial support from National Institute of
Health (Grant GM 08194) and The Welch Foundation (Grant AX-
1534) is gratefully acknowledged. We are also thankful to Professor
A. Alexakis and Dr. K. Ditrich for the generous gift of ligand L3
sample and a chiral amine for the synthesis of ligand L3,
respectively.
completely liberated from the Ir-π-allylic complex and then attack
the complex anti to iridium.
Supporting Information Available: Experimental procedures,
spectroscopic data for new compounds, and their hard copies. This
material is available free of charge via the Internet at http://pubs.acs.org.
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To shed light on the nature of the actual nucleophile and/or timing
of decarboxylation (I vs II in eq 3), ethyl cinnamyl carbonate was
treated with benzyl carbamate anion (generated in situ from benzyl
carbamate and n-BuLi at 0 °C) under the reaction conditions. No
product was observed even in trace, and all starting materials were
recovered. Hence, it might be unlikely that the benzyl carbamate
anion acts as the actual nucleophile to the Ir-π-allylic complex
(II in eq 3). Rather, the carboxylate anion (after proton shift from
the nitrogen to the oxygen), which is generated from the oxidative
addition of the substrate to the Ir catalyst, attacks the Ir-π-allylic
complex (I in eq 3) and decarboxylation occurs later in the reaction
sequence. This is in sharp contrast to the decarboxylative allylic
carbon-carbon bond formation where decarboxylation takes place
prior to the attack of a nucleophile to the π-allyl complex.2c
To demonstrate the synthetic utility of Cbz-protected chiral allylic
amines generated and to establish absolute stereochemistry at the
allylic carbon, compounds 10 and 13 were converted to 12 and 14,
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