Iridium-catalyzed regiospecific and stereospecific allylic amination for the syntheses of α,β-unsaturated γ-amino esters and the bifurcation of the reaction pathway leading to the formation of oxazolidin-2-ones

Article abstract of DOI:10.1039/c3sc50901j

A pair of iridium-catalyzed regiospecific and stereospecific reactions of the carbonates of γ-hydroxy α,β-unsaturated esters were developed. The reaction pathways are strongly affected by the choice of amines employed. A diverse range of γ-substituted α,β-unsaturated γ-amino esters were prepared in excellent yields with various amine nucleophiles such as benzylamine, diallylamine, morpholine, aniline and N-methylaniline. Substitution at the γ-position was well tolerated, encompassing alkyl, aryl and heteroaryl substituents. Enantioenriched (E)-α,β-unsaturated γ-amino esters could also be synthesized from the corresponding enantioenriched allylic carbonates with complete chirality transfer. In sharp contrast, a series of 3,4-disubstituted oxazolidin-2-ones were obtained by using allylamine as a nucleophile.

Full text of DOI:10.1039/c3sc50901j

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Iridium-catalyzed regiospecific and stereospecific allylic
amination for the syntheses of a,b-unsaturated g-amino
esters and the bifurcation of the reaction pathway
leading to the formation of oxazolidin-2-ones†‡
Cite this: DOI: 10.1039/c3sc50901j
*
Jun Hee Lee and Sang-gi Lee
A pair of iridium-catalyzed regiospecific and stereospecific reactions of the carbonates of g-hydroxy a,b-
unsaturated esters were developed. The reaction pathways are strongly affected by the choice of
amines employed. A diverse range of g-substituted a,b-unsaturated g-amino esters were prepared in
excellent yields with various amine nucleophiles such as benzylamine, diallylamine, morpholine, aniline
and N-methylaniline. Substitution at the g-position was well tolerated, encompassing alkyl, aryl and
heteroaryl substituents. Enantioenriched (E)-a,b-unsaturated g-amino esters could also be synthesized
from the corresponding enantioenriched allylic carbonates with complete chirality transfer. In sharp
contrast, a series of 3,4-disubstituted oxazolidin-2-ones were obtained by using allylamine as a
nucleophile.
Received 4th April 2013
Accepted 8th May 2013
DOI: 10.1039/c3sc50901j
www.rsc.org/chemicalscience
stereoconvergent synthesis using a combination of an asym-
metric Horner–Wadsworth–Emmons reaction and a stereo-
Introduction
selective Pd-catalyzed allylic amination.3g Despite these
advances, there still exists a need for new catalytic methods with
broad substrate scope to gain access to a,b-unsaturated
g-amino esters.
The synthesis of highly functionalized molecules in an efficient
and straightforward manner represents an ongoing challenge
in organic chemistry. Due to not only their polyfunctionality for
further manipulations, but also their abundance in bioactive
natural and non-natural products, a,b-unsaturated g-amino
acid derivatives have attracted signicant interest from the
synthetic community.1 a,b-Unsaturated g-amino esters are
generally prepared through the classical Wittig-type olenation
of the corresponding N-protected a-amino aldehydes.2 However,
such substrates are highly sensitive to base-induced epimeri-
zation and can usually be accessed from the amino acids only
through a tedious synthetic sequence. Direct catalytic methods
for their selective construction have also been developed,
including the Ru-catalyzed co-dimerization of N-acetyl a-aryl-
amines with acrylates,3a the Pd-catalyzed insertion of a-diazo-
esters into vinyl halides and subsequent trapping with
amines,3b Lewis acid-catalyzed N–H insertions of methyl styr-
yldiazoacetate with aniline,3c Rh- and Pd-catalyzed ring-opening
of vinyl epoxides with azides and amines,3d,e the Pd-catalyzed
rearrangement of a-sulfonimidoyl b,g-unsaturated esters3f and
Over the past decade, allylic substitution reactions catalyzed
by metallacyclic iridium phosphoramidite complexes have
emerged as an excellent method for the controlled formation of
carbon–carbon and carbon–heteroatom bonds.4 In general,
transition-metal-catalyzed allylic amination reactions have been
limited to the synthesis of terminal allylic amines.5 To the best
of our knowledge, Ir-catalyzed allylic aminations of substrates
bearing different substituents at the two allylic termini remain
thus far unexplored.6 Furthermore, examples of the Ir-catalyzed
allylic amination reaction of enantioenriched allylic electro-
philes that occur with high stereospecicity are rare.7 In the
context of our research program directed toward the extensions
of transition-metal-catalyzed reactions for the preparation of
synthetically useful structural motifs,8 we envisioned that the
allylic amination of electronically biased allylic electrophiles of
the type 1 possessing an alkyl, aryl, or heteroaryl substituent at
C1 and an electron withdrawing group, such as an ester func-
tionality at C3 would provide ready access to a,b-unsaturated
g-amino esters. During the course of the investigation, to our
surprise, it was also found that the reaction pathways are
strongly dependent on the amine nucleophiles employed, and
bifurcated to allow the selective synthesis of either g-aminated
a,b-unsaturated esters 2 or 3,4-disubstituted oxazolidin-2-ones
3 using an iridium catalyst (Fig. 1).
Department of Chemistry and Nano Science (BK 21), Ewha Womans University, Seoul
120-750, Korea. E-mail: sanggi@ewha.ac.kr; Fax: +82 2 3277 3419; Tel: +82 2 3277
4505
† Dedicated to Prof. Jahyo Kang (Sogang University), who passed away on
November 9, 2012, for his contributions to organic chemistry.
‡ Electronic supplementary information (ESI) available: Data for new compounds
and experimental procedures. See DOI: 10.1039/c3sc50901j
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desired amination product 2a as a single regio- and stereo-
isomer, albeit in a moderate yield of 54% (Table 1, entry 1).11
Similar or inferior results in terms of the isolated yield were
obtained in other solvents such as 1,4-dioxane, 1,2-dimethoxy-
ethane (DME), acetonitrile and dichloromethane (entries 2–5).
While a diminished yield of 41% was obtained from the reac-
tion catalyzed by an iridacyclic complex generated from the
Alexakis' phosphoramidite ligand L2 (entry 7),12 a slightly
improved yield of 62% was attained when the reaction was
carried out in nitromethane using the standard catalytic system
(entry 6). In these reactions, substantial amounts of a g-keto
ester (ethyl 4-oxo-4-phenylbutanoate) and methyl benzylcarba-
mate were isolated as by-products, presumably derived from
olen isomerization of 1a followed by aminolysis of the iso-
merized carbonate (e.g. 4a) with benzylamine. We were pleased
to nd that switching the substrate from methyl carbonate 1a to
the corresponding tert-butyl carbonate 1b resulted in a signi-
cant improvement in isolated yield. Thus, the desired a,b-
unsaturated g-amino ester 2a was isolated in 88% yield from the
reaction of 1b with benzylamine in nitromethane (entry 8).
Under these conditions, the olen isomerization side reaction
was completely suppressed, whereas a certain amount of iso-
merized by-product (e.g. (Z)-4b)13 was observed when the reac-
tions were performed in other solvents. Furthermore, the
position of the leaving group strongly affected the outcome of
the reactions. In particular, efforts using substrates bearing the
carbonate leaving group at the a-position proved fruitless under
the standard conditions (entries 9 and 11). However, both 1c
and 1d showed some reactivity when exposed to a palladium
catalyst,14 generated in situ from the pre-complexation of
Pd2(dba)3 with dppf, to afford the g-amination product 2a in
38% and 31% yields, respectively (entries 10 and 12). Finally,
the reaction of 1b using the palladium catalyst indicates the
superiority of the iridium catalyst system for this g-amination
reaction (Table 1, entry 8 versus entry 13).
Fig. 1 Bifurcation of the catalytic reaction pathways.
Results and discussion
Our investigations started with a well-dened iridium catalytic
system composed of [Ir(cod)Cl]2 and racemic Feringa's phos-
phoramidite L1 as a standard catalyst.9 In the presence of a
metallacyclic iridium phosphoramidite catalyst, generated
in situ by heating a mixture of 2 mol% [Ir(cod)Cl]2 and 4 mol%
rac-L1 with propylamine at 50 ꢀC for 20 min, as described
previously,10 the reaction of methyl carbonate 1a with benzyl-
amine (1.2 equiv.) in THF at room temperature for 13 h gave the
Table 1 Optimization studya
Entry
Substrate
Catalytic system
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1b
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Ir((S,S,S)-L2)]c
[Ir(rac-L1)]c
[Ir(rac-L1)]c
[Pd(dppf)]d
[Ir(rac-L1)]c
[Pd(dppf)]d
[Pd(dppf)]d
THF
1,4-dioxane
DME
54
55
55
40
31
62
41
88
0
38
0
31
62
With the optimized reaction conditions in hand (Table 1,
entry 8), we next explored the scope and limitations of this
g-amination reaction. As shown in Table 2, the reaction of the
standard substrate 1b allowed for the regiospecic and stereo-
specic synthesis of (E)-a,b-unsaturated g-amino esters 2 in
excellent yields with a broad range of amine nucleophiles such
as linear primary and secondary alkyl amines (entries 1 and 2), a
cyclic secondary amine (entry 3), a primary arylamine (entry 4),
and a secondary alkyl arylamine (entry 5). In stark contrast,
replacing the amine nucleophile with allylamine generated
MeCN
CH2Cl2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
9
10
11
12
13
unexpected oxazolidin-2-ones
3 without any competitive
formation of 2 (see discussion below and Scheme 1). Notably,
the Ir-catalyzed reaction can be easily scaled up, even with a
lower catalyst loading of 2 mol%, to furnish the amination
product 2d in a gram quantity, albeit at the expense of a slightly
decreased yield. Steric variation in the ester group of the
substrates 1 was also well tolerated, as both the sterically less
demanding methyl ester 1e and the more hindered tert-butyl
ester 1f gave the desired products 2f and 2g in high yields with
aniline.
a
Reactions conditions: precatalyst (4.0 mol%), 1 (0.50 mmol) and
benzylamine (0.60 mmol) in different solvents (1.0 M) at room
b
c
temperature for 13 h. Yield of isolated 2a. [Ir(cod)Cl]2 (2.0 mol%)
and a phosphoramidite ligand L (4.0 mol%). Pd2(dba)3 (2.0 mol%)
and dppf (4.0 mol%).
d
We next examined the optimized conditions with substrates
bearing different substituents at the g-position, while using
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Table 2 Ir-Catalyzed synthesis of a,b-unsaturated g-amino estersa
in these aminations and were well tolerated, providing potential
synthetic handles for further transformations (2k, 2l, 2m and
2n). Additionally, the iridium-catalyzed reaction was success-
fully employed in the synthesis of the (E)-a,b-unsaturated g-
amino ester 2o which bears a 3-furyl substituent. It should be
emphasized that only a single g-regio- and (E)-stereoisomer was
detected in the crude reaction mixture in all cases.
To gain a better understanding of the reaction mechanism,
we examined the iridium-catalyzed allylic amination of enan-
tioenriched substrate (+)-1b with 92% ee, which was synthesized
from a commercially available chiral phenyl vinyl alcohol.13
Most importantly, the reaction of (+)-1b with either an aryl-
amine or an alkylamine as a nucleophile under the standard
conditions proceeded smoothly with complete chirality trans-
fer, affording (+)-2a and (+)-2d in 84% yield with 92% ee and in
93% yield with 92% ee, respectively (eqn (1)). The absolute
stereochemistry of the substrate (+)-1b was retained during the
overall process to afford both amines 2a and 2d with (R)-
conguration at the g-position.13,15 This indicates that both the
oxidative addition of the iridium(I) precatalyst to (+)-1b and
subsequent nucleophilic attack of the amine nucleophile occur
stereospecically with inversion of conguration at the reacting
g-position.5a,16 Furthermore, the excellent degree of chirality
transfer obtained above can be rationalized by an explanation
wherein the intermediary enantioenriched p-allyliridium(III)
species does not undergo an allyl exchange reaction with the
low-valent iridium(I) complex present in the reaction mixture,
which could result in an inversion of conguration of allyl
group containing two different substituents at each allyl
terminus and concurrent erosion of the optical purity of the
product 2.17,18 It is worth noting that the present protocol could
be a general route to access chiral g-substituted a,b-unsaturated
g-amino esters19 because a diverse range of alkyl-, aryl, and
heteroaryl substituted homochiral allylic alcohols as well as
their derivatives can easily be prepared20 and their olen CM
reactions are also well documented.21,22
a
Reaction conditions: precatalyst (4.0 mol%), 1 (0.50 mmol) and amine
(0.60 mmol) in MeNO2 (1.0 M) at room temperature for 13 h and then
b
isolated yield was obtained. Precatalyst (2.0 mol%) and 1b (4.00
mmol). c Reaction in a 1 : 1 mixture of THF/MeNO2 (v/v, 0.5 M).
(1)
aniline as a nucleophile. The amination proceeded smoothly
with g-alkylated substrates 1g and 1h to yield the desired
products in excellent yields (2h and 2i), although slightly
elevated reaction temperatures were required in some cases. For
example, the reaction of 1h bearing a phenethyl group at the g-
ꢀ
position proceeded cleanly at 30 C to afford the desired ami-
nation product 2i in an excellent yield of 97%, whereas the same
reaction at room temperature (ca. 22 ꢀC) gave a somewhat
Inspired by the recent success of iridium-catalyzed decar-
decreased product yield of 77%. Though an even higher reac- boxylative allylic amidation and with a desire to further evaluate
tion temperature (40 ꢀC) was necessary, the g-unsubstituted the potential application of our new reaction,23 we turned our
substrate 1i (R1 ¼ H) similarly participated in the reaction with attention to examining a cyclic carbonate 1o under the standard
aniline to afford the corresponding product 2j in a moderate reaction conditions (eqn (2)). However, cyclic carbonate 1o did
yield of 60%. We also examined the g-arylated substrates having not show any reactivity at room temperature. To our delight,
different substituents on the aryl moiety. Both electron- ca. 70% conversion into the desired product was observed when
donating and electron-withdrawing substituents at either the the reaction was carried out at 50 ꢀC for 13 h. The reaction
ortho or para positions of the aryl moiety exerted little inuence mixture was then treated with tert-butyldimethylsilyl chloride
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(TBSCl) in the presence of imidazole in DMF to furnish
synthetically valuable O-protected a,b-unsaturated g-amino-d-
hydroxy ester 2p in 60% yield over two steps. To the best of our
knowledge, this represents the rst example of the iridium-
catalyzed intermolecular decarboxylative allylic amination of a
cyclic carbonate.24
(2)
Next, we turned our attention to the unexpected nding of
the nucleophile-dependent bifurcation of reaction pathways
(Scheme 1). When the standard substrate 1b was allowed to
react with allylamine as a nucleophile, a 10 : 1 diastereomeric
mixture of inseparable trans- and cis-oxazolidin-2-one 3a was
obtained in a combined yield of 83% under otherwise identical
conditions. Furthermore, the reactions of carbonates 1g and 1h
bearing an alkyl group at the g-position furnished the corre-
sponding oxazolidin-2-ones (3b and 3c) with comparable dia-
stereoselectivities and somewhat diminished yields. The
relative congurations of the major trans-isomers were assigned
on the basis of the vicinal coupling constants between the C-4
and C-5 protons, whose values are consistent with the ones
reported for similar oxazolidin-2-ones,25 and further conrmed
through NOESY experiments.13 At present it is difficult to know
whether this unusual oxazolidin-2-one formation with allyl-
amine is mainly due to its smaller steric demands or if a subtle
electronic difference affects the nature of the nucleophilic
addition event. Intriguingly, switching the nucleophile from
allylamine to propylamine afforded a separable 1 : 1 mixture
consisting of (E)-ethyl 4-(propylamino)-4-phenylbut-2-enoate
(2q, 36%) and a 3-propyl-substututed oxazolidin-2-one 3d
(36%); the latter was isolated as a 7 : 1 mixture of inseparable
trans- and cis-isomers.
a
Scheme 1 Synthesis of oxazolidin-2-ones. The corresponding (E)-a,b-unsatu-
rated g-amino ester (2q) was also isolated in 36% yield.
an intramolecular nucleophilic acyl substitution on the
carbonate carbonyl group (path a) or a selective formation of a
carbamate 6 through an intermolecular nucleophilic acyl
substitution with allylamine and subsequent intramolecular
conjugate addition (path b). Since the formation of 3a is not
observed in the absence of the iridium catalyst, we surmise
that the metallacyclic complex can act as a Lewis acid catalyst
for the conjugate additions. To distinguish between these
potential pathways, iridium-catalyzed cyclization of the
carbamate 6 was examined, which was separately prepared
from the corresponding a,b-unsaturated g-hydroxy ester.13
Treatment of racemic 6 with 4 mol% of the racemic metal-
lacyclic iridium phosphoramidite complex in nitromethane at
22 ꢀC for 15 h did not furnish any oxazolidin-2-one 3a. On the
basis of this observation, along with the intrinsic difficulties in
explaining the selective formation of the carbamate 6, we rule
out path b. Path a seems more likely to be a relevant mecha-
nism for the oxazolidin-2-one formation. However, further
mechanistic studies will be necessary to draw more denitive
conclusions.
Because substituted oxazolidin-2-ones are important motifs
in many pharmaceuticals26 and “privileged” chiral auxiliaries,27
the enantioenriched (+)-1b (92% ee) was examined in this
reaction, and was found to afford a 10 : 1 mixture of the desired
trans- and cis-oxazolidin-2-ones 3a in 79% combined yield and
with 71% ee for the major (trans) isomer (eqn (3)).
(3)
Although we cannot assert the mechanism of this unex-
pected reaction at this stage, two distinct mechanistic path-
ways are easily envisioned (Scheme 2):
a syn-selective
conjugate addition of allylamine with 1b to give 5 followed by Scheme 2 Proposed reaction pathways (R ¼ allyl).
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4 For selected reviews, see: (a) J. F. Hartwig and M. J. Pouy, Top.
Organomet. Chem., 2011, 34, 169–208; (b) G. Helmchen,
Conclusions
In summary, we have demonstrated the rst iridium-catalyzed
regiospecic and stereospecic intermolecular amination of
internal allylic carbonates possessing electronically differenti-
ated substituents at each terminus with a wide range of amine
nucleophiles. This process provides an expeditious synthetic
method for the stereospecic synthesis of (E)-a,b-unsaturated
g-amino esters with various substitution patterns such as alkyl,
aryl and heteroaryl at the g-position in excellent yields. Optically
active (E)-a,b-unsaturated g-amino esters could also be synthe-
sized from the corresponding chiral allylic carbonates with
complete chirality transfer using alkylamine as well as aryl
amine nucleophiles. In addition, by simply changing the
nucleophile to allylamine, the reaction pathway was bifurcated
to afford a series of 3,4-disubstituted oxazolidin-2-one deriva-
tives as a 10 : 1 mixture of trans- and cis-isomers from the same
carbonate substrates under otherwise identical conditions. The
establishment of the salient features of the nucleophile-
dependent bifurcation of the catalytic pathways will provide a
new approach to chiral oxazolidinones.
}
A. Dahnz, P. Dubon, M. Schelwies and R. Weihofen, Chem.
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J. F. Hartwig and M. L. Stanley, Acc. Chem. Res., 2010, 43,
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alkylation of enantiomerically pure (R)-pent-3-en-2-yl
acetate with dimethyl 2-sodiomalonate using P(OPh)3 as
ligand, which proceeded with 71% retention of
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7 For transition-metal-catalyzed stereospecic allylic aminations,
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Acknowledgements
This work was made possible through the support of the
National Research Foundation of Korea (NRF-2013035117). We
thank Prof. Jean Bouffard for his helpful discussions and Dr
Sung Hong Kim at the Korea Basic Science Institute, Daegu
Center, Daegu, Korea for mass spectral analysis.
4801–4804.
For
Ir-catalyzed
kinetic
asymmetric
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15 The absolute stereochemistry of (+)-2a was assigned 21 For a review on the CM of allylic alcohols, see: (a)
following
alkylation
with
bromoacetonitrile.
The
A. Lumbroso, M. L. Cooke and B. Breit, Angew. Chem., Int.
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16 For mechanistic insights into transition-metal-catalyzed
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enantioenriched unprotected branched allylic amines,
which can be readily prepared through the Ir-catalyzed
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amines and anilines, generally exhibit little reactivity in
the olen cross metathesis reaction, even under harsh
reaction conditions (i.e. high temperatures and prolonged
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references therein.
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a
recent review on transition-metal-catalyzed
ref. 16b.
decarboxylative allylation and benzylation, see:
18 During the reviewing process of this manuscript, an
insightful referee (that we thank) suggested the
intermolecular allyl exchange mechanism.
J. D. Weaver, A. Recio III, A. J. Grenning and J. A. Tunge,
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For the rhodium-catalyzed decarboxylative allylic
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19 During the preparation of our manuscript, Fu and
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¨
20 For selected examples, see: allylic alcohols (a) M. Gartner,
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Chem. Sci.
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