Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium-Catalyzed Asymmetric Allylic Alkylation

Article abstract of DOI:10.1002/anie.201903090

Morpholine ketene aminal is employed in iridium-catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ-unsaturated β-substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific substitution affords the corresponding products in high enantiomeric excess. The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones, or acyl silanes. A putative catalytic intermediate (η³-allyl)iridium(III) with achiral P,Olefin-ligand was synthetized and characterized for the first time.

Full text of DOI:10.1002/anie.201903090

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Accepted Article
Title: Morpholine Ketene Aminal as Amide Enolate Surrogate in
Iridium-Catalyzed Asymmetric Allylic Alkylation
Authors: Erick Moran Carreira, Yeshua Sempere, Jan Alfke, and Simon
Rossler
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10.1002/anie.201903090
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Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium-
Catalyzed Asymmetric Allylic Alkylation
Yeshua Sempere, Jan Alfke, Simon L. Rössler and Erick M. Carreira*
Abstract: Morpholine ketene aminal is employed in iridium-
catalyzed asymmetric allylic alkylation reactions as a surrogate for
amide enolates to prepare γ,δ-unsaturated β-substituted morpholine
amides. Kinetic resolution or, alternatively, stereospecific substitution
affords the corresponding products in high enantiomeric excess. The
utility of the products generated by this method has been showcased
by their further elaboration into amines, ketones or acyl silanes. A
putative catalytic intermediate (η3-allyl)iridium(III) with achiral
(P,Olefin)-ligand was synthetized and characterized for the first time.
decarboxylation of the corresponding products furnished the
unsubstituted amides. Notably, unactivated amide enolates have
been successfully employed in palladium catalyzed allylic
substitution, but due to the intrinsic preference of palladium to
furnish linear products, no β-stereogenic center can be
obtained.[7a] Additional examples of amide alkylations catalyzed
by Pd include decarboxylative allylations[7b-c] and the use of
oxindoles (pKa≈18 in DMSO).[3,7d-e]
Iridium-catalyzed asymmetric allylic substitution represents
a powerful method for the enantioselective formation of carbon-
carbon and heteroatom-carbon bonds.[1] Dating back to the
seminal work by Takeuchi and Helmchen,[2] stabilized enolates
have been employed as a privileged class of nucleophiles.
Despite extensive studies on enolate nucleophiles, examples of
amide enolates in iridium catalysed allylic substitution remain
scarce. This paucity originates in the attenuated C–H acidity of
amides compared to other carbonyl compounds (dimethyl
acetamide pKa≈35 in DMSO),[3] which renders their generation
in the presence of reactive allyl-iridium species challenging.
Herein, we report the use of morpholine ketene aminal 2 as a
simple, easily accessible surrogate for morpholine acetamide
enolate in iridium-catalyzed asymmetric alkylation of allylic
carbonates 1. The reaction furnishes γ,δ-unsaturated β-
substituted morpholine amides with excellent enantiomeric
excess by means of an enantioselective kinetic resolution of
racemic allylic carbonates with chiral L1 as ligand (Scheme 1,
top). Alternatively, optically pure allylic carbonates can be
employed in a stereospecific allylic alkylation catalyzed by the Ir-
complex derived from achiral ligand L2 (Scheme 1, bottom).
Due to the attenuated C–H acidity of amides, only
stabilized amides have been successfully employed in iridium
catalyzed allylic substitution. Early approaches have employed
oxazolones or thiazolones,[4] which can subsequently be
elaborated to substituted amide products. Recently, Hartwig has
reported the addition of α-substituted N-heterocyclic acetamides
Scheme 1. Morpholine ketene aminal as amide enolate surrogate in iridium-
catalyzed asymmetric allylic alkylation reaction and iridium catalyzed allylic
alkylation of acetamide enolates.
As part of our ongoing research program on studying the
reactivity of the electrophilic η3-allyl IrIII intermediates in
asymmetric transformations,[8] we sought to identify suitable
acetamide enolate equivalents. In this respect, we were
intrigued by the potential features of morpholine ketene aminal 2,
which has been employed in condensation reactions with
aromatic aldehydes by Barton.[9] We surmised that it may be
sufficiently nucleophilic to undergo reaction with our highly
electrophilic η3-allyl IrIII species, and thus function as an
unsubstituted amide enolate surrogate.[10]
Morpholine ketene aminal 2 was readily synthesized from
the corresponding orthoester and secondary amine following the
procedure reported by Baganz and Domaschke in 1962.[11] In
initial prospecting experiments with unprotected allylic alcohols
as starting material, [Ir(cod)Cl]2 (2.5 mol%), L1 (10 mol%) and 2
(1.2 equiv.) were found to lead to decomposition of nucleophile.
To overcome these issues, allylic carbonates could be employed
as suitable substrates for iridium-catalyzed asymmetric allylic
alkylation with morpholine ketene aminal. Screening a variety of
conditions, including different solvents, showed dichloromethane
as the one which provided the most promising results (Table 1,
entries 2-3).[12]
(pKa≈27 in DMSO) in
a stereodivergent fashion with a
combination of iridium and copper catalysis.[3,5] The acidity of the
α-heteroaryl amides is further enhanced through the
coordination of the copper-catalyst.[3] To date, unsubstituted
amide products have been prepared exclusively through two
step procedures. Helmchen and co-workers have reported the
use of α-amido esters (pKa≈18 in DMSO)[3] derived from
malonates as enolate precursors for the iridium catalyzed
substitution of linear allylic carbonates.[6] Subsequent
[*]
Y. Sempere, J. Alfke, S. L. Rössler, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
HCI H335, Eidgenössische Technische Hochschule Zürich
Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under xxx.
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10.1002/anie.201903090
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Table 1. Selected optimization studies of the reaction conditions[a]
Additive
(Equiv)
(R)-3
[%][b]
(S)-1
[%][b]
ee (R)-
3[%][c]
Entry
Solvent
1
2
1,4-dioxane
CHCl3
-
0
76
0
-
-
34
58
40
27
40
0
58
76
32
30
44
-
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
31
10
30
5
4
ZnBr2 (0.2)
ZnI2 (0.2)
Zn(OTf)2
KOtBu (1.3)
DIPEA (1.3)
Et3N (1.3)
Et3N (1.3)
5
6
7
0
8[d]
9[d]
10[d]
35
44
47
25
21
45
87
97
98
[a]
Reaction conditions: (±)-1 (1.0 equiv), [Ir(cod)Cl]2 (2.5 mol%), (R)-L1
(10 mol%), 2 (1.2 equiv), 0.5 M, rt, 12-18 h. [b] Determined by 1H-NMR analysis
of the unpurified reaction mixture using 1,4-dimethoxybenzene as internal
standard. [c] Enantiomeric excess determined by supercritical fluid
chromatography (SFC) on a chiral stationary phase. [d] Reaction conditions: 2
(0.6 equiv), 4h. Np = 2-naphthyl, Boc = tert-butyloxycarbonyl, DIPEA = N,N-
diisopropyletylamine.
Scheme 2. Substrate scope of the enantioselective alkylation of allylic
carbonates with morpholine ketene aminal (2). Unless noted otherwise, all
reactions were performed on 0.5 mmol scale under the standard reactions
conditions (see Table 1, entry 10). Yields refer to isolated products after
purification by column chromatography on silica gel. The ee values were
determined by SFC or GC analysis on a chiral stationary phase. [a]Recovered
enantioenriched starting material yields and ee are given in brackets.
In contrast to our earlier work with enolate surrogates,[8g] in
which Zinc-based Lewis acids were optimal promoters for the
activation of allylic carbonates in asymmetric allylic alkylation
reactions, a screening of various Lewis acids failed to yield
improved outcomes (Table 1, entries 4–6).[12] Additionally, some
decomposition of the nucleophile was evidenced by the isolation
of products stemming from direct allylic substitution from free
morpholine. Brønsted acid promoters lead to complete
decomposition of nucleophile furnishing various side products.
These observations prompted us to examine the use of bases
as additives, which could prevent the decomposition of the
nucleophile and the primary product of the reaction (vide infra).
Triethylamine was identified as an optimal additive for the
formation of product in high enantioselectivity (Table 1, entry 9).
Furthermore, over the course of our screening experiments, we
noted that the ee of the product deteriorated if conversion
increased over 50% (Table 1, entries 1–7). Optimization efforts
in this direction revealed that a shorter reaction time and
reduced amount of 2 led to a highly enantioselective kinetic
resolution (Table 1, entries 8–10). Under these optimized
conditions, we were able to show by NMR competition
experiments, that either enantiomer of starting material reacted
with vastly different rates.[12]
[b]Absolute configuration determined by X-ray analysis of a derivate.[12] NR2
=
Morpholine, Bn = benzyl, TBS = t-BuMe2Si, Ts = p-MeC6H4SO2.
Having identified the optimal reaction conditions, the scope
of allylic carbonates 1 was evaluated using morpholine ketene
aminal 2 as summarized in Scheme 2. 2-napthyl- (3a) and
phenyl- (3b) allylic carbonates furnished the corresponding
products in 47% and 41% yield, respectively, and 98% ee in
both cases. Additionally, the starting material was recovered
with good yields and high optical purity. Electron rich substrates
performed well under the reaction conditions, yielding the
desired amide products in good yields and enantioselectivities
(3c–3f) along with the recovery of optically enriched (96-99%
ee) allylic carbonates ((S)-1c–1f). Halogenated aromatic
substrates (1g-1i) were well tolerated and furnished the
corresponding amide products with high enantioselectivity (96-
98% ee). Substrates incorporating electrophilic functional groups,
such as ester (1j), could be employed without observable
competing reactions with enolate surrogate 2. Successful
conversion of thiophene and indole substituted allylic carbonates
to the corresponding amides showcases the use of
heteroaromatic substrates (1k-1l). The kinetic resolution
described herein, generally shows a selectivity factor (s) of >120,
except for substrates 3e (s = 97) and 3f (s = 68).[12,13]
The recovered enantioenriched carbonates (S)-1 proved to
be suitable substrates for stereospecific substitution in the
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10.1002/anie.201903090
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COMMUNICATION
presence of 2 and an iridium catalyst derived from achiral ligand
L2 (Scheme 1) providing optically active amide adducts (S)-3
(Scheme 4).[14] All allylic carbonates underwent stereospecific
substitution with high enantiospecificity (>93% es) and good
yields.
configuration; hence, the correct product enantiomer would form
corresponding endo isomer, presumably after rapid equilibration.
To establish the catalytic competence of the isolated
intermediate, I-1 was employed as catalyst under standard
reaction conditions. Complex I-1 effected the stereospecific
substitution of allyl carbonate (S)-1b in yields comparable to
catalyst formed in situ from [Ir(cod)Cl]2 and L2 (Scheme 5b).
Scheme 3. Substrate scope of stereospecific substitution of allylic carbonates
with morpholine ketene aminal 2. Unless otherwise noted, all reactions were
performed on 0.2 mmol scale, with 1.2 equiv of 2 and 2.6 equiv of Et3N. Yields
refer to isolated products after purification by column chromatography on silica
gel. The es values were determined by SFC or GC analysis on a chiral
stationary phase. [a]Conducted at 2 mmol scale.
During the course of our studies, we identified an unknown
intermediate, which formed during the reaction and ultimately
converted to product 3 upon acid work-up. We hypothesized that
a substituted morpholine ketene aminal I-3 would form as a
primary product.[15] We anticipated such an intermediate I-3 to
be sufficiently nucleophilic to be trapped using an external
electrophile. Accordingly, when the standard reaction was
terminated through the addition of aromatic acyl chloride, the
major product isolated corresponded to the resulting trapping
product 4.[12,16] In a similar fashion, when a reaction is treated
with allyl alcohol instead of standard work up, the Eschenmoser-
Claisen 5 product is observed, exhibiting that the intermediate
generated in our reaction has similar reactivity to the morpholine
ketene aminal.[10,12]
To gain further insight into the η3-allyl IrIII intermediates with
achiral ligand L2, we formed iridium-L2 complex in the presence
of an allylic alcohol.[17] Subsequent treatment with acid led to the
formation of an Ir(III) species I-1 as evidenced by 31P{1H}-NMR.
The exact nature of this structure could be confirmed by single-
crystal X-ray diffraction (Scheme 5). The solid-state structure of
I-1 shows the substrate bound in a η3-fashion, with two L2
bound to iridium either in a chelating fashion or solely through
phosphorous, respectively. The η3-allyl is bound with exo-
Scheme 5. Proposed mechanistic pathway and X-ray of iridium-complex I-1.
Compounds 4 and 5 were obtained using allylic carbonate 1a as substrate. I-1
was obtained with ortho-nitro substituted substrate.[12] Thermal ellipsoids are
shown at 30% probability. Selected hydrogen atoms, non-coordinating
counterions, and co-crystallized solvent molecules have been omitted for
clarity.
To showcase the synthetic utility of this method we
subjected the morpholine amide products to further synthetic
manipulations (Scheme 6). In analogy to the corresponding
Weinreb amides, morpholine amides can undergo Grignard
addition as demonstrated in the formation of ketone 6.[18,19]
Additionally, morpholine amide (S)-3b (99% ee) could be
converted to acyl silane 7, which is a versatile building block that
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COMMUNICATION
[6]
[7]
a) S. Mathias, D. Pierre, H. Günter, Angew. Chem. Int. Ed. 2006, 45,
2466; b) P. Dübon, M. Schelwies, G. Helmchen, Chem.–Eur. J. 2008,
14, 6722.
upon addition of a strong nuclephile has been shown to serve as
precursors for Brook rearrangements.[20] Moreover, the
morpholine amide products can also be smoothly reduced to
yield amines with a stereocenter at γ-position (8, Scheme 6).[21]
Following a procedure described by the Helmchen group,[6] we
synthesized known compound 9 via a Grignard addition and
subsequent ring closing metathesis in 45% overall yield and
98% ee. Notably, no erosion of enantiomeric excess was
observed in any transformation, with the exception of compound
7.
a) K. Zhang, Q. Peng, X. L. Hou, Y. D. Wu, Angew. Chem. Int. Ed.
2008, 47, 1741; For examples of other similar nucleophiles such as
lactams or oxindoles see: b) D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D.
E. White, S. C. Virgil, B. M. Stoltz, Nat. Chem. 2012, 4, 130; c) K. M.
Korch, C. Eidamshaus, D. C. Behenna, S. Nam, D. Horne, B. M. Stoltz,
Angew. Chem. Int. Ed. 2015, 54, 179; d) B. M. Trost, M. U. Frederiksen,
Angew. Chem. Int. Ed. 2005, 44, 308; e) K. Balaraman, C. Wolf, Angew.
Chem. Int. Ed. 2017, 56, 1390.
[8]
For different examples developed recently in our group see: a) T.
Sandmeier, S. Krautwald, E. M. Carreira, Angew. Chem. Int. Ed. 2017,
56, 11515; b) J. Y. Hamilton, S. L. Rössler, E. M. Carreira, J. Am.
Chem. Soc. 2017, 139, 8082; c) M. A. Schafroth, S. M. Rummelt, D.
Sarlah, E. M. Carreira, Org. Lett. 2017, 19, 3235; d) T. Sandmeier, S.
Krautwald, H. F. Zipfel, E. M. Carreira, Angew. Chem. Int. Ed. 2015, 54,
14363; e) J. Y. Hamilton, D. Sarlah, E. M. Carreira, Angew. Chem. Int.
Ed. 2015, 54, 7644; f) S. Breitler, E. M. Carreira, J. Am. Chem. Soc.
2015, 137, 5296; g) Y. Sempere, E. M. Carreira, Angew. Chem. Int. Ed.
2018, 57, 7654.
[9]
D. H. R. Barton, G. Hewitt, P. G. Sammes, J Chem Soc C 1969, 16.
[10] S. N. Gradl, J. J. Kennedy-Smith, J. Kim, D. Trauner, Synlett 2002, 411.
[11] H. Baganz, L. Domaschke, Chemische Berichte 1962, 95, 2095.
[12] For more details, see Supporting Information.
Scheme 6. Elaboration of morpholine amide products. [a]Absolute
stereochemistry determined by comparison with literature [measured: (c = 0.42,
CHCl3): –278, reported: (c = 0.51, CHCl3, 97% ee): –284].[6b] GC-II = Grubb´s
catalyst 2nd generation.
[13] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249. For
calculated s-factors see Supporting Information.
[14] Absolute configuration of recovered starting materials determined by
comparison with literature known compounds: J. Štambaský, A. V.
Malkov, P. Kočovský, J. Org. Chem. 2008, 73, 9148; and ref. 8f.
[15] Compound I-3 has been detected in the crude 1H-NMR of different
samples. But our attempts to purify it were never successful due to its
prompt hydrolysis to the corresponding amide product.
In summary, we have disclosed an asymmetric allylic
alkylation that enables the preparation of β-substituted γ,δ-
unsaturated amides. Morpholine ketene aminal was shown to be
competent nucleophile for the allylic alkylation reaction in both a
kinetic resolution and stereospecific substitution. This method
presents a new approach to the challenging iridium catalyzed
allylic alkylation of amide enolates. We have demonstrated that
the morpholine amide products can be further transformed to the
corresponding ketones, acyl silanes or amines in high
enantiomeric excess.
[16] A. Armati, P. De Ruggieri, E. Rossi, R. Stradi, Synthesis 1986, 573.
[17] For a detailed mechanism study involving chiral phosphoramidite ligand
L1, see: S. L. Rössler, S. Krautwald, E. M. Carreira, J. Am. Chem. Soc.
2017, 139, 3603.
[18] S. Nahm, S. M. Weinreb, Tetrahedron Letters 1981, 22, 3815.
[19] For some examples of Grignards additions to morpholine amides, see:
a) Z. Yu, R. J. Ely, J. P. Morken, Angew. Chem. Int. Ed. 2014, 53,
9632; b) S. R. Borkar, N. Bokolia, I. S. Aidhen, I. A. Khan, Tetrahedron
Asymmetry 2017, 28, 186; c) Y.-H. Chen, M. Ellwart, G. Toupalas, Y.
Ebe, P. Knochel, Angew. Chem. Int. Ed. 2017, 56, 4612.
Acknowledgements
ETH Zürich and the Swiss National Science Foundation
(200020_152898) are gratefully acknowledged for financial
support. We thank Dr. M.-O. Ebert, R. Arnold, R. Frankenstein
and S. Burkhardt of the NMR service and Dr. N. Trapp and M.
Solar of the X-ray crystallography service for their assistance.
[20] C. T. Clark, B. C. Milgram, K. A. Scheidt, Org. Lett. 2004, 6, 3977.
[21] N. Assimomytis, Y. Sariyannis, G. Stavropoulos, P. G. Tsoungas, G.
Varvounis, P. Cordopatis, Synlett 2009, 2777.
Keywords: Iridium • amide • allylation • enantioselective •
synthesis
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Entry for the Table of Contents (Please choose one layout)
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Yeshua Sempere, Jan Alfke, Simon
Rössler, Erick M.Carreira*
Page No. – Page No.
Morpholine Ketene Aminal as Amide
Enolate Surrogate in Iridium-
Catalyzed Asymmetric Allylic
Alkylation
Morpholine ketene aminal is employed in iridium-catalyzed asymmetric allylic
alkylation reactions as surrogate for amide enolates to prepare γ,δ-unsaturated β-
substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific
substitution affords the corresponding products in high enantiomeric excess.
Moreover, (η3-allyl)iridium(III) species with achiral P,Olefin-ligand was synthetized
and characterized for the first time.
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