Catalytic Enantio- and Diastereoselective Mannich Addition of TosMIC to Ketimines

Article abstract of DOI:10.1002/chem.201804099

Chiral amines bearing a stereocenter in the α position are ubiquitous compounds with many applications in the pharmaceutical and agrochemical sectors, as well as in catalysis. Catalytic asymmetric Mannich additions represent a valuable method to access such compounds in enantioenriched form. This work reports the first enantio- and diastereoselective addition of commercially available p-toluenesulfonylmethyl isocyanide (TosMIC) to ketimines, affording 2-imidazolines bearing two contiguous stereocenters, one of which is fully-substituted, with high yields and excellent stereocontrol. The reaction, catalyzed by silver oxide and a dihydroquinine-derived N,P-ligand, is broad in scope, operationally simple, and scalable. Derivatization of the products provides enantioenriched vicinal diamines, precursors to NHC ligands and sp³-rich heterocyclic scaffolds. Computations are used to understand catalysis and rationalize stereoselectivity.

Full text of DOI:10.1002/chem.201804099

A Journal of
Accepted Article
Title: Catalytic Enantio- and Diastereoselective Mannich Addition of
TosMIC to Ketimines
Authors: Darren James Dixon, Allegra Franchino, Jack Chapman,
Ignacio Funes-Ardoiz, and Robert Paton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201804099
Link to VoR: http://dx.doi.org/10.1002/chem.201804099
Supported by

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
Catalytic Enantio- and Diastereoselective Mannich Addition of
TosMIC to Ketimines
Allegra Franchino,[a] Jack Chapman,[a] Ignacio Funes-Ardoiz,[b] Robert S. Paton*[a] and Darren J.
Dixon*[a]
Abstract: Chiral amines bearing a stereocenter in the α position are
ubiquitous compounds with many applications in the pharmaceutical
and agrochemical sectors, as well as in catalysis. Catalytic
asymmetric Mannich additions represent a valuable method to
access such compounds in enantioenriched form. Herein, we report
the first enantio- and diastereoselective addition of commercially
available p-toluenesulfonylmethyl isocyanide (TosMIC) to ketimines,
affording 2-imidazolines bearing two contiguous stereocenters, one
of which is fully-substituted, with high yields and excellent
available, practically odorless, stable, crystalline solid. Its use in
organic synthesis has been pioneered in the 1970s by Van
Leusen and co-workers.[10] Despite the multifaceted chemistry of
TosMIC, only three catalytic enantioselective aldol reactions of
this isocyanide have been reported.[11] In 2015 Cozzi and co-
workers described the first, and to date only, catalytic
enantioselective addition of TosMIC to ketones (Scheme 1b).[11c]
Surprisingly, no enantioselective Mannich reaction of TosMIC
has yet been reported, and therefore the potential utility of this
practical, versatile N-containing building block for the synthesis
of chiral amines has remained untapped. To this end, we aimed
to develop such an enantioselective Mannich reaction using
ketimine pronucleophiles. We hoped that our Ag(I)/amino
phosphine combination (Scheme 1c) would provide both the
necessary reactivity and stereocontrol and herein we wish to
report our findings.
stereocontrol. The reaction, catalyzed by silver oxide and
a
dihydroquinine-derived N,P-ligand, is broad in scope, operationally
simple and scalable. Derivatization of the products provides
enantioenriched vicinal diamines, precursors to NHC ligands and
sp3-rich heterocyclic scaffolds. Computations are used to understand
catalysis and rationalize stereoselectivity.
Amines bearing a fully-substituted stereocentre in the α position
find many applications in the pharmaceutical and agrochemical
industry,[1] as well as in catalysis.[2] Commensurate with their
importance and abundance, numerous methods have been
developed for their preparation,[1,3] among which a prominent
approach exploits the enantioselective addition of carbanion
equivalents to imines derived from prochiral ketones.[4]
Ketimines are much more challenging electrophiles than their
aldimine counterparts, due to their lower electrophilicity and the
more difficult enantiodiscrimination between the two prochiral
faces.[4d-e] Nevertheless, in recent years impressive progress in
the development of catalytic enantioselective additions of
various pronucleophiles to ketimines has been made.[4,5] Within
this context, our group has developed a catalytic system
comprising a basic silver(I) salt and a cinchona-derived amino
phosphine ligand, able to promote the highly diastereo- and
enantioselective addition of isocyanoacetate esters to
aldehydes[6] ketones[7] and ketimines (Scheme 1a).[8]
Scheme 1. Catalytic enantio- and diastereoselective aldol and Mannich
reactions of activated isocyanides affording products with a fully-substituted
stereocenter. (a, b): Previous work. (c): This work.
Wishing to extend the structural diversity of compounds
accessible with this chemistry, we became interested in
expanding the scope of the pronucleophile component. Among
activated isocyanides,[9] i.e. possessing an electron-withdrawing
group in the α position, p-toluenesulfonylmethyl isocyanide
(TosMIC) presents a series of advantages that were particularly
attractive. Unlike most isocyanides, TosMIC is a commercially
A model reaction between N-diphenylphosphinoyl (N-DPP)
acetophenone-derived ketimine 3a and TosMIC was initially
investigated in ethyl acetate as solvent, using 5 mol% silver
oxide and 10 mol% dihydroquinine-derived ligand 1b (Table 1).
After 24 hours at room temperature the desired trans imidazoline
5a was obtained as a single diastereomer with very good yield
and enantiocontrol (89% yield, 84% ee, Entry 1). Lowering the
temperature to 0 °C improved both yield and enantioselectivity
(98% yield, 94% ee, Entry 2). At this temperature, decreasing
[a]
Dr. A. Franchino, J. Chapman, Prof. Dr. R. S. Paton, Prof. Dr. D. J.
Dixon - Department of Chemistry, Chemistry Research Laboratory
University of Oxford, 12 Mansfield Road, Oxford OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk; robert.paton@chem.ox.ac.uk
Dr I. Funes-Ardoiz - Institute of Chemical Research of Catalonia
(ICIQ), Av. Països Catalans 16, Tarragona, Spain
the Ag2O loading had
a
slight detrimental effect on
enantiocontrol (Entry 3), whereas dilution of the reaction mixture
increased the ee of the product to 96% (Entry 4). The use of 10
mol% silver acetate in conjunction with 10 mol % 1b promoted
the reaction with comparable enantioselectivity but diminished
yield, owing to a competitive cyclodimerization of TosMIC to
imidazole 6.[12]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
Table 1. Optimization of the silver-catalyzed enantioselective Mannich
reaction of ketimine 3a and TosMIC.
analogy. NOe experiments carried out on products 5o and 5q,
and separately on both diastereomers of imidazolines 5k and 5l
confirmed the relative trans stereochemistry also for
imidazolines with aliphatic and heteroaromatic substituents.
Conc
[M]
Loading
[mol%]
Entry
T [°C]
Ag(I)
Yield [%][a]
ee [%][b]
1
2
3
4
5
0.25
0.25
0.25
0.1
20
0
Ag2O
Ag2O
Ag2O
Ag2O
AgOAc
5
89
98
97
98
74
84
94
92
96
97
5
0
2.5
5
0
0.1
0
10
[a] Isolated yield for the trans diastereomer after FCC. [b] ee for the trans
diastereomer determined by HPLC on chiral stationary phase.
With optimal conditions established, substituents on the N-DPP
ketimine were systematically varied to assess the substrate
scope of the methodology (Scheme 2). All reactions proceeded
to full conversion within 24 hours yielding the trans imidazoline
as the only or largely major product (dr of the crude reaction
mixture ≥ 90:10). Aryl methyl ketimines with electron-donating
groups (OMe), as well as electron-withdrawing substituents (F,
Cl, Br) in the para, meta and ortho positions afforded products
5b-h with high yields and excellent enantiocontrol (86–97%
yield, 86–97% ee). While the small fluoro substituent in ortho
position was well-tolerated, a double loading of both ligand and
Ag2O was required to ensure full conversion for the reaction of
ketimine 3d bearing an o-methoxyphenyl group. Heteroaromatic
ketimines reacted smoothly and importantly imidazolines with 4-
pyridyl, 3-pyridyl and 2-pyridyl substituents were prepared in 86–
99% yield and 90–95% ee (5i-k). Products 5l and 5m with 2-
furanyl and 2-thienyl substitutents were obtained in 82% yield
and 98% ee, 98% yield and 96% ee, respectively. In addition, it
was possible to increase the length of the alkyl chain on the
ketimine delivering product 5n with a n-propyl group in 88% yield
and 93% ee; interestingly, a phenyl isobutyl ketimine with a β-
branched alkyl chain was completely unreactive. Aliphatic
ketimines with primary, secondary and even tertiary alkyl groups
were competent electrophiles. Aliphatic ketimines with phenethyl
and cyclohexyl substituents afforded products 5o and 5p in very
high yield and ee. Forcing conditions were necessary to
accomplish the addition of TosMIC to tert-butyl methyl ketimine,
obtaining 5q in 51% yield and 83% ee, still a remarkable result
considering the steric and electronic deactivation of this
substrate.[13]
Scheme 2. Substrate scope for the catalytic diastereo- and enantioselective
addition of TosMIC to N-DPP ketimines. Dr (trans:cis) of the crude reaction
mixture determined by 1H NMR analysis. Isolated yields and ee given for the
trans diastereomer after FCC. ORTEP diagram for 5e with ellipsoids at 50%
probability level. [a] With 20 mol% 1b and 10 mol% Ag2O. [b] At 0.25 M
concentration for 120.
As well as being operationally simple, the catalytic
enantioselective reaction between ketimine 3a and TosMIC also
proved to be scalable. While the substrate scope was conducted
on a 0.25 mmol scale, reoptimization for preparative scale (10
mmol) allowed for a reduction in the catalyst loading to 2 mol%
and a relaxation of the strictly anhydrous conditions. Thus,
nearly stoichiometric amounts of the two reagents were mixed
with 2 mol% 1b and 1 mol% silver oxide in ethyl acetate and
stirred at room temperature under air in an open vessel for 24
hours, to obtain a full conversion to the trans imidazoline. After
dilution and filtration of the crude reaction mixture to remove
insoluble silver residues, the filtrate was conveniently purified by
recrystallization. This conveniently resulted in a concomitant
augmentation of the enantiomeric excess, thus delivering the
desired product 5a in 78% yield and greater than 99.5% ee
(Scheme 3).
Single crystal X-ray diffraction allowed the determination of the
absolute configuration for the major enantiomer of imidazoline
5e (4S,5S, Scheme 2);[14] the relative and absolute
configurations of the other reaction products were assigned by
This article is protected by copyright. All rights reserved.

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
hydrogenated side chain showed slightly lower reactivity and
enantioselectivity (entries 2 and 3). Ligand 1d devoid of the
phosphine moiety delivered the product in only 8% yield and in
racemic form (entry 4), and the addition of 10 mol% exogenous
triphenylphosphine did not improve its performance significantly
(entry 5), highlighting the importance of a bidentate N,P-ligand
for reactivity and stereocontrol. Amino phosphine 1e with a
methylated amide linker promoted the reaction with diminished
reactivity, and lower diastereo- and enantioselectivity (61%
conversion, 83:17 dr, 88% ee, entry 6), suggesting that the NH
of the linker plays a role in the reaction.[8b] Ligand 1f possessing
an ester linker afforded product ent-5a in 50% yield with 90% ee
(entry 7): replacement of the NH group by an O atom decreased
the reactivity and imparted a switch in the enantiofacial
selectivity for both reaction partners, even if ligands 1b and 1f on
their own display nearly superimposable crystal structures.[14]
Scheme 3. Multigram synthesis of imidazoline 5a (40-fold scale-up).
With gram quantities of enantiopure imidazoline 5a in hand,
we focused on its derivatization into useful products to thus
demonstrate the utility of our catalytic enantioselective
methodology (Scheme 4). To this end, treatment of 5a with
excess lithium aluminium hydride removed both the DPP and the
tosyl groups affording 7 in 80% yield without affecting the
enantiopurity. The deprotected imidazoline could be hydrolysed
under basic conditions, obtaining diamine 8, or methylated on
both N atoms to give imidazolium iodide 9, a precursor to a non-
symmetrical N-heterocyclic carbene (NHC). Several acidic
conditions were tried to cleave the DPP group,[15] but the tosyl
group was not stable to the reaction conditions. When the N-
protected imidazoline 5a was treated with aqueous HCl, 4-
hydroxyl imidazolium chloride 10 was obtained as a 3:2 mixture
of epimers at C-4 in 40% yield (single crystal X-ray diffraction of
the trans diastereomer allowed structural identification).[14,16]
Treatment of 10 with sodium hydroxide provided C2-symmetric
dihydropyrazine 12 via dimerization of α-amino aldehyde 11.[17]
A two-step, one-pot procedure was developed to avoid isolation
of 10, obtaining dihydropyrazine 12 in 86% yield from 5a without
ee erosion.
Table 2. Ligand variation.
Entry
Ligand
1a
Conversion (%)[a]
Dr (%)[a]
> 95:5
> 95:5
> 95:5
33:67
68:32
83:17
91:9
Yield (%)[b] ee (%)[b]
1
96
100
81
24
53
61
54
88
98
70
8
92
96
93
0
2
1b
3
1c
4
1d
5[c]
6
1d
34
51
50
−6
88
−90
1e
7
1f
[a] Conversion and dr (trans:cis) were determined by 1H NMR analysis of the
crude reaction mixture, using mesitylene as an internal standard. [b] Isolated
yield and ee of the trans diastereomer. [c] With 10 mol% PPh3.
Scheme 4. Synthetic utility of imidazoline 5a. ORTEP diagram for 10 (trans
diastereomer) shown with ellipsoids at 50% probability level. [a] Ee of diamine
8 determined on the corresponding ditosylamide.
Furthermore, when isolated cis and trans diastereomers of
imidazoline 5l were subjected to the standard reaction
conditions, no epimerization occurred (see SI for details),
indicating that the reaction is not reversible once product
formation has occurred, suggesting that the ligand is able to
impart significant stereoselectivity in the enantiodetermining C–C
bond forming step. To rationalize these observations, quantum
chemical calculations (DFT and QM/MM) were performed.[18]
In order to better understand the importance of the various
functional groups present on amino phosphine 1b, ligands with
structural variations were screened in the model reaction (Table
2). While quinine-derived amino phosphine 1b gave product 5a
in 98% yield and 96% ee (entry 1), cinchonidine-derived 1a,
lacking the methoxy group, and quinine-derived 1c with a non-
This article is protected by copyright. All rights reserved.

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
Based on single crystal X-ray diffraction and NMR studies
providing evidence of complex formation between AgOAc and
N,P-ligand 1b,[8b] we performed a computational analysis of
competing transition structures (TSs) (Figure 2). Since N-DPP
Keywords: Mannich reaction • isocyanides • addition to
ketimines • silver • homogeneous catalysis
[1]
[2]
[3]
[4]
Chiral Amine Synthesis: Methods, Developments and Applications (Ed.:
T. C. Nugent), Wiley, Weinheim, 2010.
ketimines exist as
a mixture of E- and Z-configurated
stereoisomers rapidly interconverting at room temperature,[19] we
examined both configurations computationally. In the most
stable TSs the imine adopts an E-configuration, which is favored
sterically. In addition to N,P-coordination of silver, the ligand
plays a role in substrate activation during C-C bond formation:
the phosphinoyl oxygen was found to coordinate to the amide N-
H proton in addition to Ag in each of the most stable TSs (Fig. 2).
The major TS is perfectly staggered about the forming C-C bond,
whereas steric interactions between the quinuclidine region of
the ligand and the ketimine phenyl group result in a less-stable,
eclipsed, TS forming the minor enantiomer (G‡ 2.3 kcal/mol).
S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003, 103,
2985–3012.
A. K. Mailyan, J. A. Eickhoff, A. S. Minakova, Z. Gu, P. Lu, A. Zakarian,
Chem. Rev. 2016, 116, 4441–4557.
For reviews on catalytic enantioselective additions to C=N bonds, see
(a) A. Cordova, Acc. Chem. Res. 2004, 37, 102–112; (b) G. K. Friestad,
A. K. Mathies, Tetrahedron 2007, 63, 2541–2569; (c) D. Ferraris,
Tetrahedron 2007, 63, 9581–9597; (d) O. Riant, J. Hannedouche, Org.
Biomol. Chem. 2007, 5, 873–888; (e) M. Shibasaki, M. Kanai, Chem.
Rev. 2008, 108, 2853–2873; (f) K. Yamada, K. Tomioka, Chem. Rev.
2008, 108, 2874–2886; (g) S. Kobayashi, Y. Mori, J. S. Fossey, M. W.
Salter, Chem. Rev. 2011, 111, 2626–2704; (h) M. Yus, J. C. González-
Gómez, F. Foubelo, Chem. Rev. 2011, 111, 7774–7854; (i) Science of
Synthesis: Stereoselective Synthesis 2: Stereoselective Reactions of
Carbonyl and Imino Groups, (Vol. Ed.: G. A. Molander), Thieme,
Stuttgart, 2011; (j) T. Akiyama, in Comprehensive Organic Synthesis,
(Ed.: P. Knochel and G. A. Molander), Elsevier, Oxford, 2nd edn, 2014,
vol. 2, p. 629; (k) N. Kumagai, M. Shibasaki, Bull. Chem. Soc. Jpn.
2015, 88, 503–517.
[5]
For selected examples of catalytic enantioselective additions to
ketimines, see: (a) P. Vachal, E. N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012–10014; (b) W. Zhuang, S. Saaby, K. A. Jørgensen, Angew.
Chem. Int. Ed. 2004, 43, 4476–4478; Angew. Chem. 2004, 116, 4576–
4578; (c) Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2007,
129, 500–501; (d) C. Tan, X. Liu, L. Wang, J. Wang, X. Feng, Org. Lett.
2008, 10, 5305–5308; (e) T. Kano, S. Song, Y. Kubota, K. Maruoka,
Angew. Chem. Int. Ed. 2012, 51, 1191–1194; Angew. Chem. 2012, 124,
1217–1220; (f) T. Nishimura, A. Noishiki, G. C. Tsui, T. Hayashi, J. Am.
Chem. Soc. 2012, 134, 5056–5059; (g) S. Nakamura, S. Takahashi, D.
Nakane, H. Masuda, Org. Lett. 2015, 17, 106–109; (h) H. Jang, F.
Romiti, S. Torker, A. H. Hoveyda, Nat. Chem. 2017, 9, 1269–1275; (i) P.
Ortiz, J. F. Collados, R. P. Jumde, E. Otten, S. R. Harutyunyan, Angew.
Chem. Int. Ed. 2017, 56, 3041–3044; Angew. Chem. 2017, 129, 3087–
3090.
Figure 2. Competing C-C forming TSs for major and minor enantiomers for
the reaction between acetophenone-derived N-DPP ketimine and TosMIC
(SMD-M06/6-311++G(d,p)//ONIOM(M06/def2-SVP:UFF).
In summary, we have developed the first enantioselective
addition of the versatile, commercially available p-
toluenesulfonylmethyl isocyanide to ketimines, by using a
Ag(I)/amino phosphine catalytic system. The reaction afforded 2-
imidazolines with high yields and excellent diastereo- and
enantiocontrol, which could be elaborated to vicinal diamines,
precursors to NHC ligands and heterocyclic scaffolds such as
2,5-dihydropyrazines. The transformation was broad in scope,
encompassing several (hetero)aromatic and aliphatic ketimines,
operationally simple and scalable. Computations reveal a
bifunctional catalyst with Ag and N-H groups activating the
electrophile, and rationalize the experimental stereoselectivity.
[6]
[7]
[8]
F. Sladojevich, A. Trabocchi, A. Guarna and D. J. Dixon, J. Am. Chem.
Soc. 2011, 133, 1710–1713.
R. de la Campa, I. Ortín, D. J. Dixon, Angew. Chem. Int. Ed. 2015, 54,
4895; Angew. Chem. 2015, 127, 4977–4980.
a) I. Ortín, D. J. Dixon, Angew. Chem. Int. Ed. 2014, 53, 3462–3465;
Angew. Chem. 2014, 126, 3530–3533; b) R. de la Campa, A. D.
Gammack Yamagata, I. Ortín, A. Franchino, A. L. Thompson, B. Odell,
D. J. Dixon, Chem. Commun. 2016, 52, 10632–10635.
[9]
M. Giustiniano, A. Basso, V. Mercalli, A. Massarotti, E. Novellino, G. C.
Tron, J. Zhu, Chem. Soc. Rev. 2017, 46, 1295–1357.
[10] a) D. Van Leusen, A. M. van Leusen, Org. React. 2001, 57, 417–666;
b) T. Kaur, P. Wadhwa, A. Sharma, RSC Adv. 2015, 5, 52769–52787.
[11] a) M. Sawamura, H. Hamashima, Y. Ito, J. Org. Chem. 1990, 55, 5935–
5936; b) Y. Motoyama, H. Kawakami, K. Shimozono, K. Aoki, H.
Nishiyama, Organometallics 2002, 21, 3408–3416; c) A. R. Keeri, A.
Gualandi, A. Mazzanti, J. Lewinski, P. G. Cozzi, Chem. Eur. J. 2015, 21,
18949–18952.
Acknowledgements
The authors thank the European Union for funding (PhD
fellowship to A.F., FP7/2007–2013, 316955) and Severo Ochoa
(predoctoral training fellowship to I. F.-A., SVP-2014- 0686662).
We thank Dr Adam D. Gammack Yamagata for useful
discussion, Heyao Shi and Dr. Angel Fuentes de Arriba for X-ray
analysis and the Oxford Chemical Crystallography Service for
use of their instrumentation. This work used the RMACC Summit
cluster (NSF ACI-1532235 and ACI-1532236), supported by the
University of Colorado Boulder and Colorado State University.
[12] Cyclodimerization of TosMIC under basic conditions was already
observed: O. H. Oldenziel, D. Van Leusen, A. M. van Leusen, J. Org.
Chem. 1977, 42, 3114–3118.
[13] TosMIC analogues possessing a methyl, ethyl or phenyl group in the α
position were not competent pronucleophiles due to a competitive and
dominant cyclodimerization reaction (see SI). Ketimines possessing an
aldehyde or ketone functional group on the aromatic ring are expected
to undergo competitive oxazoline formation (see references 6, 7 and
11). A nitro group on the aromatic ring of the ketimine may also
This article is protected by copyright. All rights reserved.

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
interfere with the reaction outcome lowering yield and
enantioselectivity, as observed in
a related isocyanoacetate aldol
reaction catalyzed by a Ag2O/cinchonine-derived amino phosphine
system: A. Franchino, P. Jakubec, D. J. Dixon, Org. Biomol. Chem.
2016, 14, 93–96.
[14] CCDC 1840592 (5e), 1840589 (10), 1840590 (1b) and 1840591 (1f)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[15] R. Ramage, D. Hopton, M. J. Parrott, G. W. Kenner, G. A. Moore, J.
Chem. Soc., Perkin Trans. 1 1984, 1357–1370.
[16] The low yield reflects difficulties in the isolation, as the aqueous phase
(1 M HCl) was washed several times with 3:1 CHCl3/i-PrOH to remove
diphenylphosphinic, p-toluenesulfinic and p-toluenesulfonic acids.
[17] The formation of aldehyde 11 is supported by the presence of a peak at
δ 9.45 ppm in the 1H NMR spectrum (CDCl3) of incomplete hydrolysis
reactions; over time the peak disappears converting to 12. In an
analogous fashion, 4-tosyl and 4-alkoxy oxazolines afford α-hydroxy
aldehydes upon acidic treatment: F. J. A. Hundscheid, V. K. Tandon, P.
H. F. M. Rouwette, A. M. van Leusen, Tetrahedron 1987, 28, 5073–
5088.
[18] SMD-M06/6-31G(d)/LANL2DZ(f)//ONIOM(M06/def2-SVP:UFF)
calculations were performed using Gaussian 09 rev. D.01, M. J. Frisch
et al. Gaussian, Inc., Wallingford CT, 2009. Calculations were
performed for the isocyanoacetate aldol reaction [ref. 6] and the present
TosMIC addition to ketimines; furthermore, transition states consistent
with the major enantiomers observed were computed for N-methylated
ligand 1e and ester ligand 1f. Full details are provided in the SI.
[19] S. Masumoto, H. Usuda, M. Suzuki, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2003, 125, 5634–5635.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804099
Chemistry - A European Journal
COMMUNICATION
The first enantio- and diastereoselective addition of TosMIC to (hetero)aromatic and aliphatic ketimines provides imidazolines with two
contiguous stereocenters, that can be elaborated to vicinal diamines, precursors to NHC ligands and sp3-rich heterocyclic scaffolds.
Computations allow to rationalize the stereochemical outcome in reactions catalyzed by silver(I) and a dihydroquinine-derived N,P-ligand.
This article is protected by copyright. All rights reserved.