Copper-Catalyzed Enantioselective Alkylation of Enolizable Ketimines with Organomagnesium Reagents

Article abstract of DOI:10.1002/anie.201609963

Inexpensive and readily available organomagnesium reagents were used for the catalytic enantioselective alkylation of enolizable N-sulfonyl ketimines. The low reactivity and competing enolization of the ketimines was overcome by the use of a copper–phosphine chiral catalyst, which also rendered the transformation highly chemoselective and enantioselective for a broad range of ketimine substrates.

Full text of DOI:10.1002/anie.201609963

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Communications
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International Edition: DOI: 10.1002/anie.201609963
German Edition: DOI: 10.1002/ange.201609963
Asymmetric Catalysis
Copper-Catalyzed Enantioselective Alkylation of Enolizable
Ketimines with Organomagnesium Reagents
Pablo Ortiz, Juan F. Collados, Ravindra P. Jumde, Edwin Otten, and Syuzanna R. Harutyunyan*
Abstract: Inexpensive and readily available organomagne-
sium reagents were used for the catalytic enantioselective
alkylation of enolizable N-sulfonyl ketimines. The low reac-
tivity and competing enolization of the ketimines was over-
come by the use of a copper–phosphine chiral catalyst, which
also rendered the transformation highly chemoselective and
enantioselective for a broad range of ketimine substrates.
selectivity issues described above are particularly challenging
for alkylation, which even now is restricted to the methylation
and ethylation of a small set of activated ketimines.[6]
Since the lower electrophilicity of ketimines is one of the
major problems for this type of chemistry, the use of strong
nucleophiles could be advantageous. Highly reactive organo-
magnesium (Grignard) reagents, which are the most com-
monly used organometallic reagents both in the laboratory
and in industry,[7] would be ideal for tackling the low reactivity
of the ketimines. However, so far Grignard reagents have only
been used in combination with chiral ketimines derived from
the Ellman auxiliary.[3] It is not surprising that they have not
been used more widely for such transformations, as the
uncatalyzed addition of the Grignard reagent is a formidable
competitor. Furthermore, higher nucleophilicity goes hand in
hand with increased basicity, which can cause deprotonation
and thus enamide formation when enolizable ketimines are
used.[8] Consequently, catalytic asymmetric addition reactions
of Grignard reagents to enolizable ketimines have remained
elusive.
=
T
he asymmetric addition of organometallic reagents to C N
double bonds is a fundamentally important transformation
that provides direct access to enantiomerically enriched a-
chiral amines, which are important building blocks in organic
synthesis and abundantly present motifs in biologically active
compounds.[1] Hence, numerous variants of this reaction, with
different imine derivatives and organometallic reagents, have
been tested with the aim of achieving high levels of reactivity
and selectivity.[2]
Among the different approaches for the synthesis of
highly valuable enantiomerically enriched amines, a chiral-
auxiliary strategy involving the use of Ellman tert-butylsulfin-
imines in combination with an organometallic reagent is often
the method of choice.[3] On the other hand, catalytic
asymmetric methods are highly attractive, since only a small
quantity of a precious chiral ligand is needed. In this context,
the first catalytic asymmetric addition of nonstabilized
organometallic reagents to aldimines through Lewis base
activation by Soai et al. and, a few years later, the Lewis acid
activated copper-catalyzed addition of organozinc reagents to
aldimines by Tomioka and co-workers were important step-
s.[4a,b] These initial reports triggered intensive research effort
in this area, and a number of successful catalytic asymmetric
methods for addition to aldimines were developed as
a result.[4c–f,2a,b,d,f] In contrast, progress in the catalytic asym-
metric addition of organometallic reagents to ketimines to
give amines with a tertiary stereogenic center at the a position
has been much slower and remains a challenge owing to the
poorer electrophilicity of ketimines and the more difficult
enantiodiscrimination between the two substituents on the
prochiral azomethine carbon atom.[2b,c,e] Although several
elegant examples of the arylation, alkynylation, and allylation
of ketimines have been reported recently,[5] the reactivity and
Over the past few years, our research group has pursued
the synthesis of chiral molecules by the copper-catalyzed
asymmetric alkylation of conjugated systems and carbonyl
compounds.[9] Herein we report the first catalytic asymmetric
addition of alkyl Grignard reagents to enolizable ketimines.
The corresponding alkylated products were obtained in high
yield with high enantioselectivity.
To address the poor reactivity of the azomethine carbon
atom, we focused on N-sulfonyl- and N-phosphinoyl-pro-
tected ketimines. A model reaction between ketimines 1 and
hexylmagnesium bromide (HexMgBr) was used for the
screening of suitable conditions for the catalytic asymmetric
alkylation of acetophenone-derived imines (Table 1). The
diphenylphosphinoyl-protected ketimine 1a was tested in the
presence of a catalytic system derived from CuBr·SMe2 salt
and the diphosphanylferrocene ligand L1 at À608C.[10] The
chemoselectivity of the reaction was poor, and analysis of the
crude reaction mixture by NMR spectroscopy revealed
a complex mixture of products and ketimine 1a (Table 1,
entry 1). The starting material 1a remained owing to either
incomplete conversion or competing enolization. The crude
reaction mixture also contained a reduction product, the
result of yet another competing reaction through Meerwein–
Ponndorf–Verley reduction of the ketimine.[9c] We were able
to increase the selectivity towards the addition product by
using a Lewis acid mixture composed of BF3·OEt2 and
[*] P. Ortiz, Dr. J. F. Collados, Dr. R. P. Jumde, Dr. E. Otten,
Prof. Dr. S. R. Harutyunyan
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
[9c]
CeCl3 (entry 2). However, the enantioselectivity was low,
and any further attempted optimization with this substrate
was not successful. This result, together with the ease of
hydrolysis of diphenylphosphinoyl imines, led us to explore
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201609963.
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Table 1: Optimization of the reaction conditions.
product was only 42%. Importantly, increasing the reaction
temperature had a positive effect, and at À508C, the
conversion increased to 71% (entry 9). The last reaction
parameter studied was the solvent. It was found that diethyl
ether was a more effective solvent for this system than
MTBE, but that a mixture of both was the optimal reaction
medium (Table 1, entries 10 and 11).
The optimized reaction conditions were applied to a wide
range of aryl alkyl ketimines, and the procedure proved to be
robust, giving excellent results in most cases (Scheme 1).[11]
We first analyzed the effect of the alkyl chain in the imine.
Unexpectedly, the introduction of just one more carbon atom
led to increased reactivity and full conversion to give the
addition product 5a in 90% yield. Even more surprisingly, the
ee value reached 90%. This result was further improved with
ketimine 4b, which bears a propyl chain. The corresponding
amine 5b was isolated in quantitative yield and with excellent
97% ee. This unusual enhancement of the reactivity with an
Entry[a]
Imine L*
T [8C] Solvent
1/2/3 [%][b] ee [%][c]
1
2[d]
3[d]
4
5
6
7
8
9
10
11
1a
1a
1b
1b
1c
1d
1e
1e
1e
1e
1e
L1 À60
L1 À60
toluene
mixture
16:78:6
41:59:0
26:74:0
20:70:10
73:27:0
11:89:0
58:42:0
29:71:0
21:79:0
n.d.
10
30
24
12
30
33
59
62
66
74
toluene
toluene
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
L1 À78
L2 À78
L2 À78
L2 À78
L2 À78
L1 À78
L1 À50
L1 À50
L1 À50
Et2O/MTBE 17:83:0
[a] Reaction conditions: [1]=0.1m, reaction time: 16–20 h, (0.1 mmol),
[b] Conversion was estimated by 1H NMR spectroscopy. [c] The ee value
was determined by HPLC on a chiral stationary phase. [d] Additives
(BF3OEt2/CeCl3, 1 equiv of each) were used. Cy=cyclohexyl, MTBE=
methyl tert-butyl ether.
sulfonamide protecting groups. Moderate conversion and
encouraging enantiodiscrimination were observed in the
addition of HexMgBr to the acetophenone-derived tosyl
ketimine 1b (entry 3). To our regret, extensive screening (see
Table S1 in the Supporting Information) did not reveal
superior ligands. Nevertheless, we found that ligand L2 gave
comparable results to L1, but, interestingly, with better
chemoselectivity, since the formation of the reduction side
product was diminished (Table 1, entry 4). Therefore, further
optimization studies were carried out with ligand L2. To
evaluate the effect of the steric nature of the protecting group,
we tested different sulfonyl protecting groups. Use of the
smaller ketimine 1c with a methanesulfonyl (Ms) group,
instead of ketimine 1b with a toluenesulfonyl (Ts) group,
provided the addition product 2c with lower enantioselectiv-
ity (entry 5). On the other hand, ketimine 1d with a 2,4,6-
trimethylbenzenesulfonyl protecting group underwent the
addition reaction with slightly higher enantioselectivity, but
lower conversion.
Surprisingly, the use of ketimine 1e with a bulkier tert-
butylsulfonyl (Bus) group led to an increase in conversion
towards the addition product to 89% (Table 1, entry 7). At
this stage, L1 was evaluated again, and to our delight it
showed very promising asymmetric induction of 59% ee
(entry 8). However, the conversion towards the addition
Scheme 1. Scope of the reaction with respect to the ketimine substrate.
Reaction conditions: [1a], [4a–r]=0.1m, 16–20 h. Yields are for the
isolated product; ee values were determined by HPLC on a chiral
stationary phase. Absolute configurations were assigned by analogy
with the literature (see the Supporting Information).
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increase in the number of aliphatic carbon atoms in the
for the addition to take place, as addition to dialkyl ketimines
molecule is similar to the improvement observed when
changing from ketimine 1b to 1e. In each case, the effect
can be attributed to the increased solubility of both the
substrate and the corresponding reaction intermediates
formed with the chiral Cu catalyst.[12] Giving further credence
to the trend in the reactivity, product 5c with a butyl chain was
obtained in quantitative yield with 91% ee.
was unsuccessful.
Having established the scope of the reaction with respect
to the ketimine substrate, we turned to the Grignard reagent.
Whereas previously reported addition reactions to ketimines
were restricted to methylation and ethylation, our catalytic
system enabled the addition of a wider variety of alkyl
Grignard reagents. Our methodology enabled the introduc-
tion of Grignard reagents of various chain lengths, such as
ethyl, hexyl, and isopentyl, in quantitative yield with excellent
enantioselectivity (Table 2, entries 1, 2, and 4). Methylmag-
a-Branched imines could not be synthesized because the
corresponding enamine was formed instead. Nevertheless, the
b-branched imine 4d could be prepared and proved to behave
similarly to the ketimines with linear alkyl substituents.
Finally, we determined the configuration of ketimine 4c by
1D NOE experiments and obtained definitive proof by single-
crystal X-ray diffraction (see the Supporting Information).[13]
Next we studied the different substitution patterns of the
aromatic ring of the ketimines. Both electron-rich and
electron-deficient substituents were tolerated by this catalytic
system (Scheme 1). The use of ketimine 4e with a weakly
electron donating methyl group in the para position did not
pose a problem for the reaction, and the corresponding
addition product 5e was isolated in excellent yield (96%) and
enantioselectivity (95% ee). Ketimine 4 f with a strongly
electron donating methoxy group was tolerated as well,
although somewhat lower enantioselectivity was observed
(5 f, 84% ee). In the case of a bromine-substituted ketimine,
the respective product 5g was isolated in quantitative yield
with 94% ee. Similarly, the reaction conditions were also
compatible with the strongly electron withdrawing CF3 group
(products 5h and 5i).
Table 2: Scope of the reaction with respect to the Grignard reagent.
Entry[a]
Product
RMgBr
Yield [%][b]
ee [%][c]
1
2
5b
5s
quant.
quant.
97
91
3
5t
92
99
28
93
4[d]
5u
5
6
5v
quant.
36[e]
91
95
5w
7
5x
81
>99
Steric effects were evaluated next. Not only para-sub-
stituted substrates, but also substrates with a meta substituent
reacted smoothly: The meta-chloro-substituted product 5j
was obtained in excellent yield and enantioselectivity
(Scheme 1). When a fluorine substituent was present in the
ortho position, the corresponding product 5k was obtained in
98% yield with 96% ee. A further increase in steric bulk by
the replacement of the fluorine substituent in the ortho
position with a methyl group made the corresponding
ketimine unreactive. We were particularly interested in
performing this reaction with functionalized ketimines to
give products that would be amenable to further transforma-
tion after the addition of the Grignard reagent. These highly
reactive organometallic reagents are often incompatible with
reactive functional groups; however, remarkably, the chemo-
selectivity was excellent in this case. Imines containing vinyl,
ester, and cyano moieties on the aromatic ring underwent the
addition reaction to give the corresponding products 5l–n in
very good yields with excellent enantioselectivity. Further-
more, the S-, O-, and N-containing heteroaromatic ketimines
4o–q were also found to be highly suitable substrates for this
asymmetric transformation and provided the corresponding
addition products 5o–q in good yields with high enantiose-
lectivity. Finally, we demonstrated that the aromatic ring is
not essential for the system, and that addition to vinyl
ketimines is feasible, as exemplified by the formation of
product 5r, albeit with lower enantioselectivity (61% ee) and
in low yield. However, a p-system does seem to be necessary
[a] Reaction conditions: [4b]=0.1m, 16–20 h. [b] Yield of the isolated
product. [c] The ee value was determined by HPLC on a chiral stationary
phase. [d] The reaction was carried out at À788C. [e] The low yield is due
to impurities present in the Grignard reagent.
nesium bromide, unfortunately, gave the racemic addition
product. An increase in steric hindrance owing to branching
posed a problem and led to the formation of the product in
nearly racemic form when a-branched Grignard reagents
were used and with low enantioselectivity with b-branched
Grignard reagents (entry 3). Functionalized Grignard
reagents, which provide a handle for future transformations,
can be introduced with excellent enantioselectivity, as dem-
onstrated by the reactions in entries 5 and 6 of Table 2.
Finally, phenylethylmagnesium bromide was added smoothly
to yield the product in nearly enantiomerically pure form
(> 99% ee; Table 2, entry 7).
The robustness of the methodology was further evaluated
with the following experiments: The reaction for the synthesis
of 5b was scaled up 40-fold (4 mmol, 1 g) without a change in
the reaction outcome (99% yield, 96% ee). The copper–
ligand complex could be recovered in 91% yield and used in
a subsequent reaction, which gave the product in quantitative
yield with 95% ee. Finally, the catalyst loading could be
reduced from 5 to 1 mol% without compromising the yield
and with only a small decrease in the enantioselectivity
(93% ee).
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In summary, we have developed the first asymmetric
addition of Grignard reagents to enolizable ketimines. The
high reactivity of Grignard reagents has been exploited to
tackle the low reactivity of the ketimines. Remarkably, all
competing reaction pathways, including substrate enolization,
substrate reduction through b-hydride transfer, and non-
catalyzed addition (commonly observed with Grignard
reagents), could be avoided by the use of a highly chemo-
selective chiral copper–phosphine catalyst system.
Acknowledgements
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b) P. Fu, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2008,
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Financial support from the NWO (Vidi and ECHO to S.R.H.)
and the Ministry of Education, Culture and Science (Gravity
program, 024.001.035 to S.R.H.) is acknowledged. Solvias is
acknowledged for the supply of ferrocenyl ligands.
[7] Grignard Reagents—New Developments (Ed: H. G. Richey),
Wiley, Chichester, 2000.
Conflict of interest
[8] The zirconium-catalyzed non-enantioselective addition of
Grignard reagents to N-aryl ketimines has been reported to
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The authors declare no conflict of interest.
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Information for details).
[12] This hypothesis also correlates with the fact that the reaction
mixtures derived from the addition of Grignard reagents to
ketimines 1b–d were heterogeneous, as opposed to those
derived from additions to 4a–o.
Keywords: alkylation · asymmetric catalysis · copper catalysis ·
enolizable ketimines · Grignard reagents
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Manuscript received: October 11, 2016
Revised: December 14, 2016
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
P. Ortiz, J. F. Collados, R. P. Jumde,
E. Otten,
S. R. Harutyunyan*
&&&& — &&&&
Copper-Catalyzed Enantioselective
Alkylation of Enolizable Ketimines with
Organomagnesium Reagents
It’s best to take the Bus: Enolizable,
usually poorly reactive N-sulfonyl ket-
imines underwent catalytic enantioselec-
tive alkylation with inexpensive and read-
ily available organomagnesium reagents
in the presence of a copper–phosphine
chiral catalyst, which also rendered the
transformation highly chemoselective
(see scheme; MTBE=methyl tert-butyl
ether). The tert-butylsulfonyl (Bus) group
was found to be the most suitable
ketimine protecting group.
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