Enantioselective addition of silicon nucleophiles to aldimines using a preformed NHC-copper(i) complex as the catalyst

Article abstract of DOI:10.1002/anie.201402086

A remaining major challenge in the asymmetric addition of silicon nucleophiles to typical prochiral acceptors, the enantioselective 1,2-addition to aldimines, is addressed. Activation of the Si-B bond in the silicon pronucleophile by a copper(I) alkoxide with McQuade's chiral six-membered N-heterocyclic carbene as a supporting ligand releases the silicon nucleophile, which adds to various aldimines with high levels of enantioselectivity. The new method provides a catalytic asymmetric access to α-silylated amines.

Full text of DOI:10.1002/anie.201402086

Angewandte
Chemie
DOI: 10.1002/anie.201402086
Asymmetric 1,2-Addition
Enantioselective Addition of Silicon Nucleophiles to Aldimines Using
a Preformed NHC–Copper(I) Complex as the Catalyst**
Alexander Hensel, Kazuhiko Nagura, Lukas B. Delvos, and Martin Oestreich*
Abstract: A remaining major challenge in the asymmetric
addition of silicon nucleophiles to typical prochiral acceptors,
the enantioselective 1,2-addition to aldimines, is addressed.
ments of chiral a-amino lithium/carbanion pairs have
proven to be a valid alternative.[15] We disclose here the
enantioselective transfer of silicon nucleophiles onto aldi-
mines under copper(I) catalysis, employing Suginomeꢀs
Me2PhSiBpin[16] as the silicon pronucleophile.
The scope of our racemic copper(I)-catalyzed imine
addition is certainly broad as documented by its compatibility
with common protective groups at the aldimine nitrogen atom
and the fact that even selected ketone-derived imines reacted
in decent yields for the first time (Scheme 1).[7] However, our
ꢀ
Activation of the Si B bond in the silicon pronucleophile by
a copper(I) alkoxide with McQuadeꢀs chiral six-membered N-
heterocyclic carbene as a supporting ligand releases the silicon
nucleophile, which adds to various aldimines with high levels
of enantioselectivity. The new method provides a catalytic
asymmetric access to a-silylated amines.
T
he catalytic generation of silicon nucleophiles by trans-
metalation of the Si–B linkage at transition-metal–oxygen
bonds significantly advanced synthetic silicon chemistry.[1,2]
Its impact manifests itself in the development of asymmetric
variants of fundamental carbon–silicon bond-forming reac-
tions, namely conjugate addition[3,4] and allylic substitution.[5]
The 1,4-addition is particularly well investigated, and chiral
diphosphine [RhI-O][3] and NHC [CuI-O][4] complexes have
been identified as suitable catalysts. The latter were also
crucial in solving the problem of regio- and enantiocontrolled
allylic displacements.[5] Interestingly, the enantioselective 1,2-
=
addition of silicon nucleophiles to C X bonds (X = O or NPG
with PG = protective group) proved to be a difficult task. We
had disclosed racemic protocols for both acceptors,[6,7] and
Riant and co-workers recently accomplished the addition to
aldehydes with high levels of enantiocontrol by employing
a preformed chiral diphosphine [CuI-F] complex.[8] For
imines, a catalyst-controlled version is still elusive, and that
may be regarded a remaining major challenge in asymmetric
carbon–silicon bond formation with silicon nucleophiles. The
motif of a-silylated amines is, however, particularly relevant
to the area of silicon-containing peptide isosteres,[9–11] and
current stereoselective approaches usually make use of either
Ellmanꢀs or Davisꢀ sulfinyl group as a chiral auxiliary.[7,12–14]
Using electrophilic silicon, reverse aza-Brook rearrange-
Scheme 1. General copper(I)-catalyzed 1,2-addition of silicon nucleo-
philes to aldimines and ketimines.[7] Tol =4-tolyl.
initial attempts to render this reaction enantioselective with
representative chiral ligands did not meet with success.
Asymmetric induction, if any, was extremely low with
bidentate phosphines and amines, and somewhat higher
enantiomeric excesses obtained with N-heterocyclic carbenes
hinted that these could be the ligands of choice for this
transformation.[17]
Without further progress, we abandoned the project for
a while. In the meantime, we succeeded in the enantioselec-
tive preparation of a-chiral allylic silanes by a copper(I)-
catalyzed allylic substitution using the Si–B reagent.[5a] This
asymmetric reaction had had a track record similar to the
present challenge, and problems were overcome by the use of
the NHC–copper(I) complex L1·CuCl introduced by
McQuade and co-workers.[18] With L1·CuCl and its cognate
L2·CuCl in hand, we returned to the 1,2-addition to aldimines
and tested procedures with catalytic (Method A) and stoi-
chiometric (Method B) in NaOMe in various solvents
(Table 1). Reactions were started at 08C and then slowly
warmed to ambient temperature. This temperature program
was found to bring about the highest enantiomeric excesses;
these were significantly diminished at lower temperatures.
[*] A. Hensel,[+] Dr. K. Nagura,[+] L. B. Delvos, Prof. Dr. M. Oestreich
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
[+] These authors contributed equally to this work.
[**] This research was supported by the Deutsche Forschungsgemein-
schaft (Oe 249/3-2) and the Japanese Society for the Promotion of
Science (postdoctoral fellowship to K.N., 2013–2014). M.O. is
indebted to the Einstein Foundation (Berlin) for an endowed
professorship. We thank Dr. Devendra J. Vyas (Westfꢁlische Wil-
helms-Universitꢁt Mꢀnster) for his initial contributions.
NHC=N-heterocyclic carbene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402086.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Optimization of the reaction conditions.
diastereoselective addition to an imine derived from Davisꢀ
auxiliary but had also been able to assign the adductꢀs
configuration by X-ray analysis as S at the newly formed
stereocenter.[7] Facile oxidation of that sulfinamide to the
sulfonamide allowed for its chemical correlation with the a-
silylated amine emerging from the enantioselective catalysis
[(S,S)-2b!(S)-2a, Scheme 2]. As a result, catalyst L1·CuCl
induces R configuration in the 1,2-addition to sulfonyl-
protected imines.
Entry
Catalyst
Method
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
L1·CuCl
L1·CuCl
L1·CuCl
L1·CuCl
L1·CuCl
L1·CuCl
L1·CuCl
L2·CuCl
A
B
B
B
B
B
A
B
THF
CH2Cl2
THF
81
74
49
67
54
72
69
56
77
68
12
93
60
93
28
87
Scheme 2. Determination of the absolute configuration by chemical
correlation. mCPBA=meta-chloroperbenzoic acid.
Et2O
tBuOMe
toluene
Et2O
With the reaction conditions optimized (Method B in
Et2O), we varied the protective group at the imine nitrogen
atom (Table 2). All reactions were performed with the same
Et2O
[a] Determined after purification by flash chromatography. [b] Deter-
mined by HPLC analysis using a chiral stationary phase.
Table 2: Variation of the protective group at the nitrogen atom.
Results were promising with both Method A in THF (cf.
Scheme 1)[7] and Method B in CH2Cl2 (cf. aforementioned
allylic substitution)[5a] (Table 1, entries 1 and 2). The solvent
had a marked influence on the asymmetric induction. For
Method B, the a-silylated amine formed in good yield and
excellent 93% ee in either Et2O (entry 4) or toluene (entry 6)
but, in contrast to Method A, 12% ee was obtained when
THF was used as the solvent (entry 3 vs. entry 1). Conversely,
Method A was not compatible with Et2O as the solvent, and
the a-silylated amine was formed with 28% ee (entry 7 vs.
entry 4). We cannot explain why the different methods display
such a dramatic solvent dependence. Also, the level of
enantiocontrol was highly dependent on several unidentified
parameters, including the quality of the Si–B reagent and the
base. The reaction in Et2O (entry 4) was repeated multiple
times, and enantiomeric excesses ranged from 91% to 95%,
provided the use of freshly distilled Si–B reagent and
a relatively new homemade batch of NaOMe. Riant and co-
workers had also reported reproducibility issues in their
copper(I)-catalyzed synthesis of enantioenriched a-silylated
alcohols.[8] Neither these authors nor we are currently able to
rationalize these observations. Catalyst L2·CuCl was no
improvement over L1·CuCl (entry 8 vs. entry 4) although
McQuade and co-workers had found the former to be
superior in allylic substitution.[18c]
Entry Aldimine PG
a-Silylated amine Yield [%][a] ee [%][b]
1
2
3
4
5
6
1a
1c
1d
1e
1 f
1g
SO2Tol
P(O)Ph2
C(O)OtBu
Ph
CH2Ph
CHPh2
(R)-2a
2c
85
59
91
90
37
28
n.d.
–
2d
2e
2f
2g
76
10[c]
traces[c]
[d]
–
[a] Determined after purification by flash chromatography. [b] Deter-
mined by HPLC analysis using chiral stationary phases. [c] Conversion
estimated by 1H NMR spectroscopy to be less than 50%. [d] No
conversion. n.d.=not determined.
batch of reagents to ensure comparability within the screen-
ing. Imines 1a, 1c, and 1d with electron-withdrawing
protective groups cleanly yielded the a-silylated amines 2a,
2c, and 2d (entries 1–3), whereas 1e–1g with phenyl and
benzyl/benzhydryl substitution reacted poorly (entries 4–6).
The latter results distinguish the L1·CuCl catalyst from the
highly reactive CuCN/NaOMe/MeOH combination without
added ligand (cf. Scheme 1).[7] Enantiomeric excesses were
equally high with the SO2Tol and P(O)Ph2 groups, and we
continued using the former with its assigned absolute config-
uration.
Our attempts to crystallographically establish the absolute
configuration of the a-silylated amine failed. It crystallized as
its racemate, even from highly enantioenriched samples, and
crystals would not grow from the corresponding mother
liquors containing essentially enantiomerically pure material.
We had fortunately not only accomplished the related
The catalyst emerged as tolerant of electronic as well as
steric variation of the aryl group at the imine carbon atom
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 3: Substrate scope.
Entry Aldimine
R
a-Silylated amine Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
p-MeC6H4
p-ClC6H4
(R)-14a
(R)-15a
(R)-16a
(R)-17a
(R)-18a
(R)-19a
(R)-20a
(R)-21a
(R)-22a
(R)-23a
(R)-24a
76
94
90
95
79
91
98
85
95
85
52
89
62
p-BrC6H4
p-MeOC6H4
p-CF3C6H4
o-MeC6H4
o-BrC6H4
1-naphthyl
cyclohexyl
isopropyl
sec-butyl
63[c]
54
71
83
76[c]
85
9
10
11
32
65
52
Scheme 3. Effect of the silicon nucleophile: Me2PhSiBpin versus
MePh2SiBpin.
[a] Determined after purification by flash chromatography. [b] Deter-
mined by HPLC analysis using chiral stationary phases. [c] Performed in
toluene instead of Et2O for better solubility; yields are lower in the latter
but enantiomeric excesses are unchanged.
aldimines or even ketimines. The enantioselective 1,2-addi-
tion to these acceptors is one of the future challenges.
Received: February 4, 2014
Published online: && &&, &&&&
(Table 3, entries 1–8). Yields and enantiomeric excesses were
unaffected by substitution in the para position, except for the
electron-donating methoxy substituent (Table 3, entries 1–5).
The situation was similar for ortho substitution (entries 6 and
7), including an a-naphthyl group (entry 8). It was merely the
poor solubility of the aryl halides in Et2O that was detrimen-
tal; changing the solvent to toluene improved these yields
without any effect on enantioinduction (entries 3 and 7). The
same protocol also allowed for the enantioselective 1,2-
addition to aliphatic aldimines (Table 3, entries 9–11) but
results were mixed.[19] For example, aldimines with secondary
alkyl groups reacted either with good enantioselectivity
(entry 9) or in good yield (entry 10). In turn, good 89% ee
but moderate 52% yield were obtained for a substrate with
a primary alkyl group as a substituent (entry 11).
Keywords: asymmetric catalysis · carbene ligands · copper ·
.
silicon · transmetalation
ꢀ
[1] For a general review of Si B bond activation, see: M. Oestreich,
E. Hartmann, M. Mewald, Chem. Rev. 2013, 113, 402 – 441.
ꢀ
[2] For a brief review of Si B bond activation through trans-
metalation, see: E. Hartmann, M. Oestreich, Chim. Oggi 2011,
29, 34 – 36.
[3] a) C. Walter, G. Auer, M. Oestreich, Angew. Chem. 2006, 118,
5803 – 5805; Angew. Chem. Int. Ed. 2006, 45, 5675 – 5677; b) C.
Walter, M. Oestreich, Angew. Chem. 2008, 120, 3878 – 3880;
Angew. Chem. Int. Ed. 2008, 47, 3818 – 3820; c) C. Walter, R.
Frçhlich, M. Oestreich, Tetrahedron 2009, 65, 5513 – 5520; d) E.
Hartmann, M. Oestreich, Angew. Chem. 2010, 122, 6331 – 6334;
Angew. Chem. Int. Ed. 2010, 49, 6195 – 6198; e) E. Hartmann, M.
Oestreich, Org. Lett. 2012, 14, 2406 – 2409.
[4] a) K.-s. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898 –
2900; b) H. Y. Harb, K. D. Collins, J. V. Garcia Altur, S. Bowker,
L. Campbell, D. J. Procter, Org. Lett. 2010, 12, 5446 – 5449; c) K.-
s. Lee, H. Wu, F. Haeffner, A. H. Hoveyda, Organometallics
2012, 31, 7823 – 7826; d) V. Pace, J. P. Rae, H. Y. Harb, D. J.
Procter, Chem. Commun. 2013, 49, 5150 – 5152; e) V. Pace, J. P.
Rae, D. J. Procter, Org. Lett. 2014, 16, 476 – 479.
[5] a) L. B. Delvos, D. J. Vyas, M. Oestreich, Angew. Chem. 2013,
125, 4748 – 4751; Angew. Chem. Int. Ed. 2013, 52, 4650 – 4653
(enantioselective); b) M. Takeda, R. Shintani, T. Hayashi, J. Org.
Chem. 2013, 78, 5007 – 5017 (enantioselective); c) C. K. Hazra,
M. Oestreich, Eur. J. Org. Chem. 2013, 4903 – 4908 (diastereo-
selective); d) D. J. Vyas, M. Oestreich, Angew. Chem. 2010, 122,
8692 – 8694; Angew. Chem. Int. Ed. 2010, 49, 8513 – 8515
(racemic).
We also tested bulkier MePh2SiBpin[16] as a pronucleophile
where one of the methyl groups of Me2PhSiBpin is replaced
by a phenyl group. There are no examples of its use in
enantioselective transformations involving transmetalation.[1]
It added cleanly to the sulfonyl-protected aldimine but the
level of enantiocontrol and the yield were significantly lower
(Scheme 3, top). We explain this sharp decrease in asymmet-
ric induction (91% ee for Me2PhSiBpin vs. 60% ee for
MePh2SiBpin) with the increased steric congestion around
the silicon atom and copper(I) center in L1·CuSiMePh2
(Scheme 3, bottom). The transition state of the imine addition
is likely to be less compact than that involving L1·CuSiMe2Ph.
In summary, we have reported herein the enantioselective
transfer of silicon nucleophiles onto aldimines, affording a-
silylated amines in a catalyst-controlled reaction for the first
time. The new method closes a gap in synthetic silicon
chemistry. The chiral precatalyst, the NHC–copper(I) com-
plex L1·CuCl developed by McQuade and co-workers, is not
sufficiently reactive to promote addition to less-activated
[6] C. Kleeberg, E. Feldmann, E. Hartmann, D. J. Vyas, M.
Oestreich, Chem. Eur. J. 2011, 17, 13538 – 13543.
[7] D. J. Vyas, R. Frçhlich, M. Oestreich, Org. Lett. 2011, 13, 2094 –
2097.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[8] V. Cirriez, C. Rasson, T. Hermant, J. Petrignet, J. Dꢁaz ꢂlvarez,
K. Robeyns, O. Riant, Angew. Chem. 2013, 125, 1829 – 1832;
Angew. Chem. Int. Ed. 2013, 52, 1785 – 1788.
[9] For an authoritative review, see: a) S. M. Sieburth, C.-A. Chen,
Eur. J. Org. Chem. 2006, 311 – 322; b) S. M. Sieburth, T. Nittoli,
A. M. Mutahi, L. Guo, Angew. Chem. 1998, 110, 845 – 847;
Angew. Chem. Int. Ed. 1998, 37, 812 – 814; c) M. W. Mutahi, T.
Nittoli, L. Guo, S. M. Sieburth, J. Am. Chem. Soc. 2002, 124,
7363 – 7375.
acetone-derived sulfinyl imine.[13a] Our copper(I)-catalyzed pro-
tocol is indeed applicable to ketimines yet not with a chiral
auxiliary at the imine nitrogen atom.[7] Lu and co-workers
recently elaborated a racemic one-pot synthesis of fully sub-
stituted a-silylated amines by the sequential addition of silicon
and carbon nucleophiles to imidates: X.-J. Han, M. Yao, C.-D.
Lu, Org. Lett. 2012, 14, 2906 – 2909.
[15] a) C. Barberis, N. Voyer, Tetrahedron Lett. 1998, 39, 6807 – 6810;
b) S. M. Sieburth, H. K. OꢀHare, J. Xu, Y. Chen, G. Liu, Org.
Lett. 2003, 5, 1859 – 1861; c) G. Liu, S. M. Sieburth, Org. Lett.
2003, 5, 4677 – 4679.
[16] M. Suginome, T. Matsuda, Y. Ito, Organometallics 2000, 19,
4647 – 4649.
[17] D. J. Vyas, Dissertation, Westfꢅlische Wilhelms-Universitꢅt
Mꢆnster, 2011.
[18] a) J. K. Park, D. T. McQuade, Synthesis 2012, 1485 – 1490; for its
[10] For an account discussing various strategies to prepare silicon-
containing peptide isosteres, see: G. K. Min, D. Hernꢃndez, T.
Skrydstrup, Acc. Chem. Res. 2013, 46, 457 – 470.
[11] a) For a review of silicon-containing a-amino acids: M. Morten-
sen, R. Husmann, E. Veri, C. Bolm, Chem. Soc. Rev. 2009, 38,
1002 – 1010; b) for a recent review of silicon-containing mole-
cules with medical applications, see: A. K. Franz, S. O. Wilson, J.
Med. Chem. 2013, 56, 388 – 405; c) for a comprehensive (early)
summary of the chemistry and biology of a-silylated amines, see:
J.-P. Picard, Adv. Organomet. Chem. 2005, 52, 175 – 375.
[12] D. M. Ballweg, R. C. Miller, D. L. Gray, K. A. Scheidt, Org. Lett.
2005, 7, 1403 – 1406.
ꢀ
successful application in B B bond activation, see: b) J. K. Park,
H. H. Lackey, M. D. Rexford, K. Kovnir, M. Shatruk, D. T.
McQuade, Org. Lett. 2010, 12, 5008 – 5011 (conjugate addition);
c) J. K. Park, H. H. Lackey, B. A. Ondrusek, D. T. McQuade, J.
Am. Chem. Soc. 2011, 133, 2410 – 2413; d) J. K. Park, D. T.
McQuade, Angew. Chem. 2012, 124, 2771 – 2775; Angew. Chem.
Int. Ed. 2012, 51, 2717 – 2721 (allylic substitution).
[13] a) L. Nielsen, K. B. Lindsay, N. C. Nielsen, T. Skrydstrup, J. Org.
Chem. 2007, 72, 10035 – 10044; b) L. Nielsen, T. Skrydstrup, J.
Am. Chem. Soc. 2008, 130, 13145 – 13151; c) D. Hernꢃndez, K. B.
Lindsay, L. Nielsen, T. Mittag, K. Bjerglund, S. Friis, R. Mose, T.
Skrydstrup, J. Org. Chem. 2010, 75, 3283 – 3293; d) D. Hernꢃn-
dez, L. Nielsen, K. B. Lindsay, M. A. Lꢄpez-Garcꢁa, K. Bjer-
glund, T. Skrydstrup, Org. Lett. 2010, 12, 3528 – 3531; e) D.
Hernꢃndez, R. Mose, T. Skrydstrup, Org. Lett. 2011, 13, 732 –
735; f) Y. Bo, S. Singh, H. Q. Duong, C. Cao, S. M. Sieburth, Org.
Lett. 2011, 13, 1787 – 1789.
[19] Enolizable aliphatic imines are known to be problematic
substrates in 1,2-addition reactions: for a review of asymmetric
alkylation of imines, see: a) K.-i. Yamada, K. Tomioka, Chem.
Rev. 2008, 108, 2874 – 2886; successful methods include: b) S. E.
Denmark, N. Nakajima, O. J.-C. Nicaise, J. Am. Chem. Soc. 1994,
116, 8797 – 8798; c) J. R. Porter, J. F. Traverse, A. H. Hoveyda,
M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 10409 – 10410; d) T.
Soeta, K. Nagai, H. Fujihara, M. Kuriyama, K. Tomioka, J. Org.
Chem. 2003, 68, 9723 – 9727; e) A. Cꢇtꢈ, A. B. Charette, J. Org.
Chem. 2005, 70, 10864 – 10867.
[14] These diastereoselective additions are limited to aldimines,[7,12,13]
and there is just one example of a low-yielding addition to an
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric 1,2-Addition
A. Hensel, K. Nagura, L. B. Delvos,
M. Oestreich*
&&&& — &&&&
Enantioselective Addition of Silicon
Nucleophiles to Aldimines Using
a Preformed NHC–Copper(I) Complex as
the Catalyst
The final chapter: The enantioselective
addition of silicon nucleophiles to typical
prochiral acceptors is now well-estab-
lished methodology, except for the 1,2-
addition to imines. McQuade’s chiral
NHC–copper(I) complex catalyzes this
elusive transformation with high asym-
metric induction, finally allowing for the
catalyst-controlled preparation of a-sily-
lated amines from aldimines (see
scheme).
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!