Highly Selective Addition of a Broad Spectrum of Trimethylsilane Pro-nucleophiles to N-tert-Butanesulfinyl Imines

Article abstract of DOI:10.1002/chem.201503354

Addition of organotrimethylsilane reagents to chiral N-tert-butanesulfinyl imines can be achieved in good yields and with excellent diastereoselectivities by employing TMSO^-/Bu₄N⁺ as a Lewis base activator in THF. A variety of aliphatic, aromatic, heteroaromatic and organometallic chiral imines were utilised as electrophiles for the synthesis of enantioenriched N-tert-butanesulfinyl amides. Remarkably, the same sets of reaction conditions could be used with a highly diverse range of bench-stable organotrimethylsilane reagents, which highlights the generality and robustness of this methodology. Addition of organotrimethylsilane reagents to chiral N-tert-butanesulfinyl imines can be achieved in good yields and with excellent diastereoselectivities by employing TMSO^-/Bu₄N⁺ as a Lewis base activator in THF. A variety of aliphatic, aromatic, heteroaromatic and organometallic chiral imines were utilised as electrophiles for the synthesis of enantioenriched N-tert-butanesulfinyl amides, highlighting the generality and robustness of this methodology.

Full text of DOI:10.1002/chem.201503354

DOI: 10.1002/chem.201503354
Full Paper
&
Organic Synthesis
Highly Selective Addition of a Broad Spectrum of Trimethylsilane
Pro-nucleophiles to N-tert-Butanesulfinyl Imines
Manas Das[a] and Donal F. O’Shea*[a, b]
Abstract: Addition of organotrimethylsilane reagents to
chiral N-tert-butanesulfinyl imines can be achieved in good
yields and with excellent diastereoselectivities by employing
TMSOÀ/Bu4N+ as a Lewis base activator in THF. A variety of
aliphatic, aromatic, heteroaromatic and organometallic chiral
imines were utilised as electrophiles for the synthesis of
enantioenriched N-tert-butanesulfinyl amides. Remarkably,
the same sets of reaction conditions could be used with
a highly diverse range of bench-stable organotrimethylsilane
reagents, which highlights the generality and robustness of
this methodology.
Introduction
The diastereoselective addition of organometallic reagents to
chiral imines is arguably one of the more successful methodol-
ogies to deliver a diverse range of enantiomerically enriched
amines.[1] The value of this synthetic approach is clear for me-
dicinal chemistry discovery programs and for the production
of drugs and drug candidates.[2] Over the last decade, an in-
creasing collection of strategies based upon the chiral imines
generated from tert-butanesulfinamide with numerous organo-
metallic nucleophiles have been successfully developed
(Figure 1).[3] Nucleophiles containing metals such as lithium,
magnesium, zinc, indium, silicon and boron, with a very broad
range of reactivity, have been utilised.[3b–g] The distribution of
metal pro-nucleophiles is, as would be expected, diverse, with
the more reactive organometallics containing Li, Mg, Zn or In
requiring in situ formation and immediate use with the imine
substrate. Only Si and B offer the possibility to start from
a bench-stable pro-nucleophile, but these systems differ in
that boron reagents need in situ transmetallation with either
Rh or Pd to achieve the required reactivity. Silicon reagents
alone are unique as they are bench-stable and do not require
in situ transmetallation to participate in addition reactions. It is
evident from the literature that the broadest substrate scope
exists for the more reactive organometallics such as lithium,
magnesium and zinc, whereas for silicon the focus has been
Figure 1. Diastereoselective addition of organometallics to chiral N-tert-buta-
nesulfinyl imines.
more towards the most reactive nucleophiles such as cyanide,
the trifluoromethyl anion and related derivatives (Figure 1).[4]
The expansion of TMS pro-nucleophiles to a broader range of
organo-substrates would be of value as they are readily avail-
able bench-stable reagents, which allows for their direct use in
typical medicinal chemistry formats.[3a] A factor of equal impor-
tance to utilising bench-stable pro-nucleophiles would be to
have a common set of reaction conditions in which these re-
agents could be used. We recently reported that the Lewis
base Me3SiOÀ as its Bu4N+ salt, in THF, can promote the carb-
anion reactivity of organo-TMS reagents for addition to car-
bonyls.[5] In a preliminary study, it was found that the addition
of aromatic and heterocyclic silanes to chiral N-tert-butanesul-
finyl imines could be achieved with excellent diastereoselectiv-
ity.[6] In this account, these additions have been expanded to
encompass a broad spectrum of TMS reagents, covering
[a] M. Das, Prof. Dr. D. F. O’Shea
Department of Pharmaceutical and Medicinal Chemistry
Royal College of Surgeons in Ireland
123 St. Stephen’s Green, Dublin 2 (Ireland)
E-mail: donalfoshea@rcsi.ie
[b] Prof. Dr. D. F. O’Shea
School of Chemistry and Chemical Biology
University College Dublin
Belfield, Dublin 4 (Ireland).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503354.
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a wide span of reactivity, using a single set of reaction condi-
tions.
Table 1. Optimisation of reaction conditions with benzyltrimethylsilane.[a]
Results and Discussion
To determine the generality of trimethylsilane reactivity and
addition diastereoselectivity under Me3SiOÀ/Bu4N+ activation,
17 chiral imines 1a–q and 28 trimethylsilane reagents 2–4,
5a,b, 6a–j, 7a,b, 8a,b, 9, 10a–h were investigated (for struc-
tures see Figures 2 and 3).
Entry mol% Solvent
T
[8C]
t [h] Conv. [%] Yield [%][b] d.r.[c]
11 a/12
(1R:1S)
1
2
3
4
5
6
50
THF
THF
THF
THF
THF
THF
rt
rt
rt
0
À40
À78
6
3
3
5
5
5
50
90
100
100
100
100
35/10
63/23
81/15
86/trace
92/nd
91/nd
84:16
84:16
84:16
85:15
90:10
90:10
100
150
150
150
150
[a] PMP=p-methoxyphenyl; nd=Not detected. [b] Yield after chromatog-
1
raphy. [c] Determined by H NMR spectroscopy and HPLC.
generated in a 10% yield (Table 1, entry 1). A plausible explan-
ation for the formation of side product 12 is the partial decom-
position of (R)-1e to p-anisaldehyde, which concomitantly re-
acted with 6a. In an attempt to achieve complete conversion
of imine, 1 equivalent of activator TMSOK/Bu4NCl was used, re-
sulting in ~90% imine conversion with 11 a obtained
in higher yield and with same diastereoselectivity
(63%, 84:16 d.r.), but the yield of the alcohol 12 also
increased to 23% (entry 2). A complete conversion of
imine was accomplished with the formation 11 a
(81%, 84:16 d.r.) and 12 (15%) when 150 mol%
TMSOK/Bu4NCl was utilised (entry 3). The tempera-
ture dependence of the reaction was investigated
next; encouragingly, with 1.5 equivalents of TMSOK/
Bu4NCl at 08C in THF, complete conversion was ach-
ieved with 11 a obtained in 86% yield (85:15 d.r.) and
12 formed in only trace amounts (entry 4). Further
lowering the temperature to À408C improved the
yield of 11 a to 92% and the d.r. to 90:10 with no al-
cohol 12 detected in the crude product (entry 5). A
similar result was obtained when the reaction was
performed at À788C (entry 6). The absolute configu-
ration of the major diastereomer of N-sulfinyl amine
11 a was determined to be (1R,RS) by comparison
with reported literature data.[7] The conclusions from
this study were to use 1.5 equivalents of TMSOK/
Bu4NCl and temperatures of À408C or below to
assess the addition reactivity and selectivity performance of tri-
methylsilanes 2–10.
Figure 2. Structures of organotrimethylsilanes 2–10.
Figure 3. Structures of N-tert-butanesulfinyl imines 1a–q.
The chiral imines used included aliphatic, aromatic, heteroar-
omatic, organometallic and ethyl benzoate derivatives with the
organotrimethylsilanes having ethylacetate, difluoro(methyl)-
phosphonate, alkynyl, allyl, benzyl, dithiane, heteroaryl and aryl
substituents. For the initial screen to identify optimal reaction
conditions, (R)-N-(4-methoxybenzylidene)-2-methylpropane-2-
sulfinamide, (R)-1e, was chosen as the model imine in reaction
with benzyltrimethylsilane 6a (Table 1). The treatment of the
imine (R)-1e and 6a with 0.5 equivalents TMSOK/Bu4NCl in dry
THF at room temperature resulted in approximately 50% con-
version of the imine, forming the N-tert-butanesulfinyl amine
adduct 11 a (35%, 84:16 d.r.) with the side product alcohol 12
Addition to imines is a convenient route to b-amino acids,
which are an important class of building blocks for the synthe-
sis of natural products and pharmaceutical agents.[8] In addi-
tion, they are the underlying monomers of b-peptides, which
have received considerable attention owing to their unique
structural properties and valuable biological activities.[9] As
such, the addition of ethyl-2-(trimethylsilyl)acetate 2 to aryl,
heteroaryl and ferrocenyl (R)-imines was investigated (Table 2).
Owing to the high reactivity of 2, the chosen reaction temper-
ature was À608C, which gave the corresponding N-sulfinyl b-
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Table 2. Addition of diethyl (difluoro(trimethylsilyl)methyl)phosphonate
and ethyl-2-(trimethylsilyl)acetate to N-tert-butanesulfinyl imines[a]
Figure 4. ORTEP diagram of 14a (thermal ellipsoids are drawn on the 50%
probability level).
plexes as catalysts.[3d] However, reports on the Lewis base
mediated stereoselective reaction of alkynes with chiral sulfin-
imines are rare.[16] The importance of homoallylic amines is em-
phasised by the prevalence of chiral a-branched amines in nat-
ural products, biologically active molecules, and ligands.[17]
Among the strategies developed, diastereoselective allyl addi-
tion to chiral sulfinyl imines has received major attention.[18]
With appropriate allyl metal reagents as the nucleophiles, reac-
tions can be carried out stereoselectively and provide enantio-
[a] Yield after chromatography; d.r. determined by 1H NMR or 19F NMR
spectroscopy or HPLC.
amino ester derivatives 13a–e in good yields and with moder-
ate to excellent diastereoselectivities of 83:17 to 99:1. This
method offers an alternative to the ester enolate addition for
the synthesis of chiral b-amino esters.[10] The absolute configu-
ration of the major isomer of sulfinamide 13a was assigned as
(1R,RS) by comparison with the previously reported data and
13b–e were assigned by analogy.[10a]
Table 3. Addition of acetylenic and allylic trimethylsilanes to N-tert-buta-
nesulfinyl imines[a]
Organophosphorus compounds are important substrates in
the study of biochemical processes as isosteres of b-amino
acids.[11a] It is well documented that b-aminophosphonic acids
have shown diverse biological and biochemical properties,
such as, antibacterial activity, enzyme inhibition, activity as
haptens for catalytic antibodies, and anti-HIV activity.[11b,c] Few
efficient asymmetric synthetic methods are available for the
preparation of chiral b-aminophosphonic acid derivatives.[11b]
As such, the diethyl (difluoro(trimethylsilyl)methyl)phospho-
nate 3 was synthesized from diethyl (bromodifluoromethyl)-
phosphonate through a lithium halogen exchange and TMSCl
quench and its addition performance investigated (see the
Supporting Information). Additions of 3 were carried out at
À408C to the five different sulfinyl aldimines (R)-1a,e,h,l,m,
transforming them to their corresponding N-sulfinyl amines
14a–e with good yields and excellent diastereoselectivities
(Table 2). The absolute configuration of the major isomer of
product 14a was determined to be (1S,RS) by single-crystal X-
ray structure analysis (Figure 4).[12] The absolute configurations
for 14b–e were assigned to be same as 14a by analogy.
Chiral propargylic and homoallylic amines have great value
as structural subunits and key synthetic intermediates in or-
ganic synthesis.[13] To date, several approaches to these useful
amines have been recorded.[14,15] Among them, the most
common route is nucleophilic 1,2-addition of alkyne or allyl nu-
cleophiles to imines using Lewis acids or transition-metal com-
[a] Yield after chromatography; d.r. determined by 1H NMR or 19F NMR
spectroscopy or HPLC.
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pure amines effectively. The fluoride-promoted addi-
tion of allyltrimethylsilane to racemic sulfinyl imines
has been previously reported.[4e]
Table 4. Benzyl group addition to N-tert-butanesulfinyl imines.[a]
For this study, trimethyl(phenylethynyl)silane 4, al-
lyltrimethylsilane 5a, and trimethyl(2-methylallyl)si-
lane 5b were chosen as pro-nucleophile substrates.
The generality of the reaction with respect to imine
substrates was challenged with 12 derivatives
1a,b,d–h,l,–o,k,q, which included alkyl, aryl, heteroar-
yl and ferrocenyl aldimines and the activated keti-
mine 1q. In all cases, the desired propargylic (15a–h)
and homoallylic (16a–i) sulfinyl amines were ob-
tained in moderate to very good yields (Table 3). In
general, the d.r. values for phenylethynyl additions
(ranging from 99:1 to 89:11) were consistently higher
and better than those of the allyl additions (ranging
from 94:6 to 75:25). The absolute configuration of
the major isomer of sulfinamides 15e and 16a were
determined to be (1S,RS) and (1R,RS), respectively, by
comparison with reported literature data.[15e,18b]
Synthetic routes to substituted chiral homobenzyl
amines have been a subject of interest over the past
decade owing to the presences of this structural
motif in many pharmaceuticals and biologically
active compounds.[19] A valuable method to prepare
chiral amine compounds containing such a subunit is
the addition of benzyl organometallic reagents to
chiral sulfinyl imines. To date, the use of mixed Mg/
Zn organometallics have been successfully utilised
for benzyl additions.[7,20] The fluoride-promoted addi-
tion of unsubstituted benzylsilane 6a to racemic
imines has been previously reported.[4f]
Our primary interest was to determine the level of
generality for highly selective additions for an exten-
sive series of substituted benzyltrimethylsilanes. As
such, the electronically and structurally diverse si-
lanes 6a–j were chosen as nucleophilic substrates
and were tested against a wide range of aryl-, hetero-
1
[a] Yield after chromatography; d.r. determined by H NMR spectroscopy and HPLC.
aryl- and ferrocenyl-substituted N-tert-butanesulfinyl aldimines
and an activated ketimine (Table 4).
azole substrates and aliphatic imines. Thiazole additions are
useful as one-carbon homologating procedures as their con-
version to a formyl group is readily achievable.[22] Thiazole ad-
ditions performed very well to produce the desired aryl thi-
azole sulfonamides 17a–c each with excellent 99:1 diastereo-
selectivity (Table 5). Pleasingly, addition of other aromatic and
non-aromatic heterocycles to cyclohexyl-, isopropyl- and 3-
phenylpropane-substituted imines also gave products 17d, f
and g, respectively, with high d.r. values (Table 5).
Diastereoselective addition of aryl organometallics to chiral
imines, as a route to diarylmethyl amines, has been explored
for several nucleophilic substrates.[3b] To date, the organometal-
lics of choice for diastereoselective aryl addition reactions have
been either Li, Mg or B.[23] Although more recently, the silylox-
ide-promoted addition of ortho-substituted aryltrimethylsilanes
to N-tert-butanesulfinyl imines has been communicated.[6] The
substrate breadth for these additions has now been expanded
to ortho-, meta- and para-substituted aryltrimethylsilanes. We
were delighted to find that, in most cases, the desired diaryl-
Remarkably, all reactions were successful under the one set
of reaction conditions with all the desired products 11 b–r ob-
tained. Of note is the predominately high d.r. values with over
75% of sulfinyl amides obtained with diastereomeric ratios of
90:10 or above (Table 4). Product 11 g, obtained with a d.r. of
96:4, is of particular relevance as a precursor to a-amino acids
with quaternary stereogenic centres. The absolute configura-
tion of the major isomer of sulfinamide 11 b was determined
to be (1R,RS) by analytical correlation with the literature data[7]
and, by analogy, the other examples have been assigned iden-
tical stereochemistry.
Diastereoselective nucleophilic addition of heteroaryls to N-
tert-butanesulfinyl imines has been previously examined in the
literature by utilising lithium and magnesium reagents.[21] Re-
cently, we have reported the selective addition of heterocyclic
trimethylsilanes to aryl N-tert-butanesulfinyl imines.[6] This initial
study has now been expanded to include 2-(trimethylsilyl)thi-
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To stream-line the method, a one-pot approach from the
starting aldehyde was developed. An amino catalytic process
for in situ preparation of sulfinyl imine was performed by
using a catalytic amount of pyrrolidine in THF to effect the
condensation of aldehyde and (R)-2-methylpropane-2-sulfin-
amide via an iminium ion intermediate.[24] Chiral imine forma-
tion was monitored by TLC and upon completion the reaction
mixture was adjusted to À408C or À608C and the trimethylsi-
lane addition carried out as previously described. To showcase
the robustness of this approach, the substituted sulfinamides
11 b, 13b, 15d, 17h, 17i and 18l were produced in good
yields and with excellent diastereoselectivities (Scheme 1). It
could be anticipated that this approach would be of specific
importance for library generation by high-throughput synthe-
sis.
Table 5. Addition of heterocyclic trimethylsilanes to aliphatic and aryl N-
tert-butanesulfinyl imines.[a]
[a] Yield after chromatography; d.r. determined by 1H NMR spectroscopy
or HPLC.
sulfinamides 18a–k were obtained in moderate to good yields
(Table 6). Products were obtained with consistently high diaste-
reoselectivities, all being higher than a 90:10 ratio. The activa-
tion of phenyltrimethylsilane under these conditions was un-
successful, which marks the current reactivity limit for this
methodology.
Scheme 1. One-pot approach from aldehydes.
For completion, some representative sulfinamides
11 a–b, 13c and 16a–b were transformed to their
corresponding amines by acid deprotection.[23 g] Se-
lective cleavage of the sulfinyl group was accom-
plished in high yields without erosion of enantiomer-
ic purity to provide the chiral amines 19a–e (Table S3
in the Supporting Information).
Table 6. Addition of aryltrimethylsilanes to N-tert-butanesulfinyl imines.[a]
A qualitative experimentally observed trimethylsi-
lane reactivity trend from more to less reactive can
be summarised as follows: 2, 3, 4> 7, 8, 9> 5, 6,>
10b,c,d> 10e,f> 10g,h> 10a. For the aryl-TMS de-
rivatives 10, ortho-substituted arenes are more reac-
tive than meta- or para-substituted, with unsubstitut-
ed 10a being the least reactive. It is of interest to
note that diastereofacial selectivity is not related to
reactivity as it was seen that it remained consistently
high, for example, for both silane derivatives of type
3 and 10. The silane derivatives that showed the
widest distribution of d.r. values for differing imines
were the allyl and the benzyl derivatives. However,
overall, the selectivity is invariably high with the aver-
age d.r. for all 70 reactions performed being 95:5.
Product analysis and literature comparison indicates
that the mode of stereoinduction is common for all
[a] Yield after chromatography; d.r. determined by 1H NMR or 19F NMR spectroscopy
or HPLC. [b] Reaction performed at À208C. [c] Reaction performed at À108C. [d] Reac-
tion performed at 08C.
trimethylsilane reagents and would be consistent
with operating via a non-chelating open transition
state.[25]
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[4] Previously reported R-TMS additions to chiral imines. For TMSCF3, see:
a) G. K. S. Prakash, M. Mandal, G. A. Olah, Angew. Chem. Int. Ed. 2001, 40,
589; Angew. Chem. 2001, 113, 609; b) Y. Kawano, T. Mukaiyama, Chem.
Lett. 2005, 34, 894. For TMSCF2SPh, see: c) Y. Li, J. Hu, Angew. Chem. Int.
Ed. 2007, 46, 2489; Angew. Chem. 2007, 119, 2541. For TMSCN, see:
d) H. Wang, X. Zhao, Y. Li, L. Lu, Org. Lett. 2006, 8, 1379. For allylTMS,
see: e) W. X. Zhang, X.-L. Hou, Chinese Chem. Lett. 2006, 17, 1037. For
PhCH2TMS, see: f) W.-X. Zhang, C.-H. Ding, Z.-B. Luo, X.-L. Hou, L.-X. Dai,
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Conclusion
A general Me3SiOÀ/Bu4N+ activation in anhydrous THF has
been utilised to unmask the carbanion reactivity of a broad
spectrum of trimethylsilane reagents, allowing their diastereo-
selective addition to chiral N-tert-butanesulfinyl imines. The
procedure proved successful for a broad spectrum of sub-
strates, showing excellent functional group tolerance, and with
high diastereoselectivity obtained almost universally. These re-
sults highlight the potential of under-utilised bench-stable
TMS reagents as pro-nucleophiles, which avoid the need for in
situ generation of more strongly basic organometallics. This
use of organo-TMS reagents in this manner offers a unified ap-
proach to chiral amines through diastereoselective N-tert-buta-
nesulfinyl imines additions.
[6] M. Das, D. F. O’Shea, Org. Lett. 2015, 17, 1962.
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Experimental Section
General procedure for the addition of organotrimethylsilanes to N-
tert-butanesulfinyl imines: A solution of dried Bu4NCl (104 mg,
0.375 mmol) and TMSOK (48 mg, 0.375 mmol) in anhydrous THF
(1.0 mL) at À40 or À608C was treated with a solution of N-tert-bu-
tanesulfinyl imine 1 (0.25 mmol) and organotrimethylsilane 2–10
(0.75 mmol) in anhydrous THF (1.5 mL) under N2 atmosphere and
the resulting solution stirred for 3–5 h. The reaction mixture was
quenched with saturated ammonium chloride solution at À40 or
À608C, warmed to room temperature, water added and extracted
with diethyl ether (15 mL”3). The organic portions were com-
bined, washed with brine, dried over anhydrous sodium sulfate
and concentrated. Purification by silica gel chromatography eluting
with cyclohexane/ethyl acetate afforded the corresponding N-tert-
butanesulfinamide. The diastereomeric ratios for the products were
1
determined by H NMR or 19F NMR spectroscopy or by HPLC analy-
sis.
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Acknowledgements
We thank the European Research Association ERA-Chemistry
and the Irish Research Council (IRC) for financial support. Dr. H.
Müller-Bunz, University College Dublin, is thanked for the X-ray
analysis.
Keywords: chiral
imines
·
diastereoselectivity
·
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Received: August 24, 2015
Published online on November 12, 2015
Chem. Eur. J. 2015, 21, 18717 – 18723
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim