Z-Stereoselective Aza-Peterson Olefinations with Bis(trimethylsilane) Reagents and Sulfinyl Imines

Article abstract of DOI:10.1021/acs.orglett.5b03519

Highly stereoselective aza-Peterson olefinations from bench-stable α,α-bis(trimethylsilyl)toluene reagents and N-substituted imines have been achieved using TMSO^-/Bu₄N⁺ as Lewis base activator in THF. Remarkably, and for the first time, N-t-butanesulfinyl imines were utilized for the synthesis of Z-stilbenes with excellent selectivities, while N-aryl imines generated E-stilbenes under identical reaction conditions. The protocol proved general for numerous examples with low molecular weight byproducts formed. The origin of the Z-selectivity is proposed to be a result of diastereoselective addition to N-t-butanesulfinyl imines followed by syn-elimination of an in situ formed hypervalent silicate.

Full text of DOI:10.1021/acs.orglett.5b03519

Letter
pubs.acs.org/OrgLett
Z‑Stereoselective Aza-Peterson Olefinations with Bis(trimethylsilane)
Reagents and Sulfinyl Imines
Manas Das and Donal F. O’Shea*
Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2,
Ireland
S
* Supporting Information
ABSTRACT: Highly stereoselective aza-Peterson olefinations
from bench-stable α,α-bis(trimethylsilyl)toluene reagents and
N-substituted imines have been achieved using TMSO−/
Bu4N+ as Lewis base activator in THF. Remarkably, and for
the first time, N-t-butanesulfinyl imines were utilized for the
synthesis of Z-stilbenes with excellent selectivities, while N-aryl
imines generated E-stilbenes under identical reaction con-
ditions. The protocol proved general for numerous examples with low molecular weight byproducts formed. The origin of the Z-
selectivity is proposed to be a result of diastereoselective addition to N-t-butanesulfinyl imines followed by syn-elimination of an
in situ formed hypervalent silicate.
lefins are ubiquitous structural motifs in biologically
Scheme 1. Stereoselective Aza-Peterson Olefinations
O
relevant entities and serve as versatile precursors for a
diverse range of chemical transformations that produce
pharmaceutical and industrially important organic compounds.1
New strategies for the facile synthesis of stereochallenging
alkenes remain a considerable focus of research. Selective access
to either the E- or Z-isomer of an alkene is often the decisive
factor in the success of any alkene synthesis method. Among the
olefin-forming transformations, selective preparation of E-
isomers has been established the most, while the corresponding
methods to access the thermodynamically less favorable Z-
alkenes remain a challenge.2,3 Several transformations have been
introduced to address this issue, including hydrogenation,4
alkyne reductive coupling5 or carbocupration,6 cross-meta-
thesis,7 terminal-to-internal olefin isomerization,8 and photo-
catalytic E-to-Z isomerization.9 A general synthesis of Z-olefins is
available from the Wittig reaction variant in which N-sulfonyl
imines are used instead of carbonyl electrophiles.10
butanesulfinyl imines (Ellman imines) as substrates for aza-PO
reactions.13 To the best of our knowledge, t-butanesulfinyl
imines have not been previously utilized for any olefination
transformations. They are commonly used in diastereoselective
organometallic addition reactions for the synthesis of chiral
amines, with high selectivity attributed to either the formation of
a metal-chelated closed six-membered ring or open (non-
chelating) transition states.13 We have recently demonstrated
diastereoselective addition of benzyltrimethylsilanes to N-t-
butanesulfinyl imines using Me3SiO−/Bu4N+ in THF to promote
the addition reaction.14,15
In this work, our motivation for investigating N-t-butanesul-
finyl imines as carbonyl replacement electrophiles was the
potential for diastereoselective addition, through a chelating six-
membered transition state, brought about by interaction of the
silicon of the α-silyl carbanion with the oxygen of the sulfinyl
imine (Figure 1). This intramolecular oxygen−silicon activation
would induce hypervalency on Si, thereby facilitating an olefin-
forming syn-elimination step with participation of the six-
membered ring guiding the outcome toward the thermodynami-
The Peterson olefination (PO) reaction offers a superior atom
economy advantage over the Wittig reaction as it produces
noncrystalline low molecular weight silicon byproducts.11 Yet,
stereocontrol has always been the Achilles heel of the PO
reaction, especially for direct alkene synthesis (i.e., without
isolation of silyl−alcohol intermediates).1,11 Arguably, this
limiting factor, in addition to the necessity to preform α-silyl
carbanions using a strong base, has restricted its more widespread
use. In an effort to address these limitations, we have recently
reported stereoselective aza-PO reactions utilizing bench-stable
bis(trimethylsilane) reagents and N-phenyl imines to produce
thermodynamically favored E-alkenes with excellent selectivities
(Scheme 1).12 Despite this success, the significant limitation for
silicon-based olefination reactions is that no direct (without β-
hydroxysilane isolation) Z-selective method currently exists. As
such, we were stimulated to identify a Z-favoring electrophile,
and our attention was drawn to the potential use of N-t-
Received: December 14, 2015
© XXXX American Chemical Society
A
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Letter
2−4). These results pointed toward N-aryl sterics influencing the
reaction course toward highly selective E product.
Next, (R)-N-benzylidene-2-methylpropane-2-sulfinamide,
(R)-3a, was chosen as electrophile in the reaction with 1a
under identical conditions. To our delight, a complete inversion
of the stereo-outcome was obtained, with alkene 6a obtained in
89% yield with a Z/E ratio of 95:5 (entry 5). Using either the S-
isomer or a racemic mixture of sulfinyl imine 3a had no effect on
Z/E ratio (entries 6 and 7). A survey of the two sulfonyl imines 4
and 5 was next performed to compare their influence on the
stereochemical outcome of the reaction. When methylsulfonyl
imine 4 was treated with 1f in the presence of 1.5 equiv of
Me3SiOK/Bu4NCl in THF, alkene 6a was formed in 51% yield
with a poor Z/E ratio of 65:35 (entry 8). Employing p-
toluenesulfonyl imine 5 under the same reaction conditions
produced the product alkene 6a in 63% yield, having little Z/E
selectivity (45:55), which is a comparable result to that seen with
benzaldehyde (entry 9).12 This dramatic difference between
sulfinyl and sulfonyl imines is pertinent as p-toluenesulfonyl
imines are excellent substrates for the formation of Z-alkenes in
the Wittig reaction.10c Together, these initial results indicated
that N-phenyl imine and rac-N-t-butanesulfinyl imines could be
used for E- and Z-selective olefination, respectively, in the
presence of 1.5 equiv of Me3SiOK/Bu4NCl at −20 °C in THF.
The established reaction conditions were next evaluated by
employing a broad range of aryl 3a−f,h,j,k,n, heteroaryl 3r, and
organometallic 3s N-t-butanesulfinyl imines with
(phenylmethylene)bis(trimethylsilane) 1a (Scheme 2). Z-
Figure 1. Possible addition profiles when using N-t-butanesulfinyl imine
and N-phenyl imine electrophiles.
cally less stable Z-isomers. This would contrast with an open
nonchelating addition model for the N-phenyl imine electro-
philes, which delivers the thermodynamically favored trans-
isomers (Figure 1).
At the outset, the reaction conditions of Me3SiO−/Bu4N+ in
THF were chosen to match those previously successfully used in
our addition reactions.14 As it would be beneficial to have both E-
and Z-isomers accessible from a single set of conditions (and
allow direct comparison), these conditions were also applied to a
number of N-aryl imine reactions, some of which have been
previously observed to give high E-selectivity using CsF/DMF.12
In this initial study, 13 bis(trimethylsilane) reagents 1a−m, five
N-aryl imines 2a−e, and 19 N-t-butanesulfinyl imines 3a−s were
used (for structures, see Figures S1−S3).16
Before investigating the Z-selectivity, it was first confirmed
that changing silicon activation from a fluoride source in DMF to
Me3SiO− in THF did not impact the high E-selectivity with N-
phenyl-substituted imines. Reaction of ((3-methoxyphenyl)-
methylene)bis(trimethylsilane) 1f and N-phenyl imine 2a in the
presence of 1.5 equiv of Me3SiOK/Bu4NCl in THF at −20 °C
provided the target alkene 6a in 87% yield with a Z/E ratio of
1:99, which was consistent with our previous results using CsF in
DMF (Table 1, entry 1).12 To determine the influence, if any, of
a
Scheme 2. Z-Selective PO with N-t-Butanesulfinylimines
a
Table 1. Imine Stereoeffects on Aza-Peterson Olefinations
b
c
entry
R
imine
time (h)
yield (%)
Z/E
1
2
3
4
5
6
7
8
9
Ph
2a
2b
2c
2d
3a
3a
3a
4
3
3
3
3
2
2
2
87
76
84
85
89
88
86
51
63
1/99
1/99
1/99
1/99
95/5
95/5
95/5
65/35
45/55
p-MeOC6H4
p-CF3C6H4
3,5-(CF3)2C6H3
(R)-S(O)tBu
(S)-S(O)tBu
( )-S(O)tBu
SO2Me
a
Yield of the isolated product after chromatography; Z/E determined
d
1
4
d
by H NMR.
SO2p-MeC6H4
5
4
a
Reaction conditions: bis(silanes) (0.8 mmol), imine (0.4 mmol), and
b
Selective olefination of electron-neutral, -rich, and -poor aryl
imines having o-, m-, or p-substitution or bisubstitution worked
very well, providing the corresponding alkenes Z-6a to Z-6j in
high yields and with excellent range of Z/E ratios from 90:10 to
95:5. Pharmaceutically important heteroatomatic furan is also
compatible with the protocol to produce the corresponding
alkene Z-6k in 74% yield. Ferrocenyl imine 3s was utilized for the
first time in stereoselective olefination, providing alkene Z-6l in
69% yield and Z/E ratio of 95:5 (Scheme 2). Having successfully
explored various N-t-butanesufinyl imines, the influence of
diversely substituted bis(trimethylsilane) reagents 1b,d−f,h,j,k
Me3SiOK/Bu4NCl (0.6 mmol). Yield of the isolated product after
chromatography. Determined by H NMR. Reaction warmed to 0
c
d
1
°C for 2 h.
electronic effects of the N-aryl group on the stereochemical
outcome of the reaction, N-p-methoxyphenyl 2b, N-p-trifluor-
ometylphenyl 2c, and bis(trifluoromethyl)phenyl 2d substituted
imines were used in the reaction with 1f under the same
conditions. In each case, the product Z/E ratio remained
unchanged at 1:99, with only minor variations in yields (entries
B
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Letter
a
with imines 3a,g,i was examined (Scheme 3). Pleasingly, each
reaction was successful with good Z/E ratios in spite of the
varying substitution patterns.
Scheme 5. One-Pot Z-Selective Aza-PO from Aldehydes
a
Scheme 3. Z-Selective Olefination
a
Reaction conditions: aldehyde (0.4 mmol), sulfinamide (0.44 mmol),
bis(silanes) (0.8 mmol), and Me3SiOK/Bu4NCl (0.7 mmol); Z/E
1
determined by H NMR.
alkenes via high-throughput synthesis. As it would be a unique
advantage to have a single silicon activation to produce both Z-
and E-isomers, the use of Me3SiO−/Bu4N+ with N-phenyl imines
was next evaluated. Eight bis(trimethylsilanes) were successfully
tested with sulfinyl imine 2a, providing alkenes 6b,m−o,r,u−w in
high yields and with ratios ranging from 5:95 to 1:99 (Scheme 6).
a
Yield of the isolated product after chromatography; Z/E determined
b
1
by H NMR. Reaction performed at −20 to −10 °C.
An important feature of any new synthetic method is
robustness, as its use will often be in the hands of a nonexpert.
To showcase the generality of the current method, a dual
synthetic strategy was chosen to prepare five representative
alkenes 6u−y (Scheme 4). Under conditions A, 1a was reacted
a
Scheme 6. E-Selective Olefination
a
Scheme 4. Dual Synthetic Strategy
a
Yield of the isolated product after chromatography; Z/E determined
a
1
Yield of the isolated product after chromatography; Z/E determined
by H NMR.
1
by H NMR.
These results highlight that phenyl/sulfinyl imine E/Z
stereocontrol is general and achievable under identical reaction
conditions. This imine stereocontrolled alkene synthesis has
been applied to both Z and E chemotherapeutics combretastatin
A4 and DMU-212 (Scheme 7).18,19 The reaction of ((3,4,5-
with five different imines 3g,l,o−q, providing the corresponding
alkenes in good yields with excellent Z-selectivities. In dual
conditions B, five different bis(trimethylsilanes) 1b,g,i,l,m were
employed with 3a to produce the same alkenes. Yields and Z-
selectivity for both approaches show comparable results, many of
which are within the range of experimental error. Of specific
note, bis(trimethylsilane)pyridine derivative 1m and its N-t-
butanesulfinyl analogue 3q were both compatible with this
process (Scheme 4).
Scheme 7. Z-Combretastatin A4 and E-DMU-212
To streamline the Z-alkene synthesis from aldehydes, a one-
pot approach was adopted (Scheme 5). Reaction of aldehyde and
2-methylpropane-2-sulfinamide in THF with pyrrolidine catalyst
generated the sulfinyl imine.17 Imine formation was monitored
by TLC, and upon completion, the temperature was lowered to
−20 °C, bis(trimethylsilane) added, and the reaction carried out
as previously described. Eight diversely substituted alkenes were
produced in good yields while maintaining the excellent cis-
selectivity (Scheme 5). It could be anticipated that this approach
would be of specific importance for library generation of Z-
C
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Letter
trimethoxyphenyl)methylene)bis(trimethylsilane) 1l with sulfi-
nylimine 3m provided the therapeutic Z-6af in high yield and
with excellent geometrical purity. Notably, the phenol group was
tolerated, avoiding the need for functional group protection.
Moreover, the promising anticancer agent DMU-212 was
prepared from 1l and the E-favoring 1-(4-methoxyphenyl)-N-
phenylmethanimine 2e (Scheme 7).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: donalfoshea@rcsi.ie.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the European Research Association ERA-Chemistry
and the Irish Research Council (IRC) for financial support.
Identification of the exact mechanistic pivot point for N-
sulfinyl- and N-phenyl imine Z/E stereocontrol requires further
investigation, but some useful observational conclusions can be
drawn at this stage. Based on our previous findings that addition
of substituted benzyltrimethylsilanes to sulfinyl imines is highly
diastereoselective,14 it could be anticipated that (arylmethylene)-
bistrimethylsilanes 1 would also be, thereby primarily setting the
stereochemical outcome of the reaction at the addition step. This
poses the question as to whether a four-membered 1-aza-2-
silacyclobutane or a six-membered 1,2,3,6-azathiazasilinane
intermediate is formed as a result of this addition. Tamao et al.
have demonstrated a concerted [2 + 2] cycloreversion
mechanism of substituted 1-aza-2-silacyclobutanes with reten-
tion of stereochemistry at the carbon atoms in the alkene
product.20 This would indicate that if a concerted [2 + 2]
addition (as proposed for PO with carbonyls21) of the α-silyl
carbanion with sulfinylimine was operating, the stereochemistry
fixed at the addition stage would be reflected in the alkene
product. Intriguingly, as Z-selectivity is observed for sulfinyl but
not sulfonyl imines, it is also plausible that a six-membered
azathiazasilinane TS (or intermediate) 7 could be operating as a
lower energy alternative pathway to the four-membered
azasilacyclobutane ring (Scheme 8). For N-aryl imines, as the
■
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acyclic intermediate 8 with subsequent β-elimination could
selectively provide the trans-product.
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(trimethylsilanes) and imine electrophiles, with silicon activation
achieved by trimethylsilyloxide in THF. Stereoselectivity of the
product alkene solely depends on the nature of the imine
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03519.
General experimental procedures and characterization
data (PDF)
D
DOI: 10.1021/acs.orglett.5b03519
Org. Lett. XXXX, XXX, XXX−XXX