Stereoselective peterson olefinations from bench-stable reagents and N-phenyl imines

Article abstract of DOI:10.1002/chem.201500475

The synthesis of bench-stable α,α-bis(trimethylsilyl)toluenes and tris(trimethylsilyl)methane is described and their use in stereoselective Peterson olefinations has been achieved with a wide substrate scope. Product stereoselectivity was poor with carbonyl electrophiles (E/Z ～1:1 to 4:1) though this was significantly improved by employing the corresponding substituted N-benzylideneaniline (up to 99:1) as an alternative electrophile. The olefination byproduct was identified as N,N-bis(trimethylsilyl)aniline and could be easily separated from product by aqueous acid extraction. Evidence for an autocatalytic cycle has been obtained.

Full text of DOI:10.1002/chem.201500475

DOI: 10.1002/chem.201500475
Communication
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Organic Synthesis |Hot Paper|
Stereoselective Peterson Olefinations from Bench-Stable Reagents
and N-Phenyl Imines
¨
Manas Das, Atul Manvar, Maıwenn Jacolot, Marco Blangetti, Roderick C. Jones, and
Donal F. O’Shea*[a]
alkene stereoselectively.[3] For stabilized a-silyl carbanions (e.g.
Abstract: The synthesis of bench-stable a,a-bis(trimethyl-
R=Ar) these intermediates are not isolated and stereocontrol
silyl)toluenes and tris(trimethylsilyl)methane is described
has yet to be achieved making it a less attractive approach for
and their use in stereoselective Peterson olefinations has
such reactions.[4] A further disincentive to its use is that the
been achieved with a wide substrate scope. Product ste-
silyl anion 2 must be first generated often with strong bases
under nontrivial conditions prior to the addition of the alde-
reoselectivity was poor with carbonyl electrophiles (E/Z
~1:1 to 4:1) though this was significantly improved by
employing the corresponding substituted N-benzylidenea-
hyde.
Yet, if solutions to these two issues were in hand, an inher-
niline (up to 99:1) as an alternative electrophile. The olefi-
ent advantage of the Peterson olefination is its superior atom
nation byproduct was identified as N,N-bis(trimethylsilyl)a-
economy over the Wittig reaction as it produces low molecular
niline and could be easily separated from product by
silicon byproduct in the carbon–carbon double-bond-forming
aqueous acid extraction. Evidence for an autocatalytic
step rather than crystalline triphenylphosphine oxide.[5] An al-
cycle has been obtained.
ternative approach to the generation of the a-silyl carbanions
that does not require strong bases is to use geminal bis(tri-
methyl silanes) 4 as starting substrates and a fluoride source to
In the synthetic olefination toolbox the Peterson olefination, in
spite of its great value, remains one of the lesser utilized meth-
ods for the conversion of carbonyls to alkenes.[1] The transfor-
mation is considered as a silicon analogue of the Wittig reac-
tion with the reaction of a-silyl carbanions 2 (typically generat-
ed by deprotonation of 1 using strong lithium or magnesium
bases) with carbonyls providing the alkene product 3 and tri-
methylsilyl oxide byproduct (Scheme 1, route a).[2] Intermediate
promote generation of the a-silyl carbanion precursor 5
(Scheme 1, route b). Bis(silanes) 4 are bench stable (analogous
to the Wittig phosphonium salt), yet they have received very
limited use due to the lack of a general route for their synthe-
sis.[4e–g,6] The use of bis(silanes) as Peterson olefination reagents
offers an additional advantage in that they eliminate the need
to pre-form the carbanion species as it is generated in situ in
the presence of the aldehyde.
In this report we illustrate a new general two-step approach
for the synthesis of a,a-bis(trimethylsilyl)toluenes 7a–h from
their corresponding toluenes using identical synthetic condi-
tions for both steps. We have developed methods for their use
in olefination reactions and shown, for the first time, how ste-
reocontrol can be achieved by the use of aniline-derived N-aryl
imine electrophiles. In addition this method is extended to the
complementary tris(trimethylsilane) 9, which opens a new
route to vinyl trimethylsilanes; these compounds are in them-
selves important substrates for cross-coupling transformations
in alkene synthesis.[7]
Scheme 1. Peterson olefination.
Synthesis of (arylmethylene)bis(trimethylsilanes) 7a–h was
achieved by the regioselective benzylic metalation of the
parent toluene by using BuLi, KOtBu, and TMP(H) in THF (LiNK
conditions)[8] and TMSCl quench to form the substituted ben-
zylsilanes 6a–h with a repeat of these conditions providing
the desired olefination reagents (Scheme 2, top panel). Intro-
duction of a sensitive bromine functional group, which would
not be tolerant of the chemistry required for the geminal bis(-
silane) synthesis, was achieved from 7a to give p-bromo deriv-
ative 7i in a high 83% yield (Scheme 2, left bottom panel).
Tris(trimethylsilyl)methane 9 was generated by deprotonation
b-hydroxysilanes can be isolated when the silyl carbanion used
is not stabilized (e.g. R=alkyl), which upon treatment with
either base or acid can deliver the corresponding (E)- or (Z)-
[a] M. Das, Dr. A. Manvar, Dr. M. Jacolot, Dr. M. Blangetti, Dr. R. C. Jones,
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
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500475.
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CsF, respectively, giving the stilbene product in each case but
with virtually no stereoselectivity (Table 1, entries 1–3).
Reaction with other aldehydes showed no significant
change in product E/Z ratio, which is consistent with previous
reports (Table 1, entries 4–9).[4] Similar results were obtained
with 7a when using TBAF as an activator (entry 10). Only deriv-
ative 7g containing an electron-withdrawing group and the
tris(trimethylsilyl)methane 9 showed moderate 80:20 E/Z selec-
tivities (entries 10–13).[4d,9] While the lack of stereocontrol is
1
a major drawback, monitoring of the reaction by H NMR spec-
troscopy in [D8]THF revealed that hexamethyldisiloxane was
the reaction byproduct, which as a low-boiling solvent (988C)
can be readily removed (Table 1, Supporting Information).
As neither substrate nor reaction conditions had any signifi-
cant general influence on the stereochemical outcome of the
reaction, a new approach was sought to gain stereocontrol.
Previously reported computational studies on the Peterson ole-
fination mechanism have described that, in the absence of
a coordinating counter ion, the addition step was rate-limiting
and as such it should be sensitive to steric and electronic influ-
ences.[10] In an effort to exert such influences in a general
manner, (E)-N-benzylideneanilines were chosen as alternative
electrophiles to aldehydes which could be readily generated
by their condensation with inexpensive aniline (Table 2).[11]
Scheme 2. Synthesis of (arylmethylene)bis(trimethylsilanes) 7a–i and tris(tri-
methylsilyl)methane 9.
of bis(trimethylsilyl)methane 8 and TMSCl quench (Scheme 2,
right bottom panel).
With the olefination reagents in hand their use in the fluo-
ride-promoted reaction with aldehydes was explored to identi-
fy optimal activation conditions and record the effects of sub-
stituents on product E/Z selectivity (Table 1). It was found that
reaction of 7d with benzaldehyde proceeded smoothly in
either THF or DMF when using tetrabutylammonium fluoride
(TBAF), tetrabutylammonium difluorotriphenylsilicate (TBAT), or
Table 2. Optimization of olefination conditions with N-phenyl imines.
Entry
7d/9
Fluoride
Solvent
T [8C]
Yield [%]
E/Z[a]
Table 1. Screening of olefination reaction conditions with carbonyls.
1
2
3
4
7d
7d
7d
9
TBAT
CsF[b]
CsF[c]
CsF[b]
THF
70
10a/15
10a/59
10a/77
11 a/83
94:6
97:3
96:4
99:1
DMF
DMF
DMF
RT[c]
80
80
[a] E/Z ratio determined by 1H NMR spectroscopy of the crude product.
[b] 1 equiv CsF used. [c] 30 mol% CsF used.
Entry
7/9
Solvent
Ar
T [8C]
Yield [%]
E/Z[a]
1
2
3
4
5
6
7
8
7d
7d
7d
7d
7d
7d
7d
7d
7d
7a
7g
9
THF
THF
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Ph
Ph
Ph
RT[b]
70[b]
80[e]
70[b]
70[b]
70[b]
70[b]
70[b]
70[b]
RT[d]
RT[b]
70[f]
10a/56
10a/77
10a/82
10b/74
10c/77
10d/64
10e/73
10 f/89
10g/70
10h/70
10i/64
11 a/85
11 a/65
56:44
54:46
51:49
52:48
52:48
53:47
47:53
50:50
51:49
53:47
80:20
80:20
75:25
Gratifyingly, the reaction of 7d in either THF with TBAT at
reflux or DMF/CsF at RT gave the product 10a in modest yield
but with dramatically improved E/Z selectivity of 94:6 (Table 2,
entries 1 and 2). The product yield was found to improve to
77% when the reaction was carried out in DMF at 808C using
30 mol% CsF (entry 3). Applying similar conditions, the tris(tri-
methylsilyl)methane 9 gave 11 a in a 83% yield and E/Z ratio
of 99:1 (entry 4). Following the reaction course of 7d with N-
benzylideneaniline in [D7]DMF showed that 1,1,1-trimethyl-N-
phenyl-N-(trimethylsilyl)silanamine 12 was produced as a by-
product during the course of the reaction (see the Supporting
Information). Compound 12 was readily separable from the
alkene product by aqueous acid extraction during which it was
seen to desilylate and generate aniline.
4-BrC6H4
4-MeOC6H4
4-MeC6H4
2-naphthyl
(E)-PhCH=CH
4-CNC6H4
4-MeOC6H4
4-MeOC6H4
Ph
9
10
11
12
13
9
Ph
RT[g]
[a] E/Z ratio determined by 1H NMR spectroscopy of the crude product.
Fluoride source. [b] TBAT. [c] CsF. [d] TBAF. [e] 1 equiv CsF used.
[f] 20 mol% TBAT used. [g] 20 mol% TBAF used.
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The generality of E-product selectivity was investigated
using ten different olefination reagents 7a–i and 9, with thir-
teen different N-phenyl imines chosen to reflect differing elec-
tronic and steric factors (Table 3). Remarkably, the excellent E
Table 3. Stereochemistry control in Peterson olefination with N-phenyl
imines.
Entry
7/9
Ar
Product
Yield [%]
E/Z[a]
1
2
3
4
5
6
7
8
7a
7a
7b
7b
7c
7d
7d
7e
7e
7 f
7 f
7g
7g
7h
7h
7i
7i
9
9
9
9
9
9
9
9
9
Ph
10j
79
60
83
82
71
62
71
53
73
89
41
77
69
68
83
87
11
71
73
51
56
61
60
44
70
47
92:8
91:9
98:2
99:1
98:2
92:8
91:9
99:1
95:5
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
97:3
99:1
99:1
99:1
99:1
99:1
99:1
99:1
97:3
4-MeOC6H4
2-ClC6H4
ferrocenyl
2-ClC6H4
4-MeOC6H4
(E)-PhCH=CH
2-naphthyl
4-FC6H4
3-MeOC6H4
ferrocenyl
Ph
4-FC6H4
4-BrC6H4
4-MeOC6H4
4-FC6H4
2-MeOC6H4
2-ClC6H4
3-MeOC6H4
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-Me2NC6H4
4-MeOC(O)C6H4
2-naphthyl
ferrocenyl
10h
10k
10l
10m
10c
10 f
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
11 b
11 c
11 d
11 e
11 f
11 g
11 h
11 i
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Scheme 3. Mechanistic cycle.
tion. The expected stilbene product 10a was obtained with an
identical E/Z selectivity as observed with the CsF-promoted re-
action (Scheme 3, inset). This we believe is the first demonstra-
tion of an autocatalytic Peterson reaction.
While the synthesis of N-benzylideneanilines could be con-
sidered trivial it does add an additional synthetic step to the
overall process. As such, a one-pot method was developed
which first conducted the aldehyde/aniline condensation in
DMF following which the bis(silane) reagent was added and
olefination performed in situ. Using 7b, d, and f as representa-
tive bis(silanes), this approach worked well with the stilbenes
10a, 10x,y isolated in comparable yield and E-selectivity as the
approach outlined above (Scheme 4).
11 j
[a] E/Z ratio determined by 1H NMR spectroscopy of the crude product.
selectivity was observed in all reactions with the stilbene prod-
ucts 10 obtained in E/Z ratios ranging from 91:9 to 99:1
(Table 3, entries 1–17) and substituted trimethyl(styryl)silanes
11 ranging from 97:3 to 99:1 (entries 18–26).
While further investigation is required to fully explain the N-
phenyl imine stereocontrol two influential differences between
the imine and carbonyl reaction pathways would be the in-
creased sterics involved in the addition of 13 and the effect of
the phenyl(trimethylsilyl)amide leaving group 17. Loss of 17
could be envisaged 1) following the formation of the carban-
ion 15 by an 1,3-aza-Brook-type rearrangement of 14 or 2) fol-
lowing the concerted formation of the substituted 1-aza-2-sila-
cyclobutane 16 (Scheme 3).[12] Completion of the reaction cycle
with the formation of 12 as a byproduct indicates the possibili-
ty of an autocatalytic cycle in which 17 reacts with starting ma-
terial 7 to generate 12 and 13 (Scheme 3).[13] This was con-
firmed by the reaction of 7d with N-benzylideneaniline by
using one equivalent of 17 (generated by the reaction of 1,1,1-
trimethyl-N-phenylsilanamine with NaH) to promote the reac-
Scheme 4. One-pot (E)-selective synthesis of stilbenes.
In summary, a new general two-step synthesis of a,a-bis(tri-
methylsilyl)toluenes and tris(trimethylsilyl)methane has been
developed providing access to bench-stable Peterson olefina-
tion reagents. Poor E/Z selectivity was obtained in their reac-
tion with aldehydes but when the corresponding substituted
N-benzylideneanilines were employed as electrophiles high E
selectivity was observed for a wide range of substrates. Iden-
tification of the reaction byproduct as aqueous extractable
N,N-bis(trimethylsilyl)aniline maintains the advantage of Peter-
son olefinations in generating a readily removable byproduct.
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c) T. H. Chan, E. Chang, J. Org. Chem. 1974, 39, 3264; d) P. F. Hudrlik,
E. L. O. Agwaramgbo, A. M. Hudrlik, J. Org. Chem. 1989, 54, 5613;
e) A. R. Bassindale, R. J. Ellis, J. C.-Y. Lau, P. G. Taylor, J. Chem. Soc. Chem.
Commun. 1986, 98; f) C. Palomo, J. M. Aizpurua, J. M. Garcia, I. Ganboa,
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Taylor, V. Snieckus, J. Org. Chem. 1989, 54, 4372.
Evidence for an autocatalytic cycle has been established with
the olefin forming leaving group being capable of propagating
the reaction. As the use of imine electrophiles for aza-Peterson
olefinations has not been previously studied, the scope of this
approach is currently being further explored in conjunction
with additional mechanistic investigations.
[5] Removal of crystalline Ph3PO typically requires chromatography. For
recent developments in catalytic Wittig reactions, see: E. E. Coyle, B. J.
Doonan, A. J. Holohan, K. A. Walsh, F. Lavigne, E. H. Krenske, C J.
O’Brien, Angew. Chem. Int. Ed. 2014, 53, 12907 and references therein.
[6] a) B. Halton, Q. Lu, P. J. Stang, Aust. J. Chem. 1990, 43, 1277; b) V.
Werner, T. Klatt, M. Fujii, J. Markiewicz, Y. Apeloig, P. Knochel, Chem. Eur.
J. 2014, 20, 8338; c) K. Groll, S. M. Manolikakes, X. Mollat du Jourdin, M.
Jaric, A. Bredihhin, K. Karaghiosoff, T. Carell, P. Knochel, Angew. Chem.
Int. Ed. 2013, 52, 6776; Angew. Chem. 2013, 125, 6909; d) A. Couture, H.
Cornet, E. Deniau, P. Grandclaudon, S. Lebrun, J. Chem. Soc. Perkin Trans.
1 1997, 469.
[7] a) J. R. McAtee, S. E. S. Martin, D. T. Ahneman, K. A. Johnson, D. A.
Watson, Angew. Chem. Int. Ed. 2012, 51, 3663; Angew. Chem. 2012, 124,
3723; b) K. Oshima, Sci. Synth. 2002, 4, 713.
[8] a) P. Fleming, D. F. O’Shea, J. Am. Chem. Soc. 2011, 133, 1698; b) M. Blan-
getti, P. Fleming, D. F. O’Shea, J. Org. Chem. 2012, 77, 2870; c) M. Blan-
getti, H. Muller-Bunz, D. F. O’Shea, Chem. Commun. 2013, 49, 6125;
d) M. Das, D. F. O’Shea, J. Org. Chem. 2014, 79, 5595.
Experimental Section
General procedure for the olefination of (benzyl)bis(trime-
thylsilane) with N-phenyl imines
A solution of (benzyl)bis(trimethylsilane) (0.48 mmol) and substitut-
ed N-benzylideneaniline (0.40 mmol) in anhydrous DMF (2.0 mL)
with 4 ꢁ molecular sieves was treated with CsF (0.12 mmol) under
N2 and the resulting solution was heated at 808C until the reaction
reached completion. The reaction mixture was quenched with
water. The residue was extracted with diethyl ether (20 mLꢂ3). Or-
ganic layers were combined and washed with water and brine,
dried over anhydrous sodium sulfate, and concentrated. Purifica-
tion by silica gel chromatography eluting with petroleum ether/
ethyl acetate gave the corresponding alkene. The E/Z ratios for the
1
alkene products were determined by H NMR spectroscopic analy-
sis.
[9] a) D. J. Ager, J. Org. Chem. 1984, 49, 168; b) J. McNulty, P. Das, Chem.
Commun. 2008, 1244.
[10] P. Brandt, P.-O. Norrby, I. Martin, T. Rein, J. Org. Chem. 2002, 67, 7676.
[11] To the best of our knowledge Peterson olefination of imines has not
been previously reported. The use of N-sulfonyl imines and N-phenyl
imines for Wittig reactions has been described, for examples, see a) D.-J.
Dong, H.-H. Li, S.-K. Tian, J. Am. Chem. Soc. 2010, 132, 5018; b) D.-J.
Dong, Y. Li, J.-Q. Wang, S.-K. Tian, Chem. Commun. 2011, 47, 2168;
c) H. J. Bestmann, F. Seng, Angew. Chem. Int. Ed. Engl. 1963, 2, 393;
Angew. Chem. 1963, 75, 451.
Acknowledgements
We thank the European Research Association ERA-Chemistry
and the Irish Research Council (IRC) for financial support.
[12] For 1,3-azaBrook rearrangements, see: A. G. Brook, J. M. Duff, J. Am.
Chem. Soc. 1974, 96, 4692; for alkene generation from 1-aza-2-silacyclo-
butanes, see; K. Tamao, Y. Nakagawa, Y. Ito, J. Am. Chem. Soc. 1992, 114,
218.
Keywords: bench-stable reagents · imines · organic synthesis ·
Peterson olefination · stereoselectivity
[1] a) D. J. Peterson, J. Org. Chem. 1968, 33, 780; b) D. J. Ager, Science of
Synthesis Sect. A 2010, 47, 85; c) L. F. van Staden, D. Gravestock, D. J.
Ager, Chem. Soc. Rev. 2002, 31, 195.
[13] An additional pathway in which 17 reacts with TMSF to produce 12
and regenerate fluoride could also be occurring.
[2] T. Takeda, Modern Carbonyl Olefination Wiley-VCH, Weinheim, 2004,
pp 18–93.
[3] P. F. Hudrlik, D. Peterson, J. Am. Chem. Soc. 1975, 97, 1464.
[4] a) A. R. Bassindale, R. J. Ellis, J. C.-Y. Lau, P. G. Taylor, J. Chem. Soc. Perkin
Trans. 2 1986, 593; b) D. J. Ager, J. Chem. Soc. Perkin Trans. 1 1986, 183;
Received: February 5, 2015
Published online on && &&, 0000
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Communication
COMMUNICATION
A mild method for E-selective Peterson
olefinations is described. Bench-stable
a,a-bis(trimethylsilyl)toluenes and tris-
(trimethylsilyl)methane are used as re-
agents in reaction with substituted N-
phenyl imines (see scheme).
&
Organic Synthesis
M. Das, A. Manvar, M. Jacolot,
M. Blangetti, R. C. Jones, D. F. O’Shea*
&& – &&
Stereoselective Peterson Olefinations
from Bench-Stable Reagents and N-
Phenyl Imines
Chem. Eur. J. 2015, 21, 1 – 5
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ