Cyclopropanation of styrenes and stilbenes using lithiomethyl trimethylammonium triflate as methylene donor

Article abstract of DOI:10.1039/c4cc04929b

Lithiomethyl trimethylammonium triflate, prepared from tetramethylammonium triflate, cyclopropanates several styrenes and stilbenes with electron-donating and selected electron-withdrawing substituents efficiently. Kinetic data support a stepwise nucleophilic addition-ring closure mechanism for this methylenation. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04929b

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Cyclopropanation of styrenes and stilbenes using
lithiomethyl trimethylammonium triflate as
methylene donor†
Cite this: Chem. Commun., 2014,
50, 10608
Received 27th June 2014,
Accepted 23rd July 2014
Juan M. Sarria Toro,‡ Tim den Hartog‡ and Peter Chen*
DOI: 10.1039/c4cc04929b
www.rsc.org/chemcomm
Lithiomethyl trimethylammonium triflate, prepared from tetra- bromide8 has limited the applicability of this potential methyle-
methylammonium triflate, cyclopropanates several styrenes and stilbenes nation reagent.
with electron-donating and selected electron-withdrawing substituents
efficiently. Kinetic data support a stepwise nucleophilic addition- lithiomethyl trimethylammonium reagents, e.g. 2a, by deprotonation
Our group has recently reported10 the synthesis of soluble
ring closure mechanism for this methylenation.
of tetramethylammonium salts possessing a solubilising anion.
This reagent (2a) performs methylenation of aldehydes, ketones
Naturally occurring and synthetically prepared cyclopropane and imines efficiently (Scheme 1, top).
subunits are prominent in molecules with important biological
Nucleophilic addition of organolithium reagents to styrenes
activities.1 The synthesis of cyclopropanes,2 and their subsequent has been extensively studied since its discovery12 for diverse
use as intermediates,3 has been and still is the focus of intensive applications,13 including the formation of heterocycles14 and the
research. Popular methods for the cyclopropanation of olefins can stereoselective formation of cyclopropane derivatives.11 However,
be divided into three main groups: (1) halomethylmetal-mediated the formation of cyclopropanes via carbolithiation was limited to
cyclopropanation, i.e. Simmons–Smith reaction;4 (2) transition- substrates incorporating a leaving group. Potentially, a bigger
metal catalysed decomposition of diazocompounds;5 and (3) substrate scope for the cyclopropanation could be obtained when
Michael reaction-initiated ring closure (MIRC).6 Although these nucleophilic reagents possessing a leaving group, so-called
methodologies have been improved over the years, problems methylene donors as e.g. 2a, are used. Herein, we report our
associated with the formation of (toxic) by-products and safety
concerns for the first two groups, or the necessity to use electron
poor olefins for the third group, limit the applicability of these
methods for cyclopropanation of electron-rich olefins.
An alternative method should ideally use readily accessible
materials, be easily scalable, and have a broad substrate scope.
For industrial application the first two conditions are of most
importance. One alternative method for cyclopropanation of
electron rich olefins was reported by Franzen and Wittig in
1960;7 they used a non-stabilised ‘N–C ylide’8 as methylene
donor for the cyclopropanation of cyclohexene. However, later
attempts to reproduce their results were unsuccessful.9 To date,
the difficulty of characterising and studying a non-soluble, air
sensitive reagent such as lithiomethyl trimethylammonium
¨
¨
Laboratorium fur Organische Chemie, Eidgenossische Technische Hochschule (ETH)
¨
¨
Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich (CH), Switzerland.
E-mail: peter.chen@org.chem.ethz.ch; Fax: +41-44-632-1280
† Electronic supplementary information (ESI) available: Synthetic procedures,
data acquisition and analysis for kinetic measurements and NMR spectra are
available. See DOI: 10.1039/c4cc04929b
Scheme 1 Top: generation of soluble lithiomethyl trimethylammonium
species and their use for the methylenation of aldehydes, ketones and imines.
Middle: previously reported cyclopropanation of styrenes using carbolithiation.11
Bottom: cyclopropanation of styrenes and stilbenes with 2a.
‡ These authors contributed equally.
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Table 1 Effect of the solubilising anion on the cyclopropanation of styrenea
Table 2 Cyclopropanation of olefins at 1.2 mmol scale with lithiomethyl
trimethylammonium triflate
Entry Precursor Anion
Yield of 7ac (%) Remaining 5ac (%)
Entry
Substrate
R1
R2
Product
Yielda (%)
1
2
3
4
1b
1c
1d
1a
ÀBArF b
24
76
81
70
40
ÀN(SO2CF3)2 19
ÀOOC(CH3)3 30
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
H
H
H
H
H
H
H
E-Ph
Z-Ph
E-Ph
7a
7b
7c
7d
7e
7f
7g
trans-7h
trans-7h
trans-7j
7k
71
88
80
88
77
17b
0c
92
98
73
0d
4-CH3Ph
4-C(CH3)3Ph
4-OCH3Ph
3-OCH3Ph
4-FPh
4-NO2Ph
Ph
ÀOSO2CF3
60
a
c
b
0.3 mmol scale. Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.
Determined by GC-FID, see ESI for details.
9
10
11
Ph
results on the use of lithiomethyl trimethylammonium reagents
for the cyclopropanation of styrenes and stilbenes, as well as an
investigation of the reaction mechanism using kinetic data.
Lithiated ammonium salts with several counterions were tested
for the cyclopropanation of styrene in THF. Deprotonation of the
tetramethylammonium salts at 0 1C for 30 min, followed by addition
of styrene (5a), produced cyclopropylbenzene (7a) in all cases. THF-
5j
5k
4-OCH3Ph
Cyclohexene
a
Isolated yields after purification unless otherwise stated, see ESI for
b
c
details. Estimated from GC data. Exclusively polymeric products
were obtained. Unreacted starting material was recovered.
d
soluble salts tetramethylammonium BArF (1b) and triflimide (1c) was observed, for p-NO2 styrene 5g the polymer was the only
afforded 7a in 24% and 19% yield respectively (Table 1, entries 1 product. Methylenation of stilbenes 5h, 5i and 5j afforded trans-
and 2). Ammonium salts with pivalate (1d) and triflate (1a) anions 1,2-bis-substituted cyclopropanes15 7h and 7j exclusively, in 92,
were also evaluated. Even though these salts are only sparingly 98 and 73% yields respectively (entries 8 to 10). Finally, reaction
soluble in THF, the resulting lithiomethyl trimethylammonium of 2a with the aliphatic olefin cyclohexene (5k), the original
salts exhibit better solubility. Higher yields of 30% and 60% were substrate in Franzen and Wittig’s report,7 did not give the
obtained when 1d and 1a were used respectively (entries 3 and 4). corresponding cyclopropane; instead, unreacted starting material
The strong dependence of the reaction yield on the anion might could be recovered after workup (entry 10). This is in agreement with
correlate to the ability of the anion to coordinate the lithium the required forcing reaction conditions reported in literature for the
cation, i.e. this coordination could influence the rate of ring nucleophilic addition of carbanions to nonactivated olefins.16
closure from intermediate 6 (vide supra).
The sharp contrast in reactivity of styrenes and the total
In our experiments we found that trace amounts of (transition) inertness of cyclohexene for this methylenation supports a
metals degrade the lithiomethyl trimethylammonium reagent nucleophilic pathway. The addition of the ‘N–C ylide’ 2 to styrene
to ethylene and trimethylamine, reducing the efficiency of this 5 followed by an intramolecular ring-closure from intermediate 6
methylenation. Consequently, thorough cleaning of all glass- is therefore a plausible mechanism for the formation of cyclo-
ware (see ESI†), the use of glass stir bars, and purification of the propanes 7 (Scheme 1, bottom).
ammonium salts to ensure sub-ppm concentration of metal
The irreversible nature of carbolithiations,17 and the supposed
impurities (as assessed by ICP-MS) is necessary to achieve high irreversible formation of trimethylamine gas in the second step of
and reproducible yields. The high yield obtained with salt 1d, our mechanism, allows the straightforward kinetic study of this
as well as its straight-forward synthesis, purification, and its reaction. Monitoring the reaction of 2d with excess of styrene 5c
non-hygroscopic character, prompted us to explore the scope of using a combination of GC and ESI-MS (electrospray ionization
this methylenation using 2a as methylene source.
mass spectrometry) analysis (see ESI†) showed first order kinetics
At a 1.2 mmol scale styrene could be methylenated by 2a to for the consumption of 2d and the formation of cyclopropane 7c.
produce phenylcyclopropane 7a in 71% isolated yield (Table 2, The pre-exponential factors and kinetic constants found for both
entry 1). In a similar fashion, p-methyl substituted (5b) and curves are statistically very similar (see ESI,† Fig. S2). Assuming
p-tBu substituted (5c) styrenes afforded their corresponding the model of two consecutive, irreversible reactions (A -
cyclopropanes 7b and 7c in 88% and 80% yields, respectively B - C) a kinetic model can be deduced.18 Our kinetic data
(entries 2 and 3). Styrenes bearing methoxy substituents in the strongly support that the first reaction is much slower than the
para-position (5d) as electron-donating group (s = À0.268), second, i.e. the carbolithiation is much slower than the ring-
or in the meta-position (5e) as electron-withdrawing group closure, since the concentration of both product and reagent
(s = +0.115), can be methylenated to afford cyclopropanes 7d display an apparent first order regime with similar pre-
and 7e in 88% and 77% yield (entries 4 and 5). Substitution exponential factors and rate constants.
with electron withdrawing groups in the para position leads
Competitive kinetic measurements19 showed a marked
either to a lower yield (F, entry 6) or to no traces of cyclopropane decrease in reaction rate when electron-donating substituents
(NO2, entry 7). In both of these cases the formation of polymers on the aromatic ring are present (Fig. 1). As expected, nucleophilic
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Funding from the Swiss National Science Foundation and the
European Union Seventh Framework Programme (FP7/2007–2013)
under grant agreement PIEF-GA-2010-275400 (IEF-Marie Curie
post-doctoral grant to T d H), support from Dr P. Zumbrunnen,
Dr R. Frankenstein, Dr M.-O. Ebert (NMR service, LOC ETHZ),
Dr B. Hattendorf (ICP-MS, Gu¨nther group, LAC ETHZ), Dr K. L.
Vikse (proof-reading) and J. Gubler (kinetic experiment with
Z-4-MeOstilbene) are gratefully acknowledged.
Notes and references
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Fig. 1 Hammett plot for the methylenation of styrenes with 2a. Sigma
Hammett parameters are shown in brackets.22
attack on the olefin is strongly disfavoured when its electron
density is increased, and styrenes bearing electron-withdrawing
substituents exhibit a modestly increased methylenation reac-
tivity. Substitution with an electron-withdrawing substituent at
the meta position influences the olefin inductively but has a
minor effect on the resonance stability of intermediate 6, and
therefore only modestly affects the rate of ring closure. For an
electron-withdrawing group in the para position a much greater
influence can be observed; in fact, disappearance of ‘N–C ylide’
2d when reacted with styrene 5h is instantaneous at 0 1C,
however no cyclopropane product is formed. It is likely that
the stabilisation of the benzylic carbanion 6h by the electron-
withdrawing group slows down the ring closure enough to
kinetically favour polymerisation over cyclopropane formation.20
The opposing effect of the substituents on the two steps of this
mechanism should result in a change of rate limiting step. For
electron rich styrenes, addition is rate limiting, whereas for
electron poor styrenes, ring closure should be rate limiting. Such
3 P. Tang and Y. Qin, Synthesis, 2012, 2969.
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15 Kinetic experiments have shown that Z-4-MeOstilbene racemises to
The measured plot for this system (Fig. 1) deviates from linearity
as expected; however, the observed polymerisation does not
allow the study of methylenation kinetically dominated by a rate
limiting ring closure.
In summary, the soluble, easily accessible lithiomethyl trimethyl-
ammonium triflate 2d was found to cyclopropanate several electron
rich styrenes and stilbenes efficiently. Kinetic measurements sup-
port the proposed mechanism featuring a nucleophilic addition and
E-4-MeOstilbene before carbolithiation occurs in the presence of the
lithiomethyl trimethylammonium reagent. Also see: D. Y. Curtin
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19 H. M. Yau, A. K. Croft and J. B. Harper, Chem. Commun., 2012,
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10610 | Chem. Commun., 2014, 50, 10608--10610
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