(Z)-selective Takai olefination of salicylaldehydes

Article abstract of DOI:10.3762/bjoc.13.35

The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the

Full text of DOI:10.3762/bjoc.13.35

(Z)-Selective Takai olefination of salicylaldehydes
Stephen M. Geddis‡, Caroline E. Hagerman‡, Warren R. J. D. Galloway, Hannah F. Sore,
Jonathan M. Goodman and David R. Spring*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 323–328.
Department of Chemistry, University of Cambridge, Lensfield Rd,
Cambridge, CB2 1EW, UK
doi:10.3762/bjoc.13.35
Received: 05 October 2016
Accepted: 09 February 2017
Published: 20 February 2017
Email:
David R. Spring* - spring@ch.cam.ac.uk
* Corresponding author ‡ Equal contributors
Associate Editor: J. A. Murphy
Keywords:
© 2017 Geddis et al.; licensee Beilstein-Institut.
License and terms: see end of document.
alkenyl iodides; salicylaldehydes; stereoselectivity; Takai olefination;
transition state
Abstract
The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread
implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly
(Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification of
key factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model to
rationalise these observations.
Introduction
The Takai olefination (or Takai reaction) is a method for the alkenes ((E):(Z)-product ratios are typically around 4:1 or
conversion of aldehydes 1 into the corresponding alkenyl greater). This selectivity has found wide use, particularly in the
halides 2 using a haloform–chromium(II) chloride field of total synthesis where it is often used to install vinyl
(CHX3–CrCl2) system (Scheme 1A) [1,2]. It is believed that the iodides with high levels of geometric purity which can then be
haloform is first converted to a nucleophilic gem-dichromium utilised in metal-catalysed cross-coupling reactions [2,6].
species 3 that then attacks the carbonyl group of the aldehyde to
generate a β-oxychromium species 4 (Scheme 1B). Subsequent Hodgson et al. [7] and later Takai et al. [5] have proposed very
elimination leads to alkene formation. The Takai olefination can similar models to explain the (E)-stereoselectivity observed in
also be performed with geminal dihalide reagents rather than the chromium(II)-mediated homologation of aldehydes to
haloforms. In addition, the reaction can also be used to generate alkenes (including vinyl halides). The salient features of both
vinyl stannanes [3], silanes [4] and boronates [5].
models are the same (Scheme 2). It is presumed that the addi-
tion of the gem-dichromium species 3 to the aldehyde 1
One of the most significant features of the Takai olefination is proceeds via a six-membered pseudo-chair transition state 5
that it is generally highly selective for the formation of (E)- containing two chromium ions bridged by a halogen. The less
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Beilstein J. Org. Chem. 2017, 13, 323–328.
sition at the analogous position of the ring (Hodgson et al.
suggest the X substituent will be axial and the R1 group remains
equatorial in this less favourable transition state) [7].
As part of an on-going total synthesis programme, we subject-
ed 6-chlorosalicylaldehyde (6) to standard Takai olefination
conditions using iodoform (see Supporting Information File 1
for details) to form alkenyl iodide product 7 (Scheme 3). To our
surprise a large excess of the (Z)-isomer of 7 relative to the cor-
responding (E)-isomer was observed in the crude material
(approx. ratio of (E)-7:(Z)-7 of 15:85 according to 1H NMR
analysis, see Supporting Information File 1 for more informa-
tion). There are several other examples of poor (E)-selectivity in
the literature [8-10]; however, no detailed investigations as to
the origins of this effect have been carried out. We therefore
embarked on a study to understand the influence of the sub-
strate structure upon the (E):(Z)-product ratio under Takai olefi-
nation conditions.
Scheme 1: A) General overview of the Takai olefination for the forma-
tion of alkenyl halides 2 from aldehydes 1 and haloforms in the pres-
ence of Cr(II)Cl2. B) Proposed course of the Takai olefination. Possible
ancillary ligands omitted for clarity. X = Cl, Br or I.
sterically hindered equatorial positions are occupied by the
aldehyde substituent (R1 in Scheme 2) of 1 and halide group
(X) of 3 and the aldehyde oxygen is thought to be coordinated
to one of the Cr centres (the “coordinating” Cr centre high-
lighted in Scheme 2). The resulting β-oxychromium species
adduct 4 will exist in a conformation where the two hydrogen
atoms across the single bond are anti to each other (referred to
as the anti-4 conformation, Scheme 2). Syn-elimination is then
thought to take place before rotation of the formed bond to give
the (E)-configured olefin, (E)-2 [5]. The minor (Z)-configured
Scheme 3: An unusually high level of (Z)-stereoselectivity was ob-
served in the Takai olefination of 6. (E):(Z)-ratio determined by
1H NMR analysis of crude material obtained after reaction work-up.
See Supporting Information File 1 for more information.
product, (Z)-2, presumably results from the reaction through a Results and Discussion
less favourable transition state which is nearly identical to 5 but In order to understand the influential functional groups respon-
differs in that either the R1 substituent originating from the sible for the (Z)-selectivity of 6, a number of ortho-substituted
aldehyde or the X substituent originating from the gem- benzaldehydes were subjected to Takai olefination conditions;
dichromium species is in the sterically more hindered axial po- the results are summarised in Table 1 [11].
Scheme 2: Proposed model for the chromium(II)-mediated homologation of aldehydes to form (E)-alkenes. Hodsgon et al. [7] and Takai et al. [5]
have hypothesised that the addition of the gem-dichromium species 3 to aldehyde 1 proceeds via a six-membered pseudo-chair transition state 5.
X = Cl, Br or I. Other ligands on chromium omitted for clarity.
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acetyl protected analogue gave largely (E)-selective results
(Table 1, entry 6). The presence of an ortho-Cl resulted in a
moderate amount of (Z)-product (Table 1, entry 7).
Table 1: (E):(Z) product ratios for Takai olefination of ortho-substituted
benzaldehydes.
The above results imply that the presence of an OH group
favours the generation of the (Z)-product. The product ratio was
then determined for meta-OH benzaldehyde 22; however, this
resulted in a much lower amount of (Z)-product (Scheme 4),
implying that an ortho-relationship is optimum for the (Z)-
selectivity. Interestingly, comparison of our initial results of the
Takai olefination of 6 with entries 3 and 7 in Table 1, we can
conclude that the presence of a Cl substituent in addition to the
ortho-OH results in a higher (Z)-selectivity than for either sub-
stituent in isolation.
Entry
R
Substrate Product
(E):(Z) Ratioa
1
2
3
4
5
6
7
H
Me
8
9
100:0
78:22
10
12
14
16
18
20
11
13
15
17
19
21
OH
44:56
OAc
NH2
NHAc
Cl
67:33
decomposition
83:17
69:31
aDetermined by analysis of 1H NMR spectra of crude materials ob-
tained after reaction work-up. See Supporting Information File 1 for
more information.
Unsubstituted benzaldehyde (Table 1, entry 1) gave the usual
high (E)-selectivity expected of the Takai olefination (Takai et
al. reported an (E):(Z)-ratio of 94:6 under identical conditions).
The introduction of an ortho-methyl group (Table 1, entry 2)
resulted in a slight increase in the amount of (Z)-product; how-
Scheme 4: Takai olefination of meta-hydroxybenzaldehyde.
ever, this effect was dwarfed by the introduction of an ortho- In order to further investigate this cooperative effect, the
OH group (Table 1, entry 3), where the (Z)-alkene was pro- (E):(Z)-product ratios were determined for various substituted
duced in a higher ratio. This effect was attenuated upon acetyl salicylaldehydes (with ortho-OH substitution already demon-
protection of the OH group (Table 1, entry 4). Attempted Takai strated as optimum for favouring the (Z)-product); the results
olefination of the ortho-NH2 substrate resulted only in decom- are shown in Table 2 along with the previously obtained result
position of the starting materials (Table 1, entry 5), whereas the for 6.
Table 2: (E):(Z)-product ratios for Takai olefination of substituted salicylaldehydes. Ortho- and meta-nomenclature refers to the substituents’ relation-
ship to the aldehyde moiety.
Entry
R
2-Substituted (ortho)
3-Substituted (meta)
Substrate
Product
(E):(Z) Ratioa
Substrate
Product
(E):(Z) Ratioa
1
2
3
4
5
6
F
Cl
24
6
25
7
26:74
15:85
13:87
26:74
–
30
32
34
36
38
40
31
33
35
37
39
41
36:64
25:75
23:77
32:68
72:28
36:64
Br
26
28
–
27
29
–
I
OMe
CO2Me
–
–
–
aDetermined by analysis of 1H NMR spectra of crude materials obtained after reaction work-up. See Supporting Information File 1 for more informa-
tion.
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Beilstein J. Org. Chem. 2017, 13, 323–328.
In order to determine whether the (E):(Z)-ratios presented above
reflect those which might be obtained during the course of a
synthetic scheme, the crude yield was determined (using an
internal NMR standard) for a larger scale reaction. Unsubsti-
tuted salicylaldehyde (12) was chosen for this experiment, as it
contains the core structure present in all the examples above,
and gives approximately equal amounts of the (E)- and (Z)-
products (Scheme 5). Initially, low recovery of material was ob-
served, which we postulate was due to coordination (vide supra)
of both starting material and product to the superstoichiometric
amount of chromium present. However, work-up conditions
were found (see Supporting Information File 1 for details)
which facilitated the recovery of material accounting for 44% of
the material submitted to the reaction conditions. Volatility of
the starting material may also account for the moderate total
yield. Critically, the ratio of (E):(Z)-products did not show sig-
Figure 1: Positive correlation between the amount (Z)-product and σm
for the series of meta-halogenated salicylaldehydes.
nificant deviation from that determined during the smaller scale amount of (Z)-product, and conversely for the electron-with-
tests, and sufficient material was recovered to give confidence drawing CO2Me group.
that these ratios reflect the dominant behaviour of the reaction.
Our results highlight two key points: a) generation of the (Z)-
product during Takai olefination of benzaldehydes is favoured
by the presence of an ortho-OH group; b) this effect is magni-
fied if the substrate also possesses electron-withdrawing groups.
These observations should prove useful during the planning of
synthetic schemes by providing warning that a planned Takai
olefination may not proceed with the expected (E)-selectivity.
Additionally, with careful design of substrates, synthetic routes
utilising (Z)-selective Takai olefinations can now be considered,
a strategy which has been hitherto unprecedented.
A control experiment showed that, in the presence of 0.5 equiv-
Scheme 5: Yield for both products and residual starting material
following a scaled up Takai olefination of salicylaldehyde (12) using
alents of salicylaldehyde, benzaldehyde was converted to the
expected (E)-product (See Supporting Information File 1). This
precludes the possibility that the salicylaldehydes are func-
tioning as ligands for chromium. In light of this and the above
observations, we propose an alternative pathway by which the
optimised work-up conditions. (Yields determined from crude NMR
using 1,3,5-trimethoxybenzene as an internal standard. See Support-
ing Information File 1 for details).
Using the appropriate Hammett substituent constant (σm) [12] reaction may proceed in order to favour the (Z)-product
as a measure of the net electron-withdrawing effect of a given (Scheme 6). Our proposed mechanism commences with nucleo-
substituent, for the meta-halogenated series, a positive correla- philic addition of gem-dichromium species to the aldehyde
tion with the relative amount of (Z)-product was observed moiety via a six membered pseudo-chair transition state, as is
(Figure 1). Whilst Hammett parameters are not tabulated for generally accepted [5,7]. However, rather than proceeding via
ortho-substitution, precluding an analogous quantitative analy- the transition state which places most groups in a pseudo-equa-
sis, the trend for ortho-halogenated substrates is qualitatively torial position (pathway 1), we propose that for the substrates
similar, although with even higher amounts of (Z)-product. This under discussion, the ortho-OH group is able to coordinate to
implies that electron-withdrawing groups favour the production the neighbouring Cr centre if the aldehyde aromatic substituent
of the (Z)-product upon Takai olefination, with the effect drop- occupies a pseudo-axial conformation, thus favouring pathway
ping off with increasing distance of the electron-withdrawing 2. Following syn-elimination, this then leads to the observed
group from the aldehyde and hydroxy moieties. To further test (Z)-olefin products, (Z)-47. Whilst further experimental data is
this theory, meta-OMe and CO2Me substrates were subjected to required in order to bolster this hypothesis, our proposed mech-
the reaction conditions (Table 2, entries 5 and 6). As expected, anism should act as a starting point for future detailed mecha-
the electron-donating methoxy group caused a drop in the nistic investigations.
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Scheme 6: Proposed mechanism for (Z)-selective Takai olefination, whereby coordination of the ortho-OH to the neighbouring Cr centre causes the
aldehyde substituent to adopt a pseudo-axial orientation.
Our observation that this alternative pathway is favoured by
Supporting Information
electron-withdrawing substituents initially seems counter-intu-
itive, as it might be predicted that these could attenuate the
Supporting Information File 1
ortho-hydroxy’s ability to coordinate to the Cr centre. Al-
though the effect appears to correlate with lowered pKa of this
hydroxy group, moderate amounts of (Z)-product are generated
when this group is acetylated (14) and the relevant proton is
therefore absent. This implies that increased acidity is not the
primary factor at play. Instead, based on the higher (Z)-selec-
tivity observed whenever the electron-withdrawing group was
closer to the aldehyde moiety (Table 2), we propose that it is
withdrawal of electron density from this group which is the key.
An electron-deficient aldehyde is less able to supply electron
density to the Cr centre in transition state 44. In order to coun-
teract this deficit in electron donation, the ortho-OH chelates
the Cr, thus favouring the pseudo-axial conformation, as dis-
cussed above.
Experimental procedures and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-35-S1.pdf]
Acknowledgements
The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC grant
agreement no [279337/DOS]. In addition, the group research
was supported by grants from the Engineering and Physical
Sciences Research Council, Biotechnology and Biological
Sciences Research Council, Medical Research Council and
Wellcome Trust. Data accessibility: all data supporting this
study are provided as Supporting Information accompanying
this paper.
Conclusion
Following our observation of unusually high levels of (Z)-olefin
product following Takai olefination of a particular aromatic
substrate, systematic screening of related substrates revealed the
characteristics a substrate should possess in order to lead to (Z)-
selective Takai olefination. The substrate should possess an
ortho-OH group, and the effect will be larger if the substrate
also possesses electron-withdrawing substituents. These obser-
vations will allow synthetic chemists to predict a priori whether
a planned Takai olefination will proceed with lower (E)-selec-
tivity than predicted, and could also lead to synthetic routes
based upon the (Z)-selective Takai olefination of suitably de-
signed substrates. In addition, a modified mechanistic model
was proposed accounting for these observations.
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