Origin of the E/Z Selectivity in the Synthesis of Tetrasubstituted Olefins by Wittig Reaction of α-Fluorophosphonium Ylides: An Explanation for the Low Stereoselectivity Observed in Reactions of α-Alkoxy Aldehydes

Article abstract of DOI:10.1021/acs.orglett.7b00344

A series of tetrasubstituted fluoroalkenes were synthesized in good yield and high E/Z selectivity (up to 96/4) by Wittig reaction between α-heterosubstituted ketones and α-fluorophosphonium ylides. A detailed study of factors that control stereoselectivity in these reactions shows that stereoselectivity is the result of stabilizing CH···F and N···C=O interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity for reactions of stabilized ylides with α-alkoxy aldehydes.

Full text of DOI:10.1021/acs.orglett.7b00344

Letter
pubs.acs.org/OrgLett
Origin of the E/Z Selectivity in the Synthesis of Tetrasubstituted
Olefins by Wittig Reaction of α‑Fluorophosphonium Ylides: An
Explanation for the Low Stereoselectivity Observed in Reactions of
α‑Alkoxy Aldehydes
Dominique Depre,*,† Wim A. A. Vermeulen,† Yolande Lang,† Jean Dubois,† Jan Vandevivere,†
́
Jeremy Vandermeersch,† Longchuan Huang,† and Raphael Robiette*,‡
̈
†Janssen Pharmaceutical Companies of Johnson & Johnson, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse,
Belgium
‡Institute of Condensed Matter and Nanosciences, Universite
Louvain-la-Neuve, Belgium
́
catholique de Louvain, Place Louis Pasteur 1, Box L4.01.02, 1348
S
* Supporting Information
ABSTRACT: A series of tetrasubstituted fluoroalkenes were
synthesized in good yield and high E/Z selectivity (up to 96/
4) by Wittig reaction between α-heterosubstituted ketones and
α-fluorophosphonium ylides. A detailed study of factors that
control stereoselectivity in these reactions shows that stereo-
selectivity is the result of stabilizing CH···F and N···CO
interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity
for reactions of stabilized ylides with α-alkoxy aldehydes.
he Wittig reaction occupies a central role in organic
T
synthesis as it is one of the most widely used methods for
the synthesis of alkenes.1,2 The stereoselectivity of the Wittig
reaction depends on the substrates: nonstabilized phosphonium
ylides (R3P=CHR′, R′ = alkyl) react with aldehydes to yield
alkenes with a high Z selectivity, whereas stabilized ylides
(R3P=CHR′, R′ = EWG) furnish high E selectivity.
Comprehensive experimental studies, supported by recent
computational results, allowed for the elucidation of the
mechanism and the rationalization of the observed stereo-
selectivity in the Wittig reaction.2,3 The first step of the process
is oxaphosphetane formation4,5 and is recognized as determin-
ing the stereoselectivity. The transition-state models developed
by Vedejs et al.2 account for the Z selectivity observed in
reaction of nonstabilized ylides by preferential addition of these
latter to aldehydes through an early puckered cis TS, which
minimizes 1,2 and 1,3 steric interactions (Figure 1). For
stabilized ylides, computational studies showed that TS
structures and E/Z selectivity are controlled by a dipole−
dipole interaction as well as 1,2 and 1,3 steric interactions.3
Reactions of phosphonium ylides with ketones are scarcely
described, probably due to the fact that tri- and tetrasubstituted
alkenes are generally obtained in poor yield with a low E/Z
selectivity.1,6 In the course of the synthesis development of a
drug candidate, we investigated the Wittig reaction between the
stabilized ylide formed by deprotonation of α-fluorophospho-
nium salt 1a and N-benzylpiperidin-3-one (2a) (Scheme 1).
Much to our surprise, the desired tetrasubstituted olefin was
obtained in good yield with a high stereoselectivity for the E
isomer (3a).7 Here, we report the synthesis of a series of
Figure 1. TS structure model and rationale of selectivity for the Wittig
reaction.
fluorinated tetrasubstituted olefins in good yield and with a
high stereocontrol. A detailed study of the observed stereo-
selectivity shows that it is the result of stabilizing CH···F
Received: February 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00344
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Wittig Reaction of Ylide Formed from α-
Fluorophosphonium Salt (1a) and N-Benzylpiperidin-3-one
(2a)
Table 1. Influence of Structural Modifications on the
Stereoselectivity (3/3′)
a
b
entry
X
R
conditions yield (%) 3/3′
1
NMe (2b)
NEt (2c)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Me (1c)
t-Bu (1d)
Et (1a)
A
A
A
A
A
A
A
A
B
B
B
A
53 (3c)
65 (3d)
51 (3e)
90 (3a)
85 (3f)
76 (3g)
57 (3h)
96/4
2
84/16
93/7
hydrogen bonds and N···CO interactions in the addition TS
leading to the E isomer (3a).
3
NAllyl (2d)
NBn (2a)
4
80/20
67/33
86/14
58/42
To understand factors that govern the selectivity in reaction
of 1a and 2a, we first investigated the importance of the
fluoride substituent in the ylide and of the amine group of the
piperidin-3-one derivative. This was done by performing the
reaction with nonfluorinated phosphonium salt 1b and with
cyclohexanone derivative 4 (Scheme 2). These experiments
5
NCHPh2 (2e)
NBn (2a)
6
7
NBn (2a)
c
8
N-p-NO2Ph (2f)
0
9
52 (3i)
86 (3j)
76 (3k)
93 (3l)
59/41
72/28
80/20
10
11
12
NPh (2g)
Et (1a)
Et (1a)
Et (1a)
N-p-MeOPh (2h)
O (2i)
Scheme 2. Reaction of Non-fluorinated Phosphonium Salt
(1b) and of 3-Benzylcyclohexanone (4)
96/4
a
b
Yield in isolated product after flash column chromatography. Ratio
determined by GC, HPLC, or 1H NMR on the crude mixture.
Configuration determined by NMR (19F−1H heteroNOESY; see the
c
Supporting Information). The product of self-condensation of the
ketone was the main product (see the Supporting Information).
atom in a specific interaction in the TS. A similar interaction
must also be present in the case of an oxygen atom as
demonstrated by the high selectivity (96/4) observed with
pyran-3-one 2i (entry 12, Table 1).
Interestingly, this stereoselective synthesis of tetrasubstituted
olefins can be extended to acyclic derivatives and other α-
heterosubstituents: deprotonation of 1a and reaction of the
ylide with ketones 6 and 9 leads to olefins 8 and 11,
respectively, with a moderate to good stereoselectivity (Scheme
3). Again, the crucial role of both the fluoride atom in the ylide
showed that neither of these two structural motives can, alone,
account for the observed E selectivity in the reaction of 1a and
2a. Indeed, deletion of either one of them leads to a loss of
stereoselectivity, as the olefins are obtained in essentially equal
ratios. The observed selectivity is thus the result of a synergistic
effect between these two structural features.
Scheme 3. Wittig Reaction with Acyclic Ketones
Next, we studied the influence of the nature of the N-
protecting group in the piperidinone derivative and of the alkyl
ester moiety in the ylide (X and R, respectively; Table 1).
Increasing the steric hindrance of any of these groups leads to
an erosion of the preference for 3 (entries 1−7, Table 1). Steric
interactions favor formation of 3′; electronic factors must be
responsible for the observed selectivity in favor of isomer 3.
We also performed the reaction of 2a with the
triphenylphosphonium analogue of 1a. This reaction was,
however, very slow and low-yielding (<3% olefin 3a obtained
after 24 h; see the Supporting Information for details). The
nature of the phosphonium group (trimethylphosphonium) in
1 is thus a key factor for allowing the synthesis of
tetrasubstituted olefins.
The predominant role of electronic interactions in
determining stereoselectivity could be further demonstrated
by investigating the reaction of N-aryl derivatives 2f−h.8
Indeed, these experiments show that the 3/3′ ratio increases
(from 59/41 to 80/20) with the electron density on the
nitrogen atom of 2 as modulated by the nature of the N-aryl
group (entries 9−11, Table 1). These observations suggest the
involvement of the lone pair of the piperidin-3-one nitrogen
and the α-heterosubstituent in the ketone in determining
stereoselectivity was demonstrated. Indeed, reaction of 1b, the
nonfluorinated equivalent of 1a provides olefins 7 and 10 with
no significant (46/54) or a reversed stereoselectivity (20/80),
respectively.
In order to gain deeper insights into the origin of observed
stereoselectivity between fluorophosphonium ylides and α-
heterosubstituted ketones, we investigated the Wittig reaction
of ylides formed from 1a and 1b with N-methylpiperidin-3-one
2b and cyclohexanone by computational means. Calculations
were performed at the B3LYP-D3(toluene)/6-31+G**//
B3LYP/6-31G*(toluene) level of theory.9 In our calculations,
as observed in Wittig reactions of aldehydes,3 we find
significant barriers to formation of the oxaphosphetane,
B
DOI: 10.1021/acs.orglett.7b00344
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followed by much lower barriers to cleavage of the latter (see
the Supporting Information). This confirms that initial
cycloaddition is nonreversible. The relative energies of the cis
and trans cycloaddition TSs thereby determine E/Z selectivity.
Obtained relative free energies for cycloaddition TSs
reproduce observed trends for stereoselectivity (Table 2). In
Table 2. Relative Free Energy of Cycloaddition TSs (kcal/
mol Relative to Reactants)
Figure 3. Structure and relative free energy of TSs for the addition of
ylide 1a onto 2b.
a
TS-3 and TS-3′ are the TSs leading to 3 and 3′, respectively.
reaction of 1a with piperidin-3-one derivatives can thus be
accounted for by stabilizing N···CO and CH···F hydrogen-
bond interactions in axial TS-3. For geometrical reasons, TS-3′s
involve only one CH···F hydrogen bond and no N···CO
interactions.
This analysis provides an explanation for the sometimes
quite-low E selectivity (or even preferential formation of Z
product) observed in reactions of α-alkoxy aldehydes (Scheme
4).1f,2 This observed decrease in selectivity is also nicely
each case, two TSs involving, respectively, an axial and an
equatorial approach of the ylide were found. In reactions of
cyclohexanone, the equatorial approach is thoroughly favored,
probably due to steric factors (1,3-diaxial interactions). One can
observe, however, that this preference for equatorial positioning
of the ylide carbon decreases slightly with fluoro substitution
(compare reaction of cyclohexanone with 1a and with 1b,
Table 2). Analysis of TS structures reveals that this can be
accounted for by the presence of stronger CH···F hydrogen
bonds (with hydrogen atoms in α and β position of the ketone)
in the axial case (Figure 2).10,11
Scheme 4. Decrease in E/Z Selectivity with α-Alkoxy
Substitution of Aldehydes
reproduced by calculations: trans addition TS is computed to
be more stable than the cis one by 0.7 and 2.0 kcal/mol for
reaction of ylide 12 with methoxyacetaldehyde and butyr-
aldehyde, respectively (Figure 4). Previously, one of us
proposed that a destabilizing interaction between the dipole
of the ylide and the C−OR bond dipole in TS-trans was
responsible for this low selectivity (see Figure 4).3a,b This study
shows that it can better be accounted for by the presence of a
stabilizing O···CO interaction in TS-cis which counter-
balances the stabilizing dipole−dipole interaction present in
TS-trans (vide supra).12
Figure 2. Structure and relative free energy of axial and equatorial TSs
for the addition of ylide 1a onto cyclohexanone.
The same is true for trans TSs-3′ in reactions of N-
methylpiperidin-3-one 2b. In contrast, for TS-3s the axial
approach is now favored over the equatorial one, indicating that
another effect is in play. Indeed, analysis of the electronic
structure of the axial TS-3s reveals the presence of a stabilizing
interaction between the nitrogen lone pair and the ester
carbonyl group (Figure 3).12 Stabilization arising from this
interaction is estimated at 2.5 kcal/mol using NBO second-
order perturbation theory. The observed high E selectivity in
In summary, we have shown that the Wittig reaction between
stabilized α-fluorophosphonium ylide 1 and N-protected
piperidin-3-one derivatives yields the corresponding tetrasub-
stituted alkenes with a high E selectivity. This high selectivity
C
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Organic Letters
Letter
REFERENCES
■
(1) For reviews, see: (a) Abell, A. D.; Edmonds, M. K. In
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(2) For leading mechanistic and selectivity reviews, see: (a) Vedejs,
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Soc. 2012, 134, 9225−9239.
Figure 4. Computed free energy of addition TSs and rationale for the
decrease in E selectivity observed in Wittig reaction of stabilized ylides
when the aldehyde is α-substituted by an alkoxy group (free energies
in kcal/mol relative to reactants).
(4) In the presence of strongly coordinating ions such as lithium,
betaine intermediates may sometimes be formed, and in these cases
selectivities are different. In this work, we focus on salt-free reactions.
(5) For a recent in-depth experimental, computational, and dynamic
trajectory study on the mechanism of oxaphosphetane formation, see:
Chen, Z.; Nieves-Quinones, Y.; Waas, J. R.; Singleton, D. A. J. Am.
Chem. Soc. 2014, 136, 13122−13125.
could be extended to other cyclic and acyclic α-heterosub-
stituted ketones. A detailed investigation showed that observed
stereoselectivity can be accounted for by CH···F hydrogen
bonds and a stabilizing N···CO interaction in the cis addition
TS (TS-3) leading to 3a. Identification of this latter interaction
now allows us to rationalize the observed decrease in selectivity
for reactions of stabilized ylides with α-alkoxy aldehydes.
(6) For a review on the synthesis of tetrasubstituted olefins, see:
Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698−4745.
́
(7) Lang, Y.; Depre, D. Improved Process for Preparing 2-[(2E)-2-
Fluoro-2-(3-Piperidinylidene)Ethyl]-1H-Isoindole-1,3(2H)-Dione.
Patent WO 2013/045599 A1, 2013.
ASSOCIATED CONTENT
* Supporting Information
(8) Due to the increased acidity of α-protons in 2f, self-condensation
of the ketone was the main reaction in the presence of DBU in this
case (entry 8, Table 1). The use of a weaker base such as triethylamine
and another solvent (in which ketones were better soluble) allowed,
however, the formation of the desired alkenes as the main product,
albeit after longer reaction times (entries 9−11, Table 1).
(9) Calculations were carried out at the B3LYP-D3/aug′-cc-
pVTZ(toluene)//B3LYP/6-31G*(toluene) level of theory using the
Jaguar 8.0 program package (Jaguar 8.0; Schrodinger, LLC, New York,
NY, 2011). Thermal and entropic contributions to free energy were
computed by performing frequency calculations at the B3LYP/6-
31G(d) level of theory. See the Supporting Information for full
computational details and data.
(10) For publications discussing the nature and importance of CH···
F interactions, see: (a) Dalvit, C.; Vulpetti, A. Chem. - Eur. J. 2016, 22,
7592−7601. (b) Desiraju, G. R. Chem. Commun. 2005, 2995−3001.
(c) Kryachko, E.; Scheiner, S. J. Phys. Chem. A 2004, 108, 2527−2535.
(11) See the Supporting Information for full geometrical parameters
of these hydrogen bonds, NCI plots, and test calculations for
estimating the stabilization energy associated with these CH···F
interactions.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00344.
Experimental procedures, characterization data, NMR
spectra, computational details, other computational data,
and Cartesian coordinates for all optimized structures
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ddepre@its.jnj.com.
*E-mail: raphael.robiette@uclouvain.be.
ORCID
Dominique Depre: 0000-0001-6718-085X
́
Raphael Robiette: 0000-0002-3449-565X
Notes
̈
(12) A stabilizing O···CO interaction in TS-3′ is not possible for
geometrical reasons.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Computational resources have been provided by the Universite
■
́
catholique de Louvain (CISM/UCL) and the Fed
́
er
́
ation
́
Wallonie Bruxelles (CECI) funded by the Fond de la
Recherche Scientifique (F.R.S.-FNRS) under convention
́
2.5020.11. R.R. is a Chercheur Qualifie of the F.R.S.-FNRS.
We are grateful to Alex De Groot and Tom Vennekens (both
from Janssen Pharmaceutical Companies of Johnson &
Johnson) for recording NMR and MS spectra.
D
DOI: 10.1021/acs.orglett.7b00344
Org. Lett. XXXX, XXX, XXX−XXX