Stereoselective synthesis of fluoroalkenoates and fluorinated isoxazolidinones: N-substituents governing the dual reactivity of nitrones

Article abstract of DOI:10.1002/chem.201303509

α-Fluoroalkenoates and 4-fluoro-5-isoxazolidinones are of vast interest due to their potential biological applications. We now demonstrate the syntheses of (E)-α-fluoroalkenoates and 4-fluoro-5-isoxazolidinones by the reactions between nitrones and α-fluoro-α-bromoacetate. By altering N-substituents in nitrones, (E)-α-fluoroalkenoates and 4-fluoro-5-isoxazolidinones can be achieved, respectively, with high chemo- and stereoselectivities. Experimental and computational studies have been conducted to elucidate the reaction mechanisms. Linear free energy relationship studies further revealed that the N-substituent effects are primarily of electronic origin. Copyright

Full text of DOI:10.1002/chem.201303509

DOI: 10.1002/chem.201303509
Full Paper
&
Organic Synthesis
Stereoselective Synthesis of Fluoroalkenoates and Fluorinated
Isoxazolidinones: N-Substituents Governing the Dual Reactivity of
Nitrones
G. K. Surya Prakash,* Zhe Zhang, Fang Wang, Martin Rahm, Chuanfa Ni, Marc Iuliucci,
Ralf Haiges, and George A. Olah[a]
Abstract: a-Fluoroalkenoates and 4-fluoro-5-isoxazolidi-
nones are of vast interest due to their potential biological
applications. We now demonstrate the syntheses of (E)-a-flu-
oroalkenoates and 4-fluoro-5-isoxazolidinones by the reac-
tions between nitrones and a-fluoro-a-bromoacetate. By al-
tering N-substituents in nitrones, (E)-a-fluoroalkenoates and
4-fluoro-5-isoxazolidinones can be achieved, respectively,
with high chemo- and stereoselectivities. Experimental and
computational studies have been conducted to elucidate
the reaction mechanisms. Linear free energy relationship
studies further revealed that the N-substituent effects are
primarily of electronic origin.
Introduction
Fluorine substitution[1] has been a viable tool for modifying
biological and physicochemical properties of organic com-
pounds.[2] Among various fluorinated functionalities, mono-
fluoroalkenoates have been of immense interest due to their
potential medicinal applications.[3] While many methods have
been developed to prepare monofluoroalkenoates,[4,5] stereose-
lective syntheses of monofluoroalkenoates are limited to
a handful of reactions, such as the Horner–Wadsworth–
Emmons (HWE) reaction[4,6] and the Julia–Kocienski olefina-
tion.[7] Recently, Hu et al. demonstrated a one-step synthesis of
(Z)-monofluoroolefin by the reaction between nitrones and a-
fluoro-a-sulfoximines aryl methides,[5j,8] in which the sulfoxi-
mine moiety served as both an activating and a leaving group
(Scheme 1). Considering the high nucleofugality of bromide,[9]
we envisioned that monofluoroalkenoates can be synthesized
by a similar reaction with a-fluoro-a-bromoacetate as a pronu-
cleophile.
Scheme 1. Synthesis of monofluorinated olefins using nitrones.
noates and fluorinated isoxazolidinones can be achieved, re-
spectively, by the reactions between a-fluoro-a-bromoacetate
and nitrones. Herein, we report the stereoselective synthesis of
a-fluoroalkenoates by using ethyl a-fluoro-a-bromoacetate (3)
and nitrones. By altering the N-substituent in nitrones, (E)-a-
fluoroalkenoates (4), 4-fluoro-5-isoxazolidinones (5), and 4-
fluoro-5-isoxazolones (6) could be obtained under respective
reaction conditions.
On the other hand, isoxazolidinone derivatives have been
recognized as key heterocyclic skeletons in numerous bioactive
compounds,[10] which can be constituted through the reaction
of esters with nitrones.[11,12] In principle, with a precise modula-
tion of reaction pathways, the preparation of monofluoroalke-
[a] Prof. Dr. G. K. S. Prakash, Z. Zhang,+ Dr. F. Wang,+ Dr. M. Rahm, Dr. C. Ni,
M. Iuliucci, Prof. Dr. R. Haiges, Prof. Dr. G. A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry
University of Southern California
Results and Discussion
Our studies were initiated by adding 1a to a mixture of 3 and
KHMDS in THF at À788C, which resulted in the complete de-
University Park, Los Angeles, CA-90089-1661 (USA)
Fax: (+1)213-740-6679
E-mail: gprakash@usc.edu
composition of 3 probably through a-fluoride[13,1d, and/or a-
i]
[+] Contributed equally to this work.
bromide eliminations. Further investigation was conducted by
treating a mixture of 1a and 3 with KHMDS, expecting the in
situ capture of 3-enolate. As desired, product 4a was obtained
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303509.
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Table 1. Effects of bases on reaction yield and stereoselectivity.
Table 2. Effects of temperatures, additives, and concentrations on reac-
tion yield and stereoselectivity.
Entry[a]
Base
Yield [%][c]
E/Z
Entry[a]
T [8C]
1a [equiv]
Yield [%][b]
E/Z
1
2
3
KHMDS
NaHMDS
LiHMDS
36
38
11
94:6
90:10
94:6
1[c]
2
3
4
5
6
7
8
9[d]
10
À78
À78
À50
À30
0
À78
À78
À78
À78
À78
2.0
2.0
2.0
2.0
2.0
1.5
1.2
1.0
1.0
3.0
53
63
47
46
15
62
47
45
28
58
94:6
93:7
91:9
90:10
85:15
92:8
93:7
90:10
96:4
4
9
99:1
[d]
[d]
5
6
–
–
[d]
[d]
–
–
89:11
7[b]
8[f]
9[f]
NaH
KHMDS
NaHMDS
–
–
[e]
[d]
[a] A solution of BrFCHCO2Et (3, 1.0 equiv) in THF was added to a solution
of 1a and NaHMDS in THF within 5 min. The concentration of reaction
solution is 0.2m, i.e., 1a (0.2 mmol) in THF (1.0 mL). [b] 19F NMR yields
were determined using PhCF3 as the internal standard. [c] The concentra-
tion of reaction solution is 0.05m, i.e., 1a (0.2 mmol) in THF (4.0 mL).
[d] 2.0 equiv of 3 was used.
22
30
97:3
97:3
[a] The base in THF (0.1m, 2.0 equiv) was added dropwise to a mixture of
1a (0.05m, 1 equiv) and 3 (0.075m, 1.5 equiv) in THF at À788C within
5 min (ca. 1.2mhÀ1). [b] The reaction was performed with 1a, 3, and NaH
in a molar ratio of 1.0:3.0:3.0, respectively. [c] 19F NMR yields were deter-
mined using PhCF3 as an the internal standard. [d] Complete decomposi-
tion of 3. [e] Compound 3 was recovered. [f] 2.0 equiv HMPA was added.
Table 3. Reaction condition screening on solvent effects and substrate
proportions.
with satisfactory E/Z selectivity (Table 1, entry 1); however, the
reaction yields did not significantly improve even after an ex-
tensive screening of bases (entries 2–7). Hexamethylphosphoric
triamide (HMPA) was utilized as a cation-coordinating additive
in the hope of enhancing both the yields and the stereoselec-
tivities.[14] While this modification led to slight increase in the
E/Z ratio of the product, detrimental effects on the reaction
yield were observed (entries 1–2 and 8–9). Other solvents, such
as DMF, were found to be unsuitable for the present reaction
(see the Supporting Information).
Entry[a] Solvent
3 [equiv] Base [equiv] Yield [%][b] E/Z
1[d]
2
THF
THF
1.0
1.0
2.0
2.0
2.0
2.0
1.0
1.5
2.0
2.0
2.0
2.0
50
62
71
10
–
92:8
97.3
91:9
49:51
3
THF
4
toluene
[c]
[c]
[c]
5
6
1,2-dimethoxy-ethane
Et2O
–
[c]
Since 3 and the corresponding enolate co-existed under the
above-mentioned reaction conditions, the observed low yields
could be partially ascribed to the self-Claisen condensation of
3. To eliminate this competing reaction, an alternative addition
sequence was adopted by adding 3 to a solution of 1a and
NaHMDS, which increased the yield to 53% with slightly im-
proved stereoselectivity (Table 2, entry 1). Despite the fact that
the addition of HMPA did not show any positive effects (see
the Supporting Information), the reaction yield was enhanced
by increasing the reaction concentration (entries 1 with 2). This
was presumably due to the higher reaction order of the aldol-
like addition relative to the above-mentioned enolate decom-
position (possibly a second-order reaction versus a first-order
reaction, respectively). Further reaction condition screening
was focused on alternating reaction temperatures and propor-
tions of reagents; however, the yields did not improve (en-
tries 3–10).
–
–
[a] A solution of BrFCHCO2Et (3, 0.4 mmol) in THF (1.0 mL) was added to
a solution of 1a (1.0 equiv) and base in THF at À788C using syringe
pump over 3 h (ca. 0.13mhÀ1). [b] 19F NMR yields were determined using
PhCF3 as the internal standard. [c] Severe decomposition of 3.
[d] 1.5 equiv of 1a was used.
nificantly lower addition rate of 3 (ca. 0.13mhÀ1, Table 3, en-
tries 1–2). The product was obtained in 71% yield by employ-
ing 1a, 3, and NaHMDS in a molar ratio of 1.0:2.0:2.0, respec-
tively (entry 3). Further attempts to enhance the efficacy of the
reaction by varying solvents and bases were not successful
(entries 4-6).
Table 4 outlines the substrate scope of the present protocol.
A variety of aromatic nitrones readily reacted with 3 to afford
a-fluoroalkenoates 4 with high E/Z selectivity. Compound 4c
was obtained in poor yield probably because of the lability of
the cyano group under basic conditions,[15] whereas the low
yield of 4 f was likely due to the ipso substitution of the nitro
group with strong nucleophiles.[16] As indicated by entries 1, 4,
It was recognized that a quick addition of 3 (ca. 2.4mhÀ1)
could lead to high local concentration of 3-enolate, thereby fa-
voring the decomposition reaction over the desired addition
reaction. A syringe pump was therefore utilized to enable a sig-
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ditions, our initial investigation
led to the complete decomposi-
tion of 3 (Scheme 2). These un-
successful reactions with i–iii
could be probably ascribed to
the acidity of a-protons on the
N-alkyl groups, which not only
consumed the base but also di-
minished the reactivity of the ni-
trones.[17] N-tert-butyl nitrones
(2a) was thus chosen to react
with 3. Instead of a-fluoroalke-
noate 4a, isoxazolidinone (5a)
and the corresponding dehydro-
brominated product isoxazolone
(6a) were isolated and their
structures were confirmed by X-
ray diffraction (Scheme 2 and
Figure 1).[18]
Table 4. Preparation of E-monofluoroalkenoates by using N-phenyl nitrones 1 and a-bromo-a-fluoroacetate 3.
Entry[a]
1
R
Yield [%][b]
71 (56)
E/Z
Entry[a]
9
R
Yield [%][b]
30 (24)
E/Z
90:10
67:33
2
3
4
15 (10)
39 (28)
54 (43)
90:10
94:6
92:8
10
11
12
81 (80)
68 (61)
72 (63)
93:7
97:3
94:6
After a careful screening, the
optimal reaction conditions were
achieved with 2a, NaHMDS, and
3 in a molar ratio of 1.0:2.0:2.0,
respectively (Table 5, entry 1).
Similar to the fluoroalkenoates-
5
60 (44)
22 (21)
99:1
13
14
60 (52)
90:10
[c]
[e]
6
7
8
90:10
–
–
forming
reaction
described
above, the present reaction also
required the slow addition of 3
into reaction mixture using a sy-
ringe pump. It is worth mention-
ing that 5a could also be
formed exclusively in 54% yield
when NaHMDS and 3 were si-
multaneously added to 2a via
a syringe pump (entry 5).
[c]
[e]
[c]
[e]
–
–
–
–
15
[d]
[e]
–
–
[a] The reaction was carried out as follows: A solution of 3 (2.0 mmol) was added into a solution of
1 (1.0 mmol) and NaHMDS (2.0 mmol) in THF (5.0 mL) at À788C using syringe pump over 3 h (ca. 0.13mhÀ1).
[b] The yields are illustrated in the form of 19F NMR yield% (isolated yield%). [c] No product was observed in
19F NMR spectrum. [d] Complex mixture. [e] Not isolated.
With the optimal reaction con-
ditions in hand, we examined
the substrate scope of this reac-
5 and 10–13 in Table 4, the electron-withdrawing ability of sub-
stituents was found to exert little influence on reaction yields.
Nevertheless, the low reactivity
tion. As shown in Table 6, a variety of N-tert-butyl-substituted
nitrones reacted with 3 to afford 5 and 6 with moderate over-
of nitrones bearing ortho-sub-
stituents and bulky aryl groups
indeed revealed the pivotal role
of steric effects (entries 2, 7, 8,
14 and 15). Noticeably, nitrones
1i also participated in the pres-
ent transformation to render an
E isomer as the major product;
however, with low yield and re-
duced stereoselectivity (entry 9).
To modulate the reactivity of
nitrones, we explored the N-sub-
stituent effects in the present re-
action. By using N-methyl, ethyl,
Scheme 2. Investigation of N-substituent effects in the reaction between nitrones and a-bromo-a-fluoroacetate 3.
The indicated relative configuration of 5a was confirmed by X-ray diffraction. Other diastereoisomers were not
and isopropyl nitrones under the
above-mentioned reaction con- observed.
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dines,[21,22] phenyl-substituted 7
can be presumably ruled out as
key
reaction
intermediates
(Scheme 3c, TS1). Similarly, isoxa-
zolidinone 5a was also shown to
be fairly stable at elevated tem-
perature (À508C), therefore, ex-
cluding the intermediacy of iso-
xazolidinone in the olefination
reaction.
Figure 1. X-ray crystal structures of 5a, 6a, and 7e.[27]
Table 5. Reaction-condition optimization for the isoxazolidinone forming
reaction.
Entry[a]
Base (equiv)
Yield 5a [%][b]
Yield 6a [%][b]
1
2
3
4
5[c]
6[d]
7
NaHMDS (2.0)
NaHMDS (1.0)
NaHMDS (1.5)
NaHMDS (3.0)
NaHMDS (4.0)
KHMDS (3.0)
LiHMDS (3.0)
45
10
20
0
54
0
22
0
0
37
0
0
0
39
[a] BrFCHCO2Et (3, 0.4 mmol, 2.0 equiv) in THF (1.0 mL) at À788C was
added using a syringe pump over 3 h (ca. 0.13mhÀ1) to a solution of 2a
and base in THF (0.5 mL). [b] 19F NMR yields were determined using
PhCF3 as an internal standard. [c] A solution of base (0.8m) and another
solution of 3 (0.4m, 4.0 equiv) were added simultaneously using a syringe
pump over 3 h. [d] Complete decomposition of 3.
all yields (Table 6, entries 1–5). Nevertheless, sterically hindered
substrates demonstrated rather low reactivity (entries 6 and 7).
Differing from the fluoroalkenoation reaction, naphthyl-substi-
tuted nitrones (2i and 2j) were found to be inactive (entries 9
and 10). Nitrone 2h was found to be incompatible with the
present reaction (entry 8), although its counterpart 1i could
participate in the fluoroalkenoate-forming reaction.[19]
To gain in-depth insight into these two reactions, we have
performed detailed experimental and computational mechanis-
tic studies. As depicted in Scheme 3a, these reactions have
been proposed to initially undergo an addition reaction to
generate an aldol-type key reaction intermediate, which leads
to the formation of alkenoate product 4 and isoxazolidinone
product 5. The GCMS analysis of the reaction mixture of 3-eno-
late with N-phenyl nitrone 1a revealed the existence of imine
9a aside from nitrobenzene 8a’[20] and fluoroalkenoate 4a
(Scheme 3b, left). Although a four-membered ring intermediate
7 (R=Ph) can provide a rationale for this observation, we
found that the observed imine 9a can in fact be formed by
the reaction between N-phenyl nitrone
1 and NaHMDS
(Scheme 3d). In addition, 1,2-oxazetidine 7e was isolated as
a side product from the reaction of N-tert-butyl nitrone 2e
with 3-enolate in 15% yield. Considering the essential stability
of 7e at 508C and the inertness of many other 1,2-oxazeti-
Figure 2. Calculated reaction pathways of N-phenyl-substituted nitrones
(top) and N-tert-butyl-substituted nitrones (bottom).
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aldol-type adduct with a corre-
sponding DGIM1b of À19.0 kcal
molÀ1. Similarly, the reaction be-
tween 3-enolate and N-tert-butyl
nitrone 2a also preferentially
adopts the aldol-type addition
pathway by the TS2b transition-
state structure. However, this re-
action is kinetically and thermo-
dynamically less feasible than
the corresponding reaction with
N-phenyl nitrone 1a.
Table 6. Preparation of isoxazolidinones using N-tert-butyl nitrones 2 and a-bromo-a-fluoroacetate 3.
Entry[a] Ar
19F NMR yield
[%][b] 5/6
Isolated yield Entry[a] Ar
[%] 5/6
19F NMR yield
[%][b] 5/6
Isolated yield
[%] 5/6
[c]
[d]
1
45/35
64/0
40/28
48/0
6
7
–
–
[c]
[d]
2
–
–
Following the above-men-
tioned results, further calcula-
tions focused on elucidating dif-
ferent reaction pathways toward
the observed products. As
shown in Figure 2, through the
transition-state TS1b, an aldol-
type adduct can be formed as
IM1b, which can rearrange to
IM1b’ with similar thermostabili-
ty. The former can undergo an
elimination reaction with a barri-
er of +25.4 kcalmolÀ1 to gener-
ate the E-fluoroalkenoate 4a. Al-
though the isoxazolidinone for-
mation reaction toward 5-Ph
was also found to be kinetically
feasible, such a reaction is ther-
[c]
[d]
3
4
5
30/14
51/15
39/15
25/11
43/13
30/14
8
–
–
[d]
9
2/0
–
10
26/0
21/0
[a] The reaction was carried out by syringe pumping with 3 (2.0 mmol in 5.0 mL of THF) into a mixture of 2
(1.0 mmol) and NaHMDS in 5.0 mL of THF at À788C over 3 h (ca. 0.13mhÀ1). [b] 19F NMR spectroscopic yield
was determined using PhCF3 as the internal standard. [c] Complete decomposition of 3. [d] Not isolated.
[e] The indicated relative configuration of 5 was deduced by 19F NMR spectroscopy. Other diastereoisomers
were not observed.
To decipher the detailed mechanistic profiles of the present
reactions, we have performed DFT calculations at the M06-2X/
6-311+G(d,p)//B3LYP/6-31+G(d,p) level of theory in Gaussi-
an 09.[23,24] Solvent effects of THF were included implicitly
through the self-consistent reaction field approach, as imple-
mented in the default PCM model.[25] Thermal and entropic
corrections were obtained by frequency analysis at the B3LYP/
6-31+G(d,p) level in THF. The frequency analysis confirmed
that all considered ground structures were true minima on the
PES. The transition-state structures were indicated by a single
imaginary frequency.
modynamically unfavorable. Similarly, the aldol-type addition
of 2a also leads to the formation of IM2b and IM2b’. Despite
that E-fluoroalkenoate 4a and 1,2-oxazetidine 7-tBu are ther-
modynamically preferred products, the corresponding reac-
tions are kinetically impeded by high activation barriers of
+40.6 and +29.1 kcalmolÀ1, respectively. In comparison, the
formation of isoxazolidinone 5-tBu, although thermodynami-
cally unfavorable, was calculated to be kinetically feasible with
a barrier of +22.4 kcalmolÀ1.
As depicted in Table 7, the
barriers (DG°
and DG°TS1f) to
Table 7. Calculated thermodynamics and kinetics of the aldol and [3+2] reactions between nitrones and a-
bromo-a-fluoroacetate enolate.
TS1e
the nitrone–enolate [3+2]cyclo-
addition[12f,26] were calculated to
be +13.5~ +16.0 kcalmolÀ1. In
comparison, the aldol-type addi-
tion of 3-enolate to N-phenyl ni-
trone 1a is kinetically more fa-
vorable with the corresponding
R=Ph
activation
energies
ranging
DGTS1
DGIM1
+4.3 (TS1a)
À16.5 (IM1a)
+2.3 (TS1b)
À19.0 (IM1b)
+4.6 (TS1c)
À18.0 (IM1c)
+4.7 (TS1d)
À16.1 (IM1d)
+13.5 (TS1e)
NC (IM1e)[a]
+16.0 (TS1f)
NC (IM1f)[a]
from +2.3 to +4.7 kcalmolÀ1
(Table 7). Among the four possi-
ble aldol-type transition states,
TS1b is the most preferential
structure, which also leads to
R=tBu
DGTS2
DGIM2
+10.3 (TS2a)
À5.4 (IM2a)
+7.8 (TS2b)
À7.8 (IM2b)
+11.8 (TS2c)
À8.2 (IM2c)
+13.2 (TS2d)
À4.9 (IM2d)
+19.7 (TS2e)
NC (IM2e)[a]
+21.7 (TS2f)
NC (IM2f)[a]
[a] NC=not calculated.
a
thermodynamically favorable
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that this is due to specific THF–Na+ interactions,
which have not been considered in our implicit solva-
tion calculations. More detailed investigations of
these reaction pathways are still needed in future
work.
We have further calculated the reaction of 3-eno-
late with N-methyl and N-vinyl (Table 8a and c). Given
the N-substituent’s electronegativities cP,[28] Ham-
mett’s spara parameters,[29] Taft’s steric parameters Es[30]
and Charton’s steric parameters u (Table 8b),[31] vari-
ous correlations can be established with our compu-
tational results. As shown in Table 8d, the substituent
effects in the aldol reaction step can be primarily at-
tributed to electronic effects, as reflected by the high
°
correlation coefficients of DGIM and DGTS with spara
.
Despite the fact that DGIM also correlates with Es and
u to some extent (R2 ꢀ0.4), the relatively weaker de-
pendence suggests the diminished role of steric ef-
fects. On the other hand, the transition-state energies
of the olefination reaction correlate with both elec-
tronic and steric parameters of the N-substituents
with moderate correlation coefficients, respectively.
Although the electronic effects are predominant, the
sterics of the N-substituents also has a noticeable
contribution to the overall substituent effects. Ac-
°
cording to the strong spara–DGIM and spara–DGTS cor-
relations, the electronic effects also operate as the
major contributor to the overall substituent effects in
the five-membered ring-forming reaction. On this
basis, we can conclude that the observed different
reactivities of 1a and 2a are mainly due to the elec-
tronic effects of the N-substituents. In other words,
the phenyl ring in 1a can facilitate the formation of
nitrosobenzene as a byproduct through p-conjuga-
tion, which can stabilize the transition-state during
the olefination reaction. However, the tBu group
would increase the charge density and the nucleo-
Scheme 3. Elucidation of possible reaction pathways based on the detection of byprod-
ucts and side products.
In other words, the reaction between 2a and 3 leads to
equilibrium between IM2b’ and isoxazolidinone 5-tBu, which
can shift to the latter by acidic workup of the NaOMe side
product. Overall, with N-phenyl-substituted 1a, the generation
of fluoroalkenoates is favored by its low kinetic barrier. Howev-
er, due to the relatively high barrier to the olefination reaction,
IM2b’ can only undergo the five-membered ring-forming reac-
tion to generate isoxazolidinone 5-tBu. It is worth mentioning
that the ring-opening reactions of 7-Ph and 7-tBu were calcu-
lated to possess barriers of approximately +40 kcalmolÀ1 (see
the Supporting Information for details). This is in good agree-
ment with our experimental results, which excludes the four-
membered ring-opening reaction as a plausible pathway
toward fluoroalkenoates.
philicity of the N–OÀ moiety, therefore enabling the five-mem-
bered ring-forming reaction. This hypothesis is supported by
the significant stabilization of IM2b’ and TS6b relative to
IM2b’ and TS4b, respectively (Figure 2).
Conclusion
We report a one-step reaction between ethyl fluorobromoace-
tate and nitrones. By altering the N-substituents of nitrones,
both fluorinated alkenoates and isoxazolidinones can be ob-
tained with high stereoselectivity. Experimental mechanistic
studies have provided convincing evidence for possible reac-
tion pathways. The computational study has further revealed
the mechanistic aspects of the reactions. By correlating steric
and electronic parameters with DFT calculation results, the ob-
served N-substituent effects have been found to be primarily
of electronic origin as reflected by the good correlation of DG
and Hammett spara parameters.
Noticeably, the formation of 1,2-oxazetidine 7-Ph was calcu-
lated to be kinetically and thermodynamically favorable, which
is inconsistent with our experimental observation. Moreover,
the calculation of Z-olefination demonstrated a low barrier
(DGTS° = +1.9 kcalmolÀ1) relative to the observed E-olefination
pathway (see the Supporting Information for details). It is likely
Chem. Eur. J. 2014, 20, 831 – 838
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Full Paper
with EtOAc (3ꢁ2 mL). The combined organic phase was dried over
MgSO4, evaporated under vacuum, and purified with preparative
thin layer chromatography (hexanes/CH2Cl2 10:1).
Table 8. Correlations of steric and electronic parameters with calculated
Gibbs free energies of reaction key intermediates and transition states.[a]
a) Calculated transition states and reaction key intermediates
Theoretical calculations
DFT calculations were performed at the M06-2X/6-311+G(d,p)//
B3LYP/6-31+G(d,p) level of theory in Gaussian 09.[23,24] Solvent ef-
fects of THF were included implicitly through the self-consistent re-
action field approach, as implemented in the default PCM
model.[25] Thermal and entropic corrections were obtained by fre-
quency analysis at the B3LYP/6-31+G(d,p) level in THF. The fre-
quency analysis confirmed that all considered ground structures
were true minima on the PES. The transition-state structures were
indicated by a single imaginary frequency.
b) Steric and electronic parameters of N-substituents
R
Electronegativity cP
spara
Es
Charton’s
parameter (n)
(Pauling scale)
Ph
CH=CH2
Me
2.49
2.41
2.25
2.29
À0.01
À0.04
À0.17
À0.20
À2.55
À1.60
0.00
À1.54
0.57
1.31
0.52
1.24
Acknowledgements
tBu
c) Calculated Gibbs free energies [kcalmolÀ1
]
Support of our work by the Loker Hydrocarbon Research Insti-
tute is gratefully acknowledged. The computational studies
were supported by the University of Southern California Center
for High-Performance Computing and Communications. Mr. J.-
P. Jones is gratefully acknowledged for providing additional
computational resources.
R
Aldol reaction
Olefination
DGTS
5-Membered ring formation
°
°
°
DGTS
DGIM
DGIM
DGTS
Ph
2.3
À19.1
À16.8
À10.1
À7.8
6.4
À21.1
À20.5
À16.8
À16.0
4.3
4.3
5.6
6.4
CH=CH2 1.2
Me
tBu
13.5
14.9
16.7
5.9
7.8
d) DG steric /electronic parameters correlation coefficients (R2)
Parameters Aldol reaction Olefination 5-Membered ring formation
Keywords: fluoroalkenoates · linear free energy relationship ·
nitrone · olefination · substituent effects
°
°
°
DGTS
DGIM
DGTS
DGIM
DGTS
cP
0.676
0.910
0.230
0.250
0.884
0.996
0.425
0.425
0.762
0.707
0.454
0.408
0.885
0.999
0.441
0.451
0.720
0.948
0.240
0.249
spara
Es
n
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Experimental Section
General experimental section
Unless otherwise mentioned, all the chemicals were purchased
from commercial sources. Preparative thin-layer chromatography
was performed to isolate products using 1500 microns preparative
thin-layer chromatography plates and using suitable solvent sys-
1
tems as the eluent. H, 13C, and 19F spectra were recorded on 400
or 500 MHz Varian NMR spectrometers. 1H NMR chemical shifts
were determined relative to CDCl3 as the internal standard (d=
7.26 ppm). 13C NMR shifts were determined relative to CDCl3 at d=
77.16 ppm. 19F NMR chemical shifts were determined relative to
CFCl3 at d=0.00 ppm. Mass spectra were recorded on a high-reso-
lution mass spectrometer, in the EI, FAB, or ESI modes.
General procedure for reaction between ethyl monofluoro-
bromoacetate 3 and (Z)-aryl-N-phenylnitrones 1 and (Z)-aryl-
N-tert-butylnitrones 2
Nitrones 1 or 2 and NaHMDS were massed under a nitrogen at-
mosphere (nitrogen filled glovebox) in a 20 mL sealed tube.
BrFCHCOOEt 3 (2.0 mmol in 3.0 mL) was added with syringe pump
over 3 h to a solution of nitrones 1 or 2 (1.0 mmol) and NaHMDS
(2.0 mmol) in THF (2.0 mL) at À788C. The reaction mixture was
then warmed to room temperature. PhCF3 (0.5 mL 0.1m solution in
THF) was added and the 19F NMR spectrum was obtained. HCl (1m,
2.0 mL, in the case of nitrones 1) or saturated NH4Cl (aq, 2.0 mL, in
the case of nitrones 2) was added and the solution was extracted
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Published online on December 11, 2013
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www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim