From bifunctional to trifunctional (tricomponent nucleophile-transition metal-lewis acid) catalysis: The catalytic, enantioselective α-fluorination of acid chlorides

Article abstract of DOI:10.1021/ja2014345

We report in full detail our studies on the catalytic, asymmetric β-fluorination of acid chlorides, a practical method that produces an array of β-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this "trifunctional" reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.

Full text of DOI:10.1021/ja2014345

ARTICLE
pubs.acs.org/JACS
From Bifunctional to Trifunctional (Tricomponent
NucleophileꢀTransition MetalꢀLewis Acid) Catalysis: The Catalytic,
Enantioselective r-Fluorination of Acid Chlorides
Jeremy Erb,† Daniel H. Paull,† Travis Dudding,‡ Lee Belding,‡ and Thomas Lectka*,†
†Department of Chemistry, New Chemistry Building, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218,
United States
‡Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario, Canada L2S 3A1
S Supporting Information
b
ABSTRACT: We report in full detail our studies on the catalytic, asymmetric
R-fluorination of acid chlorides, a practical method that produces an array of
R-fluorocarboxylic acid derivatives in which improved yield and virtually complete
enantioselectivity are controlled through electrophilic fluorination of a ketene
enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis
acidic lithium salt, could be introduced into a dually activated system to amplify
yields of aliphatic products, primarily through activation of the fluorinating agent.
Through our mechanistic studies (based on kinetic data, isotopic labeling, spectro-
scopic measurements, and theoretical calculations) we were able to utilize our
understanding of this “trifunctional” reaction to optimize the conditions and obtain
new products in good yield and excellent enantioselectivity.
’ INTRODUCTION
addition to the synthetic repertoire is a practical method for the
enantioselective R-fluorination of ketene enolates (occurring at
the complementary carboxylate oxidation state) that directly
produces simple, optically enriched R-fluorinated carboxylic acid
derivatives (Figure 1).7 Such a process would provide an entrꢀe to
the synthesis of optically enriched fluorinated drugs, natural
products, and other molecules of biochemical and synthetic
interest.
In this paper, we present an asymmetric fluorination method
that employs three catalysts working cooperatively (a chiral
nucleophile, a transition metal catalyst, and an alkali metal Lewis
acid, Figure 1) to afford virtually optically pure products with
improved yields. In the search for higher yield and broader scope,
we describe how the fluorination method has evolved from an
unsatisfactory monofunctional system to a bifunctional proce-
dure and, finally, with the inclusion of an alkali metal Lewis acid
cocatalyst, a trifunctional process.8 Although mechanistically
complex, the method is operationally simple and practical. Our
rationale for a trifunctional catalytic system arose from an initial
mechanistic study that is supported by theoretical calculations
and verified by experimental findings.
In recent years, the use of fluorinated molecules has greatly
increased in medicinal and pharmaceutical chemistry alike; we
believe that chemists now rely on fluorination as a prime weapon
in their search for efficacy.1,2 All too often though, they depend
upon synthetic chemistry that has barely kept pace, especially in
the area of asymmetric fluorination.3 The number of drug
candidates that contain fluorine has increased dramatically over
the past few years, and the ability to install fluorine (in many cases
alpha to a carbonyl group)4 with stereocontrol has been increas-
ing in importance.1 Because of the unique properties of the
fluorine atom, including its high electronegativity, small atomic
radius, and high CꢀF bond strength, strategic fluorination can
drastically alter the metabolism of a drug, its bioavailability,
activity, or a host of other relevant properties. For example, one
fluorine atom, placed tactically and enantioselectively within the
candidate molecule, can lower the basicity of a nearby amino
group and enhance NꢀH acidity; it may increase the acidity of a
nearby carboxylic acid; it can block racemization at a chiral center
or inhibit cytochrome P450 promoted oxidation of the fluorine
center and nearby CꢀH bonds; and it may enhance binding
within a receptor protein.5 Add to that the fact that nowadays
new chiral drugs must be optically pure or else have an extra-
ordinary reason not to be, and methods for the asymmetric
installation of fluorine become more important.
Earlier Work. Some time ago, we began our search for a
catalytic, enantioselective fluorination method with a monofunc-
tional catalytic system (that employed benzoylquinine or benzoyl-
quinidine as a chiral catalyst, Figure 2)9 to generate R-fluorinated
products from acid chlorides 1. This unsatisfactory experiment gave
Great strides in enantioselective R-fluorination have been
made in the past few years in which β-keto esters, imides, and
aldehydes serve as substrates to produce products in high
enantioselectivity and yield.6 On the other hand, an appealing
Received: February 15, 2011
Published: April 22, 2011
r
2011 American Chemical Society
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Figure 1. Catalytic, enantioselective R-fluorination of acid chlorides.
Figure 2. Preliminary synthetic outline.
Figure 3. Initial mechanistic outline.
only small amounts of product, an outcome we rationalized by the
capricious and unselective activity of the intermediate zwitterionic
(ketene) enolate intermediate. This result motivated us to develop
a bifunctional approach with the addition of an enolate coordinat-
ing transition metal complex10 [typically (dppp)NiCl2, trans-
(PPh3)2PdCl2, or (PPh3)2PtCl2)] as a cocatalyst.11 Chiral ketene
enolate intermediates 4 (from acid chlorides), further activated by a
transition-metal-based cocatalyst, were efficiently fluorinated with
commercially available N-fluorodibenzenesulfonimide (NFSi) to
afford the presumed acyl imide 2. This intermediate was then
quenched in situ by a variety of nucleophiles (NuH) to produce
configurationally stable R-fluorinated carboxylic acid derivatives 3.
Depending on the workup conditions, a variety of highly optically
active R-fluorinated carboxylic acid derivatives are made available
by the choice of quenching nucleophile (Figure 2).12
A standard reaction includes NFSi, H€unig’s base, and acid
chloride 1 (1 equiv. each), 0.1 equiv of cinchona alkaloid catalyst,
and 0.05 equiv of metal complex cocatalyst [(dppp)NiCl2,
trans-(PPh3)2PdCl2, or (PPh3)2PtCl2)] in THF at ꢀ78 °C for
6ꢀ12 h, followed by a quench with the desired nucleophile,
standard workup, and chromatography. With this method we
could consistently produce products in superb ee (enantiomeric
excess) and good to excellent yield only where R is an aromatic
ring or otherwise conjugated system (Figure 3). Along with the
aromatic substrates, much of the scope results from the quench-
ing nucleophile; R-fluorinated carboxylic acids, amides, esters,
and even peptides are all accessible depending on the nucleophile
employed to quench the reaction. For example, a water quench
affords R-fluoro carboxylic acids, compounds that potentially are
of broad utility as derivatizing agents. Weinreb amides can also be
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readily obtained, thus allowing access to R-fluoro ketones.13,14 As
per usual for cinchona alkaloid-promoted ketene enolate reac-
tions, both antipodes of the product are available in similarly high
ee by selection of either BQd (benzoylquinidine) or its “pseu-
doenantiomer” BQ (benzoylquinine).15 On the other hand, most
aliphatic substrates (R = alkyl) worked poorly, initially producing
the desired fluorinated products in low yield. As our major
remaining goal was to provide a more broadly applicable method
of R-fluorination, the introduction of a third catalyst to the
system was investigated. We now report in detail a trifunctional
(or “tricomponent”) method that increases product yield and
scope while maintaining excellent enantioselectivity, and recount
our rationale behind this approach as well.
Table 1. Effect of Reagents on the Initial Rate of Reaction
entry
reagent
rate dependence
1
2
3
4
5
BQd
[BQd]a,b
[acid chloride]a,b
acid chloride
NFSi
0a
0a
trans-(PPh3)2PdCl2
H€unig’s base
(0.5ꢀ1.1 equiv)
H€unig’s base
(0.01ꢀ0.05 equiv)
1/[H€unig’s base]b
6
[H€unig’s base]b
a When the concentration of the specified reagent is altered, the initial
rate of acid chloride consumption changes by the factor indicated.
b When the concentration of the specified reagent is altered, the initial
rate of product formation changes by the factor indicated.
’ RESULTS AND DISCUSSION
Initial Kinetic Studies on the Bifunctional System. Inten-
sive kinetic study on catalytic, asymmetric reactions has proven
to be an excellent starting point to optimize reaction conditions,
as well as to postulate a mechanism.16 Our investigations began
by altering the concentration of a single reagent and measuring
the rate of product formation as compared to the unmodified
reaction. For example, to five dry flasks were added trans-
(PPh3)2PdCl2 (0.05 equiv) and benzoylquinidine (BQd, 0.1 equiv).
Under a nitrogen atmosphere, 1 mL of THF was added to each
flask and the solutions were cooled to ꢀ78 °C. H€unig’s base (1.1
equiv) was added neat to each mixture, followed by a solution of
N-fluorodibenzenesulfonimide (NFSi, 1 equiv) in 0.33 mL of
THF. After 5 min, a solution of phenylacetyl chloride (1 equiv) in
0.66 mL of THF was added to each reaction mixture. At time
intervals of 30, 40, 50, 60, and 70 s, MeOH (0.5 mL) was injected
to quench each reaction separately, and all were then allowed to
warm to 25 °C overnight. The measured rates were then
extrapolated to 0% conversion.
observed KIE of 3.12, which indicates that dehydrohalogenation
may be rate-limiting.
There also exists another possibility; the observed isotope
value could be indicative of an equilibrium isotope effect. We
hypothesized that reversible enolate formation (and the effect of
the cocatalyst thereupon) could be documented by introduction
of the DCl salt of H€unig’s base and quantification of the label in
the product (scenario b, Figure 4). In the experiment, no
incorporation of deuterium was seen in THF as the solvent. As
methylene chloride also works well with this reaction system and
possesses the ability to solubilize H€unig’s base salts, it was tested
to determine whether the lack of incorporation occurred due to
insolubility. Still, no incorporation was seen, suggesting that
reversible enolate formation does not occur, thus negating the
possibility of an equilibrium isotope effect. Finally, through
analysis of the rate of acid chloride consumption, it was evident
that the rate of reaction is proportional to the concentration of
the acid chloride and base, confirming dehydrohalogenation as
the rate-determining step.
A surprise emerged while discerning the order of each reagent;
the rate of reaction is inversely proportional to the concentration
of H€unig’s base in the regime of 0.5ꢀ1.1 equiv, whereas it is
proportional at low concentrations (0.01ꢀ0.05 equiv). A number
of rationales are conceivable: namely, H€unig’s base may be
responsible for ketene dimerization; it may react with NFSi in
a nonproductive way; or it may bind to the metal cocatalyst or act
to convert the Pd(II) catalyst to Pd(0) at high concentrations
(Figure 3). Each of these possibilities should reveal a quantifiable
trace. For example, ketene dimers can be readily isolated, but no
dimer products were identified in any reaction mixtures. Like-
wise, when NFSi was mixed with H€unig’s base at ꢀ78 °C, no
interaction between the two species was detected by 19F NMR
(although they do react readily at 25 °C). Outside of the unusual
rate dependence on H€unig’s base, BQd and the acid chloride
each displayed a proportional dependence on the rate of acid
chloride consumption, while there was no observed dependence
on this rate with NFSi or the Pd catalyst. The results from the
bifunctional kinetic experiments are summarized in Table 1.
KIE Studies. Kinetic isotope effect (KIE) studies can also shed
light on the reaction mechanism.17 For example, observation of
a primary KIE upon introduction of deuterium labels in the
R-position of the acid chloride would indicate rate-determining
dehydrohalogenation, whereas an inverse secondary isotope effect
could point instead toward rate-limiting fluorination (scenario a,
Figure 4). The rate of product formation for R,R-dideuteriophe-
nylacetylchloride compared with phenylacetylchloride gave an
All in all, these kinetic data suggest that a slow addition of
H€unig’s base might be beneficial to take advantage of its peculiar
concentration dependence on the initial rate of product forma-
tion. In a standard fluorination of octanoyl chloride, an increased
yield of 60% (from 40%) was obtained upon slow addition of
H€unig’s base over 12 h (quenched with aniline, >99% ee). For
hydrocinnamoyl chloride, the yield increases from 4% to 22% to
35% when the slow addition is increased from zero time to 12
to 24 h, respectively (aniline quenched, 99% ee). This result
prompted a series of experiments to determine the optimum
slow addition length of time of H€unig’s base. When increasing
the slow addition time to 24 h, the yield did not increase past 60%
for any aliphatic acid chloride tested with the notable exception
of the quirky substrate phthalimidopropionyl chloride (which
contains a metal binding site),12 and longer slow additions over
48 h showed no signs of improvement. Most aliphatic acid
chlorides treated with NFSi and a slow addition of H€unig’s base
showed similar improvements in yield. While the slow addition of
H€unig’s base was an important discovery, we envisioned that a
Lewis acid could selectively enhance the electrophilicity of NFSi
and thereby increase the yield of the desired product. Never-
theless, the kinetic measurements were less illuminating than
desired as the first (and least interesting) step proved to be rate-
determining.
A Trifunctional System. The possibility of trifunctional
catalysis came to mind when investigating ways to improve the
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Figure 4. Isotope labeling studies.
Table 2. Trifunctional Catalysis Screening
Table 3. Products from r-Aliphatic Acid Chloride Substrates
under Optimized Conditions
entrya
third catalyst (equiv)
R
NuH
% yield
1
none
LiPF6-THF (0.1)
LiClO4 (1)
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Ph
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
<4
21
2
3
trace
21
4
LiClO4 (0.1)
La(OTf)3 (0.1)
Sm(OTf)3 (0.1)
Yb(OTf)3 (0.1)
LiClO4 (0.1)b
(PPh3)2Pd(ClO4)2 (0.05)b
none
5
8
6
5
7
3
8
trace
trace
4
22c
39c
44d
15
9
10
11
12
13
14
15
16
CH2Ph
CH2Ph
CH2Ph
CH2Ph
i-Pr
none
LiClO4 (0.1)
LiClO4 (0.1)
none
LiCIO4 (0.1)
LiCIO4 (0.1)
i-Pr
50
73c
i-Pr
a Reaction conditions: 1 equiv of NFSi, 1 equiv of acid chloride, 0.1 equiv
of BQd, 0.05 equiv of trans-(PPh3)2PdCl2, 1.1 equiv of H€unig’s base,
THF, ꢀ78 °C, followed by nucleophilic quench at ꢀ78 °C after 8 h. b No
trans-(PPh3)2PdCl2 catalyst. c Slow addition of H€unig’s base over 12 h.
d Slow addition of H€unig’s base over 24.
yield of aliphatic acid chlorides. We speculated that a second
Lewis acid could specifically coordinate with the NFSi, thereby
increasing its electrophilicity. Among various metals tested for
this purpose (Table 2),18 earlier work on Lewis acid catalysis by
Nelson19 inspired us to try both LiClO4 and LiPF6, which turned
out to be the only two metal salts that gave unambiguously
increased yields (no difference in yield was seen by changing the
counterion).20 Additionally, when 10 mol % LiClO421 was added
to a standard reaction with isovaleryl chloride (no slow addition),
an increase in yield of the fluorinated product from 15% to 50%
was observed (entries 14, 15). This demonstrates the potential
power of the trifunctional catalytic system, at least for reactions
that suffer from low yield. When lithium addition is combined
with the slow addition of H€unig’s base over 12 h, the yield
increases further to 73% (Table 2, entry 15). Table 3 shows the
products of a variety of aliphatic acid chlorides that were tested
under the optimized conditions (trifunctional catalysis with slow
a Reaction conditions: 1 equiv of NFSi, 1 equiv of acid chloride, 0.1 equiv
of LiClO4, 0.1 equiv of BQd, 0.05 equiv of trans-(PPh3)2PdCl2, 1.1 equiv
of H€unig’s base (slow addition over 12 h), THF, ꢀ78 °C, followed by
nucleophilic quench after slow addition at ꢀ78 °C. b BQ was used
instead of BQd.
addition of base) that gave a good yield and excellent enantios-
electivity. It is important to highlight that octanoyl chloride gave
an 83% yield (Table 3, entry 1) when 10 mol % LiClO4 was used
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in addition to the slow addition of H€unig’s base, up from 60% yield
with solely the slow addition. In every instance, the combination
of the slow addition and the catalyst trio resulted in a remarkable
increase in yield from what was often originally a trace amount
of product. Slow addition by itself typically produces yields about
25%ꢀ50% less than those by lithium addition.
Table 4. Investigations on the Rate of Fluorination with
Preformed Methylketene
rate factor
increaseb
entry
reagent changea
1
2
3
[NFSi] f 2x [NFSi]
2
“Knockout” Kinetic Experiments: Subdivision of the Reac-
tion into Steps. As the rate-determining step occurs so early in
the reaction sequence, it leaves the most interesting steps (which
crucially affect the chemoselectivity of the reaction) “down-
stream.” Given the complexity of the reaction, it makes sense
to subdivide the overall reaction into four discrete processes:
dehydrohalogenation of the acid chloride 1 (which is rate-
determining); fluorination to form a chiral acylammonium-
sulfonimide 5 (enantioselectivity-determining); acylation of the
sulfonimide anion to form 2, and finally, transacylation by an
adventitious nucleophile to provide 3. The downside of such a
subdivision is that each of the pieces studied separately departs
from a holistic ideal and could change its character when
separated from the others.
[trans-(PPh3)2PdCl2] f 2x [trans-(PPh3)2PdCl2]
2
no LiCIO4 f 0.1 equiv LiClO4
1.2
a Reaction conditions: 1 equiv of NFSi, excess methylketene, 1.1 equiv of
BQd, 0.05 equiv of trans-(PPh3)2PdCl2, THF, ꢀ78 °C, followed by
nucleophilic quench at ꢀ78 °C. b Rate of product formation.
The nature of the first step is clear enough from our overall
kinetic study. What about the second, enantioselectivity-deter-
mining step? In prior work, we have been able to gain additional
insight into complex reactions involving ketenes by preformation
of the ketene22 to study reaction rates that happen after the rate-
determining step. A simple approach was thus taken to under-
stand the complexities of the fluorination step. In the event, we
employed high concentrations of BQ and the preformed ketene
(pseudo first order conditions). In this scenario, we do not have
to worry about catalyst turnover due to slow acylation of
sulfonimide; in essence, we obviate this step, as a reaction quench
where an adventitious alcohol leads to the observed product. In
order to “knock out” the RDS (rate-determining step) and preform
the ketene, five dry flasks were supplied with trans-(PPh3)2PdCl2
(0.05 equiv, 0.5 mL of THF) and cooled with liquid N2. Excess
methylketene was generated23 from a solution of THF (1.5 mL)
and distilled into each flask and then warmed to ꢀ78 °C. A
solution of N-fluorodibenzenesulfonimide (NFSi, 1 equiv) in
0.33 mL of THF was added to the reaction mixture, followed by
benzoylquinine (BQ) (1.1 equiv). At time intervals of 30, 60, 90,
120, and 150 s a solution of benzyl alcohol and HCl (1.1 equiv of
benzyl alcohol) was injected to quench each reaction, and all
were then allowed to warm to 25 °C overnight. The data are
shown in Table 4.
By starting with a preformed ketene, the rate-limiting step was
observed to be the reaction of the ketene enolate with NFSi. The
rate of reaction was also found to be dependent on the concen-
tration of PdII. However, a strict proportionality was observed;
for example a doubling of the Pd(II) concentration resulted in a
doubling in rate. On the other hand, the addition of lithium to the
“knock out” reaction increases the rate by 20% while increasing
the yield by 30%. These data indicate that lithium not only acts to
increase the rate of formation of the desired product but also may
act as well to suppress possible side reactions (dimerization and
polymerization).
Figure 5. Possible Roles of LiClO4.
ꢀ
with ClO4 on the Pd(II) catalyst. However, when the Pd
cocatalyst was replaced with (PPh3)2Pd(ClO4)2 or (PPh3)2Pd-
(ClO4)Cl, the reaction gave only trace amounts of product
(Table 2, entry 9), suggesting that the lithium salt does not
perturb the transition metal catalyst and that both metals
need to act independently of each other in order to administer
their effect.
Interestingly, UV measurements show that the addition of
LiClO4 (1 equiv, 0.0045 mmol) to phenylethylketene (1 equiv,
0.0045 mmol) in the presence of BQd (1 equiv, 0.0045 mmol) in
THF (3 mL) diminishes the concentration of the ketene enolate
at ꢀ78 °C by 8.5% (Figure 6, EQ-B). By contrast, Pd(II) acts to
promote ketene enolate concentration.24 When 1 equiv of the
lithium salt is added to a fluorination reaction of hydrocinnamoyl
chloride with slow addition of H€unig’s base, only trace amounts
of product were obtained (Table 1, entry 3). This was a sur-
prising result because a large increase in lithium was expected to
demonstrate better binding with NFSi, resulting in improved
yield. One possibility is that LiClO4 binds to BQd, quenching
both catalysts (Figure 5, EQ-C), but when 1 equiv of BQd and
LiClO4 were mixed together in THF, no binding was observed by
1H NMR or IR spectroscopy. Another option is that lithium
preferentially binds to the ketene (as opposed to the enolate).
This would explain the increase in ketene concentration (and
decrease in ketene enolate concentration) that was observed by
UV. Since these isolated situations do not always account for our
experimental observations, another scenario was considered. As
NFSi binds to lithium, this must allow enough of the ketene to
operate independently of lithium when all the reagents are added
together. When excess lithium was used, it may severely reduce
the concentration of ketene enolate so much so that the reaction
barely proceeds. A balance must be achieved with the third
Role of Liþ. These findings prompted us to undertake a spec-
troscopic inquiry into the possible role of LiClO4. Binding
between LiClO4 and NFSi (each 0.2 mmol) in THF (1 mL)
was observed by 19F NMR by a shift from 37.89 to 40.25 ppm at
25 °C, suggesting (along with the aforementioned rate data)
Lewis acid activation of the fluorinating agent. Another possible
effect of the lithium salt is that an ion methathesis replaces Clꢀ
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Figure 6. Quenching of LiClO4 by TMEDA.
Figure 7. Methanolysis of an acylsulfonimide.
catalyst to achieve a superior benefit in yield, where 10 mol % was
found to be the optimum concentration for substrates.
When 1 equiv of TMEDA is added to a fluorination reaction
(1 equiv of hydrocinnamoyl chloride, NFSi, and H€unig’s base,
plus 0.1 equiv of BQd at ꢀ78 °C in THF), the yield increases to
20% from trace amounts, but the ee erodes to 50%. When 1 equiv
of lithium is added under the same reaction conditions, the yield
drops to 10% (from 20%), but the ee is restored to >99%. The
added TMEDA mimics the catalytic role of BQd but lacks the
ability to induce optical activity to the product. The addition of
lithium sequesters the TMEDA, preventing the achiral base from
participating in the reaction, and restoring the ee (Figure 6).25
Remarkably, lithium does not hinder BQ or BQd in a similar way
but acts only to promote the reaction.
The rate enhancement imparted by lithium in our kinetic
study of the ketene enolate fluorination step (ca. 20%), while
significant, may not explain completely the increase in yield. One
other putative role of lithium may be as a catalyst for the acylation
of the quenching nucleophile. To shed light on this possibility,
the methanolysis of an acylsulfonimide control was also studied
(Figure 7). If lithium binds to NFSi and increases its electro-
philicity, it should also bind to acylsulfonimides in a similar
fashion and increase their susceptibility to nucleophilic attack. In
the event, the acylsulfonimide was allowed to react with MeOH
in THF at 25 °C, in one instance with 10 mol % lithium
perchlorate present and in the other instance with no lithium
source. The extent of methanolysis was monitored by 19F NMR;
as expected, the inclusion of a lithium ion in the reaction
increases the rate of methyl ester formation, giving 4.9% con-
version without lithium and 8.4% conversion with lithium after
15 min of stirring, indicating an approximate 2-fold rate increase
when extrapolated to 0% conversion. This suggests that lithium
may act to increase rates and yields by acylsulfonimide activation
in situ as well and that its role in the overall reaction is quite
complex. However, the fact that the lithium ion exerts only
marginal increases in yields for arylketene-type substrates sug-
gests that this effect should be moderate at most.
Figure 8. UVꢀvis spectrum of metalꢀH€unig’s base mixtures.
Transition Metal Roles. (PPh3)2PdCl2 was also tested for
possible binding to BQd. Not surprisingly, when investigated by
1H, 13C, and 31P NMR and IR spectroscopy, no apparent binding
was observed in THF at 25 °C. Next, (PPh3)2PdCl2 was examined
for any potential interaction with NFSi. Monitoring by 19F NMR
and IR shows no change in the chemical shift of NFSi in THF at
25 °C or its absorbance profile, which suggests that no binding to
NFSi occurs.
When H€unig’s base is mixed with an equimolar amount of
[(tris(4-butylphenyl)phosphine)2]PtCl2 (used as a highly solu-
ble surrogate for trans-(PPh3)2PdCl2 that performs equally well
in fluorination reactions) and monitored by UV spectroscopy,
the resulting absorbance at 202 nm is larger than the individual
absorbances at 202 nm of each reagent added together, an
observation that points toward metal complexation (Figure 8).26
The λmax shifts slightly upon mixing to a single maximum at 202 nm
at 25 °C (the λmax of H€unig’s base is at 207 nm, and the λmax of the
metal is at 203 nm). Another question concerns whether the metal
catalyzes the oxidation of H€unig’s base; acetone can usually be found
(clearly identifiable by 13C NMR) in crude reaction mixtures in
which H€unig’s base is oxidized,27 yet none was observed by NMR
in the mixture. The role of H€unig’s base is as the terminal HCl
acceptor in the shuttle base system where it regenerates the
kinetic base, BQd; however, if its concentration builds beyond
that which is necessary for its primary function, it may bind to the
metal catalyst, thereby reducing its efficacy.28
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THF at 25 °C, deprotonation of the sulfonimide occurs almost
quantitatively by 1H NMR (eq 1).
One way to shed light on catalyst turnover is a crossover
experiment, employing 15N labeled sulfonimide30 (Figure 10).
“Shuffling” of sulfonimide ions through solvent separation of ion
pairs should result in incorporation of the label, which can be
15
detected in the intermediate acylsulfonimide by a 19Fꢀ N or
15
1Hꢀ N vicinal coupling during an in situ NMR experiment.31
Indeed, when 0.15 equiv of 15N labeled dibenzenesulfonimide is
added to a standard fluorination reaction with 1 equiv of phenyl-
acetyl chloride, incorporation is seen in the splitting of the 19F
NMR signals of the crude, unquenched reaction at 25 °C.
However, when the reaction is monitored at ꢀ78 °C, no incor-
poration is seen. This is consistent with a tight ion pair at low
temperature that does not solvent separate; instead, it turns over
the chiral catalyst through transacylation and does not “shuffle.”
Not surprisingly, species 2 was found to be stable enough to exist
at 25 °C in solution, but it could not be isolated efficiently. For
example, quenching with methanol at ꢀ78 °C, after the reaction
was allowed to reach 25 °C, still resulted in the formation of 3 in
identical yield.
Figure 9. Rate experiments with lithium cocatalyst.
Computational Studies. Computational chemistry is often
used to account for stereochemical and energetic preferences,32
and we took advantage of modeling programs to gain insight into
the observed enantioselectivity and reaction energetics. Several
calculations were performed on various possible transition states
for fluorination at the KohnꢀSham hybrid-DFT B3LYP level
(Figure 11).33,34 In two of the transition state (TS) metal-
coordinated cases (TS-B, and TS-D), the Pd(II) is bound to
the ketene enolate oxygen. These transition states revealed that
TS-B is lower in free energy than the uncoordinated case (TS-A)
by 7.7 kcal/mol. When compared to starting fragments, TS-D is
lower than TS-B by 11.8 kcal/mol and 19.5 kcal/mol lower than
TS-A (we know that the Pd(II) binds to the ketene enolate,
enhancing its chemoselectivity and increasing its concentration).
TS-C is only slightly lower in energy than TS-A (1.6 kcal/mol),
suggesting that TS-C is unlikely in light of the other possible
transition states that are much lower in energy. TS-D is the
lowest energy transition state (and thus the most likely pathway),
lengthening the partial CꢀF bond in an evidently “earlier,” more
exothermic, transition state. The lower energy of TS-D suggests
that the addition of both Li(I) and Pd(II) could result in a lower
transition state energy that favors the desired product formation,
a fact that was also demonstrated experimentally. Replacing BQ
with BQd gives similar results, and TS-A, TS-B, TS-C, and TS-D
then give ΔG‡ = 30.1, 22.3, 28.4, and 10.5 kcal/mol respectively.
Transition state calculations using BQ predict the stereochem-
istry at the fluorinated carbon as S while BQd gives R; this
corresponds to what is observed experimentally.
Figure 10. Transacylation crossover experiments.
Lastly, the rate of starting material consumption on the entire
reaction was again studied, this time with the addition of the new
alkali metal (Figure 9). The kinetic experiments show that the
rate of acid chloride consumption has no dependence on the
concentration of lithium perchlorate, confirming that it plays no
identifiable part in the rate-limiting dehydrohalogenation step.
A Unified Mechanistic Scenario. The complete mechanistic
outline is proposed in Figure 12. First the acid chloride under-
goes a rate-determining dehydrohalogenation to form the basic
ketene enolate involving the chiral nucleophilic catalyst. Next,
the ketene enolate can either react with NFSi, NFSi bound to
lithium, or bind to the palladium cocatalyst, which can then go on
to react with NFSi in the same fashion. Note that the kinetic data
on the “knock out” reaction reflect these conclusions; although
the rates of reaction increase with each introduction of a
cocatalyst, the reaction also proceeds to a measurable extent in
the absence of the cocatalysts, especially in the case of Liþ. Thus,
the “monofunctional” and “bifunctional” reaction terms must be
taken into account in the overall equation.
Transacylation Experiments. One outstanding ambiguity is
how transacylation of the intermediate acyl ammonium salt
(Figure 10, 5) occurs.29 Transfer of fluorine to the ketene enolate
is expected to form a tight ion pair that can undergo transacyla-
tion. However, in THF solvent, H€unig’s•HCl salt could proto-
nate the sulfonimide ion rapidly, and one would expect such
proton transfers to be fast. A control experiment showed that
when (PhSO2)2NH is treated with 1 equiv of H€unig’s base in
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Figure 11. Transition state calculations.
In Figure 12, side reactions that happen at the ketene enolate
stage producing unwanted side products are not shown. The four
kinetic pathways represented by (k3, k4, k5, k6) after the RDS each
have a different rate. Addition of Pd to the reaction increases
the rate of product formation, so k5[Pd] is larger than k4.
The rate dependence on Pd(II) shows the Pd coordinated
reaction pathways are dominant compared to the transition-
metal-free pathways. Since addition of lithium and Pd
increases the rate of product formation beyond the rate
represented by k5, pathways involving k6 or k3 must be faster
than those involving k5.
lithium. This leaves the trifunctional pathway, characterized by
k6, as potentially the fastest. The resulting rate equation for the
trifunctional system, focusing on the isolated fluorination step
after “knock out,” reflects contributions from competing bifunc-
tional and monofunctional pathways, shown in eq 2, with the
dominant pathways highlighted in blue. In the final reaction step,
the chiral
Additionally, when lithium is added without Pd, the reaction
affords product very slowly, which indicates that k3 represents a
slow path. Of course, the pathway involving k4 is a minor
contributor as well. The kinetic data also agree that the rate of
product formation is much greater if not dominant for the addition
of lithium with Pd vs the rate of product formation with only
catalyst is released through transacylation of the bis(sulfon-
imide). The resulting acylsulfonimide intermediate is then quen-
ched by a nucleophile to yield product, a process that is catalyzed
by a lithium ion as well (3).
Conclusion. We have chronicled the evolution of a practical pro-
cedure for the catalytic, asymmetric R-fluorination of acid chlorides.
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Figure 12. A unified mechanistic proposal.
Through the knowledge that we gained from reaction development
in tandem with mechanistic studies, we were able to
develop a new trifunctional catalytic system that affords, in a
wide scope, optically active, fluorinated amides, esters, and other
car-
’ ACKNOWLEDGMENT
T.L. thanks the NIH (Grant GM064559) and the John Simon
Guggenheim Memorial Foundation for support. D.H.P. thanks
Johns Hopkins University for a Zeltmann Graduate Fellowship.
boxylic acid derivatives in fair to high yield and excellent enan-
tiomeric excess directly, from a variety of acid chlorides. In so
doing, we are able to propose a mechanistic scenario that accounts
for the very diverse aspects of this polyfunctional catalytic system
and to provide a basis for the further study of polycomponent
catalysis.
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures compound characterization, and complete ref 34a. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
lectka@jhu.edu
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