Regio- and stereoretentive synthesis of branched, linear (E)- and (Z)-allyl fluorides from allyl carbonates under Ir-catalysis

Article abstract of DOI:10.1039/c2sc21789a

This paper describes a new catalytic method for the regio- and stereocontrolled fluorination of allylic carbonates. This transformation uses TBAF·4tBuOH as the fluoride source and [Ir(COD)Cl]₂ as the catalyst; the most commonly used [Ir(COD)Cl]₂/phosphoramidite system is ineffective. Synthetically, this reaction is characterized by a high degree of structural conservation in going from substrates to the products. The fluorination of (E)-allylic carbonates leading to linear (E)-allylic fluorides (l : b > 20 : 1, E : Z > 20 : 1) is unprecedented and a unique feature of fluoride as the nucleophile. The first examples of transition metal catalyzed fluorination affording (Z)-allyl fluorides (Z : E ratio >20 : 1) are disclosed along with the successful fluorination of branched, linear (E)- and (Z)-allyl carbonates with [¹⁸F] fluoride in the presence of [Ir(COD)Cl]₂. ¹⁸O-Labeling of the reactant reveals internal return during the allylic ionization step, and pathways for effective intra- and intermolecular isotope exchange.

Full text of DOI:10.1039/c2sc21789a

Chemical Science
EDGE ARTICLE
Regio- and stereoretentive synthesis of branched, linear
(E)- and (Z)-allyl fluorides from allyl carbonates under
Ir-catalysis†
Cite this: Chem. Sci., 2013, 4, 89
Elena Benedetto, Matthew Tredwell, Charlotte Hollingworth,
*
*
´
Tanatorn Khotavivattana, John M. Brown and Veronique Gouverneur
This paper describes a new catalytic method for the regio- and stereocontrolled fluorination of allylic
carbonates. This transformation uses TBAF$4tBuOH as the fluoride source and [Ir(COD)Cl]2 as the
catalyst; the most commonly used [Ir(COD)Cl]2/phosphoramidite system is ineffective. Synthetically, this
reaction is characterized by a high degree of structural conservation in going from substrates to the
products. The fluorination of (E)-allylic carbonates leading to linear (E)-allylic fluorides (l : b > 20 : 1, E : Z
> 20 : 1) is unprecedented and a unique feature of fluoride as the nucleophile. The first examples of
transition metal catalyzed fluorination affording (Z)-allyl fluorides (Z : E ratio >20 : 1) are disclosed along
with the successful fluorination of branched, linear (E)- and (Z)-allyl carbonates with [18F] fluoride in the
presence of [Ir(COD)Cl]2. 18O-Labeling of the reactant reveals internal return during the allylic ionization
step, and pathways for effective intra- and intermolecular isotope exchange.
Received 19th October 2012
Accepted 23rd October 2012
DOI: 10.1039/c2sc21789a
www.rsc.org/chemicalscience
trichloroacetimidate leaving group led to the development of
the rst iridium-catalyzed allylic uorination leading to
Introduction
Extensive efforts have been dedicated to allylic uoride
synthesis because these versatile building blocks are useful for
many chemical disciplines including medicinal chemistry,
clinical imaging and material science.1 An ideal toolbox of
synthetic methods would allow access to branched and linear
allylic uorides of E or Z geometry with perfect control over
regio- and enantioselectivity. Atom economical processes are
the most sought aer, especially those using readily available
starting materials and inexpensive uoride sources.2 Pursuit of
these goals has led to major advances. Our own contribution
established that the Pd-catalyzed uorination of allyl p-nitro-
benzoates and carbonates is feasible using TBAF$4tBuOH as the
uoride source. The short uorination time allowed for the [18F]
labeling of allyl carbonate precursors under very mild condi-
tions.3 Doyle and co-workers demonstrated that the combina-
tion of allyl chlorides and AgF is highly effective under Pd
catalysis for the synthesis of enantioenriched cyclic and acyclic
allylic uorides.4 Cinnamyl phosphorothioate esters are also
suitable substrates for regioselective uorination under Pd
catalysis; this reaction is performed in THF and requires AgF as
the uoride source.5 Recently, the unique properties of the
terminal branched secondary and tertiary allylic uorides, the
product being formed at the site where the leaving-group
departs. Under these conditions, primary allylic tri-
chloracetimidates were unreactive.6 For this reaction, the unli-
gated [Ir(COD)Cl]2 complex (COD ¼ cycloocta-1,5-diene) was
used as the catalyst and TEA$3HF was identied as the optimal
uoride source. It was noted that allylic acetates did not react,
and allylic carbonates led mainly to undesired allylic ethers. The
development of a more general Ir-catalyzed uorination using
readily accessible allylic carbonates is highly desirable because
of the distinctive characteristics of Ir versus Pd in allylic
substitution, as noted in the initial reports.7 Preferential
formation of the more highly branched allylic products from
branched and linear E-allylic precursors with C-nucleophiles
and heteronucleophiles other than uoride is well documented
for Ir-catalyzed reactions, as is the conservation of regio- and
stereochemical integrity for Z-allylic substrates.8,9 Herein, we
report that allylic carbonates are amenable to uorination
through iridium catalysis using our originally proposed uoride
source, TBAF$4tBuOH.3 This catalytic process allows access to
both branched allylic uorides as well as their linear E- and Z-
regioisomers. In addition to expanding the synthetic value of
transition metal catalyzed allylic uorination with the rst
examples of (Z)-allyl uorides, the present body of work reveals
unexpected results. The catalytic system [Ir(COD)Cl]2/phos-
phoramidite,8–10 commonly used in allylic alkylation and ami-
nation since the initial discoveries,10 is not effective for
Chemistry Research Laboratory, University of Oxford, 12, Manseld Road, OX1 3TA
Oxford, UK. E-mail: veronique.gouverneur@chem.ox.ac.uk; john.brown@chem.ox.ac.
uk; Fax: +44 (0)1865 285002; Tel: +44 (0)1865 275644
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c2sc21789a
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Having established that allyl carbonate 1a is more reactive
than allyl uoride 2a, we embarked on a study aimed at devel-
oping a route to 2a from 1a under Ir catalysis. An extensive
screening of reaction conditions was instructive and led to the
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identication of the optimal catalyst, uoride source and
solvent for this transformation (TableV1ie)w. JIonurenaalr|lyVieewxpIsesureiments,
the [Ir(COD)Cl]2 complex A was used as the pre-catalyst with two
different P-ligands; TBAF$4tBuOH was selected as the uoride
source, based on our previous success in Pd-catalyzed uori-
nation.3 The use of the phosphoramidite ligand (S,S,S)-L, now
established as the norm in Ir catalysis,8–10 was superior to the p-
acceptor ligand P(OPh)3, but led, at most, to 25% of the desired
allylic uoride 2a (entries 1 and 2). The use of the pre-formed
[Ir(COD)(P,C-L)(L)] catalytic intermediate B prepared from
(R,R,R)-L gave a complex reaction mixture, with only trace
amount of 2a (entry 3). This was unexpected, and led us to
examine the precursor complex [Ir(COD)Cl]2 A as a possible
source of catalytic turnover. Indeed, this was found to be a
much more efficient catalyst (entries 4 and 5). In the absence of
Ir catalyst, the starting material was recovered, but contami-
nated with signicant amount of allylic alcohol 4a (ꢁ15%)
(entry 6). Some improvement was observed when the reaction
was carried out in the presence of molecular sieves (entry 7), but
an inferior result was observed at RT (entry 8). The use of
TBAF$3H2O afforded the allylic alcohol 4a as the major product
(entry 9). HF$pyridine gave a complex product mixture whereas
mainly starting material was recovered with CsF (entries 10 and
11). The use of Et3N$3HF led to unreacted starting material and
allyl methyl ether, whilst AgF was unreactive (entries 12 and 13).
A solvent screen identied DCM as the best solvent for this
reaction (entries 14–17). The yield was somewhat improved in
the presence of molecular sieves, although more diene 5a was
formed.
The allylic alcohol 4a and the diene 5a are consistently seen
as side-products but their formation was minimized by con-
ducting the reaction at a higher dilution [1a (0.02 M)] (entry
18). In no instance was the linear allyl uoride detected in the
crude reaction mixture. The appearance of products was
monitored by 1H NMR spectroscopy. As the reaction did not
progress aer 2 h, portion-wise addition of the catalyst (4
portions) was attempted; this protocol did improve the yield of
the reaction (entry 19). Further experiments13 showed that
alternative leaving groups were less efficient with large recovery
of the starting material for allylic benzoate or acetate (>90%
starting material, <10% of 2a aer 24 h). The uorination of
the allylic p-nitrobenzoate gave 31% of 2a. These initial studies
led to the identication of optimal conditions for the reaction:
1a (0.02 M), 2 mol% [Ir(COD)Cl]2ꢀA (added in 4 portions), 2
equiv. of TBAF$4tBuOH, DCM, 40 C, 3 h (as entry 19). Under
these conditions, the branched allylic uoride 2a was isolated
in 57% yield.‡
Fig. 1 Pd- and Ir-catalyzed allylic fluorination by displacement of O-leaving
groups.
uorination. In addition, unusual regioselectivity trends
specic to the use of uoride as the nucleophile or additive have
been observed (Fig. 1).
Results and discussion
A
Validation and optimization studies
The lack of precedent for Ir-catalyzed substitution of allyl uo-
rides encouraged us to examine the leaving group propensity of
carbonate vs. uoride in alkylation with malonate. The
branched allylic carbonate 1a and branched allylic uoride 2a
were subjected to alkylation with sodium dimethylmalonate in
the presence of 2 mol% of [Ir(COD)Cl]2 complex A in THF at
40 ꢀC for 24 h. Both substrates led predominantly to the
branched product 3a; branched over linear selectivity was
slightly superior for 2a (4 : 1) in comparison with 1a (2 : 1).
Compound 1a was totally consumed while only 56% of allyl
uoride 2a was converted into products, a pattern indicating
that in this system, methyl carbonate is a more reactive leaving
group than uoride. Prior work by our group has shown that a
similar order of reactivity was observed under Pd catalysis,11 but
uoride was a more reactive leaving group than methyl
carbonate in Pt-catalyzed allylic alkylation (Scheme 1).12
B
Fluorination of linear allylic carbonates (E)- and (Z)-1b
Our next objective was to examine the reactivity of linear allylic
carbonates under the preferred reaction conditions (Scheme
2). Fluorination of the isomerically pure linear allylic carbonate
Scheme 1 Leaving group propensity of carbonate versus fluoride; NaCHE2
¼
NaCH(CO2Me)2.
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Table 1 Fluorination of 1a under Ir catalysis: initial studies
Entrya
Catalystb
F sourcec
Solvent
Time/h
Ratiod 1a : 2a : 4a : 5a : 6a
1
2
3
4
A/P(OPh)3
I
I
I
I
I
I
I
I
II
III
IV
V
VI
I
I
I
I
I
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
Toluene
DCM
DCM
DCM
DCM
24
24
24
5
2
5
50 : 0 : 25 : 25 : 0
38 : 25 : 25 : 12 : 0
—
A/(S,S,S)-Le
f
B
A
C
—
A
A
A
A
A
A
A
A
A
A
A
A
A
0 : 55 : 41 : 4 : 0
7 : 48 : 41 : 4 : 0
86 : 0 : 14 : 0 : 0
0 : 69 : 29 : 2 : 0
33 : 33 : 33 : 1 : 0
0 : 15 : 81 : 4 : 0
5
6
7g
5
3
8h
9h
24
24
24
24
24
2
2
2
2
4
10h
11h
12h
13h
14
15
16j
17g,j
18k
19k,l
—
i
82 : 0 : 9 : 9 : 0
63 : 0 : 6 : 1 : 30
100 : 0 : 0 : 0 : 0
24 : 12 : 62 : 2 : 0
0 : 61 : 35 : 4 : 0
0 : 80 : 13 : 7 : 0
0 : 84 : 6 : 10 : 0
18 : 70 : 4 : 8 : 0
6 : 83 : 5 : 6 : 0
I
3
a
b
c
4 mol% of [Ir], [Ir] : ligand ¼ 1 : 2; 2 equiv. of uoride; 1a (0.1 M); 50 ꢀC. A ¼ [Ir(COD)Cl]2, B ¼ [Ir(COD)(P,C-L)(L)], C ¼ [Ir(COD)acac]. I ¼
TBAF$4tBuOH, II ¼ TBAF$3H2O, III ¼ HF$pyridine, IV ¼ CsF, V ¼ Et3N$3HF, VI ¼ AgF. Analysis by 1H NMR of the crude reaction mixture.
d
e
f
g
h
i
˚
Addition of 0.1 equiv. of DABCO. Complex reaction mixture containing diene 5a. Addition of crushed 3 A sieves. At RT. Complex
reaction mixture. j At 40 ꢀC. k At 40 ꢀC, 1a (0.02 M). A added in 4 portions.
l
(E)-1b afforded the linear allylic uoride (E)-2b (E : Z > 20 : 1) in
55% isolated yield (eqn (1)). Careful analysis of the crude
reaction mixture indicated that neither allylic methyl ether nor
branched product 2a had formed (l : b > 20 : 1). The high
degree of structural conservation observed upon uorination
of (E)-1b is unexpected; indeed, a control experiment demon-
strated that (E)-1b gave a mixture of branched and linear
product of alkylation 3a and (E)-3b (b : l ¼ 55 : 45) with sodium
dimethylmalonate (eqn (2)). The (Z)-1b isomer also underwent
regioselective uorination affording (Z)-2b in 64% yield, with a
high ratio of linear over branched products (l : b > 20 : 1) and Z
selectivity (Z : E > 20 : 1) (eqn (3)). Similar selectivity was
observed for the reaction with sodium dimethylmalonate (eqn
(4)). A preliminary investigation suggests that the rate of
uorination followed the order: 1a > (Z)-1b ꢁ (E)-1b. Faster
reaction rates for branched vs. linear substrates were reported
by Helmchen for Ir(I) catalyzed allylic alkylation of allyl
acetates with malonate.14
Scheme
2
Reactivity of the linear allyl carbonate (E)-1b and (Z)-1b with
TBAF$4tBuOH and with NaCHE2 (¼ NaCH(CO2Me)2).
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Table 2 Ir-catalyzed fluorination of allylic carbonates 1c–l.a The product shown is the preferred regioisomer (>20 : 1) and diastereomer (>20 : 1)b
Entry
Allyl carbonate
Product
Yieldc (%)
1
2
3
4
5
1c
2c
64
1d
2d
32d
66d,e
68
1e
2e
(E)-1f
(E)-1g
(E)-2f
(E)-2g
64
6
(E)-1h
(E)-2h
48f
7
8
9
(Z)-1i
(Z)-1j
(Z)-1k
(Z)-2i
(Z)-2j
(Z)-2k
52
65
65
10
(Z)-1l
(Z)-2l
50d,g
a
Allyl carbonate (0.02 M), 2 mol% [Ir(COD)Cl]2 A, 2 equiv. of TBAF$4tBuOH, DCM, 40 ꢀC, 2–24 h. b b/l (branched/linear) and E/Z ratio determined by
19F NMR spectroscopy on the crude product. c Yield of isolated product. d 4 mol% [Ir(COD)Cl]2 A. e NMR yield. f l/b ratio ¼ 15 : 1. g E/Z ratio ¼ 1 : 18.
C
Substrate scope: Ir-catalyzed uorination of branched and
D
Radiolabeling with [18F] uoride
The allylic carbonates 1a, (E)-1b and (Z)-1b are amenable to [18F]
linear allyl carbonates
The regioselectivity trend observed upon uorination of 1a, (E)- radiolabeling using either [18F] KF$Kryptox or [18F] Et4NF[15] as
1b and (Z)-1b was consistent throughout a seriesof branched and the uoride source; the results were superior and more
linear allyl carbonates (Table 2). The branched allyl carbonates
1c–e underwent uorination with retention of regiochemistry
(entries 1–3). The non-terminal branched allylic carbonate (E)-1e
gave (E)-4-uoropent-2-en-1-ylbenzene 2e as a single regio- and
E-isomer in 66% yield (NMR) (entry 3). The uorination of the
linear allyl carbonates (E)-1f–h followed the unusual pattern of
regiocontrol observed for (E)-1b (entries 4–6). Linear 2f–h were
formed exclusively with excellent E-stereoselectivity. Pleasingly,
the allylic uorides (Z)-2i–l were also obtained as pure regio- and
Z-isomers from the corresponding allylic carbonates (Z)-1i–l
(entries 7–10). The tolerance of these Ir-catalyzed uorinations is
broad since ether, ester, carbamate and imide functional groups
can all be accommodated within the substrate.
For most uorinations, the major side-product was the
[
18F] Fluorination of 1a, (E)-1b and (Z)-1b with [18F] Et4NF in the
allylic alcohol that was separated by silica gel column
chromatography.
Scheme 3
presence of [Ir(COD)Cl]2.
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reproducible with the later reagent (Scheme 3).13 For the radio- precedents, we examined the inuence of TBAF$4tBuOH as an
uorination, 1a (5 mg in 440 ml DCM) and [Ir(COD)Cl]2 (60 ml of additive in Ir-catalyzed allylic alkylation of 1a and 1b with
a 1 mg mLꢂ1 solution in DCM) were added to [18F] Et4NF (ꢁ30 malonate (Scheme 4, eqn (1)–(3)). For substrates 1a and (E)-1b,
ꢀ
MBq in 30 ml MeCN). Aer 30 minutes at 40 C, the reactions the addition of TBAF$4tBuOH enhanced branched/linear
were analyzed by radio TLC and HPLC for radiochemical yield selectivity, favoring a much higher degree of structural conser-
(RCY) and product identity, respectively.16 The RCYs were vation. The results are particularly striking for (E)-1b which led
higher for the branched precursor 1a than for the linear exclusively to (E)-3b (l : b ratio > 20 : 1). We noted that the
precursors; the reaction was found to be signicantly more addition of uoride had a detrimental effect on the reaction rate
effective for allylic carbonate (E)-1b despite doubling the as starting material was recovered for all reactions aer
quantity of [Ir(COD)Cl]2 for (Z)-1b. Control experiments extended reaction times. A control experiment using tetrabutyl
conrmed that no [18F] uorination took place in the absence of ammonium chloride revealed that this additive had a similar
[Ir(COD)Cl]2 for 1a and (E)-1b.
effect on regioselectivity (l : b ratio ¼ 16 : 1) to TBAF$4tBuOH.13
Mechanistically, we considered the transient formation of an
allyl uoride that would undergo alkylation with malonate;
control experiments conrmed that both (E)-2b and (Z)-2b
underwent allylic alkylation with the malonate adding to the
point of departure of uoride but the regioselectivity observed
for (E)-2b is, however, less pronounced than observed with allyl
carbonate/TBAF$4tBuOH (Scheme 4, eqn (4) and (5)).
We next examined the uorination of the branched enan-
tioenriched allylic carbonate (S)-1a (95% ee) (Scheme 5). Under
our standard reaction conditions, two products were isolated,
the desired allylic uoride (S)-2a (46% yield, 37% ee) and the
allylic alcohol (S)-4a (43% yield, 20% ee). Control experiments
conducted in the absence of TBAF$4tBuOH gave unreacted
starting material (77%, 87% ee) and diene 5a (23%). When the
reaction was conducted at room temperature for 24 h, the allylic
uoride (S)-2a was formed with a higher ee of 48%. Under these
milder conditions, the starting material was recovered in 93%
ee. Overall retention is the predominant pathway;19 the leakage
of stereochemical integrity is signicant although far less
pronounced than previously observed with trichloroacetimidate
as the leaving group.6 The signicant degree of racemization is
consistent with the formation of a s-species that could undergo
rapid C–C bond rotation prior to uoride addition. These data
contrast with previous studies (using C-nucleophiles) suggest-
ing that the sole use of [Ir(COD)Cl]2 without ancillary ligands
typically leads to the highest degree of conservation of enan-
tiomeric purity.14
E
Probing the origin of regio- and stereoselectivity
The regioselectivity observed for 1a and (E)-1b implies that their
reactions did not proceed through similar (h3-allyl) intermedi-
ates, or alternatively that the initially formed s-complex
underwent slow s–p–s allylic isomerization relative to the rate
of uorination. The sense of regioselectivity observed for the
(E)-isomers is unusual under Ir-catalysis, but was documented
for Rh-catalyzed17 and Fe-catalyzed18 allylic alkylations. Evans
and co-workers provided mechanistic evidence for an enyl
organorhodium intermediate accounting for the conservation
of regio- (and stereochemistry).17 A s-allyl intermediate was also
advanced for iron-catalyzed allylic alkylation.18 An additional
consideration is the inuence of the counter-ion on regio- and
stereocontrol. Helmchen reported superior b : l selectivity and
ee for [Ir(COD)Cl]2 catalyzed allylic alkylation (malonate) of a
branched allylic acetate when the reaction was conducted in the
presence of 1 equivalent of LiF or LiCl.14 Based on these
Scheme 5 Fluorination of (S)-1a.
F
[
18O] Labeling experiments
With the initial intention of understanding the origin of the
alcohol side-product, the 18O-isotopomer of allylic methylcar-
bonate 1b (E : Z 81 : 19, 98% 18O at C1) was synthesized via the
doubly-labeled acetate and alcohol intermediates according to
Scheme 4 Influence of TBAF$4tBuOH on Ir-catalyzed allylic alkylation of 1a, (E)-
1b and (Z)-1b with NaCHE2 (eqn (1)–(3)); reactivity of (E)-2b and (Z)-2b with
NaCHE2 under Ir-catalysis (eqn (4) and (5)).
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literature guidelines.13,20 Four reactions were conducted with
initial analysis aided by the upeld 18O isotopic shi in the
quantitative 13C spectrum (CH2O signal):
(i) With labeled 1b under Ir-catalyzed uorination conditions
in DCM, uoride product 2b was accompanied by recovered but
isotope-depleted 1b (33% 18O at C1, similar E : Z ratio), and
alcohol 4b (34% 18O at C1).
(ii) Ir-catalyzed uorination of unlabeled (Z)-1b under stan-
dard conditions with 2 equiv. added 18OH2 led to comparable
incorporation of label in both recovered reactant and alcohol 4b
(ca. 40% 18O at C1).
Scheme 6 Inter-and intramolecular isotopic exchange observed through 18O-
labeling; experiment (ii) with (Z)-1b and 18OH2 used to illustrate likely
mechanisms.
(iii) The 18O label in enriched 1b (98% 18O at C1) remained
intact in the presence of the Ir catalyst under standard reaction
conditions, but in the absence of TBAF$4tBuOH.
This observation minimally requires that an ion-paired
intermediate scrambles the label by internal return,22 as has
been described for 18O-labeled sulfonates and carboxylates in
SN1 reactions. Taken together with the high degree of regio- and
stereospecicity observed in allyl uoride formation, this
labeling result supports the reversible intermediacy of an
unsymmetrical enyl rather than a fully developed h3-allyl, as has
been suggested for Rh-catalyzed allylic substitution.17 In addi-
tion, the formation of doubly-labeled and label-depleted
recovered reactant in both (i) and (ii) requires a further
exchange process between water and the substrate, or between
water and a reversibly-formed intermediate. In (i) adventitiously
present water is the reagent. The presence of both iridium
catalyst and uoride ion is required for the exchange processes
(iv) Reaction of unlabeled (Z)-1b with TBAF$4tBuOH in the
presence of 18OH2 (2 equiv.) at 40 ꢀC overnight led to some
hydrolysis (11% (Z)-4b recovered) with no signicant label
incorporation in either reactant or product.
These results are unexpected, the more so on closer analysis
of the C]O region of the 13C spectrum in the two catalytic
turnover experiments (i) and (ii). All four possible oxygen iso-
topomers of the CH2O–C]O component are observed,
including signicant amounts of the doubly labeled one,
conrmed by ES-MS (Fig. 2 and ESI†).21
to occur (Scheme 6). The more deep-seated equilibration of 18
O
labels with external water most likely involves reversible Ir-
promoted carbonyl addition of water to the C]O double bond.
As an analogy for (II), Lloyd-Jones et al. have demonstrated Pd-
catalyzed label equilibration between 13CO2 and diallyl
carbonate that rst involves ionic C–O dissociation.23 The
metal-mediated pathway involved in Mosey and Brown's
dramatic Pd-catalysed thioamide methanolysis24 offers support
for iridium involvement in (I), the intermolecular component of
isotope exchange observed here.
G
Synthesis and reactivity of [(allyl)Ir(COD)(P,C-L)(L)] D
Mechanistically, the inability of [Ir(COD)(P,C-L)(L)] B (prepared
from (R,R,R)-L) to induce allylic uorination was unexpected
and led us to investigate the origin of this result. Helmchen and
co-workers had initially indicated the efficacy of phosphor-
amidite ligands in Ir allylic alkylation,10a further developed by
Hartwig and co-workers10b in their original demonstration of Ir-
catalyzed asymmetric allylic aminations. Improvements in the
ligand emerged from the Alexakis group.25 Mechanistic insights
were contributed by both Helmchen and Hartwig, a key feature
being the identication of the isolable reactive intermediate
[Ir(COD)(P,C-L)(L)] B formed by a stereospecic internal methyl
C–H activation of the phosphoramidite side-chain.26 The
cycloocta-1,5-diene (COD) ligand is maintained throughout,
allylic carbonates are the preferred reactants, and the stereo-
chemical course follows the palladium case with double inver-
sion leading to overall retention. Based on these solid
precedents, the novel allyl Ir-intermediate D was prepared from
Fig. 2 The 13C NMR carbonyl region of recovered (E)-1b following experiment (i)
described above and showing the four possible isotopomers; likewise for (Z)-1b in
experiment (ii).
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[18F] radiolabeling of representative branched and linear (E)-
and (Z)-allyl carbonates was successfully validated. Future work
aims at identifying the active catalytic Ir-species and our next
synthetic challenge is the development of a method using allylic
alcohols as starting materials.
Acknowledgements
This research was nancially supported by the European Union
FP7-ITN-238434 (E.B.), the EPSRC (M.T., C.H.), CRUK (M.T.), the
Nuffield Foundation (T. K.) and the Royal Thai Government (T.
K.). We thank Dr T. D. W. Claridge, Dr B. Odell, Dr J. Wickens,
Dr J. S. O. McCullagh (Chemistry Research Laboratory, Univer-
sity of Oxford) for key NMR spectroscopy and mass spectro-
metry experiments.
Scheme 7 Synthesis and reactivity of [Ir(COD)(P,C-L)(L)] D.
Notes and references
1a applying a literature protocol,27 and subjected to three
reactions (Scheme 7). Upon treatment of complex D with
sodium dimethylmalonate in d8-THF at room temperature fol-
lowed by addition of PPh3, the branched and linear products of
substitution 3a and (E)-3b were obtained in a ꢁ4 : 1 ratio, a
result corroborating the product distribution observed in the
catalytic mode. In contrast, the diene 5a was the major product
when exposing complex D to TBAF$4tBuOH, with no signals
characteristic of branched allylic uoride 2a, or Ir–F or P–F
bond formation. Under these conditions, complex D had
decomposed. The combined use of malonate and TBAF$4t-
BuOH also led to decomposition of D with 3a (7%), 5a (23%)
and a trace amount of (E)-3b (ꢁ3%) detectable in the crude
reaction mixture. Collectively, these data demonstrate that the
allyl Ir-intermediate D is inactivated by uoride in d8-THF.
Further NMR studies13 indicate that D did not react with
TBAF$4tBuOH in d2-DCM at room temperature but decom-
posed with diene formation aer 30 minutes at 40 ꢀC. These
results discouraged further work with phosphine-Ir catalysts
and encouraged us to focus on [Ir(COD)Cl]2 A.
‡ During these initial studies, the paper from Nguyen's group that describes an
effective catalytic synthesis of branched allylic uorides from branched allylic
trichloracetimidates appeared (ref. 6).
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Conclusions
In conclusion, we have developed a method that converts allyl
carbonates into allyl uorides under iridium catalysis using
TBAF$4tBuOH as the uoride source. This study has unveiled a
series of novel features in Ir catalysis and its application to
allylic uorination. The inability of the [Ir(COD)Cl]2/(S,S,S)-L
catalytic system to induce uorination was unexpected; control
experiments demonstrated that [Ir(COD)(P,C-L)(L)] is inacti-
vated in the presence of uoride. This complication was
addressed by using the unligated [Ir(COD)Cl]2. The sense and
level of regiocontrol for the uorination of (E)-allyl carbonate
leading to linear (E)-allyl uoride is a distinct characteristic of
uoride as the incoming nucleophile and is unprecedented.
This uoride effect has been extended to allylic alkylation of
malonate that delivered linear (E) isomers from linear precur-
sors when the reaction was performed in the presence of
TBAF$4tBuOH. The rst examples of transition metal catalyzed
uorination affording (Z)-allyl uorides are disclosed and the
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16 HPLC analysis conrmed that the retention time of the [18F]
labeled product corresponds to the cold unlabeled material.
The retention times of 2a, (E)-2b and (Z)-2b are too similar
(6.9 min, 6.8 min and 6.4 min respectively) to differentiate
unambiguously between the three possible [18F] labeled
allyl uoride products. Branched versus linear and E/Z
selectivity for the radiolabeling experiments was therefore
assigned by analogy with the uorinations performed
using the unlabeled reagent TBAF$4tBuOH.
¨
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As featured in:
Showcasing research from the laboratories of
Professors Véronique Gouverneur and John Brown
FRS, Chemistry Research Laboratory, University of
Oxford, UK.
Regio- and Stereoretentive Synthesis of Branched, Linear (E)- and
(Z)- Allyl Fluorides from Allyl Carbonates under Ir-Catalysis
A new catalytic method for the regio- and stereocontrolled
fluorination of allylic carbonates is presented, using TBAF•4tBuOH
as fluoride source and [Ir(COD)Cl]2 as catalyst. The high degree of
structural conservation observed upon fluorination is a distinct
characteristic of fluoride as nucleophile and is unprecedented.
See J. Brown, V. Gouverneur et al.,
Chem. Sci., 2012, 4, 89.
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