Angewandte
Chemie
rect isotope pattern) as the only strong signal in the region
m/z 500–1000.[14]
These results demonstrate the viability of fluoride as a
leaving group in catalytic allylic alkylation, but do not
quantify its reactivity as a leaving group. The availability of
racemic fluoroesters 8a and 8b,[15] and ready access to the
related fluorocarbonate 8c informed the ensuing strategy.
Initial reactions were carried out using acetate 8a. Rapid loss
of allylic fluoride was attested by direct detection by 19F NMR
spectroscopy of Me3SiF, which formed rapidly under BSA-
promoted conditions.[7] In the most revealing experiments
(Table 2, entries 1–8) some intermediate species 9 was
retained. The more reactive isomer syn-9 was only detected
under reagent-limited conditions (Table 2, entry 3). 19F NMR
indicated the absence of organofluorine species. In separate
reactions with independently synthesized isomers,[16] syn-9
gave 76:24 syn/anti-10 under the conditions of entry 2, but
anti-9 was unreactive. When a chelating diphosphine, biphep
Scheme 3. Synthesis of racemic allylic fluoride 5 (for further details see
the Supporting Information): a) DAST, CH2Cl2, ꢀ788C!room temper-
ature, syn/anti 40:60, 59%; b) trifluoroacetic anhydride, pyridine, then
Pd-catalyzed silylation with (Me3Si)2; c) Mitsunobu inversion, then
as (b); d) Selectfluor (1-chloromethyl-4-fluorodiazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate)), NaHCO3, CH3CN, syn/anti 87:13;
72%; e) as (d), syn/anti 10:90, 74%.
or
1,3-bis(diphenylphosphanyl)propane
(dppp),
was
employed as a ligand in place of PPh3 (Table 2, entries 4–8),
more anti-isomer was detected in total, but the reaction
remained unselective. Entries 7 and 8 in particular indicated a
higher tendency to form anti-9 in the first step.
Table 1: Allylic alkylation of allyl fluoride 5 with malonate ion.[a]
Allyl benzoates are far more reactive than allyl acetates
towards alkylation.[17] With substrate 8b, both leaving groups
were displaced under standard conditions, with selective
formation of the monoinverted product syn-10 (Table 2,
entries 9 and 10). However, with the chelating ligand biphep
in place of PPh3, overall retention to give anti-10 was
Entry
Syn/anti
ratio in 5
Solvent
t [h]
Syn/anti
ratio in 7
1
2
3
4
40:60
10:90
87:13
40:60
40:60
40:60
40:60
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
0.25
0.25
0.25
18
24
0.25
24
76:24
72:28
73:27
73:27
72:28[a]
37:63
1
preferred by a ratio of 2:1. Further H NMR experiments
revealed the order of the two allylic alkylation steps. In
addition to doubly alkylated products, intermediate 11 was
formed with predominant retention of configuration (87%
anti) with CHF resonating at d = 5.1 ppm in 1H NMR
spectroscopy. The minor product is tentatively assigned as
the isomeric anti-homoallylic fluoride 12 (d(CHF) =
4.78 ppm), indicating that benzoate is a superior leaving
group to fluoride, and the subsequent fluoride-substitution
step occurs with predominant inversion of configuration
(Table 2, entries 9 and 10).
5
6[b]
7[b]
CH2Cl2
THF
32:68[a]
[a] 10 mol% catalyst was used in the absence of [15]crown-5, approx-
imately 50% conversion was detected; syn/anti ratio in recovered 5 was
not significantly altered. [b] Catalyst was [{(h3-C3H5)PdCl}2], biphep.
When
2,2’-bis(diphenylphosphanyl)biphenyl
(biphep)
Carbonates are known to be significantly more reactive
than benzoates and other carboxylates in allylic alkylation
reactions.[18] Synthesis of 8c (2:98 syn/anti ratio) was accom-
plished by the previously described method. On subjecting 8c
to standard conditions, pure anti-11 was isolable in 40% yield
after relatively short reaction times, (Scheme 4). Crude anti-
11 contained 10% of 12, but syn-11 was not detected. In this
case, an unambiguous preference is demonstrated for reten-
tion of configuration, with carbonate as the leaving group in
the first step, and inversion of configuration with fluoride as
leaving group in the second step.
The data demonstrate unequivocally that allyl fluorides
are active in palladium-catalyzed allylic alkylations. The
leaving group propensity is OCO2Me > OBz @ F @ OAc.
More surprisingly, the stereochemical course of displacement
of Fꢀ is not governed by the normal double-inversion
retention mechanism. In contrast, palladium-catalyzed reac-
tion of the malonate ion with the allyl chloride analogue of
fluoride 5 occurs with complete retention of configuration.[19]
replaced PPh3 as the ligand, the syn/anti ratio in product 7
changed to 1:2 and, again, the reactant recovered from an
incomplete reaction in THF was not epimerized (Table 1,
entries 6 and 7), reinforcing the observations regarding allyl
fluoride reactivity, but also demonstrating an unusual mech-
anistic pathway; under optimized reaction conditions, the
corresponding allyl acetates give ꢂ 98% retention of config-
uration.[11]
Treatment of related allyl chlorides with [Pd(PPh3)4] in
CDCl3 gives the corresponding h3-allyl complex.[12] When 5
(40:60 syn/anti) was treated with [Pd(dba)2] (dba = dibenzy-
lideneacetone) and PPh3 in CDCl3 and monitored by NMR
spectroscopy, complex changes occurred, with initial broad-
ening and then disappearance of the CHF signal (faster for
anti-5). The known allyl cation,[13] derived from C F ioniza-
tion, was not detected in the NMR spectrum, but ES-MS
analysis of the reaction mixture showed a strong signal for
that cation (m/z calcd: 769.1611; found: 769.1574, with cor-
ꢀ
Angew. Chem. Int. Ed. 2009, 48, 1296 –1299
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1297
Hazari, Amaruka
