Organic Letters
Letter
in the yields due to steric effects (2g, 2h, and 2t). Fluorination
of complex molecules also occurred smoothly (2u−2w).
Surprisingly, cis-cyclic alcohol 1x was exclusively converted
into cis-product 2x. To further demonstrate the synthetic
potential of this protocol, fluorination of substrate 1a was
carried out on a gram scale. To our delight, product 2a was
isolated in a high yield (1.17g, 88%).
We propose that the reaction may proceed via the first
iodination or bromination of alcohols, and the subsequent
fluorination of tertiary iodides or bromides. Indeed, the
Ph2PCH2CH2PPh2/ICH2CH2I system can effectively convert
alcohol 1a into the corresponding iodide 3a (Scheme 3, eq 1).
Ph2PCH2CH2PPh2 is not soluble in the reaction solvent,
CH3CN, and thus, it would be present as a solid in CH3CN.
However, after ICH2CH2I was added, the solid disappeared
quickly with stirring the reaction mixture. No solid remained
after stirring for about 1 min, and 31P NMR analysis revealed
that Ph2PCH2CH2PPh2 was almost completely transformed
into a species whose resonance signal appearing at 51.3 ppm,
which should correspond to a diiodophosphonium salt,
[Ph2P+(I)CH2CH2P+(I)Ph2] 2I−, according to our previous
investigations (Scheme 4, eq 1).13a The diiodophosphonium
Scheme 4. Need for Sequential Addition of Reagents
Scheme 3. Experimental Evidence for the Iodination and
Bromination Paths
a
1
The yield was determined by H NMR spectroscopy.
salt is quite reactive and may easily undergo side reactions.
However, if the substrate alcohol is added before ICH2CH2I,
the phosphonium salt generated in situ may specifically
coordinate to the alcohol and thus side reactions may be
suppressed. Indeed, when an alcohol was present, the hydroxyl
group was effectively activated and iodination product was
obtained in 43% yield right after the solid disappeared (eq 2).
For the fluorination procedure, after alcohol/
Ph2PCH2CH2PPh2/ICH2CH2I was added and the solid
disappeared (about 1 min), ZnBr2 and Selectfluor were then
sequentially added without time interval. The issue of
incompatibility could be avoided by this procedure.
Based on the above results, we propose the reaction
mechanism as shown in Scheme 5. Ph2PCH2CH2PPh2 reacts
a
b
1
Determined by H NMR spectroscopy. Determined by 19F NMR
spectroscopy.
Scheme 5. Plausible Reaction Mechanism
When ZnBr2 was present, bromide 4a was also provided (eq
2). Fluorination of both iodide 3a and bromide 4a occurred
rapidly (eqs 3 and 4), reflecting that iodination and
bromination are involved in the fluorination of alcohols.
Since the Ph2PCH2CH2PPh2/ICH2CH2I system alone can
efficiently promote iodination, a question arose why bromina-
tion with ZnBr2 should be involved to increase the fluorination
yield. The reaction of Ph2PCH2CH2PPh2 with ICH2CH2I
would generate iodide anion,13 which could readily undergo a
redox reaction with Selectfluor.15 The consumption of iodide
anion and Selectfluor would suppress iodination and
fluorination, respectively. However, ZnBr2 cannot be com-
pletely dissociated to release bromide anion, and thus the
redox reaction of ZnBr2 with Selectfluor would not easily
occur. Although not completely dissociated, ZnBr2 still can
effectively promote bromination. Therefore, ZnBr2 is quite
important for this fluorination process. Although the redox
reaction of I− with Selectlfuor would generate fluoride anion,15
nucleophilic fluorination could still be excluded on the basis
that no desired product was observed by using CsF instead of
Selectfluor (eq 5) and that bromide 4a cannot be converted
into fluorinated product within 15 min (eq 6).
with ICH2CH2I rapidly to generate diiodophosphonium salt
[Ph2P+(I)CH2CH2P+(I)Ph2] 2I−, which can act as a Lewis acid
to activate hydroxyl group for the iodination or bromination of
alcohols.13a A redox reaction of Selectfluor with I− anion
produces radical cation A, which abstracts a halogen atom from
tertiary iodides or bromides to deliver alkyl radical.
Fluorination of this radical with Selectfluor provides the final
product.4 The stereoselectivity for the formation of product 2x
should be because of a double-inversion process, iodination or
bromination of alcohols with inversion of configuration,13a and
I−/Selectfluor is not the only incompatible pair in the
reaction system. Ph2PCH2CH2PPh2 is not compatible with
Selecfluor either.14 The issue of this incompatibility can be
addressed by sequential addition of reagents because
Ph2PCH2CH2PPh2 reacts with ICH2CH2I very fast.
C
Org. Lett. XXXX, XXX, XXX−XXX