C-F bond formation with fluoride anions-highly selective iodofluorination of simple allenes

Article abstract of DOI:10.1039/c3cc42014k

A highly regioselective (up to 99:1) iodofluorination reaction of simple allenes occurs under mild conditions with Et₃N·3HF or Py·9HF to afford 2-iodoalken-3-yl fluorides.

Full text of DOI:10.1039/c3cc42014k

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C–F bond formation with fluoride anions – highly
selective iodofluorination of simple allenes†
Cite this: Chem. Commun., 2013,
49, 5651
Can Xue, Xinpeng Jiang, Chunling Fu* and Shengming Ma*
Received 19th March 2013,
Accepted 22nd April 2013
DOI: 10.1039/c3cc42014k
www.rsc.org/chemcomm
A highly regioselective (up to 99 : 1) iodofluorination reaction of
simple allenes occurs under mild conditions with Et3NÁ3HF or
PyÁ9HF to afford 2-iodoalken-3-yl fluorides.
As we know that the introduction of a fluorine atom into
organic molecules would have a remarkable effect on the
chemical, physical and biological properties due to its mimic
effect and very high electronegativity,1,2 thus, much attention
has been directed towards regio- and stereoselective mono-
Scheme 1 Monofluorination reactions of typical organic intermediates.
fluorination. Recently, there have been numerous reports on and the limited substrate scopes: for example, highly regio-
the metal-mediated C–F bond formation: an actively explored and stereoselective electrophilic fluorination reactions of 2,3-
process leading to aryl fluoride is direct reductive elimination allenoic acids,17 3-aryl-1,2-allenes,18 1,2-allenyl phosphine
from [ArPdF] intermediates via either a Pd(0)/Pd(II)3,4 or Pd(II)/ oxides,19 or 2,3-allenoates20 with Selectfluor have been observed;
Pd(IV)3,5 cycle; the conversion of aryl boronic acids (AgOTf),6 electrophilic fluorination of allylic silanes was reported to afford
silanes (Ag2O),7 stannanes (AgOTf),8 and halides (CuOTf(CH3CN)4)9 allylic fluorides with a branch selectivity;21 a-fluorination of
to arylfluorides with electrophilic fluorine reagents6–9 has also carbonyl compounds,22 such as ketones, aldehydes, and esters,
been reported (Scheme 1a); transition metal-catalyzed tandem with electrophilic fluoride reagents has also been established
cyclization and fluorination of alkenes, alkynes, or allenes are (Scheme 1b). We envisioned a C–F bond formation via the
reported to be efficient ways to construct fluorinated hetero- reaction of cationic species generated from electrophilic addi-
cycles;10 palladium-11 or iridium-mediated12 nucleophilic fluor- tion of allenes18,19,23,24 with a fluoride anion (Scheme 1c).22,25–28
ination of allylic electrophiles has been developed as the regio-
We chose trideca-1,2-diene 1a and NIS to conduct the
and enantioselective route to allylic fluorides; C–F bond for- iodofluorination reaction in DCE. The effect of the fluoride
mation has also been realized through the Au(I)-catalyzed anion was studied first: no fluorine-containing products were
hydrofluorination of alkynes;13 in addition, a five-coordinate afforded when applying NH4F, (NH4)HF2, NaHF2, and KHF2 in
fluoro complex of ruthenium(II)-catalyzed fluorination of allylic the reaction (entries 1–4, Table S1, ESI†); interestingly, with
or alkyl bromide with TlF (1.1 equiv.) has also been reported.14 PyÁ9HF,28 a mixture of regio- and stereoisomeric iodofluorination
On the other hand, due to the toxicity and the cost of transition products, 3-fluoro-2-iodotridec-1-ene 2a, (Z)-1-fluoro-2-iodo-
metal catalysts or metallic reagents, metal-free processes with tridec-2-ene (Z)-3a and (E)-1-fluoro-2-iodotridec-2-ene (E)-3a
readily available fluorine sources has always been attracting the (2a : (Z)-3a : (E)-3a = 88 : 8 : 4), were obtained in 53% combined
attention of chemists, although fluorination using elemental yield (entry 5, Table S1, ESI†); when Et3NÁ3HF was used, the
fluorine15 and pyrolysis of diazonium tetrafluoroborate16 are reaction at 0 1C could afford a better yield with a similar
less attractive due to harsh or dangerous reaction conditions regioselectivity (entry 6, Table S1, ESI†). Increasing the amount
of Et3NÁ3HF had almost no impact on the yields and selectivity
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, Zhejiang, People’s Republic of China.
E-mail: masm@sioc.ac.cn; Fax: +86-21-626-09305; Tel: +86-21-622-37360
† Electronic supplementary information (ESI) available: Optimization of the
reaction conditions for iodofluorination of trideca-1,2-diene 1a and all of the
relevant synthetic details as well as NMR spectra for all new compounds see DOI:
10.1039/c3cc42014k
(entries 7–9, Table S1, ESI†). Running the reaction at a lower
temperature led to a much slower conversion (entries 10
and 11, Table S1, ESI†), while there was a slight decrease in
regioselectivity when the reaction was conducted at room
temperature (entry 12, Table S1, ESI†). No reaction occurred
in anhydrous DMF (entry 1, Table S2, ESI†); only trace amounts
c
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of fluorinated products were detected by the analysis of 1H and (entries 8 and 9, Table 1); in addition, a trace amount of
19F NMR spectra when using toluene, acetone, THF, and elimination product, i.e., (Z)-2-iodo-3-phenylpent-1,3-diene
dioxane as the solvent (entries 2–5, Table S2, ESI†); only a (Z)-5h (9%) (entry 8, Table 1), was detected. The presence of
mixture of 2a and 3a (2a : (Z)-3a : (E)-3a = 90 : 9 : 1) in 23% an aryl group within R2 led to a slightly lower regioselectivity
combined yield was afforded when CH3CN was used as the (entry 11, Table 1); with R2 as the allyl group, the electrophilic
solvent (entry 6, Table S2, ESI†); with CH3NO2 as the solvent, addition reaction occurred exclusively to the allene unit (entries 12
there was almost no improvement (entry 7, Table S2, ESI†); the and 13, Table 1); with R1 and R2 both being alkyl groups, the yields
reaction in DCM or CHCl3 afforded very similar results as and selectivity are still remarkable (entries 14 and 15, Table 1). It is
compared to DCE (entries 8 and 9, Table S2, ESI†). By consider- noted that when PyÁ9HF was used instead of Et3NÁ3HF, the yield of
ing the yields together with the regio- and stereoselectivities, 2g, 2i, and 2k were slightly lower, however, with a better regio-
the reaction conditions presented in entry 6 of Table S1 (ESI†) selectivity (entries 7, 10, and 13, Table 1).
have been defined as the standard for further studies (eqn (1)).
The iodofluorination reactions of geminally disubstituted
It should be noted that no reaction occurred on the remaining allenes containing an oxygen-related functionality 2n and 2o
CQC bonds in these products.29–31
may also proceed with a nice selectivity (Scheme 2).
(1)
Then we attempted the iodofluorination reaction of geminally
disubstituted allenes with different types of R1 and R2 under
the optimized reaction conditions, with the results being
summarized in Table 1. To our delight, when R1 is an aryl
Scheme 2 Iodofluorination reactions with functionalized allenes.
group and R2 is a cyclic alkyl group, such as Bu or Pr, the
reaction could afford iodofluorination products 2 in good yields
with an excellent regioselectivity (up to 99 : 1) (entries 1–6,
Table 1). Even with R2 being normal alkyl groups, the regio-
selectivity of the iodofluorination reaction is also satisfactory
t
i
These 2-iodoallylic fluorides have been demonstrated to be
very attractive building blocks in organic synthesis as shown in
Scheme 3. The 6 mmol scale reaction of 1a affording a mixture
of 2a and 3a (2a : (Z)-3a : (E)-3a = 87 : 11 : 2) in 71% combined
yield (Step A, Scheme 3a) could afford pure 3-fluoro-2-phenyl-
tridec-1-ene 6a after a highly selective Pd-catalyzed Suzuki
coupling reaction with PhB(OH)2 (Step B, Scheme 3a);32 pure
3-fluorotridec-1-yne 4a was obtained via simple extraction,
Table 1 Iodofluorination reaction of geminally disubstituted allenes with a
nucleophilic fluoride aniona
Entry R1
R2
Time (h) Isolated yield of 2 (%) 2 : 3b
1
Ph
Ph
c-C6H13 (1b) 11
c-C5H11 (1c) 16
65 (2b)
68 (2c)
71 (2d)
75 (2e)
71 (2f)
85 (2g)
73 (2g)e
67 (2h)f
60 (2i)e
45 (2i)
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
98 : 2
99 : 1
94 : 6
91 : 9
93 : 7
84 : 16
88 : 12
93 : 7
92 : 8
92 : 8
2c
3c
4c
5
4-PrC6H4 c-C6H13 (1d) 11
4-FC6H4 c-C6H13 (1e)
Ph
Ph
Ph
Ph
Ph
9
13
15
15
10
t-Bu (1f)
i-Pr (1g)
i-Pr (1g)
Et (1h)
6
7d
8
9c
Ph(CH2)3 (1i) 12
Ph(CH2)3 (1i) 12
10c,d Ph
11
12
Ph
Ph
Ph (1j)
Allyl (1k)
Allyl (1k)
19
15
12
11
19
72 (2j)g
54 (2k)
36 (2k)
69 (2l)h
63 (2m)h
13d Ph
14
15
n-Bu
n-Bu (1l)
Ph(CH2)3 n-Bu (1m)
a
Conditions: 1.0 equiv. of 1, 1.5 equiv. of NIS, 1.0 equiv. of Et3NÁ3HF or
b
PyÁ9HF, DCE as a solvent, reacted at 0 1C. The ratios were determined
by the analysis of 19F NMR spectra of crude products. The scale of the
c
d
e
reaction is 6 mmol. PyÁ9HF was used instead of Et3NÁ3HF. The yields
were detected by 1H NMR spectra of crude products using mesitylene as
f
g
the internal standard. (Z)-5h (9%) was afforded. Separated using low
temperature column chromatography with a À18 to À16 1C circulating
Scheme 3 (a) The iodofluorination reaction of 1a and the subsequent conver-
sion of 2-iodoalken-3-yl fluoride 2a. (b) Sonogashira coupling of 2-iodoallylic
fluorides 2d and 2g with phenylacetylene.
h
EtOH outside the column. There were trace products obtained by the
elimination of HF of the main product 2.
c
5652 Chem. Commun., 2013, 49, 5651--5653
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`
9 A. Casitas, M. Canta, M. Sola, M. Costas and X. Ribas, J. Am. Chem.
Soc., 2011, 133, 19386.
concentration of the mixture of 2a and 3a and subsequent
treatment with KOtBu (2.4 equiv.) in anhydrous THF at 0 1C for
6 h in 51% combined isolated yield for two steps from 1a (Steps
A and C, Scheme 3a);33 alkyne 4a may be further converted to
4-fluorotetradeca-1,2-diene 7a by its treatment with (HCHO)n
and Cy2NH (Step D, Scheme 3a),34 and alkyne 8a by its
sequential treatment with LDA and MOMCl, respectively
(Step E, Scheme 3a). The synthetic potential of these 2-iodoallylic
fluorides has been further demonstrated by applying the
Sonogashira reaction of 2d and 2g with phenylacetylene affording
2-(1-fluoro-1-phenyl-2-methylpropyl)-4-phenyl-buten-3-yne 9d and
2-(1-fluoro-1-phenyl-2-methylpropyl)-4-phenyl-buten-3-yne 9g,
respectively (Scheme 3b).35 These 2a, 4a, 6a, 7a, 8a, 9d, and
9g-type products are difficult to prepare by following conven-
tional synthetic methods.
In summary, we have developed a highly regioselective
iodofluorination reaction for the convenient synthesis of
2-iodoallylic fluorides. Considering the potential of the electro-
philic monofluorination products and the ready availability of
the starting materials,36 this method shall open a new window
for the chemistry of organofluorine compounds based on
allenes. Further studies in this area including the asymmetric
version of this reaction are undergoing in our laboratory.
We gratefully acknowledge the National Natural Science Founda-
tion of China (No. 21232006). Shengming Ma is a Qiu Shi Adjunct
Professor at Zhejiang University. The results presented in entries 4,
6, and 14 of Table 1 have been kindly reproduced by Mr Chen Bo.
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