Expedient synthesis of α-substituted fluoroethenes

Article abstract of DOI:10.1039/c2ob07031f

A mild and efficient synthesis of 1-aryl-1-fluoroethenes from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, under DBU- or Cs₂CO₃-mediated conditions at room temperature, is described. A comparable diethyl fluoro(naphthalen-2-yl)methylphosphonate reagent does not react with paraformaldehyde under these mild conditions. The utility of the methodology for synthesis of terminal α-fluoroalkenes bearing electron-withdrawing functionalities is also shown.

Full text of DOI:10.1039/c2ob07031f

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Volume 10 | Number 16 | 28 April 2012 | Pages 3133–3344
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B. Zajc et al.
1477-0520(2012)10:16;1-E
Expedient synthesis of α-substituted fluoroethenes

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Expedient synthesis of α-substituted fluoroethenes†
Samir K. Mandal, Arun K. Ghosh, Rakesh Kumar and Barbara Zajc*
Received 5th December 2011, Accepted 25th January 2012
DOI: 10.1039/c2ob07031f
HWE counterparts.13b,c Thus, we wanted to assess whether olefi-
nations of fluorinated BT-sulfones not containing a highly acti-
vated methylene group would proceed under mild conditions.
Mild conditions would be important in the case of relatively
complex and/or labile aryl derivatives.
Olefination conditions using mild bases were screened in reac-
tions of fluoro(1-naphthyl)methyl BT-sulfone (2a, Table 1) and
paraformaldehyde (10 molar equiv) at room temperature. When
either NEt3 or K3CO3 was used as base, no reaction (entries 1
and 2) or low conversion was observed (entry 3). On the other
hand, (1-naphthyl)fluoroethene 3a (Table 1) was isolated in 57%
yield with Cs2CO3, but the yield decreased to 49% when a lower
excess of the base was used (entries 4 and 5). When TMG was
used as base, no starting sulfone was observed after an overnight
reaction, but 3a was isolated in only 25% yield (entry 6). Good
yield of product 3a was obtained in DBU-mediated condensation
in CH2Cl2 (entry 7), and the yield was slightly lowered with a
lower excess of DBU (entry 8). Changing the solvent to THF
A mild and efficient synthesis of 1-aryl-1-fluoroethenes from
benzothiazolyl (aryl)fluoromethyl sulfones and paraformal-
dehyde, under DBU- or Cs2CO3-mediated conditions at
room temperature, is described. A comparable diethyl fluoro
(naphthalen-2-yl)methylphosphonate reagent does not react
with paraformaldehyde under these mild conditions. The
utility of the methodology for synthesis of terminal α-fluoro-
alkenes bearing electron-withdrawing functionalities is also
shown.
The unique influence fluorine atom exerts on the properties of
organic molecules1 is reflected in wide interest in fluorinated
compounds, ranging from agrochemicals, pharmaceuticals, to
drug discovery purposes, and materials.2–4 Regiospecific intro-
duction of fluorine into organic molecules therefore continues to
be of significance.5 In this context, terminal 1-aryl-1-fluoro-
ethenes are synthetically useful building blocks,6 and recently
potent antibacterial activity of an arene containing a terminal
α-fluorovinyl group has been shown as well.7 Current synthetic
approaches for the preparation8 of 1-aryl-1-fluoroethenes involve
a halofluorination–elimination sequence on styrenes,9 elimin-
ation from fluorohydrin tosylates,9b fluoroselenenylation–elimin-
ation,10 cross-coupling methods,11 and hydrofluorination–
elimination reaction of phenylacetylene.12
Table 1 Screening of reaction conditionsa
We13 and others14 have been involved with development of
the Julia–Kocienski olefination15 for the synthesis of variously
functionalized fluoroalkenes.16 However, to the best of our
knowledge, there are no reports on the use of this approach for
the synthesis of 1-aryl-1-fluoroethenes. In order to evaluate its
use for the synthesis of 1-aryl-1-fluoroethenes, appropriate 1,3-
benzothiazol-2-yl (BT) reagents were synthesized following our
protocol of heterogeneous metalation–electrophilic fluorina-
tion.13a These were subjected to olefinations with paraformalde-
hyde (Table 1). Condensations of paraformaldehyde with
Horner–Wadsworth–Emmons (HWE) reagents containing reac-
tive methylene groups have been reported either with strong
base17–19 or under mild conditions.14e We have previously
shown fluorinated BT-sulfones to be more reactive than their
Entry
Base (molar equiv)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
NEt3 (10)
CH2Cl2
Acetone
THF–H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
NRb
NRb
23c
57d
49d
25d
67d
62d
68d
67d
71d
K2CO3 (10)
K2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (2)
TMGe (10)
DBUe (10)
DBU (3)
DBU (10)
Cs2CO3 (10)
Cs2CO3 (2)
9
10
11
THF
THF
Department of Chemistry, The City College and The City University of
New York, New York, New York 10031-9198, USA. E-mail: barbaraz@
sci.ccny.cuny.edu; Fax: +01 212 650 6107; Tel: +01 212 650 8926
†Electronic supplementary information (ESI) available: Synthetic pro-
cedures, spectral data and copies of 1H and 13C spectra. See DOI:
10.1039/c2ob07031f
a For synthesis of 2a, 1a, and the sulfide precursor, see the ESI.† b No
reaction. c Not isolated, conversion determined by 19F NMR. d Isolated
yield. e TMG: 1,1,3,3-tetramethylguanidine; DBU: 1,8-diazabicyclo-
[5.4.0]undec-7-ene.
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Table 2 1-Aryl-1-fluoroethenes synthesizeda
Scheme 1 Reactivity of the Horner–Wadsworth–Emmons analog
under mild conditions.
Entry
Product:
Ar =
Methodb (solvent)
Yieldc (%)
electrophilic fluorination under our heterogeneous conditions.13a
In an unoptimized experiment, only 30% of the desired fluoro
(phenyl)methyl 1-phenyl-1H-tetrazol-5-yl sulfone (PT analog of
BT-sulfone 2b) was isolated, and the remaining material was the
starting unfluorinated PT-sulfone. Reaction of the fluorinated PT-
sulfone with paraformaldehyde (DBU, CH2Cl2) proceeded to
completion and 3b was formed in the reaction, but due to the
low fluorination yield, no further attempts were made to optimize
and pursue this.
Next, the reactivity of paraformaldehyde was compared to that
of aqueous formaldehyde (37 wt%). Reaction of fluoro(1-
naphthyl)methyl BT-sulfone 2a with this formaldehyde solution
(10 molar equiv of CH2O) was performed in THF, with either
Cs2CO3 (2 molar equiv), or with DBU (10 molar equiv). Only
starting sulfone 2a and no product was observed in the Cs2CO3
mediated condensation after 24 h at room temperature. In the
DBU-mediated reaction, 2a disappeared but only small amount
of 3a was formed (8% isolated yield of a slightly impure product
after a 24 h reaction).
In order to compare the reactivity of (aryl)fluoromethyl sul-
fones 2 to Horner–Wadsworth–Emmons (HWE) reagents, the
HWE analog of Julia reagent 2f was synthesized. The unknown
HWE reagent 4 was obtained by fluorination of the known
diethyl (naphthalen-2-yl)methylphosphonate20 (see the ESI†)
and reacted with paraformaldehyde under various conditions
(Scheme 1). No reaction was observed in 24 h under DBU–THF,
DBU–CH2Cl2, or Cs2CO3–CH2Cl2 conditions. This shows a
higher reactivity of the Julia reagent, as compared to the HWE
analog, likely due to the differences in the pKa values of the
proton being abstracted.
We were curious to evaluate whether reaction of unfluorinated
(aryl)methyl BT-sulfone would also proceed under mild con-
ditions. An overnight room-temperature reaction of 1a (1 molar
equiv) with paraformaldehyde (10 molar equiv) in CH2Cl2 using
Cs2CO3 (2 molar equiv) gave 1-vinylnaphthalene in 58% iso-
lated yield. This preliminary result indicates that this approach
could be useful for mild synthesis of unfluorinated styrene-like
compounds as well.
1
2
3b:
A (CH2Cl2)
B (CH2Cl2)
71
86
3
4
5
6
7
8
3c:
3d:
A (CH2Cl2)
B (CH2Cl2)
B (THF)
A (CH2Cl2)
B (CH2Cl2)
B (THF)
57, 51d
61
54
92, 95d
81
90
9
10
11
3e:
3f:
A (CH2Cl2)
B (CH2Cl2)
B (THF)
76d
78
71
69, 92d
74
91
12
13
14
A (CH2Cl2)
B (CH2Cl2)
B (THF)
15
16
3g:
3h:
B (CH2Cl2)
B (THF)
53
63
17
18
19
A (CH2Cl2)
B (CH2Cl2)
B (THF)
99
92
83
a Sulfone 2b–h: 1 molar equiv; paraformaldehyde: 10 molar equiv.
b Method A: DBU (10 molar equiv); Method B: Cs2CO3 (2 molar
equiv). c Yield of isolated, purified products. d 3 Molar equiv of DBU
were used.
gave a comparable yield in DBU-mediated reaction (compare
entries 7 and 9). Use of Cs2CO3 (10 molar equiv, entry 10) in
THF gave 3a in 67% yield, which was comparable to the 71%
yield when a lower excess of Cs2CO3 (2 molar equiv, entry 11)
was used.
To assess the generality of condensations, a series of BT-
sulfides was prepared either from benzyl bromides or from alco-
hols via the Mitsunobu reaction. Oxidation of the sulfides gave
sulfones 1b–1h. For experimental procedures and NMR data of
sulfides and sulfones, please see the ESI.† Metalation–fluorina-
tion of 1b–1h yielded fluoro BT-sulfones 2b–2h (isolated yields
of 76%–90%). Sulfones 2b–2h were reacted with paraformalde-
hyde using Method A (DBU, CH2Cl2) and/or Method B
(2 molar equiv of Cs2CO3, for economic considerations) and the
results are shown in Table 2. In the cases tested, comparable
results were obtained with either 3 or 10 molar equiv of DBU,
except for sulfone 2f, where the use of 3 molar equiv gave a
much better yield (entry 12).
We next wanted to assess whether benzothiazolyl fluoro-
methyl sulfones, activated with an additional electron-withdraw-
ing substituent, could also be reacted with paraformaldehyde
under these mild conditions. As described earlier, a single con-
densation reaction of paraformaldehyde and an activated HWE-
analog (a fluorinated arylsulfonylmethanephosphonate) under
mild conditions, has been reported.14e Therefore, fluoromethyl
BT-sulfones with electron withdrawing groups (EWG) were syn-
thesized (5a–e, for synthesis and spectral data, please see the
ESI†). Olefinations of 5a–e (Table 3) gave typically good yields
To evaluate the influence of the heteroaryl moiety on reactiv-
ity, (phenyl)methyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfone
(PT analog of BT-sulfone 1b) was subjected to metalation–
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Table 3 Synthesis of EWG-substituted α-fluoroolefinsa
Scheme 2 Suzuki conversions of α-fluorovinyl derivative 3c.
Entry
Product:
EWG =
Methodb (solvent)
Yieldc (%)
1
2
6a:
B (CH2Cl2)
B (THF)
75
paraformaldehyde under these mild conditions. Further conver-
sion of the α-fluoro-α-(2-bromophenyl)vinyl product was
demonstrated in a Suzuki coupling. This simple methodology is
also effective for the preparation of terminal fluoroalkenes
bearing electron withdrawing substituents, demonstrating its
broad generality.
39d
3
6b:
6c:
6d:
B (CH2Cl2)
64
4
5
A (CH2Cl2)
B (CH2Cl2)
54
66
6
B (CH2Cl2)
68
Acknowledgements
This work was supported by NIH (NIGMS) Grant S06
GM008168 and PSC CUNY awards. Infrastructural support was
provided by NIH RCMI Grant 5G12 RR03060. We thank
Dr. Andrew Poss (Honeywell) for a sample of NFSI.
7
6e:
6a:
B (CH2Cl2)
89
8e
9e
A (CH2Cl2)
B (CH2Cl2)
89
76
Notes and references
a Sulfone 5a–e: 1 molar equiv; paraformaldehyde: 10 molar equiv.
b Method A: DBU (3 molar equiv); Method B: Cs2CO3 (2 molar equiv).
c Yield of isolated, purified product. d Other unidentified products were
formed. e Reaction was performed with Horner–Wadsworth–Emmons
reagent Ph-SO2-CH(F)-P(O)(OEt)2.
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(O)(OEt)2, on the other hand, gave a better yield with DBU in
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