Access to new 4-fluorocyclohexa-2,5-dienimines using hypervalent iodine and pyridinium polyhydrogen fluoride

Article abstract of DOI:10.1016/j.tetlet.2007.12.082

Nucleophilic para-fluorination of substituted anilines to afford 4-fluorocyclohexadieneimine derivatives is achieved in the presence of hypervalent iodine and pyridinium polyhydrogen fluoride.

Full text of DOI:10.1016/j.tetlet.2007.12.082

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1551–1554
Access to new 4-fluorocyclohexa-2,5-dienimines using
hypervalent iodine and pyridinium polyhydrogen fluoride
*
`
Lynda Basset, Agnes Martin-Mingot, Marie-Paule Jouannetaud , Jean-Claude Jacquesy
`
´ ´
Universite´ de Poitiers, UMR 6514 ‘Synthese et reactivite des Substances Naturelles’, 40, Avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
Received 25 May 2007; revised 13 December 2007; accepted 18 December 2007
Available online 23 December 2007
Abstract
Nucleophilic para-fluorination of substituted anilines to afford 4-fluorocyclohexadieneimine derivatives is achieved in the presence of
hypervalent iodine and pyridinium polyhydrogen fluoride.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hypervalent iodine; Fluorination; Anilines; Cyclohexadienimines
The introduction of fluorine in organic molecules
strongly modifies their physical, chemical and biological
properties.1 The mild and selective introduction of a fluo-
rine atom has been largely investigated over the past three
decades and remains a great field of investigation.
With this aim we previously reported a novel synthesis
of 4-fluorocyclohexa-2,5-dienones from 4-alkylphenols
using pyridinium polyhydrogen fluoride (PPHF) in combi-
nation with hypervalent iodine(III) reagents.2 It had previ-
ously been shown that hypervalent iodine reagent could
also be an efficient reagent to access 4-alkoxy-4-alkylcyclo-
hexa-2,5-dienimines from the corresponding substituted
anilines, such new compounds being efficiently used in
the synthesis of more complex structures.3
In our research for the synthesis of new fluorinated
building blocks we now wish to report the synthesis of
4-fluoro-4-substituted cyclohexa-2,5-dieneimines from ani-
lines with phenyliodine-(diacetate) (PIDA) and PPHF.
A typical experimental procedure for the reaction is as
follows: To a stirred solution of aniline derivatives (1 mmol)
in dry methylene chloride (20 mL) was added first PPHF
(HF/pyridine 70/30 w:w, 0.1 mL), then PIDA (1.2 equiv)
at room temperature. The mixture was stirred for 15 min.
The Na2CO3 is added until neutralization of the mixture.
After filtration, the organic layer is concentrated under
vacuum and the residue is quickly purified by chromatogra-
phy. The results are summarized in Table 1.
1
Products gave satisfactory spectral data (MS, H, 13C,
19F NMR) and expected analytical results (HRMS).4 The
19F NMR spectra showed expected signals at
À150 ppm < d < À140 ppm for the ipso fluorinated alkyl-
ated compounds, at À106 ppm for the chlorofluorinated
one and at À97 ppm for the difluorinated dieneimine.
1
The H NMR showed typical signals for vinylic hydrogen.
It should be pointed out that the shielding of the hydrogen
in a position of the imine function is approximately
1.3 ppm, due to the shielding zone of the p electron system
of the tosyl group (Scheme 1).
Structures were also supported by the presence in 13C
NMR of the characteristic coupling between fluorine and
carbon, 160 Hz < 1JCF < 170 Hz for monofluorinated
products and the typical triplet at 109.4 ppm with a
225 Hz coupling constant for the difluorinated imine.
The reported results in Table
comments.
It appears that the protecting group on the aniline nitro-
gen atom and the substitution of the aromatic moiety play
a crucial role.
1 deserve several
*
Corresponding author. Tel.: +33 05 49 45 38 93; fax: +33 05 49 45 35
01.
E-mail address: marie.paule.jouannetaud@univ-poitiers.fr (M.-P.
Jouannetaud).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.082

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L. Basset et al. / Tetrahedron Letters 49 (2008) 1551–1554
Table 1
Entry
Substrate
CH3HN
Products
Yield (%)
1
2
3
4
No reaction
Complex mixture
CH3COHN
75a
18
F
TsHN
TsHN
TsN
F
F
TsN
F
F
5
6
7
F
47
51
TsHN
TsHN
TsHN
TsHN
TsN
Cl
Cl
F
TsN
Br
X
Complex mixture
No reaction
8
X = NO2, COCH3
9
61
57
F
TsHN
TsHN
TsN
Ts
F
F
10
N
N
F
11
12
77 (58/42)
+
Ts
Ts
TsHN
TsHN
N
No reaction
F
13
24
TsHN
TsN
a
The use of PIFA (phenyliodine-(ditrifluoracetate)) instead of PIDA lowered the yield of the reaction.
Under our reaction conditions (PIDA, PPHF), N-
methyl-para-toluidine did not react (entry 1) and para-
methyl acetanilide led to complex mixture (entry 2). This
is in agreement with the previously reported results. It
was reported that N-methyl derivatives of aniline did not
react with PIDA in methanol.6 The behaviour of acetani-
lide in the presence of hypervalent iodine depends on the
reaction conditions: in acetic acid they led to meta-acetoxy
derivatives,6 in toluene only complex mixtures were
obtained7 and in a mixture of CHCl3 and TFA, hydrolyla-

L. Basset et al. / Tetrahedron Letters 49 (2008) 1551–1554
1553
ortho-substituted aniline yielded only one conformer
(methyl and tosyl groups in anti conformation),4 meta-
substituted aniline yielded syn and anti conformers in
almost the same ratio (entries 10 and 11).
The fluorination of N-tosyl-5-aminoindan (entry 13)
confirmed the ability to use such a technology to access
polycyclic fluorinated building blocks.
O
O
S
N
H
H
In summary, the reaction of N-tosyl-para-substituted
anilines in the presence of PIDA and PPHF was studied
and afforded an easy access to new 4-fluorinated cyclo-
hexa-2,5-dienimines.
F
Scheme 1.5
This reaction is a novel example of the great scope of the
hypervalent iodine compounds in organic synthesis.
Furthermore, this investigation sets the stage for the appli-
cation to more elaborated substrates and makes this tech-
nology an attractive route to synthetic, highly valued
fluorinated building blocks.
tion to N-para position and/or N-iodophenylation of ace-
tanilides was observed.8 Furthermore, no reaction occurred
with 4-tert-butylacetanilide in the presence of PIFA and
Et3NÁ3HF in CH2Cl2 at room temperature and only 4-flu-
oroacetaniline was obtained in a modest yield after one day
at reflux.9
References and notes
The presence of
a
more electron withdrawing
group such as tosyl makes sulfonamides weak organic
acids, with a pKa in the region of that of phenols.10 As a
result the following mechanism could be proposed:
(Scheme 2).
1. (a) Cartwright, D. In Organofluorine Chemistry: Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Taltow, J. C.,
Eds.; Plenum: New York, 1994; p 237; (b) Mann J. Chem. Soc. Rev.
1987, 16, 346–381; (c) Welch, J. T. Tetrahedron 1987, 43, 3123–3197;
´
´
(d) Begue, J. P.; Bonnet-Delpon, D. Tetrahedron 1991, 47, 207–3258;
(e) Resnati, G.; Soloshonok, V. A. Tetrahedron 1996, 52, 1–330.
Tetrahedron Symposia-in-Print No. 58; (f) Isanbor, C.; O’Hagen, D.
It implies the reaction of the hypervalent iodine deriva-
tive with nitrogen atom, the resulting intermediate being
trapped by the nucleophilic fluoride ion.
However, we cannot exclude the mechanism proposed
by Langlois co-workers9 in which the initial binding of
the hypervalent iodine compound occurred on an oxygen
atom of the sulfonamide moiety.
Substitution on the para position of the aromatic moiety
was also studied. The presence of an electron withdrawing
substituent prevented from any reaction (entry 8) whereas
substitution with an electron donating group (except with
the more oxidizable and bulkiest bromine atom) made this
reaction easier (entries 3–7).
It must be also noticed that substitution at the ortho
position of tosylated anilines clearly disfavoured the
reaction yield probably due to steric effect, which was con-
firmed by the absence of reaction starting from di-ortho-
substituted aniline (entry 12).
´
´
J. Fluorine Chem. 2006, 127, 303–319; (g) Begue, J. P.; Bonnet-
Delpon, D. Chimie Bioorganique et Me´dicinale du Fluor; Eds, EDP
Sciences; CNRS Editions, 2005.
2. (a) Karam, O.; Jacquesy, J. C.; Jouannetaud, M. P. Tetrahedron Lett.
1994, 35, 2541–2544; (b) Martin, A.; Jouannetaud, M. P.; Jacquesy, J.
C.; Cousson, A. Tetrahedron Lett. 1996, 37, 43. pp. 7735–7738; (c)
Karam, O.; Martin, A.; Jouannetaud, M. P.; Jacquesy, J. C.;
Cousson, A. Tetrahedron Lett. 1999, 40, 4186–4193; (d) Karam, O.;
Martin, A.; Jouannetaud, M. P.; Jacquesy, J. C.; Cousson, A.
Tetrahedron 2004, 60, 6629–6638.
3. (a) Zawada, P. V.; Banfield, S. C.; Kerr, M. A. Synlett 2003, 7, 971–
974; (b) Wells, G.; Berry, J. M.; Bradshaw, T. D.; Buerger, A. M.;
Seaton, A.; Wang, B.; Westwell, A. D.; Stevens, M. F. G. J. Med.
Chem. 2003, 46, 532–541.
4. Selected spectral data: Product entry 5: 1H NMR (300 MHz, CDCl3,
TMS as an internal standard): d 6.44 (dd, J = 10.1 Hz, J = 2.3 Hz,
1H), 6.70–6.78 (m, 2H), 7.26 (s, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.74
(dd, J = 10.1 Hz, J = 2.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d 21.6, 109.4 (t, J = 225 Hz), 124.6 (t, J = 9 Hz),
127.5, 132.9, 133.1 (t, J = 9 Hz), 135.7 (t, J = 25 Hz), 136.1 (t,
J = 25 Hz), 136.9, 144.7, 160.9 (t, J = 5 Hz). 19F {H} NMR
(282 MHz, CDCl3 external standard C6F6 (dF—162.90)): d À97.1.
Steric influence of the substitution was also demon-
strated after the submission of the ortho and meta methyl
substituted anilines on reaction conditions: while mono-
I
Ts
Ts
H
Ts
CH3COO
PhI(OCOCH3)2
N
N
N
-
- CH3CO2
- CH3CO2H
- PhI
F
-
F
Scheme 2.

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L. Basset et al. / Tetrahedron Letters 49 (2008) 1551–1554
MS (EI) m/z: 283 (M+). HRMS Calcd: 283.04783. Found: 283.0475
(1 ppm).
5. Geometry optimization was executed with Chem 3D by applying the
PM3 semi-empirical methods in MOPAC.
Product entry 10: 1H NMR (300 MHz, CDCl3,TMS as an internal
standard): d 1.58 (d, J = 21.0 Hz, 3H), 1.88 (d, J = 2.5 Hz, 3H), 2.44
(s, 3H), 6.72 (dm, J = 7.8 Hz, 1H), 6.77–6.84 (m,1H), 7.33 (d,
J = 8.0 Hz, 2H), 7.51 (d, J = 10.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H).
13C NMR (75 MHz, CDCl3): d 17.3, 21.6, 25.5 (d, J = 27 Hz), 86.7 (d,
J = 160 Hz), 122.1 (d, J = 8 Hz), 127.1, 129.58, 135.1 (d, J = 9 Hz),
138.4, 141.9 (d, J = 20.5 Hz), 143.7, 146.0 (d, J = 21 Hz), 164 (d,
J = 6 Hz). 19F {H} NMR (282 MHz, CDCl3, external standard C6F6
(dF—162.90)): d À145.0. MS (EI) m/z: 293(M+). HRMS Calcd:
293.08858. Found: 293.071 (4 ppm).
6. Kokil, P. B.; Patil, S. D.; Ravindranathan, T.; Madhavan Nair, P.
Tetrahedron Lett. 1979, 11, 989–992.
7. Abramovitch, R. A.; Ye, X. J. Org. Chem. 1999, 64, 5904–5912.
8. Itoh, N.; Sakamoto, T.; Miyazama, E.; Kikugawa, Y. J. Org. Chem.
2002, 67, 7427–7428.
9. Bienvenu, A.; Barthelemy, A.; Boichut, S.; Marquet, B.; Billard, T.;
Langlois, B. R. Collect. Czech Chem. Comm. 2002, 67, 1467–
1478.
10. (a) Thakur, A. ARKIVOC 2005, XIV, 49–58; (b) Remko, M.; Von der
Lieth, C.-W. Bioorg. Med. Chem. 2004, 12, 5395–5403.