Nucleophilic aromatic substitution on 4-fluorophenylsulfonamides: Nitrogen, oxygen, and sulfur nucleophiles

Article abstract of DOI:10.1055/s-2005-862363

Improved conditions are reported for the stoichiometric reaction of nitrogen, oxygen, and sulfur nucleophiles with weakly activated 4-fluorophenylsulfonamides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862363

LETTER
449
Nucleophilic Aromatic Substitution on 4-Fluorophenylsulfonamides:
Nitrogen, Oxygen, and Sulfur Nucleophiles
S
A
r
on 4-Fluo
l
rophen
e
n
des a Badetti, Marcial Moreno-Mañas,* Roser Pleixats, Rosa M. Sebastián, Anna Serra, Roger Soler,
N
Adelina Vallribera
Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Fax +34(9)35811254; E-mail: marcial.moreno@uab.es
Received 10 November 2004
DMF in the presence of potassium carbonate (method B)
to afford 4c (entries 3 and 4). Aniline and a N-substituted
aniline, 4-chloro-N-methylaniline, were also active under
method A (entries 6 and 7), diarylamines 4e,f being isolat-
ed in reasonable yields. Finally, 1-aza-18-crown-6 gave
4g (entry 8). Stoichiometric amounts or only slight ex-
cesses (1.2 molar) of amine were used in all cases. Cyclo-
hexylamine and diphenylamine were inert under all tested
conditions. Addition of tetramethylethylenediamine
(TMEDA) did not improve the results. Even in one case,
when working with di-n-octylamine, a small amount of 4
(R1 = R2 = CH3) was isolated. Dimethylamine required
for the formation of this by-product must come from
TMEDA under BuLi initiation as suggested by one ref-
eree. Therefore this additive was not considered further.
Abstract: Improved conditions are reported for the stoichiometric
reaction of nitrogen, oxygen, and sulfur nucleophiles with weakly
activated 4-fluorophenylsulfonamides.
Key words: nucleophilic aromatic substitution, phase transfer
catalysis, cesium, macrocycles, diaryl oxides, diarylamines
In the course of a project we sought substitution of
fluorine with nucleophiles in triolefinic macrocycle 1
(Scheme 1)1,2 Large excesses of nucleophiles and harsh
experimental conditions were required. This solution is
not applicable to reactions of more valuable nucleophiles
when only one mol of nucleophile per fluorine atom is
preferred. Milder experimental conditions are also desir-
able.
Whereas nucleophilic aromatic substitution (SNAr) on 4-
nitrofluoroaromatics is a reaction of broad applicability,4
activation by electron-acceptor functional groups other
than nitro has met with less success. This is a consequence
of the decreased ability to stabilize the negative charge in
the intermediate anion formed along SNAr processes. The
F
X
SO2
N
SO2
N
a, b, c
–
stabilizing power can be estimated from the sp values of
the different groups: -NO2 (1.27), -SO2-CH3 (1.13), and -
SO2-NMe2 (0.99).5 Therefore it is not surprising that re-
ports on replacement of fluorine on aromatic sulfones
with nitrogen,6 oxygen,7 or sulfur8 nucleophiles are
scarce. In these cases either large excess of nucleophiles,
or severe experimental conditions, or both had to be intro-
duced. Examples of such a reaction on 4-fluorophenyl-
sulfonamides are even more rare.1,9
N
N
SO2
SO2
N
N
O2S
O2S
F
X
F
X
2a X = -NMe2
2b X = -N(C8H17 2
2c X = -SC16H33
1
)
We endeavored to find improved methods to perform
SNAr reactions on aromatic fluorosulfonamides choosing
sulfonamide 3 as a model.10
Scheme 1 a) Excess 2 M HNMe2 in THF, 100 °C, 6 d in closed
reactor; b) excess HN(C8H17)2, THF, 170 °C, 2 months in closed
reactor; c) HSC16H33 (3-fold molar excess), K2CO3, DMSO, 100 °C,
2 d.3
We report here that fluorine can be exchanged in com-
pound 3 with a variety of primary and secondary aliphatic
and aromatic amines (Table 1) through their lithium
amides formed with buthyllithium in THF (method
A).11,12 Thus, hexylamine, di-n-octylamine, and diethyl-
amine react to afford 4a,b,d in good yields (entries 1, 2,
and 5). However, laurylamine did not react under condi-
tions of method A. Nevertheless, reaction did occur in hot
Oxygen nucleophiles react with 3 (Scheme 2 and Table 2)
to afford the corresponding ethers. Thus, three aliphatic
alcohols as well as phenol gave ethers 5a–d in good yields
when their sodium salts (HNa in THF) were treated with
3 (entries 1, 3–5, Table 2). We noticed that addition of
tetrabutylammonium chloride (method C) improved the
result. In theory the ammonium salt could be used in sub-
stoichiometric amounts since it is a catalyst. Indeed, for-
mation of sodium chloride generates the quaternary salts
Bu4N(RX) which, upon reaction, regenerate the quaterna-
ry salt in the form of fluoride. We never made attempts to
SYNLETT 2005, No. 3, pp 0449–0452
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862363; Art ID: G39704ST
© Georg Thieme Verlag Stuttgart · New York

450
E. Badetti et al.
LETTER
NR1R2
4a
4b
4c
X-R
NH-C6H13
N(C8H17 2
)
5a
5b
5c
O-C4H9
NH-C12H25
N(C2H5)2
O-C12H25
NR1R2
F
X-R
4d
4e
O-CH2CH(Et)C4H9
NH
5d
O
6a
6b
S-C3H7
4f
N
Cl
SO2NEt2
SO2NEt2
SO2NEt2
S-C16H33
CH3
4
3
5 X = O
6 X = S
O
6c
6d
S
O
O
O
4g
S-CH2CH2C8F17
O
N
Scheme 2 Replacement of fluorine by amines (Table 1), alcohols, and thiols (Table 2).
use Bu4NF as catalyst. Since the ammonium was easily the use of cesium carbonate (method D) gave excellent
eliminated in the working up we decided to use one mol results (entries 11, 12).
of Bu4NCl for oxygen nucleophiles.13
In summary we present in this letter methods to perform
Cesium carbonate is an interesting alternative. Thus, SNAr reactions of weakly activated 4-fluorophenylsul-
lauryl ether 5b was obtained by treating the alcohol fonamides. Furthermore, we tested our method on macro-
with 3 in THF in the presence of Cs2CO3 and Bu4NCl cycle 1 (Scheme 3). Thus, a triple substitution was
(method D, entry 2, Table 2).14 All attempts to make achieved by reaction of 1 with 1H,1H,2H,2H-perfluoro-
ethers from fluorinated 1H,1H,2H,2H-perfluorodecanol decanethiol under method D conditions using 1.4 mol of
or 1H,1H,2H,2H-perfluorooctanol failed, both by meth- thiol per fluorine atom to afford macrocycle 7 (mp 187–
ods C or D.
192 °C) in 95% yield.
Finally sulfur nucleophiles were tested under conditions C
and D (Scheme 2 and Table 2). Thus, excellent results
were secured for both aliphatic and aromatic thiols that
gave sulfides 6a–c in excellent yields (entries 6–8,
Table 2) in the presence of substoichiometric amounts of
Bu4NCl. Cesium carbonate, always in the presence of
Bu4NCl, also was used successfully (entry 9). The heavily
fluorinated 1H,1H,2H,2H-perfluorodecanethiol gave no
complete reaction under method C (entry 10). However,
Acknowledgment
Financial support from Ministerio de Ciencia y Tecnología (Project
BQU 2002-04002) and Generalitat de Catalunya (Project
2001SGR00181 and ‘Distinció per a la Promoció de la Recerca
Universitaria’ (to M.M.-M) is gratefully acknowledged. R.M.S. was
incorporated into the research group through a ‘Ramón y Cajal’
contract (MCyT-FEDER/FSE). We thank one referee for a helpful
suggestion on the formation of dimethylamine.
Table 1 Replacement of Fluorine in Sulfonamide 3 with Aminesa
Entry
Yield of 4 (%)
4a (74)
R1
R2
Mp (°C)
Oil
Method
1
2
3
4
5
6
7
8
H
C6H13
C8H17
C12H25
C12H25
C2H5
A
A
B
A
A
A
A
A
4b (100)
4c (80)
C8H17
Oil
H
45
4c (0)
H
4d (93)
4e (53)
C2H5
35–39b
71–74
142–144
Oil
H
C6H5
4f (62)
CH3
C6H4-Cl-4
4g (59)
-(CH2CH2O)5CH2CH2-
a Method A: BuLi, THF. Method B: K2CO3, DMF, 160 °C (bath temperature).
b Picrate: mp 109–110 °C.
Synlett 2005, No. 3, 449–452 © Thieme Stuttgart · New York

LETTER
SNAr on 4-Fluorophenylsulfonamides
451
Table 2 Replacement of Fluorine in Sulfonamides 1 and 3 with Oxygen and Sulfur Nucleophilesa
Entry
1
Yield of 5–7 (%)
5a (61)
X-R
Bu4NCl (mol)
Mp (°C)
60–62
Method
O-C4H9
1
C
D
C
C
C
C
C
C
D
C
D
D
2
5b (83)
5b (80)b
5c (76)
O-C12H25
O-C12H25
O-CH2CH(Et)-C4H9
O-Ph
1
33–35
b
3
1
–
4
1
Oil
5
5d (83)
6a (87)
1
80–82
59–61
41–43
63–66
63–66
56–58
56–58
187–192
6
S-C3H7
0.01
0.06
1
7
6b (81)
6c (73)
S-C16H33
8
S-Ph
9
6c (61)
S-Ph
1
10
11
12
6d (80)b
6d (84)
7 (95)
S-CH2CH2-C8F17
S-CH2CH2-C8F17
S-CH2CH2-C8F17
1
0.01
0.1
a Method C: NaH. Method D: Cs2CO3. In both methods: Bu4NCl, THF.
b Conversion. Product not isolated.
(5) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(6) (a) Navidpour, L.; Karimi, L.; Amini, M.; Vosooghi, M.;
Shafiee, A. J. Heterocycl. Chem. 2004, 41, 201. (b) Wang,
C.-C.; Li, J. J.; Huang, H.-C.; Lee, L. F.; Reitz, D. B. J. Org.
Chem. 2000, 65, 2711. (c) You, F.; Twieg, R. J.
F
C8F17CH2CH2S
SO2
N
SO2
N
Tetrahedron Lett. 1999, 40, 8759. (d) Smith, W. J.; Scott
Sawyer, J. Tetrahedron Lett. 1996, 37, 299. (e) Miller, A.
O.; Furin, G. G. J. Fluorine Chem. 1995, 75, 169.
a
(7) (a) Koyama, H.; Boueres, J. K.; Han, W.; Metzger, E. J.;
Bergman, J. P.; Gratale, D. F.; Miller, D. J.; Tolman, R. L.;
MacNaul, K. L.; Berger, J. P.; Doebber, T. W.; Leung, K.;
Moller, D. E.; Heck, J. V.; Sahoo, S. P. Biorg. Med. Chem.
Lett. 2003, 13, 1801. (b) Zask, A.; Jirkovsky, I.; Nowicki, J.
W.; McCaleb, M. L. J. Med. Chem. 1990, 33, 1418.
N
N
SO2
SO2
N
N
O2S
O2S
F
C8F17CH2CH2S
(c) Markley, L. D.; Tong, Y. C.; Dulworth, J. K.; Steward,
D. L.; Goralski, C. T.; Johnston, H.; Wood, S. G.;
Vinogradoff, A. P.; Bargar, T. M. J. Med. Chem. 1986, 29,
427. (d) Idoux, J. P.; Madenwald, M. L.; Garcia, B. S.; Chu,
D.-L.; Gupton, J. T. J. Org. Chem. 1985, 50, 1876.
F
SCH2CH2C8F17
1
7
Scheme 3 Triple substitution. a) HSCH2CH2C8F17 (4.2 mol); condi-
tions D.
(8) Baxter, I.; Ben-Haida, A.; Colquhoun, H. M.; Hodge, P.;
Kohnke, F. H.; Williams, D. J. Chem.–Eur. J. 2000, 6, 4285.
(9) For examples with nitrogen nucleophiles see: (a) Pal, M.;
Madan, M.; Padakanti, S.; Pattabiraman, V. R.; Kalleda, S.;
Vanguri, A.; Mullangi, R.; Rao Mamidi, N. V. S.; Casturi, S.
R.; Malde, A.; Gopalakrishnan, B.; Yeleswarapu, K. R. J.
Med. Chem. 2003, 46, 3975. (b) Tollefson, M. B.;
References
(1) Moreno-Mañas, M.; Spengler, J. Tetrahedron 2002, 58,
7769.
Kolodziej, S. A.; Fletcher, T. R.; Vernier, W. F.; Beaudry, J.
A.; Keller, B. T.; Reitz, D. B. Bioorg. Med. Chem. Lett.
2003, 13, 3727. (c) Levin, J. I.; Chen, J. M.; Cheung, K.;
Cole, D.; Crago, C.; Delos Santos, E.; Du, X.; Khafizova, G.;
MacEwan, G.; Niu, C.; Salaski, E. J.; Zask, A.; Cummons,
T.; Sung, A.; Xu, J.; Zhang, Y.; Xu, W.; Ayral-Kaloustian,
S.; Jin, G.; Cowling, R.; Barone, D.; Mohler, K. M.; Black,
R. A.; Skotnicki, J. S. Biorg. Med. Chem. Lett. 2003, 13,
2799. (d) Steffan, R. J.; Ashwell, M. A.; Solvibile, W. R.;
Matelan, E.; Largis, E.; Han, S.; Tillet, J.; Mulvey, R.
Bioorg. Med. Chem. Lett. 2002, 12, 2963. (e) Morgan, T. K.
Jr.; Lis, R.; Lumma, W. C. Jr.; Nickisch, K.; Wohl, R. A.;
(2) For reviews on 15-membered triolefinic macrocycles of type
1 see: (a) Moreno-Mañas, M.; Pleixats, R.; Sebastián, R. M.;
Vallribera, A.; Roglans, A. ARKIVOC 2004, iv, 109;
available from http://www.arkat-usa.org. (b) Moreno-
Mañas, M.; Pleixats, R.; Sebastián, R. M.; Vallribera, A.;
Roglans, A. J. Organomet. Chem. 2004, 689, 3669.
(3) Compound 2a (72%): mp 230 °C. Compound 2b (40%): oil.
Compound 2c (65%): mp 84–85 °C.
(4) March, J. Advanced Organic Chemistry. Reactions,
Mechanism, and Structure, 4th ed.; Wiley-Interscience:
New York, 1992, Chap. 13, 641–676.
Synlett 2005, No. 3, 449–452 © Thieme Stuttgart · New York

452
E. Badetti et al.
LETTER
(12) When our work was finished a paper was published on
Phillips, G. B.; Gomez, R. P.; Lampe, J. W.; Di Meo, S. V.;
Marisca, A. J.; Forst, J. J. Med. Chem. 1990, 33, 1091.
(f) For example with oxygen nucleophile see: Levin, J. I.;
Du, M. T. Synth. Commun. 2002, 32, 1401. (g) For example
with sulfur nucleophile see ref. 9c.
similar results obtained with 2-fluoropyridine: Pasumansky,
L.; Hernández, A. R.; Gamsey, S.; Goralski, C. T.;
Singaram, B. Tetrahedron Lett. 2004, 45, 6417.
(13) Method C of Table 2; Typical Experiment
A solution of 3 (1.05 g, 4.55 mmol) and tetrabutyl-
ammonium chloride (1.52 g, 5.2 mmol) in anhyd THF
(5.5 mL) was added under argon via cannula to a stirred
suspension of sodium phenolate in anhyd THF (4 mL), made
from NaH (60% suspension in mineral oil, 0.30 g, 7.55
mmol) and phenol (0.52 g, 5.52 mmol). The mixture was
stirred overnight and MeOH (2 mL) was added. The solvents
were evaporated and the residue was taken in EtOAc. The
organic solution was washed with 5% aq NaOH, dried
(Na2SO4), and evaporated to afford a dark yellow oil that
crystallized upon standing (83%). It was recrystallized from
t-butyl methyl ether to afford pure 5d (52%); mp 80–82 °C.
IR (ATR): 3090, 2972, 2932, 2879, 1579, 1491, 1332, 1238,
1200, 1169, 1089, 1014, 934 cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.14 (t, J = 7.0 Hz, 3 H), 3.23 (q, J = 7.0 Hz, 4
H), 7.02 (d, J = 9.0 Hz, 2 H), 6.94–7.08 (m, 2 H), 7.21 (tt,
J = 6.9 and 1.2 Hz, 1 H), 7.40 (m, 2 H), 7.75 (d, J = 9.0 Hz,
2 H). 13C NMR (62.5 MHz, CDCl3): d = 14.2, 42.0, 117.6,
120.2, 124.8, 129.1, 130.1, 134.2, 155.3, 161.1. HRMS calcd
for C16H19NO3S: 305.1086; found: 305.1100.
(10) Compound 3, mp 39–40 °C, was prepared by reaction of 4-
fluorobenzenesulfonyl chloride with diethylamine in
CH2Cl2.
(11) Method A of Table 1. Typical Experiment:
A 1.6 M solution of n-BuLi in hexane (3.4 mL, 5.34 mmol)
was added dropwise into a solution of di-n-octyl amine (1.1
mL, 3.56 mmol) in anhyd THF (3 mL) cooled at –40 °C
(MeCN–liquid nitrogen bath). The mixture was stirred at
–40 °C for 15 min. Then, a solution of sulphonamide 3
(0.82 g, 3.56 mmol) in anhyd THF (5 mL) was added. The
mixture was stirred at r.t. for one day and evaporated. The
residue was partitioned between CHCl3 and diluted HCl, the
organic layer was dried (Na2SO4) and evaporated to afford
1.6 g (ca. 100%) of 4b as an ochre oil. IR (Attenuated Total
Reflectance, ATR): 2924, 2853, 1594, 1333, 1147 cm–1. 1H
NMR (250 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 6 H), 1.12
(t, J = 7.2 Hz, 6 H), 1.29 (m, 20 H), 1.57 (m, 4 H), 3.18 (q,
J = 7.2 Hz, 4 H), 3.26 (t, J = 7.1, 4 H), 6.56 (d, J = 9.1 Hz, 2
H), 7.57 (d, J = 9.1 Hz, 2 H). 13C NMR (62.5 MHz, CDCl3):
d = 14.2, 14.4, 22.7, 27.2, 29.4, 29.5, 31.9, 42.1, 51.1, 110.5,
124.7, 129.1, 150.8. Anal. Calcd for C26H48N2O2S: C, 68.98;
H, 10.69; N, 6.19; S, 7.08. Found: C, 68.79; H, 10.69; N
6.05; S, 6.74.
Good elemental analyses (at least three elements) were
secured for 5a–c, 6a–d, and 7.
(14) For recent examples on the use of cesium compounds in
related substitutions see the following references.
Good elemental analyses (at least three elements) were
secured for 4b,c,e–g (with 0.5 mol of H2O), and 4d (as
picrate, mp 109–110 °C). Product 4a: HRMS: m/z calcd for
C16H28N2O2S: 312.1871; found: 312.1867.
(a) CsOH: Varala, R.; Ramu, E.; Alam, M. M.; Adapa, S. R.
Synlett 2004, 1747. (b) Cs2CO3: Cui, S.-L.; Jiang, Z.-Y.;
Wang, Y.-G. Synlett 2004, 1829.
Synlett 2005, No. 3, 449–452 © Thieme Stuttgart · New York