Fluorous scavenger for parallel preparation of tertiary sulfonamides leading to secondary amines

Article abstract of DOI:10.1016/j.tetlet.2007.09.110

Alkylation of secondary sulfonamides by alkyl halides or alcohols (Mitsunobu reaction) is an efficient method for secondary amines preparation. However, its application to parallel chemistry is often difficult due to partial reaction. In this Letter, we propose a fluorous technique to bypass this problem. Thus, o-nitrobenzenesulfonamides were prepared and alkylated in parallel (Fukuyama method) with various alkyl halides or alcohols. Depending on the nature of the alkyl halide or alcohol, this step remained incomplete. A reactive fluorous alkyl iodide was then used to trap the unreacted sulfonamide allowing for a rapid and efficient fluorous solid-phase extraction (FSPE). Some examples of the isolated tertiary sulfonamides were converted in parallel to the corresponding secondary amines with good purity.

Full text of DOI:10.1016/j.tetlet.2007.09.110

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Tetrahedron Letters 48 (2007) 8138–8140
Fluorous scavenger for parallel preparation of tertiary
sulfonamides leading to secondary amines
*
´
Emmanuel Basle, Mickae¨l Jean, Nicolas Gouault, Jacques Renault and Philippe Uriac
UPRES EA 4090, Substances Liche´niques et Photoprotection, Universite´ de Rennes I,
Faculte´ des Sciences Biologiques et Me´dicales, 2, Av. du Pr. Le´on Bernard, 35043 Rennes, France
Received 28 June 2007; revised 11 July 2007; accepted 18 September 2007
Available online 21 September 2007
Abstract—Alkylation of secondary sulfonamides by alkyl halides or alcohols (Mitsunobu reaction) is an efficient method for
secondary amines preparation. However, its application to parallel chemistry is often difficult due to partial reaction. In this Letter,
we propose a fluorous technique to bypass this problem. Thus, o-nitrobenzenesulfonamides were prepared and alkylated in parallel
(Fukuyama method) with various alkyl halides or alcohols. Depending on the nature of the alkyl halide or alcohol, this step
remained incomplete. A reactive fluorous alkyl iodide was then used to trap the unreacted sulfonamide allowing for a rapid and
efficient fluorous solid-phase extraction (FSPE). Some examples of the isolated tertiary sulfonamides were converted in parallel
to the corresponding secondary amines with good purity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The parallel obtaining of pure secondary amines from
primary amines remains a problematic purpose in
organic synthesis.1 Reductive aminations or direct
alkylations of primary amines by alkyl halides may lead
to mixtures of unreacted primary amines, secondary and
tertiary amines whose separation remains difficult. A
solution to this problem can be provided by the use of
ortho- and/or para-nitrobenzenesulfonamides (nosyl
groups, Fukuyama method,2) whose alkylation is possi-
ble by alkyl halides or under Mitsunobu conditions.3
The compounds can be isolated as tertiary sulfonamides
and their nosyl part is quantitatively removed to lead
under mild conditions to secondary amines.4,5 In spite
of this advantage, incomplete alkylations may occur
and limit the use of this method to activated agents in
parallel syntheses. In response to this limitation, we pro-
pose here a rapid and efficient parallel method (Scheme
1) using a fluorous scavenger of the unreacted nosyl-
sulfonamide portion allowing for the parallel isolation
of pure tertiary sulfamides leading to secondary amines.
examples of nosylsulfonamide 4 with various alkyl
halides, using classical conditions of the Fukuyama
method (1.1 equiv of R2X, 2.2 equiv of K2CO3, 60 ꢁC,
20 h, DMF).5 Some of these attempts resulted in com-
plete reactions for activated R2X such as allyl bromide
and benzyl chloride or sterically unhindered alkyl
halides (1-bromo or 1-iodobutane). However, under
the same conditions, many alkylations of nosylamide 4
remained partial even with excessive R2X and increase
of the experiment duration. If this drawback is not an
obstacle for individualized compound preparation, it
requires a purification that clearly hinders its use in
parallel synthesis. In response to this problem, we
decided to trap the unreacted sulfonamide with a fluor-
ous alkyl iodide6 (Scheme 2).
The alkylation was initially attempted with C8F17CH2-
CH2I (1.1 equiv, 20 h) but revealed incomplete. The
use of C8F17CH2CH2CH2I (1.1 equiv added to the mix-
ture of sulfonamide, R2X and K2CO3 in excess in DMF)
was necessary to obtain a total alkylation of the remain-
ing starting material.7 The resulting fluorinated nosyl-
sulfonamide was then easily removed from the
reactional mixture by the use of a fluorous solid-phase
extraction leading to the isolated compound 4a–f. This
method was applied to other sulfonamides (nosylated
aniline4 5 and nosylated tryptamine8 6) and revealed
comparable results (Table 1). Even if the yields appear
variable, the purity, checked by TLC and HPLC, did
Our first attempts started with benzylamine 1 that was
converted to the corresponding 2-nitrobenzenesulfon-
amide4 4 (90%). We have carried on many alkylation
Keywords: FSPE; Secondary amines preparation; Parallel synthesis;
Fukuyama method, 2-Nitrobenzenesulfonamide.
*
Corresponding author. Tel.: +33 22323 48 66; fax: +33 22323 44
25; e-mail: Jacques.Renault@univ-rennes1.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.110

E. Basle´ et al. / Tetrahedron Letters 48 (2007) 8138–8140
8139
R2
R1
R1
N
R2
1) C8F17CH2CH2SH
R1
R1
R2X
H
Various
Secondary
Amines
1) I
C8F17
Ns
+
Primary
Amine
N
N
2)
or Mitsunobu
(R2OH)
aq. HCl 1 M
2) FSPE
H
Ns
Ns
N
R1
N
Ns
C8F17
Ns
Scheme 1.
1
1
1
1
Ns
Ns
R
Ns
Ns
R
R
H
R
i
ii
N
N
R
N
N
+
2
H
H
H
4-6
4a-6f
4-6
1-3
iii
iv
1
1
1
1, 4, 7: R1 = Ph-CH2-
2, 5, 8: R1 = Ph-
Ns
R
R
Ns
R
N
N
N
+
(CH2)2-
1
2
2
Ns
R
R
3, 6, 9: R1
=
R
N
C F
8
17
N
H
4a-6f
4a-6f
7-9
7-9
C F
8
17
Scheme 2. Reagents and conditions: (i) 2-nitrobenzenesulfonyl chloride (NsCl, 1.2 equiv), Et3N (1.2 equiv), CH2Cl2, rt, 2 h; (ii) R2X (1.1 equiv, a:
chlorobutane, b: 2-bromobutane, c: bromocyclopropane, d: bromocyclopentane, e: 2-bromopropane, f: 2-iodoethanol), K2CO3 (2.2 equiv), DMF,
60 ꢁC, 20 h; (iii) C8F17CH2CH2CH2I (1.1 equiv), DMF, 60 ꢁC, 20 h; (iv) FSPE (MeOH/H2O: 8/2).
Table 1. Yields (%) of the various sulfonamides obtained by alkylation and Mitsunobu reaction
R2X
R2OH
Ns
Ns
Ns
R2
Ns
R2
N
N
N
N
R2
R2
4a- f
4g-l
N
5a-
f
H
6a-f
Yield (%)
Yield (%)
59
a
Cl
44
82
79
72
73
66
g CH3A(CH2)AOH
h CH3AOH
Br
b
c
d
65
47
47
37
76
46
81
60
59
i
Br
OH
OH
j
Br
S
e
f
82
96
60
85
59
84
k
18
51
Br
OH
OH
O
HO
l
I
O
not reveal the presence of impurities. This result was
(nosylsulfonamide 4 in our work) and its alkylated
analogue 4g–l (Scheme 3). Its treatment, previously
described in Scheme 1 (1.1 equiv of C8F17CH2CH2CH2I
and K2CO3 in DMF for 20 h at 60 ꢁC), showed that
trapping of the starting material and its easy elimination
led to the pure sulfonamides 4g–l (Table 1). The purity
of the desired compounds was checked as presented
for compounds 4a–f and showed very satisfactory
results.
1
conforted by H and 13C NMR. Only the examples 4e,
5a and 5c showed the presence of small amounts of fluo-
rinated sulfonamide in HPLC.
The feasibility of a comparable parallel method was
then studied in the case of Mitsunobu reaction applied
to nosylsulfonamide 4. The procedure chosen was
described by Pelletier and Kincaid9 and used 1.2 equiv
of an alcohol, supported triphenylphosphine (1.5 equiv),
di-tert-butylazo-1,2-dicarboxylate (DBAD, 1.5 equiv) in
CH2Cl2 for 20 h.7 The parallel elimination of DBAD
and the supported triphenylphosphine by appropriate
treatment furnished a mixture of starting material
The parallel removal of the sulfonamide moiety giving
access to secondary amines was realized according to a
procedure previously described by Christensen et al.10
Some examples of our tertiary sulfonamides11

8140
E. Basle´ et al. / Tetrahedron Letters 48 (2007) 8138–8140
4. Cardullo, F.; Donati, D.; Fusillo, V.; Merlo, G.; Paio, A.;
Ns
Ns
Ns
Ph
Ph
Ph
N
H
4
N
R2
N
H
4
i
Salaris, M.; Solinas, A.; Taddei, M. J. Comb. Chem. 2006,
8, 834.
5. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
+
ii
4g-l
Scheme 3. Reagents and conditions: (i) R2OH [1.2 equiv, g: octan-1-ol,
h: methanol, i: propan-2-ol, j: 2-(3-thienyl)-ethanol, k: 2-(2-naphtyl)-
ethanol, l: diethyleneglycolmonomethylether], triphenylphosphine
polystyrene (1.5 equiv), DBAD (1.5 equiv), CH2Cl2, rt, 20 h; (ii)
TFA/CH2Cl2: 1/1, rt, 1 h.
6. For recent reviews on FSPE, see: (a) Zhang, W. Chem.
Rev. 2004, 104, 2531; (b) Zhang, W.; Curran, D. P.
Tetrahedron 2006, 62, 11837; For the use of fluorous
scavengers, see: (c) Lindsley, C. W.; Zhao, Z.; Leister, W.
H. Tetrahedron Lett. 2002, 43, 4225; (d) Zhang, W.;
Curran, D. P.; Hiu-Tung Chen, C. Tetrahedron 2002, 58,
3871; (e) Zhang, W.; Hiu-Tung Chen, C.; Nagashima, T.
Tetrahedron Lett. 2003, 44, 2065; (f) Lindsley, C. W.;
Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.;
Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J.
R.; Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem.
Lett. 2005, 15, 761; (g) Zhang, W.; Lu, Y. QSAR Comb.
Sci. 2006, 25, 728.
C F
8
17
1
1
H
Ns
R
R
i
N
N
R
+
2
2
R
S
4e, 4g, 5b or 6b
NO
2
ii
7. General procedure for synthesis and purification of tertiary
sulfonamides: (a) From alkyl halides R2X: Secondary
sulfonamide 4, 5 or 6 (1 equiv), K2CO3 (2.2 equiv), alkyl
halide (1.1 equiv) and DMF (1 mL) were stirred at 60 ꢁC
for 20 h. The iodide C8F17CH2CH2CH2I (1.1 equiv) was
added and the mixture was stirred at 60 ꢁC for 20 h. After
filtration of the K2CO3, the solution was concentrated
under reduced pressure and purified by FSPE. The identity
and purity of the compounds were evaluated by TLC,
HPLC, 1H and 13C NMR. (b) From alcohols R2OH:
Secondary sulfonamide 4 (1 equiv), alcohol (1.2 equiv) and
triphenylphosphine polystyrene (1.5 equiv) were placed in
CH2Cl2. The DBAD (1.5 equiv) in CH2Cl2 was added and
the mixture was stirred at room temperature for 20 h.
Then, TFA was added and the stirring was maintained for
1 h. After filtration of the resin, the mixture was concen-
trated under reduced pressure and the residue was
dissolved in DMF (1 mL). K2CO3 (1.1 equiv) and
C8F17CH2CH2CH2I (1.1 equiv) were added and the solu-
tion was stirred again at 60 ꢁC for 20 h. After removal of
the K2CO3, the mixture was concentrated under reduced
pressure to obtain a mixture of secondary and the tertiary
sulfonamide. The pure tertiary sulfonamide was purified
by FSPE. The identity and purity of the compounds were
H
1
R
N
H
2
, Cl
R
Scheme 4. Reagents and conditions: (i) C8F17CH2CH2SH (2.5 equiv),
Cs2CO3 (5 equiv), Et2O, rt, 2 h; (ii) aq. HCl (1 M) extraction.
(compounds 4e, 4g, 5b and 6b) were individually reacted
with a perfluorinated thiol in diethyl ether and led to
perfluorinated 2-nitrobenzenethioether and to the corre-
sponding secondary amines (Scheme 4). The latter were
extracted with aqueous hydrochloric acid and furnished
the desired ammonium salts in an average yield of 70%
and in good purity (>90%, controlled through TLC,
1
HPLC, H and 13C NMR).
In conclusion, this procedure aiming to trap the unre-
acted portion of starting material is suitable for parallel
alkylation of sulfonamides with diverse alcohols and
alkyl halides especially if these latter were little reactive.
Indeed, secondary amines were easily obtained in
variable yields but always with good purity.
1
evaluated by TLC, HPLC, H and 13C NMR. (c) FSPE:
The residue was then loaded onto a 5 g fluorous silica gel
cartridge (Silica gel 60 C8-reversed phase perfluorinated
35–70 lm, Fluka) which had been preconditioned in
methanol. The non-fluorous tertiary sulfonamides were
first eluted with 3 · 10 mL of MeOH/H2O (80/20).
Subsequent wash with 4 · 10 mL of diethyl ether allowed
the fluorous tertiary sulfonamides to be eluted. The
MeOH/H2O fractions were combined and concentrated
under reduced pressure. After washing with 10 mL of
methanol, the fluorous silica gel cartridge could be reused.
8. Murugesan, N.; Macor, J. E.; Gu, Z.; Fadnis, L. U.S.
Patent 2006063823, 2006.
Acknowledgement
The authors are very grateful to Bioproject-Biotech that
provided financial support.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.110.
9. Pelletier, J. C.; Kincaid, S. Tetrahedron Lett. 2000, 41, 797.
10. Christensen, C.; Clausen, R. P.; Begtrup, M.; Kristensen,
J. L. Tetrahedron Lett. 2004, 45, 7991.
11. General procedure for conversion of tertiary sulfonamides
into secondary amines: A mixture of a tertiary sulfonamide
(1 equiv), Cs2CO3 (5 equiv), C8F17CH2CH2SH (2.5 equiv),
in Et2O was stirred at room temperature for 2 h. After
elimination of the Cs2CO3 by filtration, the organic layer
was extracted with 1 M aqueous HCl and concentrated
under reduced pressure to obtain the final amine as its
hydrochloride salt.
References and notes
1. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785.
2. Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
3. Mitsunobu, O. Synthesis 1981, 1.