Probing the amino-end reactivity of sulfonimidamides

Article abstract of DOI:10.1055/s-2008-1078014

The amino terminus of sulfonimidamides was functionalized through a Mitsunobu reaction. The new sulfonimidamides were engaged in oxidative reactions to provide N-heterocycles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078014

LETTER
2253
Probing the Amino-End Reactivity of Sulfonimidamides
Reactivity of
S
t
ulfoni
é
Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire (FR 2769),
Université Pierre et Marie Curie-Paris 6, C. 229, 4 Place Jussieu, 75005 Paris, France
Fax +33(1)44277360; E-mail: louis.fensterbank@upmc.fr; E-mail: emmanuel.lacote@upmc.fr; E-mail: max.malacria@upmc.fr.
Received 15 May 2008
as a nucleophile and/or radical partner. In this Letter, we
report our findings.
Abstract: The amino terminus of sulfonimidamides was function-
alized through a Mitsunobu reaction. The new sulfonimidamides
were engaged in oxidative reactions to provide N-heterocycles.
We examined first the Mitsunobu reaction of sulfonimida-
mides (Scheme 1), in which the nitrogen atom should be-
have as a nucleophile (Table 1).
Key words: aminations, diastereoselectivity, iodine, Mitsunobu re-
action, sulfur
DIAD, Ph3P
R1
N O
R1
R1
1a–e
N
O
ROH
Sulfonimidamides are chiral analogues of sulfonamides
(Figure 1), which have been introduced in the 1960s and
1970s.1 Since those pioneering reports, sulfonimidamides
have been introduced for medicinal chemistry purposes.2
The more recent development of metal-mediated nitro-
gen-atom introductions has triggered renewed interest in
those molecules.3 Indeed, their inherent chirality is an ap-
pealing feature in the quest for better nitrogen sources.4
S
R
S
R1
N
NH
R2
THF, 0 °C
R2
2a–i
Scheme 1
In a typical reaction, sulfonimidamide 1a was reacted
with butenol in the presence of diisopropyl azodicarboxy-
late (DIAD) and triphenylphosphine in cold THF. Grati-
fyingly, the substituted sulfonimidamide 2b was isolated
in acceptable yield (56%, Table 1, entry 2), thus showing
that the nitrogen was nucleophilic enough to react under
Mitsunobu conditions. The yields were generally around
70%, but dropped when a secondary alcohol was used
(Table 1, entry 7). The reaction was limited to sulfonimi-
damides with withdrawing groups attached to the second
nitrogen (Table 1, entries 9 and 10). This situation is rem-
iniscent of results in the aziridinations, for which similar
electronic effects were observed.6,7 Finally, N-substituted
sulfonimidamides reacted smoothly (Table 1, entry 11).
In fact, some of the N,N-disubstituted products were iso-
lated as byproducts during the reactions of 1a.
R2
R1
sulfonimidamide
N
O
O
O
S
S
R1
NH2
NH2
Figure 1
As part of our program devoted to the organic chemistry
of sulfur,5 we have used the stereogenic sulfur atom of sul-
fonimidamides to build chiral nitrenes for asymmetric
aziridinations.6 The latter are more reactive than their sul-
fonamide-based equivalents, but led to relatively poor di-
astereoselectivities. This latter fact was independently
confirmed by Dauban and Dodd’s group, who demon-
strated that double induction (with chiral catalysts) led to
consistently high selectivities.7 Dauban and Dodd ele-
gantly broadened the scope of this enantiocontrolled ni-
trogen insertion to asymmetric C–H insertions.8
With our functionalized sulfonimidamides in hand, we de-
cided to examine whether N-centered radicals could be
generated and reacted (Scheme 2, Table 2).
R1
R1
N
O
R1
R1
N
O
DIB, I2
Nonetheless, as was expected, the replacement of one ox-
ygen of sulfonamides with a nitrogen substituent led to
some changes in reactivity. While some were favorable –
such as the enhanced reactivity of sulfonimidamide ni-
trenes – some were less favorable. For example, it was not
possible to obtain nitrenes without electron-withdrawing
moieties attached to the unreactive nitrogen. We thus de-
cided to assess the scope of eligible reactions involving
the nitrogen terminus of sulfonimidamides. In particular,
we were interested in probing the behavior of this nitrogen
S
hν
S
NH
N
DCE, r.t.
*
I
Scheme 2
The suitably substituted sulfonimidamides were oxidized
using the (diacetoxyiodo)benzene (DIB)/I2 system9 with
the aim of generating the corresponding N-centered radi-
cals. The reactions were particularly efficient for mono-
substituted olefins (Table 2, entries 1, 2, and 5).
Unfortunately, no diastereoselectivity was observed in
any of those reactions. Furthermore, all the cyclized com-
pounds included an extra iodine atom.
SYNLETT 2008, No. 15, pp 2253–2256
1
5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078014; Art ID: D15908ST
© Georg Thieme Verlag Stuttgart · New York

2254
S. Azzaro et al.
LETTER
Table 2 Iodine-Mediated Cyclizations of Sulfonimidamides
Table 1 Mitsunobu Reactions of Sulfonimidamides
Entry Starting
material
Product
Yield (%) ds
Entry Starting material
Product
Yield (%)
43
O
NBz
O
O
O
O
O
O
O
NBz
O
S
1
2
3
4
5
6
7
S
S
S
S
S
S
S
N
N
N
N
Ph
p-Tol
N
H
p-Tol
NH2
p-Tol
S
N
1
2
3
4
2c
2e
2f
85
48
54
79
60:40
1a
O
O
O
O
2a
*
I
O
O
O
O
O
O
NBz
NBz
NH2
S
S
S
S
S
S
56
68
76
75
69
20
3a
p-Tol
N
H
2
3
4
3
p-Tol
O
Ph
1a
2b
p-Tol
S
N
a
NBz
–
NBz
NH2
*
I
p-Tol
N
H
p-Tol
3b
1a
2c
O
NBz
Ph
NBz
NH2
p-Tol
S
N
a
p-Tol
N
H
–
p-Tol
*
I
1a
2d
NBz
3b
NBz
NH2
O
p-Tol
N
H
t-Bu
t-Bu
p-Tol
p-Tol
S
N
1a
2h
50:50
50:50
2e
*
NBz
NBz
NH2
I
p-Tol
N
H
3
3c
p-Tol
O
1a
2f
N
p-Tol
S
N
NBz
NBz
NH2
O
*
5
2j
92
p-Tol
N
H
Cy
p-Tol
I
Ph
1a
2g
Ph
t-Bu
N
t-Bu
N
3d
O
O
a A mixture of all possible diastereomers was isolated.
O
8
60
O
S
S
p-Tol
N
H
3
p-Tol
NH2
presumably generated through oxidation of the sulfon-
imidamide by the hypervalent iodine derivative. The ni-
trene chemistry of sulfonimidamides tells us that such an
outcome is possible.
1b
2h
O
O
O
NPh
S
S
S
9
Degradation
Degradation
–
–
p-Tol
NH2
On the other hand, when only iodine was added to the so-
lution, the same products were obtained, albeit in low
yield (Table 3, entry 4). In this case, the products can only
arise from an ionic reaction. Overall, we cannot definitely
discard one of the two mechanisms, which may coexist.
That said, because the reactions were faster upon irradia-
tion, a dominant radical pathway seems the most likely.
1c
NBu
NH2
10
p-Tol
1d
NBz
NHBu
O
NBz
S
11
100
p-Tol
p-Tol
NBu2
1e
2i
In conclusion, we have extended the number of reactions
compatible with sulfonimidamide moieties. The ste-
reochemical outcomes of those processes were rather dis-
appointing. Work to increase the chiral transfer from
sulfur as well as identify other transformations applicable
to sulfonimidamides is pursued in our laboratory and we
will report on this in due course.
We wondered whether the reaction followed a radical
pathway, or an alternative electrophilic iodocyclization.10
In order to ascertain the exact mechanism, we ran several
control experiments with sulfonimidamides 2c and 2j
(Table 3).
The optimal yields were obtained when iodine and DIB
were present, and when the reaction was irradiated. Re-
moval of iodine was fatal to the reactivity (Table 3, entry
2). When either DIB or light was omitted, the conversions
were much poorer, and starting material was recovered
General Procedure for the Mitsunobu Reaction
Triphenylphosphine (1.5 equiv) and the alcohol (2 equiv) were add-
ed to a solution of sulfonimidamide (1 equiv) in THF at 0 °C. Diiso-
(Table 3, entries 3 and 5). Those reactions hint at a radical propyl azodicarboxylate (1.4 equiv) was then added dropwise, and
the reaction mixture was slowly warmed to r.t. and left overnight.
mechanism featuring homolytic cleavage of an N–I bond
Synlett 2008, No. 15, 2253–2256 © Thieme Stuttgart · New York

LETTER
Reactivity of Sulfonimidamides
2255
Table 3 Control Experiments
Entry
Starting material
Conditions
DIB, I2, hn, 1 h
DIB, hn, 1.5 h
I2, hn, 1 h
Product, yield (%)
Observation
1
2
3
4
5
6
7
2c
2c
2c
2c
2c
2j
2j
3a, 85
–
–
Recovered starting material
Starting material (44%)
Starting material (47%)
3a, 32
3a, 33
–
I2, 1h
DIB, 1 h
Starting material (50%) + degradation
DIB, I2, hn, 1 h
DIB, I2, 1 h
3d, 92
3d, 70
–
Some starting material
After concentration in vacuo, the crude mixture was purified by
flash chromatography.
Acknowledgment
We thank Université Pierre et Marie Curie, CNRS, IUF, and ANR
(grant 06_BLAN0309 ‘Radicaux Verts’) for funding.
Compound 2c
Colorless oil. IR (diamond): 3066, 2924, 1604 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.64 (quin, J = 7.0 Hz, 2 H, CH2CH2N), 2.07 (q,
J = 7.0 Hz, 2 H, CH2CH=), 2.41 (s, 3 H, ArMe), 2.88–2.93 (m, 1 H,
CHHN), 3.10–3.15 (m, 1 H, CHHN), 4.94–5.01 (m, 2 H, =CH2),
5.65–5.75 (m, 1 H, =CH), 7.30–7.49 (m, 6 H, Ph + NH), 7.87 (d,
J = 8.1 Hz, 2 H, Tol), 8.13 (d, J = 8.1 Hz, 2 H, Tol). 13C NMR (100
MHz, CDCl3): d = 21.5 (ArMe), 28.7 (CH2CH2), 30.5 (CH2CH2),
41.2 (CH2N), 115.6 (=CH2), 127.2 (CH arom.), 127.9 (CH arom.),
129.4 (CH arom.), 129.8 (CH arom.), 132.1 (CH arom.), 135.6 (C
arom.), 136.2 (C arom.), 136.9 (CH arom.), 144.2 (CS), 172.9
(C=O). HRMS: m/z calcd for C19H23N2O2S [MH+]: 343.1480;
found: 343.1496. Anal. Calcd (%) for C19H22N2O2S (342.46 g·mol–1):
C, 66.64; H, 6.48; N, 8.18. Found: C, 66.44; H, 6.58; N, 8.19.
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General Procedure for the DIB-Mediated Cyclizations
(Diacetoxyiodo)benzene (3 equiv) and I2 (1.2 equiv) were added to
a solution of sulfonimidamide in 1,2-dichloroethane. The mixture
was irradiated at r.t. with a tungsten lamp (300 W) for 1 h under an
argon atmosphere. After completion, the mixture was poured into
sat. aq Na2S2O3 and then extracted with CH2Cl2. The combined or-
ganics were dried over Na2SO4. After concentration in vacuo, the
crude mixture was purified by flash chromatography.
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Compound 3a
Two diastereomers, colorless oils.
1
Diastereomer 1: IR (diamond): 3063, 2924, 1718, 1631 cm–1. H
NMR (400 MHz, CDCl3): d = 1.77–1.82 (m, 1 H, NCH2CHH),
1.91–2.04 (m, 2 H, NCH2CHH + CHCHH), 2.11–2.16 (m, 1 H,
CHCHH), 2.43 (s, 3 H, ArMe), 3.11–3.19 (m, 2 H, NCH2), 3.43 (B
of ABX, J = 9.4, 9.4 Hz, 1 H, CHHI), 3.70 (B of ABX, J = 9.4, 2.5
Hz, 1 H, CHHI), 4.58–4.62 (m, 1 H, CHN), 7.35–7.55 (m, 5 H, Ph),
7.96 (d, J = 8.1 Hz, 2 H, Tol), 8.16 (d, J = 8.1 Hz, 2 H, Tol). 13C
NMR (100 MHz, CDCl3): d = 12.4 (CH2I), 21.6 (ArMe), 24.3
(CH2CH2), 31.4 (CH2CH2), 48.8 (CH2N), 61.9 (CHN), 127.8 (CH
arom.), 128.0 (CH arom.), 129.4 (CH arom.), 130.0 (CH arom.),
132.1 (CH arom.), 135.2 (C arom.), 135.7 (C arom.), 144.4 (CS),
172.8 (C=O). HRMS: m/z calcd for C19H22N2O2SI [MH+]:
469.0447; found: 469.0461. Anal. Calcd (%) for C19H21N2O2SI
(468.35 g·mol–1): C, 48.72; H, 4.52; N, 5.98. Found: C, 49.04; H,
4.51; N, 5.71.
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Diastereomer 2 has similar signals. Full characterization will be re-
ported in a forthcoming full paper.
Synlett 2008, No. 15, 2253–2256 © Thieme Stuttgart · New York

2256
S. Azzaro et al.
LETTER
(9) (a) Arencibia, M. T.; Freire, R.; Perales, A.; Rodriguez, M.
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DIB-mediated oxidation of sulfonamides, see: (b) Lu, H.;
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Synlett 2008, No. 15, 2253–2256 © Thieme Stuttgart · New York

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