Catalytic coupling of N-benzylic sulfonamides with silylated nucleophiles at room temperature

Article abstract of DOI:10.1039/c0cc00765j

In the presence of 2-10 mol% of Tf₂NH, a range of N-benzylic sulfonamides smoothly react with allylic, propargylic, benzylic, or hydrido silanes at room temperature via sp³ carbon-nitrogen bond cleavage to afford structurally diverse products in moderate to excellent yields and with high chemo- and regioselectivity.

Full text of DOI:10.1039/c0cc00765j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Catalytic coupling of N-benzylic sulfonamides with silylated nucleophiles
at room temperaturew
Bai-Ling Yang and Shi-Kai Tian*
Received 5th April 2010, Accepted 30th June 2010
DOI: 10.1039/c0cc00765j
In the presence of 2–10 mol% of Tf2NH, a range of N-benzylic
sulfonamides smoothly react with allylic, propargylic, benzylic,
or hydrido silanes at room temperature via sp3 carbon–nitrogen
bond cleavage to afford structurally diverse products in moderate
to excellent yields and with high chemo- and regioselectivity.
ZnCl2/TMSCl.3d However, such a combination of double
Lewis acids proved to be ineffective in catalyzing the coupling
of N-benzylic sulfonamides with silylated nucleophiles. To find
an effective catalyst, we evaluated a number of Brønsted and
Lewis acids in the model reaction of N-toluenesulfonyl benz-
hydrylamine (1a) with allyltrimethylsilane (2a) in dichloro-
methane at room temperature (Table 1, entries 1–7). While the
coupling reaction proceeded very sluggishly with many other
acidic catalysts, the use of bis(trifluoromethanesulfonyl)imide
(Tf2NH) resulted in the formation of product 3a in 57% yield
(Table 1, entry 3). It is noteworthy that Tf2NH has been
reported to react with allylic silane 2a to generate Tf2N(TMS)
that serves as the actual acidic catalyst.4,5 The efforts to
enhance yield proved fruitless by replacing dichloromethane
with chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile,
or tetrahydrofuran (Table 1, entries 8–12) and by replacing the
toluenesulfonyl group of sulfonamide 1a with another sulfonyl
group, an acyl group, or an alkoxycarbonyl group (Table 1,
entries 13–18). Finally, the yield was increased to 79% by
employing 2.0 equiv. of allylic silane 2a in the reaction to
suppress the unwanted alkylation of product 3a with sulfonamide
1a (Table 1, entry 19).6
Benzylic halides are traditionally employed for the benzylic
alkylation of nucleophiles under acidic conditions to construct
carbon–carbon and carbon–heteroatom bonds through the
cleavage of sp3 carbon–halogen bonds to generate benzyl
cation intermediates (e.g. the Friedel–Crafts reaction).1
Nevertheless, strongly acidic hydrogen halides are inevitably
generated as byproducts in the reaction and are able to
promote undesired side reactions such as elimination and
overalkylation. In this regard, N-benzylic sulfonamides have
recently emerged as useful benzylic alkylating agents to avoid
such problems by yielding primary sulfonamides as byproducts,
and consequently, to enhance reaction selectivity and efficiency.
Certain Brønsted2 and Lewis acids3 have been demonstrated
to be able to catalyze the coupling of N-benzylic sulfonamides
with protic nucleophiles, such as aromatics, active methylene
compounds, thiols, thiocarboxylic acids, and sulfinic acids,
which involves the catalytic cleavage of the sp3 carbon–nitrogen
bonds to generate benzyl cation intermediates (Scheme 1).
Herein, we wish to report an unprecedented coupling reaction
of N-benzylic sulfonamides with silylated nucleophiles
through acid-catalyzed sp3 carbon–nitrogen bond cleavage at
room temperature.
A range of N-bisbenzylic and N-monobenzylic sulfonamides
coupled with allylic silane 2a in the presence of 2–10 mol% of
Tf2NH at room temperature to give the corresponding alkene
products in moderate to excellent yields (Table 2, entries 1–8).
Substituted allyltrimethylsilanes 2b and 2c also served as
suitable substrates to couple with N-benzylic sulfonamides
under similar reaction conditions (Table 2, entries 9–11).
It is noteworthy that electron-rich aromatic rings and
carbon–carbon triple bonds were well tolerated, and no
rearrangement was observed for the carbon–carbon double
bonds in the alkene products under the acidic reaction
conditions.7 Moreover, excellent chemoselectivity was
observed for the cleavage of the sp3 carbon–nitrogen bonds
in N-benzylic N-alkyl sulfonamides. For example, secondary
amine derivative 1i0 exclusively donated its 4-methoxybenzyl
group in the coupling reaction with allylic silane 2c in
the presence of 10 mol% of Tf2NH at room temperature
(Table 2, entry 12).
We discovered recently a highly efficient alkylation reaction
of protic carbon and sulfur nucleophiles with N-benzylic
sulfonamides in the presence of a catalytic amount of
The reaction of optically active N-benzylic sulfonamide 1f
(95% ee) with allylic silane 2a under similar conditions
afforded alkene 3f in nearly racemic form (Table 2, entry 6).
This result suggests that a benzyl cation is generated from the
corresponding N-benzylic sulfonamide through catalytic sp3
carbon–nitrogen bond cleavage and consequently, the coupling
reaction is confirmed to proceed via an SN1 mechanism as
shown in Scheme 1.2,3
Scheme
1 Reactions of N-benzylic sulfonamides with various
nucleophiles.
Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, China. E-mail: tiansk@ustc.edu.cn;
Fax: (+86) 551-360-1592; Tel: (+86) 551-360-0871
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H and 13C NMR
spectra for products. See DOI: 10.1039/c0cc00765j
Next, a few other types of silylated carbon nucleophiles were
examined with regard to their reactivity toward N-benzylic
c
6180 Chem. Commun., 2010, 46, 6180–6182
This journal is The Royal Society of Chemistry 2010

View Article Online
Table 1 Optimization of reaction conditionsa
Table 2 Catalytic coupling of N-benzylic sulfonamides with allylic
silanesa
Yield
(%)b
Entry 1a–1ag
X
Catalyst
Solvent
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1ab
1ac
1ad
1ae
1af
1ag
1a
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H2SO4
TfOH
Tf2NH
TMSOTf
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
Time/ Yield
(%)b
Trace
57
Trace
Trace
0
Entry Sulfonamide
1
2
Product
h
1a 2a
3a 24
79
InCl3ꢀ4H2O CH2Cl2
SnCl4ꢀ5H2O CH2Cl2
14
19
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
CHCl3
(ClCH2)2 45
9
2
1b 2a
3b 22
88
10
11
12
13
14
15
16
17
18
19c
EtOAc
MeCN
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
14
0
22
26
19
Trace
0
4-O2NC6H4SO2
2,4,6-Me3C6H2SO2 Tf2NH
3
4
5
1c 2a
1d 2a
1e 2a
3c 30
3d 24
52
70
91
2-thienylsulfonyl
n-C8H17SO2
PhCO
PhCH2OCO
Ts
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
0
79
a
Reaction conditions: amine derivative 1a–1ag (0.20 mmol), allylic
silane 2a (0.24 mmol), catalyst (10 mol%), solvent (0.30 mL), rt, 24 h.
b
Isolated yield. c 0.40 mmol of allylic silane 2a was used.
3e
3
sulfonamides under acidic conditions. The desilylative coupling
of propargylic silane 4a with sulfonamide 1g proceeded
smoothly in the presence of 10 mol% Tf2NH at room
temperature to give allene 5a in a moderate yield (eqn (1)).
Notably, a highly regioselective Friedel–Crafts reaction rather
than a desilylative coupling reaction took place between
benzylic silane 6a and sulfonamide 1a under similar reaction
conditions (eqn (2)), and significantly, the trimethylsilyl group
preserved in the resulting Friedel–Crafts product can serve as a
handle for further synthetic elaboration.8,9
6
1f 2a
3f
4
1
81
7
1g 2a
1h 2a
3g
97
45
8c
3h 24
ð1Þ
9c
1g 2b
1a 2c
3i
4
95
83
10
3j 12
3k 12
11
1i 2c
1i0 2c
75
71
12
3k 5
ð2Þ
a range of N-bisbenzylic and N-monobenzylic
a
Reaction conditions: sulfonamide 1 (0.20 mmol), allylic silane 2
(0.40 mmol), Tf2NH (10 mol%), dichloromethane (0.30 mL), rt.
Finally,
sulfonamides were reduced smoothly with triethylsilane
(1.2 equiv.) in the presence of 2–10 mol% of Tf2NH at room
temperature to give the corresponding products in good to
excellent yields (Table 3). It is noteworthy that the sulfonamido
groups were removed cleanly without reduction of the
carbon–carbon multiple bonds present in N-benzylic
sulfonamides 1g and 1h (Table 3, entries 4 and 5).
b
c
Isolated yield. 2 mol% of Tf2NH was used.
In summary, we have developed an unprecedented coupling
reaction of N-benzylic sulfonamides with silylated nucleo-
philes through catalytic sp3 carbon–nitrogen bond cleavage
under acidic conditions. In the presence of 2–10 mol% of
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6180–6182 6181

View Article Online
Table 3 Catalytic reduction of N-benzylic sulfonamides with triethyl-
silanea
Chem., 2008, 3623; (c) D. Enders, A. A. Narine, F. Toulgoat and
T. Bisschops, Angew. Chem., Int. Ed., 2008, 47, 5661; (d) C.-R. Liu,
M.-B. Li, D.-J. Cheng, C.-F. Yang and S.-K. Tian, Org. Lett., 2009,
11, 2543; (e) Q.-L. He, F.-L. Sun, X.-J. Zheng and S.-L. You,
Synlett, 2009, 1111; (f) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He and
S.-L. You, Eur. J. Org. Chem., 2010, 47.
3 (a) J. Esquivias, R. Gomez-Arrayas and J. C. Carretero, Angew.
Chem., Int. Ed., 2006, 45, 629; (b) I. Alonso, J. Esquivias, R. Gomez-
Arrayas and J. C. Carretero, J. Org. Chem., 2008, 73, 6401;
(c) C.-R. Liu, M.-B. Li, C.-F. Yang and S.-K. Tian, Chem. Commun.,
2008, 1249; (d) C.-R. Liu, M.-B. Li, C.-F. Yang and S.-K. Tian,
Chem.–Eur. J., 2009, 15, 793.
4 For examples, see: (a) B. Mathieu and L. Ghosez, Tetrahedron Lett.,
1997, 38, 5497; (b) N. Kuhnert, J. Peverley and J. Robertson,
Tetrahedron Lett., 1998, 39, 3215; (c) K. Ishihara, Y. Hiraiwa and
H. Yamamoto, Synlett, 2001, 1851; (d) B. Mathieu and L. Ghosez,
Tetrahedron, 2002, 58, 8219; (e) M.-J. Tranchant, C. Moine,
R. B. Othman, T. Bousquet, M. Othman and V. Dalla, Tetrahedron
Lett., 2006, 47, 4477; (f) K. Takasu, N. Hosokawa, K. Inanaga and
M. Ihara, Tetrahedron Lett., 2006, 47, 6053.
5 In sharp contrast, only a trace amount of product 3a was observed
by thin layer chromatography (TLC) analysis for the reaction in the
presence of 10 mol% of TfOH (Table 1, entry 2), a stronger
Brønsted acid relative to Tf2NH (pKa values in acetic acid: 4.2
and 7.8, respectively). Both Brønsted acids have been reported to
serve as precatalysts that react with allylic silane 2a to generate the
corresponding actual catalysts, TfO(TMS) and Tf2N(TMS). Signifi-
cantly, Tf2N(TMS) has been demonstrated to exhibit stronger
Lewis acidity relative to TfO(TMS) according to 29Si NMR
analysis. See ref. 4a and d.
6 The reaction of allylic silane 2a with benzhydryl bromide, a
conventional benzylic alkylating agent, afforded product 3a in
53% yield in the presence of 10 mol% of Tf2NH at room tempera-
ture. Byproduct TMSBr was generated in this reaction and could
promote undesired side reactions that consumed product 3a. For
examples of the reaction of allylic silanes with benzylic halides under
acidic conditions, see: (a) Y. Morizawa, S. Kanemoto, K. Oshima
and H. Nozaki, Tetrahedron Lett., 1982, 23, 2953; (b) H. Mayr and
R. Pock, Tetrahedron, 1986, 42, 4211; (c) G. Hagen and H. Mayr,
J. Am. Chem. Soc., 1991, 113, 4954; (d) J.-P. Dau-Schmidt and
H. Mayr, Chem. Ber., 1994, 127, 205; (e) H. Mayr, G. Gorath and
B. Bauer, Angew. Chem., Int. Ed. Engl., 1994, 33, 788.
Time/
h
Yield
(%)b
Entry
Sulfonamide
Product
1
2
1a
1b
8a
8b
5
2
93
98
3c
1c
8c
2
99
4
5
1g
1h
8d
8e
1
8
98
73
6
8f
48
71
1j
a
Reaction conditions: sulfonamide 1 (0.20 mmol), Et3SiH (0.24 mmol),
b
Tf2NH (10 mol%), dichloromethane (0.30 mL), rt. Isolated yield.
c
2 mol% of Tf2NH was used.
Tf2NH,
a range of N-bisbenzylic and N-monobenzylic
sulfonamides smoothly react with allylic, propargylic,
benzylic, or hydrido silanes at room temperature to afford
structurally diverse products in moderate to excellent yields
and with high chemo- and regioselectivity. This study adds a
useful entry to the synthetic applications of sp3 carbon–nitrogen
bond cleavage.
7 However, a highercatalyst loading and prolonged reaction time
resulted in the rearrangement of 1,1-disubstituted carbon–carbon
double bonds. For example, the reaction of sulfonamide 1g with
allylic silane 2b proceeded in the presence of 10 mol% of Tf2NH at
room temperature for 6 h to afford a 9 : 91 mixture of product 3i and
(1E)-1,3-diphenyl-5-methyl-1,4-hexadiene (3i0).
8 For reviews, see: (a) I. Fleming, A. Barbero and D. Walter,
Chem. Rev., 1997, 97, 2063; (b) G. L. Larson, J. Organomet. Chem.,
1992, 422, 1.
We are grateful for the financial support from the National
Natural Science Foundation of China (20972147 and 20732006),
the National Basic Research Program of China (973 Program
2010CB833300), and the Chinese Academy of Sciences.
Notes and references
1 For a review, see: G. A. Olah, R. Krishnamurti and G. K. Surya, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, vol. 3, p. 293.
2 (a) M. R. Seong, H. J. Lee and J. N. Kim, Tetrahedron Lett., 1998,
39, 6219; (b) H.-H. Li, D.-J. Dong and S.-K. Tian, Eur. J. Org.
9 The reaction of vinyltriphenylsilane with sulfonamide 1a was very
sluggish in the presence of 10 mol% of Tf2NH at room temperature.
By contrast, a complex mixture was obtained from the reaction of
trimethyl(phenylethynyl)silane with sulfonamide 1a under similar
conditions.
c
6182 Chem. Commun., 2010, 46, 6180–6182
This journal is The Royal Society of Chemistry 2010