2-(Trimethylsilyl)ethanesulfonyl amide as a new ammonia equivalent for palladium-catalyzed amination of aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.05.099

2-(Trimethylsilyl)ethanesulfonyl amide (SES-NH₂) is an ammonia equivalent for the palladium-catalyzed amination of aryl bromides and aryl chlorides. Using these amine derivatives, it has been observed that anilines and anilines with sensitive functional groups can be readily prepared.

Full text of DOI:10.1016/j.tetlet.2008.05.099

Tetrahedron Letters 49 (2008) 4585–4587
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-(Trimethylsilyl)ethanesulfonyl amide as a new ammonia equivalent
for palladium-catalyzed amination of aryl halides
b,c,
Prakash Anjanappa a, Dibakar Mullick a, Kumaravel Selvakumar a, , Manickam Sivakumar
*
*
a Synthetic Chemistry, Syngene International Ltd, Biocon Park, Plot 2 and 3, Jigani Link Road, Bommasandra Industrial Area, Bangalore 560 099, India
b Department of Pharmaceutical Engineering and Technology, Bharathidasan Institute of Technology, Bharathidasan University, Tiruchirappalli 620 024, India
c School of Chemical and Environmental Engineering, University of Nottingham (Malaysia campus), Semenyih 43500, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Trimethylsilyl)ethanesulfonyl amide (SES-NH2) is an ammonia equivalent for the palladium-catalyzed
amination of aryl bromides and aryl chlorides. Using these amine derivatives, it has been observed that
anilines and anilines with sensitive functional groups can be readily prepared.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 26 December 2007
Revised 21 May 2008
Accepted 21 May 2008
Available online 27 May 2008
Keywords:
Palladium catalysis
Ammonia surrogates
Cross-coupling
2-(Trimethylsilyl)ethanesulfonyl amide
During the past few years, great progress has been made in the
development of the transition metal-catalyzed amination of aryl
halides. Despite the existence of copper- and nickel-catalyzed ver-
sions of this reaction, palladium remains the metal of choice for
this transformation. This is due principally to the higher efficiency
of palladium complexes in aryl amination, benefiting from devel-
opments in related palladium-catalyzed cross-coupling reac-
tions.1–3
As a result, a wide variety of arylamines can now be prepared
efficiently using this methodology. While a variety of amines and
other nitrogen nucleophiles undergo this reaction in the presence
of a base, ammonia does not form exclusively primary arylamines.4
Thus, reactions have been conducted with ammonia surrogates.
Allylamine was used as an ammonia equivalent and the allyl group
from the resulting aryl alkyl amine was conveniently cleaved using
methanesulfonic acid and palladium on carbon.5
Benzophenone imine has frequently been used as an effective
ammonia equivalent. The coupling reactions with this imine are
high yielding and can be performed under extremely mild reaction
conditions. Moreover, the resulting N-aryl imines can be cleaved
using several orthogonal methods that are compatible with a vari-
ety of protecting groups.6 The groups of Hartwig and Buchwald
independently reported inexpensive silyl reagents such as
(LiN(SiMe3)2) and Ph3SiNH2 as ammonia equivalents for the
palladium-catalyzed amination and the resulting aryl silylamines
were easily deprotected.7 The above situation necessitates using
a stable ammonia surrogate for the amination, and it is also impor-
tant that the resulting aminated compound should be stable during
further transformations. Toluene sulfonamides have been used as
an ammonia surrogate for the palladium-catalyzed amination.8
Unfortunately, the resulting sulfonamide requires strong acidic
conditions for its cleavage. In the search for other suitable and sta-
ble ammonia surrogates we found that 2-(trimethylsilyl)etha-
nesulfonyl amide (SES-NH2) is an ammonia surrogate for
palladium-catalyzed amination (Scheme 1).
Weinreb developed the 2-(trimethylsilyl)ethanesulfonyl group
for the protection of amines. This sulfonyl protection can be re-
moved under mild conditions using a fluoride source. The fluoride
ion attacks the silicon atom which leads to b-elimination and this
releases the deprotected amine and volatile products such as flu-
orotrimethylsilane, ethylene, and sulfur dioxide.9 SES-Cl can be
prepared from vinyltrimethylsilane by free-radical addition of so-
dium bisulfite to the double bond catalyzed by tert-butyl perb-
enzoate and the resulting sulfonate can be transformed directly
O
O
H
S
X
N
SiMe3
Me3Si
NH2
S
R
R
O
O
Pd(OAc)2, Xantphos
Cs2CO3, Dioxane, 100 o
C
* Corresponding authors. Tel.: +60 3 8924 8156; fax: +60 3 8924 8017 (M.S.).
E-mail addresses: selva.kumar@syngeneintl.com (K. Selvakumar), Sivakumar.
Manickam@nottingham.edu.my (M. Sivakumar).
Scheme 1. Synthesis of SES-protected anilines.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.099

4586
P. Anjanappa et al. / Tetrahedron Letters 49 (2008) 4585–4587
Table 1
Table 2
SES-NH2 as an ammonia surrogate in the palladium-catalyzed coupling of aryl and
heterocyclic bromides
SES-NH2 as an ammonia surrogate in the palladium-catalyzed coupling of aryl and
heterocyclic chlorides
Entry
Substrate
Product
EtO2C
OHC
Yielda (%)
Entry
Substrate
Product
Yielda (%)
NHSES
NHSES
Br
Cl
NHSES
1
98
1
92
EtO2C
MeOC
MeOC
Br
Cl
NHSES
NHSES
2
3
4
5
90
80
91
85
2
3
88
90
OHC
Br
OHC
OHC
NHSES
CHO
Cl
CHO
MeO2C
MeO2C
Br
NHSES
Cl
NHSES
4
5
88
89
NC
NC
NC
NO2
NC
NO2
Br
NHSES
Cl
NHSES
H3COC
NO2
Cl
H3COC
NO2
NHSES
CF3
EtO2C
ButO2C
NC
Br
EtO2C
ButO2C
NC
NHSES
NHSES
6
7
95(91)
92(80)
6
7
8
84
75
74
H3COC
O2N
CF3
H3COC
O2N
Br
Cl
NHSES
CN
Br
NHSES
CN
8
9
88
97
Cl
NO2
NHSES
NO2
MeO
Br
MeO
NHSES
H3CO
H3CO
MeO2C
F
MeO2C
F
Cl
NHSES
Br
NHSES
9
73
10
11
95
NC
NC
NO2
N
NO2
N
Br
NHSES
NO2
Cl
NHSES
85(87)
10
11
67(80)
72
NO2
Br
NHSES
N
N
Cl
Cl
N
N
NHSES
NHSES
12
13
91
97
NC
NC
Br
NHSES
F3C
F3C
12
80
90
Br
NHSES
CN
N
CN
N
14
15
16
82
0
Cl
NHSES
13
N
N
Br
NHSES
NHSES
a
Isolated yield is given. Yield given in parentheses is for the deprotected product
obtained from the amination product.
MeO
O2N
N
MeO
O2N
N
Br
In the present investigation, we have studied the potential of
SES-NH2 as a reagent for the synthesis of primary arylamines from
4-bromoethylbenzoate using a palladium source such as Pd(OAc)2
or Pd2(dba)3 with rac-BINAP in toluene and dioxane as solvent. The
maximum yield obtained using this catalyst system was only 30%.
Although the yield was low, product formation from SES-
NH2was apparent and thus we have screened different catalysts.
Changing the ligand from BINAP to Xantphos resulted in an in-
crease in the yield. Also, by changing the solvent, base and reaction
temperature, we were able to obtain a 98% isolated yield of product
from ethyl 4-bromobenzoate using a Pd(OAc)2–Xantphos–Cs2CO3
85
85
N
N
17
Br
NHSES
a
Isolated yield is given. Yield given in parentheses is for the deprotected product
obtained from the amination product.
into the sulfonyl chloride (SES-Cl) using thionyl chloride.10 SES-
NH2 was prepared from SES-Cl by reaction with ammonia.11

P. Anjanappa et al. / Tetrahedron Letters 49 (2008) 4585–4587
4587
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2001, 3, 2077; (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793; (c) Okano,
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catalyst system in dioxane at 100 °C for 15 h. Aryl bromides with
various functional groups such as cyano, ester, nitro, and aldehyde
groups worked well under the above optimized conditions without
undergoing any other side reactions (Table 1).12 Unfortunately, no
reaction occurred when the same conditions were applied to an
aryl bromide containing an electron-donating group (Table 1, entry
15).13
Having been successful with aryl bromides, we next extended
this reaction to aryl chlorides. Aryl chloride bond activation is an
industrially important field of research due to the lower cost of aryl
chlorides compared with aryl bromides and aryl iodides.14 We
have used the same reaction conditions for the coupling of SES-
NH2 with aryl chlorides and the temperature was increased from
100 °C to 120 °C. The reaction worked well with aryl chlorides hav-
ing different substituents such as cyano, ester, keto, nitro, and alde-
hyde, and the yields obtained were more than 80% in most cases.
This reaction was not successful with chlorobenzene and aryl chlo-
rides having electron-donating groups. Heterocyclic aryl chlorides
also reacted with SES-NH2 (Table 2).
The aminated aryl trimethylsilylethane sulfonamide products
were very stable and could be used for further transformations
without affecting the sulfonamide group. The SES group was
cleaved selectively from the sulfonamide using CsF in DMF without
affecting other functional groups (Table 1, entry 7).15 We carried
out the deprotection of SES with several products having acid sen-
sitive groups, for example, the SES group was deprotected selec-
tively from the product containing an acid sensitive tert-butyl
ester.
4. Ammonia has been used recently as an amine for palladium-catalyzed aryl
amination: (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028; (b)
Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354.
In summary, we have reported the synthesis of several sulfo-
nated aryl anilines from aryl bromides and aryl chlorides using
SES-NH2. The SES group can be cleaved selectively without affect-
ing other functional groups and establishes SES-NH2 as an excel-
lent ammonia surrogate for aryl amination reactions. Further
studies on N-substituted SES-NH2 are in progress.
5. Liu, Y.; Muchowski, J. M.; Putman, D. G. Tetrahedron Lett. 1998, 39, 1313.
6. (a) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron
Lett. 1997, 38, 6367; (b) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas,
C. J. Am. Chem. Soc. 1998, 120, 827; (c) Cioffi, C. L.; Berlin, M. L.; Herr, R. J. Synlett
2004, 841.
7. (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729; (b) Huang, X.;
Buchwald, S. L. Org. Lett. 2001, 3, 3417.
8. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101; (b) Yin, J.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 6043; (c) Okano, K.; Tokuyama, H.; Fukuyama, T. Org.
Lett. 2003, 5, 4987; (d) He, H.; Wu, Y.-Jin. Y.-J. Tetrahedron Lett. 2003, 44, 3385;
(e) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X. Tetrahedron Lett. 2005, 46,
7295.
9. (a) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P. Tetrahedron Lett.
1986, 27, 2099; (b)2-(Trimethylsilyl)-ethanesulfonamide (SES-NH2): Protective
Groups in Organic Synthesis; Greene, T. W., Wuts, P. G. M., Eds., third ed.; Wiley:
Acknowledgments
The authors, P.A., D.M., and K.S. thank Goutam Das, CEO, Syn-
gene international Ltd for granting permission to carry out this
work at Syngene. M.S. thanks Bharathidasan and Anna Universities
for all the support.
New York, 1999;
p
612; (c) Weinreb, S. M.; Ralbovsky, J. L.
(Trimethylsilyl)ethanesulfonyl Chloride. In Handbook of Reagents for Organic
Synthesis: Activating Agents and Protecting Groups; Pearson, A. J., Roush, W. J.,
Eds.; Wiley: Chichester, 1999; p 425; (d) Kocienski, P. J. (Trimethylsilyl)-
ethanesulfonyl (SES) Derivatives. In Protecting Groups; Corrected ed.; Enders, D.,
Noyori, R., Trost, B. M., Eds.; Thieme: Stuttgart, New York, 2000; p. 215.; (e)
Chambert, S.; Desire, J.; Decout, J.-L. Synthesis 2002, 2319.
Supplementary data
Supplementary data (the experimental and analytical data for
new compounds) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.05.099.
10. (a) Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. Org. Synth. 1998, 75,
161; (b) Huang, J.; Widlanski, T. S. Tetrahedron Lett. 1992, 33, 2657.
11. Parker, L. L.; Gowans, N. D.; Jones, S. W.; Robins, D. J. Tetrahedron 2003, 59,
10165.
12. General procedure: An oven-dried Schlenk tube was charged with Pd(OAc)2
(6.7 mg, 0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), SES-NH2 (217 mg,
1.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The Schlenk tube was evacuated
and back-filled with argon. Ethyl 4-bromobenzoate (230 mg, 1.0 mmol) and
dioxane (7 ml) were added and the Schlenk tube was then sealed with a Teflon
screw cap and placed in a preheated oil bath at 100 °C for 15 h for aryl
bromides and 120 °C for aryl chlorides. After cooling to room temperature,
water was added and the reaction mixture was extracted with ethyl acetate.
The combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The product was purified by flash
chromatography. Yield: 324 mg, 98%.
13. We have observed that aryl bromides with electron-donating groups coupled
with SES-NH2 in the presence of a copper catalyst. This result will be published
elsewhere.
14. (a) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004, 248, 2283; (b)
Beller, M.; Zapf, A. Top. Catal. 2002, 19, 101.
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