InBr3 Catalyzed intermolecular hydroamination of unactivated alkenes

Article abstract of DOI:10.1016/j.tetlet.2007.03.068

InBr₃ has been demonstrated to be a simple catalyst for the intermolecular hydroamination of unactivated alkenes to produce tosyl- and mesyl-protected amines in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2007.03.068

Tetrahedron Letters 48 (2007) 3375–3377
InBr3 Catalyzed intermolecular hydroamination
of unactivated alkenes
b
b
b,
*
Jing-Mei Huang,a,c, Chek-Ming Wong, Feng-Xia Xu and Teck-Peng Loh
*
aSchool of Chemical Science, South China University of Technology, Guangzhou 510640, China
bDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 639798, Singapore
cKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering,
Suzhou (Soochow) University, Jiangsu 215123, China
Received 7 December 2006; revised 1 February 2007; accepted 13 March 2007
Available online 15 March 2007
Abstract—InBr3 has been demonstrated to be a simple catalyst for the intermolecular hydroamination of unactivated alkenes to
produce tosyl- and mesyl-protected amines in moderate to good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Table 1. Intermolecular hydroamination with different indium(III)
compounds as catalysts
Hydroaminaion of alkenes to form saturated carbon–
nitrogen bond is an atom-economical and efficient way
to synthesize many nitrogen containing compounds.1
conditions
NHTs
Thus far, catalytic intermolecular hydroamination of
unactivated alkenes remains an important and challeng-
ing strategy, and only a few examples are known.2
TsNH2
Entry
Catalyst
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
8
—
120 ꢁC, 60 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 16 h
120 ꢁC, 8 h
120 ꢁC, 16 h
160 ꢁC, 16 h
90 ꢁC, 16 h
0
0
0
The previous work in our group had showed that some
Indium(III) compounds were very active in many organ-
ic transformations.3 Here we provide the first examples
of In(III) bromide catalyzed intermolecular hydroamin-
ation of unactivated alkenes.
In(TFA)3
In(TFacac)3
InF3
InF3Æ3H2O
InI3
InCl3
InBr3
InBr3
InBr3
0
<5
39
88
92
69
53
81
67
The readily available p-toluenesulfonamide and cyclo-
hexene were used for preliminary study. The effects of
various Indium(III) compounds to catalyze the hydro-
amination reaction were investigated (Table 1).
9
10c
11
12
InBr3
InBr3
As we can see from Table 1, InBr3 stood out to be an
excellent catalyst for this reaction. Other In(III)
compounds, either were not active (entries 2–5) or gave
lower yields (entries 6 and 7). Thus, N-cyclohexyl-p-
toluenesulfonamide could be prepared in 92% isolated
yield by reacting TsNH2 with 4 equiv of cyclohexene
in toluene with catalytic amount of InBr3 (20 mol %)
TFA = trifluoroacetate; TFacac = trifluoroacetylacetonate.
a Typical reaction conditions: p-toluenesulfonamide (1 mmol), cyclo-
hexene (4 mmol), Lewis acid (0.2 mmol), toluene (2 mL), in a sealed
tube. The temperatures listed in the table are oil bath temperatures.
b Isolated yield after purification by column chromatography.
c 10 mol % of catalyst was used.
at 120 ꢁC for 16 h. THF and mixtures of toluene with
THF were found to be unsuitable as reaction solvents.
Reducing the reaction time (from 16 h to 8 h, entry 9),
and the amount of Lewis acid (from 20 mol %
to 10 mol %, entry 10) resulted in decreasing yields.
*
Corresponding authors. Tel.: +86 20 88370027; fax: +86 20 87110622
(J.-M.H.); e-mail: chehjm@scut.edu.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.068

3376
J.-M. Huang et al. / Tetrahedron Letters 48 (2007) 3375–3377
Meanwhile, changing the reaction temperature (from
120 ꢁC to 160 ꢁC, entry 11, from 120 ꢁC to 90 ꢁC, entry
12) afforded lower yields.
products were collected and 6a was favored (entry 6)
due to the less hindrance of 1,4 position. In the case of
terminal olefins, Markovnikov addition products were
observed (entries 7–11) and in these cases, usually two
types of products were obtained: 2-hydroamination
(7a–10a) and 3-hydroamination (7b–10b) products.
The 3-hydroamination products (7b–10b) could be
formed from an initial terminal double bond
isomerization to an internal one followed by Markovni-
kov addition by p-toluenesulfonamide. The ratio of 2-
and 3-hydroamination products varied with different
Next, we investigated the reactions with various alkenes
using the optimal conditions stated above. The results
are summarized in Table 2.4 A range of different unacti-
vated olefins was studied in the reaction. Cyclohexene,
cycloheptene and cyclopentene gave the desired prod-
ucts in excellent yields (entries 1–3). For 4-methyl-cyclo-
hexene, a mixture of 1- and 2-hydroamination (6a,6b)
Table 2. Intermolecular hydroamination of p-toluenesulfonamide with various alkenes
Entry
Alkene
Producta
NHTs
1a
Yieldb (%)
92
1
2
3
4
5
6
7
94
NHTs
2a
NHTs
86
3a
NHTs
67
4a
NHTs
5a
44
NHTs
65 (77:23)c
78 (50:50)
+
6b
6a
NHTs
NHTs
+
7b
7a
NHTs
MeO
Ph
8
78
MeO
8a
NHTs
+
NHTs
9d
10
11d
50 (94:6)
41 (70:30)
60 (65:35)
Ph
Ph
Ph
NHTs
Ph
9a
9b
NHTs
Ph
+
+
Ph
Ph
10b
10b
NHTs
NHTs
10a
10a
NHTs
Ph
a Typical reaction conditions: p-toluenesulfonamide (1 mmol), olefins (4 mmol), Lewis acid (0.2 mmol), toluene (2 mL), in seal tube, 120 ꢁC, 16 h.
b Isolated yield after purification by column chromatography.
c Ratio of the two isomers.
d Reaction run for 40 h.

J.-M. Huang et al. / Tetrahedron Letters 48 (2007) 3375–3377
3377
terminal olefins. For allylbenzenes (entries 8 and 9), 3-
References and notes
hydroamination products were minimum as the internal
olefins (prop-1-enylbenzenes), isomerized from the ter-
minal olefins, could not furnish the desired hydroamin-
ation product under our conditions.
1. For recent reviews, see: (a) Hong, S.; Marks, T. Acc. Chem.
Res. 2004, 37, 673–686; (b) Beller, M.; Seayad, J.; Tillack,
A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368; (c)
Molander, G. A.; Romero, A. C. Chem. Rev. 2002, 102,
2161–2185; (d) Senn, H. M.; Blo¨chl, P. E.; Togni, A. J. Am.
Noticeably, the reaction also worked well with alkylsulf-
onamides (Eq. 1). But with other nitrogen-based mole-
cules, such as anilines (11) and carbamates (12, 13),
reactions gave no desired products.
Chem. Soc. 2000, 122, 4098–4107; (e) Muller, T. E.; Beller,
¨
M. Chem. Rev. 1998, 98, 675–703.
2. For recent examples, see: (a) Liu, X.-Y.; Li, C.-H.; Che,
C.-M. Org. Lett. 2006, 8, 2007–2710; (b) Zhang, J. L.;
Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798–
1799; (c) Taylor, J. G.; Whittall, N.; Hii, K. K. Org. Lett.
2006, 8, 3561–3564; (d) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J.
Am. Chem. Soc. 2003, 125, 12584–12605; (e) Utsunomiya,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286–
14287; (f) Utsunomiy, M.; Kuwano, R.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608–5609; (g)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
122, 9546–9547; (h) Waster, J.; Nambu, H.; Carreira, E. J.
Am. Chem. Soc. 2005, 127, 8294–8295; (i) Anderson, L. L.;
Amold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127,
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Am. Chem. Soc. 2005, 127, 12640–12646; (k) Brunet, J. J.;
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Widenhoefer, R. A. Organometallics 2004, 23, 1649–1651;
InBr3 (0.2 mmol)
NHMs
+
MsNH2
1 mmol
toluene (2 mL), 16 h, 120 0C
4 mmol
Yield 82%
ð1Þ
O
O
NH2
H2N
OBu-n
H2N
OBn
11
12
13
It was interesting to note that this reaction also worked
in the presence of small amount of water (Eq. 2). Unfor-
tunately, the reactions with unprotected hydroxyl con-
taining olefins (14 and 15) did not furnish the desired
products. For styrene (16), a mixture of undeterminable
polymerized products was observed.
´
´
(m) Barluenga, J.; Jimenez, C.; Najera, C.; Yus, M.
J. Chem. Soc., Perkin Trans. 1 1984, 721–725; (n) For
alkali metal catalyzed reactions, see Ref. 1b.
3. For recent review, see: Loh, T.-P.; Chua, G.-L. Chem.
Commun. 2006, 2739–2749.
4. Illustrative experimental procedure (synthesis of N-cyclo-
hexyl-p-toluenesulfonamide): To a 15 mL sealed tube was
added p-toluenesulfonamide (171.2 mg, 1.0 mmol), cyclo-
hexene (0.4 mL, 4.0 mmol), InBr3 (70.8 mg, 0.2 mmol) and
followed by toluene (2 mL). After shaking, the tube was
sealed and heated in an oil bath at 120 ꢁC. The reaction
was left at this temperature for 16 h. After the sealed tube
was slowly cooled to room temperature, the solvent was
removed by Rotary Evaporator, and the residue was
purified using flash silica gel chromatography to afford a
product (231.8 mg, 92%); white solid; Rf = 0.40 (ethyl
acetate/hexane = 1:4). FTIR (KBr) cmꢀ1: 3246, 3063,
3053, 2934, 2851, 2801, 1597, 1497, 1443, 1323, 1155,
1094, 989, 883, 816, 667, 575, 546; 1H NMR (300 MHz,
CDCl3): d 7.77 (d, J = 8.3 Hz, 2H, PhH), d 7.31 (d,
J = 8.0 Hz, 2H, PhH), d 4.30 (d, J = 7.1 Hz, 1H, NH), d
3.23–3.09 (m, 1H, NHCH), d 2.45 (s, 3H, PhCH3), d
1.82–1.73 (m, 2H, CH2), d 1.70–1.62 (m, 2H, CH2), d 1.33–
1.08 (m, 6H, 3 · CH2); 13C NMR (100 MHz, CDCl3): d
143.1, 138.5, 129.6, 126.9, 52.6, 33.8, 25.1, 24.6, 21.5;
HRMS Calcd for C13H19NO2S [M+]: 253.1136. Found:
253.1105.
5. (a) Teo, Y.-J.; Loh, T.-P. Chem. Commun. 2005, 1318–1320;
(b) Teo, Y.-J.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7,
2743–2745; (c) Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh, T.-P.
Chem. Commun. 2005, 1010–1012; (d) Teo, Y.-J.; Goh,
J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2539–2541; (e) Lu, J.;
Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159–161;
(f) Lu, J.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 2345–
2347; (g) Teo, Y.-J.; Goh, E.-L.; Loh, T.-P. Tetrahedron
Lett. 2005, 46, 4573–4575; (h) Teo, Y.-J.; Goh, E.-L.; Loh,
T.-P. Tetrahedron Lett. 2005, 46, 6209–6211; (i) Lu, J.; Ji,
S.-J.; Teo, Y.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46,
7435–7437.
toluene : water =20:1 (2 mL)
NHR
+
RNH2
InBr3 (0.2 mmol)
stirring for 16 h, 120 C
º
1 mmol
Yield 76% (R=Ts)
81% (R=Ms)
4 mmol
ð2Þ
OH
OH
14
16
15
In summary, InBr3 had been found to be a good catalyst
for the intermolecular hydroamination of simple olefins
to afford Markovnikov addition products. It is notewor-
thy that as an air and water stable Lewis acid, InBr3
catalyzed the reaction in the presence of water. Further
work is to explore the scope of the reaction, and stereo-
selective hydroamination using chiral Indium com-
plexes5 is also under investigation.
Acknowledgments
The authors thank the financial support from the Nan-
yang Technological University and the Key Laboratory
of Organic Synthesis of Jiangsu Province (Project No.
KJS0613).