InX3-catalyzed haloamidation of vinyl arenes: a facile synthesis of α-bromo- and α-fluoroamides

Article abstract of DOI:10.1016/j.tetlet.2008.12.090

A variety of alkenes are converted into the corresponding α-fluoroamides in high yields by selectfluor^TM in the presence of 10 mol % of InF₃ in nitrile solution. α-Bromoamides are obtained with NBS in the presence of 10 mol % InBr₃ under similar conditions. The use of Lewis acid in haloamidation significantly improved the yields and reaction rates.

Full text of DOI:10.1016/j.tetlet.2008.12.090

Tetrahedron Letters 50 (2009) 1136–1138
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InX3-catalyzed haloamidation of vinyl arenes: a facile synthesis of a-bromo- and
a-fluoroamides
*
J. S. Yadav , B. V. Subba Reddy, D. Narasimha Chary, D. Chandrakanth
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
A variety of alkenes are converted into the corresponding a
-fluoroamides in high yields by selectfluorTM
in the presence of 10 mol % of InF3 in nitrile solution. a-Bromoamides are obtained with NBS in the pres-
ence of 10 mol % InBr3 under similar conditions. The use of Lewis acid in haloamidation significantly
improved the yields and reaction rates.
Article history:
Received 22 October 2008
Revised 15 December 2008
Accepted 18 December 2008
Available online 24 December 2008
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium(III) halides
Vinyl arenes
Haloamidation
a-Fluoroamides
The haloamidation is an important process for the preparation of
-haloamides. They are useful precursors for the synthesis of aziri-
simplicity, low catalyst loading, and strong tolerance to oxygen
and nitrogen-containing substrates.
a
dines and oxazolines, which in turn are used as intermediates for
vic-amino alcohols (from oxazolines by reduction and hydrolysis)
or trans-b-substituted amines (via ring opening of N-acyl aziri-
dines).1 SelectfluorTM, [1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane-bis-(tetrafluoroborate)], has been the subject of
considerable interest as a powerful and user-friendly (non-gaseous,
non-explosive, and less toxic) site-selective, electrophilic fluorinat-
ing agent.2 It has also been used as an oxidant to generate iodonium
ions [I+] from molecular iodine for the nuclear iodination of arenes3a
In continuation of our research on the use of indium(III)
reagents for various organic transformations,10,11 we herein report
a simple and efficient protocol for
a-haloamidation of alkenes
using indium(III) halides. Initially, we attempted the bromoamida-
tion of styrene (1) with N-bromosuccinimide (2) and acetonitrile in
the presence of 10 mol % InBr3. The reaction was complete in
10 min at room temperature, and the desired N-(2-bromo-1-phen-
ylethyl)acetamide 3a was isolated in 85% yield (Scheme 1).
Similarly, various vinyl arenes such as b-methyl styrene,
and for
a
-iodination of aryl alkyl ketones to produce
a
-iodoke-
a-methyl styrene, and p-methyl styrene reacted smoothly with
tones.3b Recently, this has been used to generate useful electrophiles
acetonitrile under these reaction conditions to provide substituted
vic-bromoamides in good yields (Table 1). Various nitriles such as
propionitrile and butyronitrile were also found to react with vinyl
arenes to furnish the corresponding bromoamides in good yields.
The reactions were carried out in nitrile solution at room tempera-
ture using 0.1 equiv of InBr3 as a catalyst. The previous reports
showed the superiority of CH3CN in bromoamidation and the
requirement of a Lewis acid to activate the Br+ donor.1 The bro-
moamidation proceeds via the nucleophilic attack of nitrile on
initially formed bromonium ion, in a fashion analogous to the
such as Cl+, Br+, SCN+, and NO2 from their respective sodium and
þ
potassium salts in acetonitrile, to accomplish aromatic electrophilic
substitution and the Markovnikov-type addition reactions of
alkenes.4,5 There have also been some reports on bromoamidation
of alkenes to provide vic-bromoamides,1,5,6 while only a few exam-
ples are reported for vic-fluoroamidation of alkenes.7 However,
many of these uncatalyzed methods involve low conversions and
high temperature, and are limited to acetonitrile.8
In recent years, indium reagents have received increasing atten-
tion as water-tolerant green Lewis acid catalysts for organic syn-
thesis demonstrating highly chemo-, regio-, and stereoselective
results.9 Compared to conventional Lewis acids, indium halides
have advantages of water stability, recyclability, operational
NHCOCH3
Br
10 mol% InBr3
CH3CN, R.T.
NBS
+
1
2
3a
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.090

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 1136–1138
1137
Table 1
InX3-catalyzed ct-haloamidation of vinyl arenes
Entry
a
Alkene
Nitrile
Producta
Time (min)
10
Yieldb (%)
85
NHCOCH3
CH3CN
3a: X = Br
X
4a: X = F
3b: X = Br
4b: X = F
3c: X = Br
4c: X = F
3d: X = Br
4d: X = F
3e: X = Br
4e: X = F
3f: X = Br
4f: X = F
25
15
15
15
20
10
20
10
30
20
25
20
30
25
30
20
25
25
25
30
25
30
20
35
25
82
87
90
84
82
85
80
83
85
78
87
75
83
72
75
75
78
80
85
82
87
80
75
75
80
NHCOCH3
X
b
c
d
e
f
CH3CN
NHCOCH3
X
CH3CN
NHCOCH3
X
CH3CN
NHCOCH3
X
CH3CN
NHCOCH2CH3
CH3CH2CN
CH3CH2CN
CH3CH2CN
CH3CH2CN
X
NHCOCH2CH3
X
g
h
i
3g: X = Br
4g: X = F
3h: X = Br
4h: X = F
3i: X = Br
4i: X = F
NHCOCH2CH3
X
NHCOCH2CH3
X
NHCOCH2CH2CH3
j
CH3CH2CH2CN
CH3CH2CH2CN
CH3CH2CH2CN
CH3CN
3j: X = Br
4j: X = F
X
NHCOCH2CH2CH3
X
k
I
3k: X = Br
4k: X = F
3l: X = Br
4l: X = F
NHCOCH2CH2CH3
X
NHCOCH3
Ph
X
Ph
m
3m: X = Br
4m: X = F
a
All products were characterized by 1H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
well-known Ritter reaction.8 However, the bromoamidation of
bromosuccinimide and 0.1 equiv of InBr3 in CH3CN at room temper-
cyclic olefins, such as 1,2-dihydronaphthalene, with 1.2 equiv of N-
ature for10 mingave the trans-bromoacetamide stereoselectively in

1138
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 1136–1138
2. (a) Singh, R.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31–44; (b) Nyffeler, P. T.;
NHCOCH3
R
R
Duran, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed.
2005, 44, 192–212.
3. (a) Stavber, S.; Kralj, P.; Zupan, M. Synlett 2002, 598–600; (b) Stavber, S.; Jereb,
M.; Zupan, M. Chem. Commun. 2002, 488–489; (c) Stavber, S.; Kralj, P.; Zupan,
M. Synthesis 2002, 1513; (d) Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron Lett.
1997, 38, 6305–6306.
10 mol% InBr3
CH3CN, R.T.
NBS
+
Br
3m
4. Syvret, R. G.; Butt, K. M.; Nguyen, T. P.; Bulleck, V. L.; Rieth, R. D. J. Org. Chem.
2002, 67, 4487–4493.
Scheme 2.
5. Ye, C. F.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561–8563.
6. Qi, X.; Lee, S. H.; Kwon, J. Y.; Kim, Y.; Kim, S. J.; Lee, Y. S.; Yoon, J. J. Org. Chem.
2003, 68, 9140–9143.
7. (a) Stavber, S.; Pecan, T. S.; Papez, M.; Zupan, M. Chem Commun. 1996, 2247–
2248; (b) Stavber, S.; Pecan, T. S.; Zupan, M. J. Chem. Soc., Perkin Trans. 2 2000,
1141–1145.
8. (a) Hassner, A.; Levy, L. A.; Gault, R. Tetrahedron Lett. 1966, 3119–3123; (b)
Belluci, G.; Bianchini, R.; Chiappe, C. J. Org. Chem. 1991, 56, 3067–3073.
9. (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149–11176; (b) Babu, G.;
Perumal, P. T. Aldrichim. Acta 2000, 33, 16; (c) Ghosh, R. Indian J. Chem., Sect. B
2001, 40, 550–557.
NHCOR
F
10 mol% InF3
R-CN, R.T.
SelectfluorTM
+
4e
Scheme 3.
10. Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Saritha Raj, K.; Prasad, A. R.; Kiran Kumar,
S.; Kunwar, A. C.; Jayaprakash, P.; Jagannadh, B. Angew. Chem., Int. Ed. 2003, 42,
5198–5201.
11. (a) Yadav, J. S.; Sunny, A.; Reddy, B. V. S.; Sabitha, G. Tetrahedron Lett. 2001, 42,
8063–8065; (b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M. Synlett 2001, 1781–
1783; (c) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Prabhakar, A.; Kunwar, A. C.
Tetrahedron Lett. 2003, 44, 2221–2224; (d) Yadav, J. S.; Reddy, B. V. S.; Reddy,
Ch. S. Tetrahedron Lett. 2004, 45, 4583–4585.
12. Typical procedure: To a stirred solution of b-methyl styrene (118 mg, 1.0 mmol)
and Selectfluor or NBS (1.2 mmol) in acetonitrile (4.0 mL) was added InX3
(0.1 mmol) at room temperature. The resulting solution was stirred for the
appropriate time, until the complete consumption of b-methyl styrene as
indicated by TLC. Then, reaction mixture was quenched with water (5 mL) and
was extracted with ethyl acetate (2 ꢀ 15 mL). The organic layer was separated,
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel using hexane/EtOAc (3:1)
83% yield (entry e, Table 1). In the case of b-substituted styrenes such
as b-methyl styrene and stilbene, the desired bromoamides were
obtained with trans-stereoselectivity (Scheme 2).
The stereochemistry of products 3m and 4e was assigned as
trans by coupling constants of protons and also by comparison of
their spectral data with authentic samples.1b Next, we studied
a-
fluoroamidation of alkenes with Selectfluor using InF3 as an acti-
vating Lewis acid. Interestingly, various alkenes underwent
smooth
a-fluoroamidation to give N-(2-fluoro-1-alkyl)acetamides
in high yields (Scheme 3).
Similarly, b-methyl styrene and stilbene also gave the corre-
sponding trans-fluoroamides. The formation of vic-fluoroamides
to afford pure a-haloamide. Spectral data for selected compounds: N-1-(2-fluoro-
1-phenylpropyl)acetamide: 4b: IR (KBr): m(max) 3783, 3697, 3321, 3060, 2989,
2935, 2359, 1883, 1813, 1651, 1543, 1443, 1375, 1302, 1070, 1029, 742,
can be rationalized by assuming the formation of
p-fluoro carbo-
700 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.20–7.44 (m, 5H), 6.3 (d, J = 8.8 Hz,
.
cationic intermediate, which is attacked by the nucleophilic nitro-
gen of the nitrile like the Ritter-type reaction. Of various
indium(III) reagents such as In(OTf)3, In(ClO4)3, and In(NO3)3
tested, InX3 was shown to be effective for this conversion. In the
absence of catalyst, low conversions (20–35%) were achieved even
at 80 °C over 24 h. The use of 10 mol % of InX3 is essential for the
success of the reaction. The scope and generality of this process
are illustrated with respect to various vinyl arenes, and the results
are presented in Table 1.12
In summary, this Letter describes a rapid and an efficient cata-
lytic method for the haloamidation of vinyl arenes using a catalytic
amount of indium(III) halides. The use of water-tolerant InX3
makes this procedure quite simple and convenient. This method
offers significant advantages such as low catalyst loading, high
conversions, water-tolerant catalyst, and operational simplicity.
1H), 4.97–5.16 (m, 1H), 4.78–4.91 (m, 1H), 2.02 (d, J = 10.0 Hz, 3H), 1.09–1.47
(m, 3H). 13C NMR (75 MHz, CDCl3): d 170.1, 169.8, 138.3, 137.2, 128.6, 128.4,
127.6 127.0, 93.8, 93.6, 91.4, 91.2, 64.0, 63.8, 63.7, 63.7, 23.4, 18.2, 18.1. LC–
MS: m/z: 218 (M+Na). HRMS calcd for C11H14FNONa: 218.0951; Found,
218.0961. N-1-(2-bromo-1-phenylpropyl)acetamide: 3b: IR (KBr) m(max) 3308,
3062, 3031, 2965, 2873, 1736, 1651, 1538, 1454, 1375, 1261, 1184, 1089, 753,
700 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.15–7.35 (m, 5H), 4.57 (d, J = 7.5 Hz,
.
1H), 4.29–4.38 (m, 1H), 2.07 (d, J = 1.5 Hz, 3H), 1.46 (d, J = 16.0 Hz, 3H). LC–MS:
m/z: 176 (M+Na) (–HBr). HRMS calcd for C11H14NONa: 176.1075; Found:
176.1073. N-1-(2-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide: 4e: IR
(KBr): m(max) 3286, 3063, 2921, 2852, 1638, 1544, 1437, 1370, 1057, 744,
701 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.03–7.30 (m, 4H), 6.0 (d, J = 8.3 Hz,
.
1H), 4.85–5.41 (m, 2H), 2.96–3.16 (m, 1H), 2.65–2.79 (m, 1H), 2.24–2.41 (m,
1H), 2.12 (s, 3H), 1.79–2.07 (m, 1H). 13C NMR (75 MHz, CDCl3): d 170.0, 169.8,
139.2, 137.0, 128.6, 128.6, 128.5, 128.0, 127.0, 93.4, 93.2, 91.0, 90.8, 57.4, 57.2,
56.6, 56.2, 23.0, 19.6, 19.4, 18.6, 18.4. LC–MS: m/z: 208 (M+1). HRMS calcd for
C12H14FNONa:
phenylethyl)propanamide: 4h: IR (KBr): m(max) 3288, 3068, 2928, 2853, 1654,
1550, 1496, 1456, 1371, 1264, 1015, 697 cmꢁ1 1H NMR (300 MHz, CDCl3): d
230.0957;
Found,
230.0953.N-1-(2-fluoro-1-methyl-1-
.
7.22–7.34 (m, 5H), 5.73 (s, 1H), 4.67–4.76 (m, 1H), 4.56 (dd, J = 9.2, 18.8 Hz,
1H), 2.23 (dd, J = 8.3, 15.8 Hz, 2H), 1.75 (d, J = 2.2 Hz, 3H), 1.16 (t, J = 7.5 Hz,
3H). LC–MS: m/z: 232 (M+Na). HRMS calcd for C12H16FNONa: 232.1113; Found,
References and notes
232.1122.N-1-(2-bromo-1,2-diphenylethyl)acetamide: 3m: IR (KBr):
m(max) 3384,
2922, 1643, 1537, 1451, 1377, 1216, 1056, 761, 700 cmꢁ1 1H NMR (200 MHz,
.
1. (a) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic
Synthesis; Elsevier: Amsterdam, 2005. pp 382–383; (b) Yeung, Y. Y.; Gao, X.;
Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644–9645; (c) Yeung, Y.-Y.; Hong, S.;
Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311.
CDCl3): d 7.15–7.44 (m, 10H), 5.15 (d, J = 7.3 Hz, 1H 1H), 4.93–5.01 (m, 1H),
2.21 (d, J = 1.4 Hz, 3H). LC–MS: m/z: 238 (M+Na) (–HBr). HRMS calcd for
C16H16NONa: 238.1231; Found, 238.1243.