InCl3 catalyzed C-C coupling of aryl alcohols and TosMIC

Article abstract of DOI:10.1016/j.tetlet.2007.09.164

The InCl₃ mediated C-C coupling reaction between aryl alcohols and TosMIC gives the corresponding amides in good to high yields.

Full text of DOI:10.1016/j.tetlet.2007.09.164

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9048–9050
InCl3 catalyzed C–C coupling of aryl alcohols and TosMIC
Palakodety Radha Krishna,* E. Raja Sekhar and Y. Lakshmi Prapurna
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 8 August 2007; revised 21 September 2007; accepted 26 September 2007
Available online 29 September 2007
Abstract—The InCl3 mediated C–C coupling reaction between aryl alcohols and TosMIC gives the corresponding amides in good to
high yields.
ꢀ 2007 Published by Elsevier Ltd.
Carbon–carbon bond formation under nearly neutral
conditions would be a fascinating and a valuable proce-
dure in synthetic organic chemistry.1,2 There has been a
recent increase in activity towards the direct coupling
between an alcohol and an active methylene-containing
species due to the intrinsic energy saving properties.2
p-Toluenesulfonylmethyl isocyanide3 (TosMIC) is a
versatile, widely applicable reagent that constitutes a
densely functionalized building block bearing an active
methylene group. Recently, we reported TosMIC medi-
ated synthesis of C-nucleosides4 as well as its use in
diastereoselective Passerini reactions.5 Apart from the
inherent advantage of possessing an isonitrile function-
ality, the active methylene group of TosMIC is available
for secondary reactions through various methods.
Owing to these potential uses, we became interested in
further expanding the utility of TosMIC. Consequently,
a Lewis acid mediated direct C–C coupling was envis-
aged between TosMIC and aryl alcohols, which would
result in a-alkylated TosMIC as products (Fig. 1),6 how-
ever, an N-substituted amide was obtained instead. To
the best of our knowledge, this is the first report on
the use of an isonitrile in such a mechanistic pathway.7
C-nucleosides
(Ref. 4)
R'
R
R
R
Tos
NC
O
OH
R'
R'
C
N
Passerini
(Ref. 5)
S
O
O
TosMIC
Figure 1.
O
R
NH
R'
Tos
OH
InCl3 (5 mol%)
CH3CN, 80 oC
+
TosMIC
R
R'
1a-9a
10
1-9
Scheme 1.
along with the corresponding dimeric ether (9%) as a
byproduct. In order to minimize the byproduct forma-
tion, different Lewis acids such as BF3ÆOEt2, ZrCl4,
Sc(OTf)3 and InCl3 were screened under similar reaction
conditions to afford 1a and the dimeric ether in varying
yields (Table 1).
Herein, a novel synthetic protocol is reported which
leads to the formation of amides from the corresponding
aryl alcohols and TosMIC (Scheme 1). Initially, the cou-
pling reaction was performed between benzhydrol 1 and
TosMIC 10 in the presence of FeCl3 (5 mol %) at 80 ꢁC
in acetonitrile as solvent to afford amide 1a in 73% yield
It was found that when the reaction was carried out
using InCl3 as the catalyst, the amide 1a (92%) was
formed in a shorter reaction time (Table 1). Amide 1a
was identified from its spectral data. The 1H NMR spec-
trum revealed characteristic methylene protons at d 4.63
as a doublet (J = 7.0 Hz), the aryl methyl at d 2.44 as a
singlet and the benzylic proton at d 4.76 as a singlet. The
Keywords: Indium chloride; Aryl alcohols; TosMIC; N-Substituted
amides.
*
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.09.164

P. Radha Krishna et al. / Tetrahedron Letters 48 (2007) 9048–9050
9049
Table 1. Coupling reaction of benzhydrol 1 with TosMIC using
different catalysts at 80 ꢁCa
Table 2. Coupling reaction between various alcohols and TosMIC
under optimized conditionsa
Entry
Catalyst
Time (h)
Product 1a (%)
Entry Alcohol
Productb Time (h) Yieldc (%)
1
2
3
4
5
FeCl3
BF3ÆOEt2
ZrCl4
Sc(OTf)3
InCl3
8
4
6
3
2
73 (9)
76 (7)
84 (5)
87 (5)
92 (3)
OH
1
1a
2a
2
4
92
87
Ph
Ph
1
OH
Ph
a The figure in parenthesis reflects the yields of the dimeric ether.
2
3
4
5
Ph
13C NMR spectrum revealed the carbonyl carbon
resonating at d 171.2. This amide product was further
supported by the IR spectrum which revealed
characteristic stretching frequencies at 3319 and
1675 cmÀ1 due to the –NH and –C@O functional
groups, respectively.
2
OH
3a
4a
5a
8
4
3
76
85
88
Ph CH3
3
OH
The versatility of the methodology was studied with
various substrates. Thus, alcohols 2–9, including an
a,b-unsaturated alcohol 2, a tertiary alcohol 4, bicyclic
benzylalcohol 5, and heteroaryl benzylalcohol 6 afforded
the corresponding amides under standard reaction
conditions in good to high yields (75–88%). The corres-
ponding dimeric ethers were isolated in less than 8%
yields. All the products were characterized from spectral
data (see Table 2).
Ph
CH3
Ph
4
OH
5
6
OH
6
7
6a
7a
4
4
80
76
S
Amide formation can be rationalized via the plausible
mechanism depicted in Figure 2. The ambiphilic reactiv-
ity of isonitriles serving both as a nucleophile or an elec-
trophile is well known in the literature7 and is exploited
herein. The Lewis acid initially coordinates (InCl3,
Fig. 2) with the alcohol (A) due to its greater nucleophi-
licity,8 thereby generating an incipient carbocation, to
facilitate nucleophilic attack of TosMIC onto A result-
ing in intermediate B. Next, the alcohol adds to the
more electrophilic isonitrile carbon to generate the
corresponding N-substituted acetimidic acid C, which
tautomerises to the stable N-substituted amide with con-
comitant regeneration of InCl3.
Ph
OH
Ph
HO
7
OH
Ph
8
9
8a
9a
3
6
78
75
8
9
OH
In conclusion, we have reported a new InCl3 mediated
C–C coupling reaction between aryl alcohols and
TosMIC to afford the corresponding amides in good
to high yields.9,10 This reaction besides being atom
economical in nature is also a novel protocol that paves
the way for further exploitation of TosMIC.
a All reactions were conducted as described in the general experimental
procedure in the reference section.
b All the products were characterized from spectral data.
c Isolated yields are after purification by column chromatography.
Tos
N
C
R
Cl3In
R
OH
H
R
N
R
InCl3
O
InCl3
'R
Tos
OH
N
Tos
'R
OH
'R
B
R'
Alcohol
C
InCl3
A
O
R
N
Tos
-InCl3
H
R'
Amide
Figure 2. A plausible mechanism.

9050
P. Radha Krishna et al. / Tetrahedron Letters 48 (2007) 9048–9050
10. Spectral data of selected compounds: Compound 1a: white
Acknowledgements
solid; mp: 145–148 ꢁC; 1H NMR (200 MHz, CDCl3):
d = 7.61 (d, 2H, J = 7.0 Hz, Ar-H), 7.29–7.18 (m, 8H,
Ar-H), 7.10–7.05 (m, 4H, Ar-H), 6.59 (br s, 1H, NH), 4.76
(s, 1H, benzylic), 4.63 (d, 2H, J = 7.0 Hz, CH2), 2.44 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3): d = 171.2, 145.2,
138.3, 135.3, 133.4, 129.8, 128.6, 127.3, 80.7, 60.1, 58.2,
29.6, 21.7. IR (KBr): 3319, 2924, 2854, 1745, 1675,
1141 cmÀ1. ESI: m/z = 380 [M++1], 402 [M++23]. Anal.
Calcd for C22H21NO3S: C, 69.63; H, 5.58; N, 3.69. Found:
C, 69.70; H, 5.42; N, 3.65. Compound 2a: white solid; mp:
158–162 ꢁC; 1H NMR (300 MHz, CDCl3): d = 7.60 (d, 2H,
J = 6.7 Hz, Ar-H), 7.29–7.12 (m, 12H, Ar-H), 6.39–6.35
(m, 3H, NH, olefin), 4.60 (d, 2H, J = 6.0 Hz, CH2), 4.17 (d,
1H, J = 5.2, benzylic), 2.33 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d = 171.3, 145.2, 133.3, 132.9, 129.8,
128.8, 128.7, 128.4, 128.0, 127.7, 127.5, 126.7, 126.3, 60.1,
56.0, 21.5. ESI: m/z = 405 [M++1]. Anal. Calcd for
C24H23NO3S: C, 71.08; H, 5.72; N, 3.45. Found: C,
71.12; H, 5.62; N, 3.38. Compound 4a: white solid; mp:
155–160 ꢁC; 1H NMR (200 MHz, CDCl3): d = 7.62 (d, 2H,
J = 8.9 Hz, Ar-H), 7.31–7.21 (m, 8H, Ar-H), 7.06–7.02 (m,
4H, Ar-H), 6.15 (t, 1H, J = 6.7 Hz, NH), 4.61 (d, 2H,
Two of the authors (E.R.S. and Y.L.P.) thank the CSIR
and UGC, New Delhi, respectively, for financial assis-
tance in the form of fellowships.
References and notes
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9. General experimental procedure: A solution of alcohol
(1.0 mmol), TosMIC (1.0 mmol) and InCl3 (0.05 mmol) in
acetonitrile (2.0 mL) was stirred at 80 ꢁC for 2–8 h until
complete conversion of the alcohol was observed (tlc). The
resulting solution was partitioned between an equimolar
ratio of diethyl ether and water (30 mL, 1:1), the organic
layer separated and then the aqueous layer was washed
with ether (2 · 20 mL).The combined organic layers were
washed with brine, dried (Na2SO4), evaporated in vacuo
and the residue thus obtained was purified by column
chromatography (silica gel 60–120 mesh, EtOAc:n-hexane,
2.5:7.5) to afford amides 1a–9a in 75–92% yields.
J = 6.7 Hz, CH2), 2.48 (s, 3H, CH3), 1.79 (s, 3H, CH3). 13
C
NMR (50 MHz, CDCl3): d = 174.3, 145.2, 143.7, 133.8,
129.8, 128.7, 128.5, 128.2, 127.9, 127.2, 127.0, 60.2, 56.8,
26.9, 21.6. ESI: m/z = 416 [M++23]. Anal. Calcd for
C23H23NO3S: C, 70.20; H, 5.89; N, 3.56. Found: C, 70.11;
H, 6.05; N, 3.52. Compound 5a: white solid; mp: 160–
165 ꢁC; 1H NMR (200 MHz, CDCl3): d = 7.71 (d, 2H,
J = 7.7 Hz, Ar-H), 7.31 (d, 2H, J = 7.7 Hz, Ar-H), 7.24 (s,
2H, Ar-H), 7.20–7.11 (m, 2H, Ar-H), 6.94 (d, 1H,
J = 6.9 Hz, NH), 5.96 (br s, 1H, benzylic), 4.59 (br s, 2H,
CH2), 2.83–2.73 (m, 2H, CH2), 2.47 (s, 3H, CH3), 2.05–2.02
(m, 2H, CH2), 1.83–1.61 (m, 2H, CH2). 13C NMR
(75 MHz, CDCl3): d = 174.1, 145.3, 137.8, 133.8, 132.5,
129.8, 128.7, 127.6, 126.2, 60.1, 47.4, 46.5, 30.0, 29.6, 28.9,
27.0, 21.7, 20.1, 19.8. ESI: m/z = 344 [M++1]. Anal. Calcd
for C19H21NO3S: C, 66.45; H, 6.16; N, 4.08. Found: C,
66.75; H, 6.05; N, 4.03. Compound 6a: white solid; mp:
128–132 ꢁC; 1H NMR (200 MHz, CDCl3): d = 7.61 (d, 2H,
J = 8.0 Hz, Ar-H), 7.38 (t, 1H, J = 6.5 Hz, NH), 7.20–7.08
(m, 8H, Ar-H), 6.84 (dd, 1H, J = 3.6, 5.1 Hz, Ar-H), 6.75
(d, 1H, J = 3.6 Hz, Ar-H), 4.98 (s, 1H, benzylic), 4.60 (dd,
2H, J = 2.1, 7.3 Hz, CH2), 2.37 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d = 170.5, 145.2, 140.7, 138.3, 133.2,
129.8, 128.6, 128.4, 128.2, 127.6, 127.1, 126.5, 126.0, 125.5,
124.6, 60.2, 53.4, 47.5, 29.6, 21.6. ESI: m/z 386 [M++1].
Anal. Calcd for C20H19NO3S2: C, 62.31; H, 4.97; N, 3.63.
Found: C, 62.15; H, 5.12; N, 3.59.