Thorpe-Ingold effect in copper(II)-catalyzed formal hydroalkoxylation- hydroarylation reaction of alkynols with indoles

Article abstract of DOI:10.1016/j.tetlet.2009.09.057

The use of Cu(OTf)₂ as a catalyst for tandem hydroalkoxylation-hydroarylation reaction of alkynes tethered with hydroxyl group is reported. The reaction proceeds at 60 °C or even at room temperature with 5 mol % catalyst loading and produces C-

Full text of DOI:10.1016/j.tetlet.2009.09.057

Tetrahedron Letters 50 (2009) 6576–6579
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thorpe–Ingold effect in copper(II)-catalyzed formal
hydroalkoxylation–hydroarylation reaction of alkynols with indoles
*
Nitin T. Patil , Vivek S. Raut, Rahul D. Kavthe, Vaddu V. N. Reddy, P. V. K. Raju
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2009
Revised 8 September 2009
Accepted 10 September 2009
Available online 15 September 2009
The use of Cu(OTf)2 as a catalyst for tandem hydroalkoxylation–hydroarylation reaction of alkynes teth-
ered with hydroxyl group is reported. The reaction proceeds at 60 °C or even at room temperature with
5 mol % catalyst loading and produces C-3-substituted indoles in good to high yields. The method was
shown to be applicable to a broad range of indoles, containing electron-withdrawing and electron-donat-
ing substituents, and alkynol substrates bearing sterically demanding substituents in the tether. Interest-
ingly, it was found that Thorpe–Ingold effect is operating for this cyclization reaction. Easy availability
and low cost of Cu(OTf)2 make this method attractive and amenable for large-scale synthesis compared
to known literature methods.
Keywords:
Alkynes
Indoles
Copper catalyst
Hydroalkoxylation
Hydroarylation
Ó 2009 Published by Elsevier Ltd.
In the past ten years, significant research has been directed to-
ward the development of metal-catalyzed reactions for the addi-
tion of C–H bonds on to alkynes (hydroarylation).1 Similarly,
addition of oxygen nucleophiles across C–C triple bonds (hydroalk-
oxylation)2 represents valuable tool for making oxygen-containing
compounds. The combination of both the procedures (hydroalk-
oxylation–hydroarylation)3 under the catalysis of a single metal
salt may enable new transformation for maximum molecular com-
plexity with minimum organic wastes.4
Indoles are versatile and useful heterocycles for the synthesis of
a wide range of biologically active important molecules and natu-
ral products.5 The synthesis and functionalization of indoles have
been the object of research for over a century, and a variety of
well-established classical methods and metal-catalyzed processes
are now available.6 The most commonly known method for the
functionalization of indoles involves their treatment with electro-
philes such as aldehydes, ketones, imines, Michael acceptors, and
allylic substrates. Echavarren and co-workers7 and Cheng and
co-workers8 independently reported an elegant process for the
synthesis of C-3-functionalized indoles, by gold- and platinum-cat-
alyzed reactions between alkynols and indoles. Recently, Barluenga
and co-workers reported the use of cationic gold complexes for
similar reactions.9 However, all these methods suffer from the
use of expensive catalysts. Moreover, the scope of this reaction
with respect to alkynols is limited. Therefore, the introduction of
new and robust methods for this transformation is highly desired.
As a part of our ongoing interest on alkyne activation,10 we report
herein an efficient Cu(OTf)2-catalyzed tandem hydroalkoxylation–
hydroarylation reaction between indoles and alkynols bearing steri-
cally demanding substituents in the tether (Scheme 1).
Our study began with the reaction between alkynol 1a and N-
methyl indole 2a in the presence of copper salts11 in THF (Table
1). The use of 5 mol % CuI and CuBr in THF did not give the desired
product (entries 1 and 2). The results can be attributed to the fact
that Cu(I) salts have poor Lewis acidic properties which are neces-
sary as shown in Figure 1 (catalytic cycle II, vide infra). Next, we
screened Lewis acidic copper(II) catalysts. The use of 5 mol %
Cu(OAc)2 gave only a trace amount of 3a along with recovery of
1a (entry 3). The yield was significantly improved when
CuCl2ꢀ2H2O, CuBr2, and Cu(OTf)2 were employed and out of them
the latter catalyst12 showed excellent catalytic activity (entries
4–6). Next, the activity of Cu(OTf)2 was examined in different sol-
vents such as toluene, acetonitrile, methanol, and 1,4-dioxane (en-
tries 7–10). Among them, toluene was proved to be more effective
(entry 7). As can be judged from entry 11 that the reaction can be
R
O
5 mol%
n
Cu(OTf)2
n
R
R
+
R
N
R
OH
toluene, 60 °C
N
R
1
2
3
* Corresponding author. Tel.: +91 40 27191471; fax: +91 40 27193382.
E-mail address: nitin@iict.res.in (N.T. Patil).
Scheme 1. Copper(II)-catalyzed reaction between 1 and 2.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.09.057

N. T. Patil et al. / Tetrahedron Letters 50 (2009) 6576–6579
6577
Table 1
lent yields. However, 2e containing electron-withdrawing –Ts
group proved to be inert and 3e was not formed at all.
Optimization studiesa
Ph
Ph
Next, we studied the scope and limitations with respect to in-
doles and alkynols (Table 2). The alkynols bearing sterically
demanding substituents in the tether such as 1b and 1c reacted
well giving the corresponding products 3f and 3g in high yields
(entries 1 and 2). A mixture of diastereomers 3h + 3h0 and 3i + 3i0
O
Ph
Ph
5 mol%
Cu salts
+
N
Me
OH
°
solvent, 60 C
N
H
1a
2a
3a
Table 2
Entry
Catalysta
Solvent
Yieldb (%)
Cu(OTf)2-catalyzed hydroalkoxylation–hydroarylation of alkynesa
c
1
2
3
4
5
6
7
8
9
CuI
CuBr
THF
THF
THF
THF
THF
THF
Toluene
CH3CN
MeOH
1,4-Dioxane
Toluene
—
R
c
—
O
c
5 mol%
Cu(OTf)2
Cu(OAC)2
CuCl2ꢀH2O
CuBr2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
70
78
95
98
50
R
R
+
N
Me
toluene, 60 °C
OH
X
N
Me
X
1
2
3
c
—
—
c
Entry
1
2
3, Yieldb (%)
10
11
95d
a
R
Reaction conditions: 0.46 mmol 1a, 0.38 mmol 2a, 5 mol % copper salts, solvent
(0.25 M), 60 °C, 3 h.
R
b
Isolated yields based on 2a.
Indole 2a was recovered in almost quantitative yields.
Reaction was run at rt for 12 h.
OH
c
d
1
2
1b R = –(CH2)5–
1c R = –(CH2)4–
2a
2a
3f, 97
3g, 70
OH
Ph
Ph
3
4
5
6
2a
2a
2a
3h + 3h0, 72c
3i + 3i0, 62d
3j, 20e
O
1d
LnCu
CuLn
Ph
Ph
1a
3a
Ph
N
4
OH
Me
OH
1e
8
2a
Ph
II
I
CuLn
Ph
OH
Ph
1f
Ph
O
LnCu
LnCu
7
O
5
1a
1a
3k, 96
O
H
N
2f
Ph
Ph
Me
Me
OBn
6
Figure 1. Plausible mechanism.
7
3l, 85
2g
N
Me
conducted at room temperature without significant decrease in
yield, however, long time was required.
After establishing the proper reaction conditions (5 mol %
Cu(OTf)2, toluene, 60 °C, 3 h),13 the effect of various groups on in-
dole nitrogen was examined. A series of indoles 2a–e, bearing –
H, alkyl, aryl, and sulfonyl group were subjected to copper catalysis
under these newly established conditions (Scheme 2). The indoles
2a–d were reacted well with 1a to afford 3a–d,14 in good to excel-
BnO
8
9
1a
1a
3m, 90
3n, 95
2h
N
Me
2i
N
Br
F
Ph
Ph
Me
O
N
5 mol%
Cu(OTf)2
Ph
Ph
+
N
R
toluene, 60 °C, 3h
OH
1a
10
11
1a
1a
3o, 94
3p, 91
2j
N
R
Me
2a R = Me
2b R = H
2c R = Bn
2d R = Ph
2e R = Ts
3a R = Me, 98% (table 1)
3b R = H, 68%
3c R = Bn, 69%
2k
3d R = Ph, 93%
3e R = Ts, no reaction
N
Me
MeOOC
(continued on next page)
Scheme 2. Effect of various groups on indole nitrogen.

6578
N. T. Patil et al. / Tetrahedron Letters 50 (2009) 6576–6579
Ph
Ph
Table 2 (continued)
O
N
Entry
12
1
2
3, Yieldb (%)
5 mol% Cu(OTf)2
O
+
NO2
N
toluene, 60 °C
91%
Ph
Ph
3a
Me
2a
6
1a
3q, 78f
Me
2l
N
Me
Scheme 3. Cu(OTf)2-catalyzed reaction between 2a with 6.
3rg
2m
13
1a
N
Me
nHex
N
5 mol% Cu(OTf)2
a
Reaction conditions: 1 (0.46 mmol), 2 (0.38 mmol), 5 mol %, Cu(OTf)2, toluene
nHex
+
(0.25 M), 60 °C, 3 h.
N
Me
toluene, 60 °C
b
N
Me
Isolated yields based on indoles.
Inseparable mixture of diastereomers in the ratio of 1:1 was obtained.
Inseparable mixture of diastereomers in the ratio of 2:1 was obtained.
Indole 2a was recovered in 70% yield. Average of two runs.
c
2a
9
d
e
Scheme 4. Cu(OTf)2-catalyzed reaction between 2a with 1-octyne.
f
Reaction mixture was stirred for 12 h.
g
Only trace amount of product was detected by 1H NMR spectroscopy.
5 mol% Cu(OTf)2
O
was obtained from 1d and 1e, respectively (entries 3 and 4). To our
surprise, alkynol 1f after reacting with 2a gave 3j only in 20% yield;
2a was recovered in 70% yield (entry 5). This observation is in con-
trast to the previously known reactions wherein the authors have
reported the reaction of 1f with N-methyl indole 2a in high
yields.7,8 The reason for this lack of reactivity is not clear at pres-
ent; however, it became obvious that the Thorpe–Ingold effect15
is necessary for this formal hydroalkoxylation–hydroarylation
reaction.16 Next, we investigated the reactions of various indoles
with 1a. The reaction of 1a with indoles 2f, 2g, and 2h gave prod-
ucts 3k, 3l, and 3m, respectively, in excellent yields (entries 6–8).
As shown in entries 9 and 10, halo-substituted indoles 2i and 2j
also reacted well with 1a giving rise to the products 3n and 3o,
respectively. The reaction of 2k, bearing –COOMe group at C-6,
with 1a gave 3p in high yield (entry 11), while that of 2l having
strong electron-withdrawing –NO2 group at C-4 required longer
reaction time to obtain 3q in 78% yield (entry 12). However, meth-
ylated 7-azaindole 2m reacted sluggishly with 1a to give 3r only in
trace amount even after stirring for 12 h (entry 13). This could be
probably due to the deactivation of Cu(OTf)2 catalyst by the co-
ordination with pyridine nitrogen in 2n. It should be noted that
the reaction is applicable to alkynols containing terminal al-
kynes.17 3-Decyne-1-ol did not give the desired product when re-
acted with 2a under the present reaction conditions.
Concerning mechanism, the first step would be the complexa-
tion of Cu(II) catalysts to the alkyne function in 1a which leads
to intermediate 4 (Fig. 1, cycle I). The cyclization step may then oc-
cur directly by the attack of proximal hydroxyl group leading to
vinylcopper intermediate 5. The next step would be the proto-
demetalation to generate exocyclic enol ether 6 with release of cat-
alyst. Once 6 is formed, it enters another catalytic cycle where
Cu(OTf)2 is supposed to act as a Lewis acid (cycle II). Thus, the Le-
wis acid catalyzes the formation of oxonium ion 7 from enol ether
6. Intermolecular nucleophilic addition of the indole 2a to 7 (cf. 8)
followed by re-aromatization and proto-demetalation leads to the
final product 3a with liberation of catalyst. Thus, in short, Cu(OTf)2
acts as transition metal catalyst in cycle I and Lewis acid catalyst in
cycle II.18 Such kind of dual role exhibited by a single metal cata-
lyst has been documented in the literature.19
+
1a
N
N
toluene, 60 °C
82%
Ph
Ph
Ph
Ph
10
Scheme 5. Cu(OTf)2-catalyzed reaction between 1a with N-benzyl pyrrole.
under the standard copper catalysis conditions (Scheme 4). The
product 9 was not formed; 2a was recovered in quantitative yield.
The catalyst Cu(OTf)2 was also shown to be appropriate for C-2
functionalization of pyrroles. Thus, when a toluene solution of N-
benzyl pyrrole reacted with 1a in the presence of 5 mol % catalyst,
the C-2 functionalized pyrrole 10 was obtained in 82% yield
(Scheme 5).
In conclusion, we have shown that inexpensive and easily avail-
able Cu(II) salts catalyze the formal hydroalkoxylation–hydroaryla-
tion of alkynes. Interestingly, it was found that the Thorpe–Ingold
effect is operating for this cyclization reaction. An applicability of
this catalytic system has also been shown for the C-2 functionali-
zation of N-benzylpyrroles. The reaction can also be run at room
temperature at the expense of time. The tolerance of indoles con-
taining electron-withdrawing and electron-donating substituents,
and alkynol substrates bearing sterically-demanding substituents
in the tether are the important features of this copper(II)-catalyzed
transformation.
Acknowledgments
We gratefully acknowledge financial support by the Council of
Scientific and Industrial Research, India. NTP is grateful to Dr. J. S.
Yadav, Director, IICT, and Dr. T. K. Chakraborty, Director, CDRI,
for their support and encouragement.
References and notes
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Nevado, C.; Echavarren, A. M. Synthesis 2005, 167–182; Recent examples: (c)
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F. J.; Sordo, T.; Campomanes, P. Chem. Eur. J. 2005, 11, 5735–5741; (d) Peng, A.-
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To confirm unequivocally the intermediacy of exocyclic enol
ether, we have conducted an experiment as shown in Scheme 3.
Treatment of N-methyl indole 2a with 2-methylene-4,4-diph-
enyltetrahydrofuran 620 under standard condition gave C-3 func-
tionalized indole 3a in 91% yield (Scheme 3).
To completely rule out the mechanism involving direct addition
of C3–H bond of indoles to alkynes, we treated 2a with 1-octyne
3. (a) Fañanás, F. J.; Fernández, A.; Çevic, D.; Rodríguez, F. J. Org. Chem. 2009, 74,
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N. T. Patil et al. / Tetrahedron Letters 50 (2009) 6576–6579
6579
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J = 9.0 Hz, 1H), 3.70 (s, 3H), 3.27 (d, J = 12.5 Hz, 1H) 2.95 (d, J = 12.5 Hz, 1H),
1.50 (s, 3H); 13C NMR (100 MHz, CDCl3): d 147.2, 146.1, 137.5, 128.2, 127.9,
127.2, 127.1, 125.9, 125.8, 125.2, 124.4, 122.8, 121.2, 120.0, 118.7, 109.2, 82.7,
75.9, 56.9, 51.8, 32.6, 30.1; IR (film):
m
max 3019, 2976, 1521, 1476, 1423, 1210,
1046, 928, 769 cmꢁ1
368.2014.
;
HRMS calcd for C26H25NO (M++H) 368.2020, found
15. (a) Eliel, E. L. Stereochemistry of Carbon Compounds; McGraw-Hill: New York,
1962; (b) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107, 1080–
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Saito, A.; Oka, Y.; Nozawa, Y.; Hanzawa, Y. Tetrahedron Lett. 2006, 47, 2201–
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775–779.
12. One of the reviewers suggested that trace amount of TfOH generated in the
reaction mixture may be responsible for catalyzing the reaction. However, the
reaction between 1a and 2a with 5 mol % TfOH under standard conditions did
not give 3a, clearly indicating that copper salts are necessary to catalyze the
present transformation.
17. For metal catalyzed reactions of terminal alkynes, see: (a) Barluenga, J.;
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G. C. J. Am. Chem. Soc. 2002, 124, 4572–4573.
18. The catalyst is essential for both catalytic cycles and this has been confirmed
by the following facts; Alkynol 1a did not form 6 without Cu(OTf)2 in toluene at
60 °C when being heated for 3 h. Similarly under the same reaction conditions
6 did not react with 2a without Cu(OTf)2 catalyst.
13. To a toluene (1.5 ml, 0.25 M) solution of 1a (108 mg, 0.46 mmol) and 2a
(50 mg, 0.38 mmol) in 2 ml vial was added Cu(OTf)2 (8 mg, 5 mol %) under
nitrogen atmosphere. The mixture was stirred at 60 °C for 3 h. Then, the
reaction mixture was filtered through a pad of silica gel with ethyl acetate as
an eluent and the solvent was removed under reduced pressure. The residue
was purified by flash silica gel column chromatography using ethyl acetate/
hexane (10:90) as eluent to obtain 3a (137 mg, 98%, based on indole).
14. Characterization data for 3a: Thick liquid, Rf 0.6 (hexane/EtOAc = 80/20); 1H
NMR (300 MHz, CDCl3): d 7.6 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.28 (t,
J = 7.7 Hz, 2H), 7.21–7.01 (m, 9H), 6.83 (s, 1H), 4.76 (d, J = 9.0 Hz, 1H), 4.24 (d,
19. Selected examples: (a) Pérez, A. G.; López, C. S.; Marco Contelles, J.; Faza, O. N.;
Soriano, E.; de Lera, A. R. J. Org. Chem. 2009, 74, 2982–2991; (b) Xiao, Y.; Zhang,
J. Angew. Chem. Int. Ed. 2008, 47, 1903–1906; (c) Asao, N.; Nogami, T.;
Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764–765.
20. The exocyclic enol ether 6 was prepared by the following procedure: To a
toluene (1.5 ml, 0.28 M) solution of 1a (100 mg, 0.42 mmol) in a 2 ml vial was
added Cu(OTf)2 (7 mg, 5 mol %) under nitrogen atmosphere. The mixture was
stirred at 60 °C for 3 h. Then, the reaction mixture was filtered through a pad of
silica gel with ethyl acetate as an eluent and the solvent was removed under
reduced pressure. The residue was directly used without further purification.