Domino sonogashira coupling/cyclization reaction catalyzed by copper and ppb levels of palladium: A concise route to indoles and benzo[b]furans

Article abstract of DOI:10.1002/adsc.201000730

Both indoles and benzo[b]furans can be obtained in high yield by the reactions of 2-iodoaniline derivatives and 2-iodophenols with terminal alkynes under mild conditions, namely in the presence of cuprous iodide (10-mol%) and a base in ethanol or 1,4-dioxane. Further investigation reveals that palladium contaminants as low as 100 ppb are responsible for these successful couplings. It is worth noting that simple aliphatic substituted terminal alkynes could be tolerated to smoothly produce indole and benzo[b]furan derivatives. Copyright

Full text of DOI:10.1002/adsc.201000730

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DOI: 10.1002/adsc.201000730
Domino Sonogashira Coupling/Cyclization Reaction Catalyzed by
Copper and ppb Levels of Palladium: A Concise Route to Indoles
and Benzo[b]furans
Ruiping Wang,a Song Mo,a Yongzhong Lu,a and Zengming Shenb,*
a
Department of Chemistry, College of Life and Environment Sciences, Shanghai Normal University, 100 Guilin Road,
Shanghai, 200234, Peopleꢀs Republic of China
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240,
b
Peopleꢀs Republic of China
Fax : (+86)-21-5474-1297; e-mail: shenzengming@sjtu.edu.cn
Received: December 8, 2010; Published online: March 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000730.
Abstract: Both indoles and benzo[b]furans can be
obtained in high yield by the reactions of 2-iodoani-
line derivatives and 2-iodophenols with terminal al-
kynes under mild conditions, namely in the pres-
ence of cuprous iodide (10 mol%) and a base in
ethanol or 1,4-dioxane. Further investigation reveals
that palladium contaminants as low as 100 ppb are
responsible for these successful couplings. It is
worth noting that simple aliphatic substituted termi-
nal alkynes could be tolerated to smoothly produce
indole and benzo[b]furan derivatives.
Indole and benzo[b]furan are important compounds
which display a wide range of biological activities and
exist in many natural products as a backbone of their
structural frameworks.[9] Classic methods for making
indoles and benzo[b]furans generally involve multi-
step reactions, a particular substrate, or display unsat-
isfactory functional group tolerance.[10] In comparison
to the conventional synthetic approaches, domino
transition metal-catalyzed coupling/cyclization reac-
tions for the synthesis of indoles and benzo[b]furans
starting from 2-haloanilines and 2-halophenols with
alkynes are particularly attractive.[7,8,10c] Recently,
Cacchi et al.[11a] and Ma et al.[11b] independently de-
scribed the Cu-catalyzed one-pot synthesis of 2-substi-
tuted indoles from 2-halotrifluoroacetanilide and ter-
minal alkynes by a Sonogashira-type coupling/cycliza-
tion sequence using Venkataramanꢀs catalyst
Keywords: benzo[b]furans; copper catalysis; in-
doles; palladium contaminant; ppb levels
{[CuACHTUNGTRNENUG(phen)HCATUNTGERN(NUNG PPh3)2]NO3} or CuI/PPh3 and CuI/l-pro-
The palladium-catalyzed Sonogashira reaction has line, respectively. The analogous approach to synthe-
proven to be a powerful approach for preparing aryl- sizing benzo[b]furans in the presence of catalytic Cu/
ACHTUNGTRENNUNG
alkynes and conjugated enynes by coupling of aryl or ligand has also been reported by several groups.[12] In
alkenyl halides or triflates to terminal alkynes in the their important pioneering studies, however, the
presence of a copper(I) cocatalyst.[1] The use of 1– scope of these approaches for synthesizing indoles is
10 mol% PdACHTUNGTRENNUNG(PPh3)2Cl2 and CuI as the catalytic generally limited to aryl terminal alkynes and it
system in the typical Sonogashira coupling is prob- cannot be extended to simple aliphatic terminal al-
lematic for large-scale industrial use due to the cost kynes. Moreover, ligands play a significant role in re-
of palladium. In order to overcome this disadvantage, action efficiency and selectivity in these cases. More
much effort has been directed toward exploring new recently, Novꢁk reported the effect of ppb levels of
catalytic systems.[2,3,4,5,6] Owing to the cheap and envi- palladium on the “copper-catalyzed” Sonogashira
ronmentally friendly aspects of copper catalysis, much coupling.[13a] Similar phenomena were also found in
attention has been paid to investigating the Cu-cata- other coupling reactions.[3e,13b–f] Herein, we wish to
lyzed Sonogashira-type reactions in the absence of demonstrate the synthesis of indoles and benzo[b]fur-
palladium species.[6] Some reported successful exam- ans by the CuI-catalyzed Sonogashira coupling/cycli-
ples encouraged us to explore the cascade reaction of zation reactions of 2-haloaniline derivatives and 2-hal-
2-haloanilines or 2-halophenols with terminal alkynes ophenols with aryl and alkyl terminal alkynes in the
to produce indoles or benzo[b]furans in one pot.
absence of a phosphine ligand. Further investigation
Adv. Synth. Catal. 2011, 353, 713 – 718
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713

Ruiping Wang et al.
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Table 1. Effect of base on the domino coupling/cyclization
pling-cyclization process performed in the presence of
CuI (10 mol%) and DBU in EtOH at reflux could
provide the desired indole product 3 exclusively.
proACHTUNGTRENNUNG
cess.[a]
Under these optimal conditions, we examined the
scope of this reaction by varying the substituents on
the nitrogen atom of 2-iodoaniline and the terminal
alkyne component. Gratifyingly, when R1 was an elec-
tron-withdrawing group, a wide range of aryl or
simple alkyl substituted terminal alkynes could be tol-
erated (Table 2). p-Tolylacetylene 2b reacted with N-
mesyl-2-iodoaniline 1a to afford the corresponding 3b
in 76% yield as well as 14% yield of 4b with cleavage
of the Ms group, likely due to the in situ alcoholysis
Entry
Base
Yield[b] [%]
1
2
3
4
5
6
7
8
t-BuOK
KOH
K2CO3
DABCO
Et3N
pyridine
quinoline
isopropylamine
dimethylamine
benzylamine
DBU
N.R.
N.R.
<1
N.R.
N.R.
N.R.
<1
<1
2
[14]
À
of the N Ms group in the basic system
(Table 2,
entry 2). An electron-withdrawing CF3 substituent on
the aryl ring seems to facilitate the cleavage of the
À
N Ms group, giving 3c and 4c in 58% and 42% yields,
respectively (Table 2, entry 3). It is worth noting that
simple aliphatic terminal alkynes were also trans-
formed to indole products with remarkable efficiency,
which were not tolerated in previous reports of
domino Cu-catalyzed coupling/cyclization.[11] The n-
propyl, n-butyl and n-hexyl substituted terminal al-
kynes smoothly underwent coupling/cyclization with
1a to produce indoles 3d–3f in good to high yields
(70–88%, Table 2, entries 4–6). To our delight, the
tert-butyl substituted indole 3g was also successfully
isolated in moderate yield (Table 2, entry 7). Upon
heating the solution to 1208C in a sealed tube, the
9
10
11[c]
12[c,d]
31
78
90
DBU
[a]
Reaction conditions: 1a (0.07 mmol, 1 equiv.), 2a
(0.19 mmol, 2.7 equiv.), CuI (10 mol%), base (0.35 mmol,
5 equiv.), i-PrOH (2 mL), reflux, 48 h.
Yield determined by GC with naphthalene as an internal
standard.
[b]
[c]
[d]
Isolated yield.
EtOH as solvent.
À
yield of 2-tert-butylindole 4g with a free N H moeity
indicates that palladium contaminants in the reagents was increased to 83% (Table 2, entry 8). Furthermore,
used for these reactions are responsible for these suc- the reactions of alkyl substituted terminal alkynes
cessful couplings.
bearing free hydroxy and ether functional groups with
We started with readily available N-mesyl 2-iodo- 1a favorably led to the formation of indoles 3h and 3i
ACHTUNGTRENNUNG
shown in Table 1, a significant base effect was ob-
In addition, when the R1 on the nitrogen of 2-io-
served: DBU (1,8-diazabicyclo-[5.4.0]undec-7-ene) doaniline was a tosyl or a CF3CO group, the indole
was the most effective base for promoting the domino products with different substituents at the 2-position
coupling/cyclization, affording indole 3a in 78% iso- could be obtained (Table 2, entries 11–17). Interest-
lated yield (Table 1, entry 11) along with a trace ingly, we observed that the N-trifluoroacetyl group
amount of the competing homocoupling product from was completely alcoholysed in situ under basic condi-
À
phenylacetylene. Benzylamine was a less effective tions, affording only indole 4 with a free N H moiety
base to mediate the formation of indole 3a (31% (Table 2, entries 15–17). However, when the substitu-
yield, Table 1, entry 10). Other bases, such as t-BuOK, ent on the nitrogen atom was an acetyl group, or a hy-
KOH, K2CO3, DABCO, Et3N, pyridine, quinoline, iso- drogen, or a methyl group, the reactions did not work
À
propylamine and dimethylamine, were ineffective for well, which may be due to the lower acidity of the N
this cascade reaction (Table 1, entries 1–9). Among H proton as compared to that of the N-sulfonyl or N-
the solvents screened, we found that the protic i- trifluoroacetyl analogues (Table 2, entries 18–21).
PrOH and EtOH could efficiently afford N-mesyl-2-
Next, we attempted to apply this method to synthe-
phenylindole 3a in 78% yield and 90% yield, respec- size benzo[b]furans. However, the reaction of 2-iodo-
tively (Table 1, entries 11 and 12). At the same time, phenol 5 with phenylacetylene 2a under the standard
À
we observed the formation of the free N H indole 4a conditions optimized for indole synthesis exclusively
in a small amount (10%) when using ethanol gave the phenylacetylene homocoupling product with-
(Table 2, entry 1). Accordingly, the Cu-catalyzed cou- out the formation of the desired benzo[b]furan 6a.
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Adv. Synth. Catal. 2011, 353, 713 – 718

Domino Sonogashira Coupling/Cyclization Reaction Catalyzed by Copper and ppb Levels of Palladium
Table 2. Domino Sonogashira coupling/cyclization for the synthesis of indoles.[a]
Entry
1
R2
Time [days]
Yield [%] of 3[b]
Yield [%] of 4[b]
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1d
1e
1f
Ph (2a)
2
2
2
3
3
3
3
3
3
1
2
3
6
4
1
3
2.5
6
6
4
3
90 (3a)
76 (3b)
58 (3c)
83 (3d)
88 (3e)
70 (3f)
51 (3g)
–
93 (3h)
90 (3i)
>99 (3j)
67 (3k)
84 (3l)
54 (3m)
–
10 (4a)
14 (4b)
42 (4c)
–
–
–
–
83 (4g)
–
–
–
–
–
–
p-tolyl (2b)
p-CF3C6H4 (2c)
n-Pr (2d)
n-Bu (2e)
(CH2)5CH3 (2f)
t-Bu (2g)
t-Bu (2g)
CH2OH (2h)
CH2OPh (2i)
Ph (2a)
n-Bu (2e)
CH2OPh (2i)
CH2OH (2h)
Ph (2a)
4[c,d]
5[c]
6
7[c,d]
8[d,e]
9
10
11
12[c]
13
14
15
16
17
68 (4a)
65 (4n)
50 (4c)
38 (4o)
0
A
–
–
–
0
0
0
p-CF3C6H4 (2c)
n-Pr (2e)
Ph (2a)
Ph (2a)
Ph (2a)
18[c,d]
19[f]
20[f]
21
0
0
[a]
Reaction conditions: 1 (0.25 mmol, 1 equiv.), 2 (0.5 mmol, 2 equiv.), CuI (10 mol%), base (5 equiv.), EtOH (1 mL), reflux.
Isolated yield.
Performed in a sealed tube at 808C.
2 (1.25 mmol, 5 equiv.).
Performed in a sealed tube at 1208C.
[b]
[c]
[d]
[e]
[f]
t-BuOK as a base (0.5 mmol, 2 equiv.).
After screening a series of bases and solvents, we dis-
On the other hand, prompted by recent findings on
covered that inexpensive KOH as a base in 1,4-diox- the Sonogashira coupling catalyzed by ppb-level Pd
ane could facilitate the synthesis of 2-phenylbenzo[b]- contaminants from reagents or glassware,[3e,13] we de-
furan 6a in 91% yield and efficiently suppress the pro- cided to investigate whether the palladium contami-
duction of the homocoupling product (Table 3, nants are responsible for the successful coupling in
entry 1). Under these mild conditions, other aryl sub- our reactions. In order to exclude the ppb-level im-
stituted terminal alkynes, such as p-tolyl and p- purities as much as we could, all the equipment, in-
CF3C6H4, smoothly underwent transformation to pro- cluding glassware, new stir bars, etc., were washed
duce benzo[b]furans 6b and 6c in high yields (Table 3, well with detergent, and then soaked in aqua regia for
entries 2 and 3). The n-butyl, n-hexyl and even the at least 1 hour followed by washing well with distilled
sterically bulky tert-butyl substituted benzo[b]furans water. The organic reagents employed in the reaction
6d–f could also be afforded in moderate yields were purified prior to use and the Pd contaminants
(Table 3, entries 4–6). We were pleased that the ether were determined by AAS (1.7 ng/g Pd in substrate 1b,
and amine substituted alkyl terminal alkynes 2i–k <1 ng/g Pd in phenylacetylene and DBU, respective-
could smoothly participate in these reactions to afford ly). To insure the purity of the copper source, we pur-
the corresponding benzo[b]furans 6h and 6i in >99% chased two bottles of CuI (99.999%) from Aldrich
and 76% yields, respectively (Table 3, entries 7 and with different batch numbers. The remaining Pd im-
8). However, 2h containing a free hydroxy group gave purities were ascertained by ICP-MS, which showed
benzo[b]furan 6g in low yield even after 6 days one bottle to contain only 4 ng/g of Pd, while the
(Table 3, entry 9).
other one has 627 ng/g of Pd contaminant, and CuI
Adv. Synth. Catal. 2011, 353, 713 – 718
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Ruiping Wang et al.
Table 4. Effect of ppb levels of palladium.[a]
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Table 3. Domino Sonogashira coupling/cyclization for the
synthesis of benzo[b]furans.[a]
CuI/Pd(PPh3)2Cl2
Yield[b]
Entry
R2
Time [days]
Yield [%] of 6[b]
>99% (Aladdin, purified, 35 ng/g Pd content)
>99.999% (Aldrich, 4 ng/g Pd content)
>99.999% (Aldrich, 627 ng/g Pd content)
>99.999% (Aldrich, 4 ng/g Pd)+100 ppb [Pd]
>99.999% (Aldrich, 4 ng/g Pd)+no DBU
32%
36%
86%
93%
N.R.
N.R.
N.R.
1
2
Ph (2a)
2
1
1
4.5
4.5
6
1.5
6
91 (6a)
82 (6b)
88 (6c)
48 (6d)
40 (6e)
46 (6f)
>99 (6h)
76 (6i)
p-tolyl (2b)
p-CF3C6H4 (2c)
n-Bu (2e)
ACHTUNGTRENNUNG(CH2)5CH3 (2f)
t-Bu (2g)
CH2OPh (2i)
CH2NHPh (2k)
CH2OH (2h)
3
4[c]
5
no CuI+100 ppb PdCAHTUNGTRENNUNG
no CuI+no PdACTHUNGTRENNUNG
6[c]
7
[a]
8
9
Substrate 1b, phenylacetylene and DBU were purified by
recrystallization or fresh distillation prior to use.
GC yield.
6
20 (6g)
[b]
[a]
Reaction conditions: 5 (0.3 mmol, 1 equiv.), 2 (0.6 mmol,
2 equiv.), CuI (10 mol%), base (0.6 mmol, 2 equiv.), 1,4-
dioxane (1 mL), performed in a sealed tube at 1008C.
Isolated yield.
tigate the cause of these findings, small amounts of
Pd were added to the reaction with >99.999% CuI
(4 ng/g Pd content). Using only a 100 ppb level of
[b]
[c]
2 (1.5 mmol, 5 equiv.).
Pd
from Aladdin used in the previous reactions contains served. In contrast, in the absence of CuI, the added
35 ng/g of Pd. Pd(PPh3)2Cl2 could not catalyze this transfomation.
ACHTUGNTNERN(UNG PPh3)2Cl2, a significant increase in yield was ob-
AHCTUNGTRENNUNG
We started examining the role of trace amounts of Not surprisingly, no reaction was observed when nei-
Pd contaminants for the reaction with 1b as a model ther CuI nor Pd were added. These experiments dem-
substrate since this substrate did not afford the free onstrated the essential role of the copper catalyst for
À
N H indole 4j. As shown in Table 4, when >99% this reaction and reveal that our reaction is catalyzed
CuI (35 ng/g Pd) and >99.999% CuI (4 ng/g Pd) were by both CuI and Pd contaminants down to a level of
empoyed low yields were obtained, however, when 100 ppb from reagents. At the same time, we were
the reation was run using 10 mol% CuI (627 ng/g Pd pleased that the reaction can be reproducible in the
content), in fact, 112 ppb of palladium from CuI was presence of trace amounts of Pd.
introduced into the reaction, affording the desired
Based on previous mechanistic studies,[13a,15] a plau-
product 3j in 86% yield. These findings led us to be- sible reaction mechanism is outlined in Scheme 1.
lieve that, although the reaction occurs without the First, Pd/Cu-catalyzed Sonogashira coupling of 2-io-
direct addition of a Pd catalyst, it is catalyzed by ppb doaniline or 2-iodophenol with the terminal alkyne
levels of palladium contaminants originating from the affords intermediate 7. Then, with the assistance of a
commercially available CuI. In order to further inves- base, the nitrogen atom or oxygen acts as a nucleo-
Scheme 1. Plausible mechanism for Pd/Cu-catalyzed coupling/cyclization reaction.
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Adv. Synth. Catal. 2011, 353, 713 – 718

Domino Sonogashira Coupling/Cyclization Reaction Catalyzed by Copper and ppb Levels of Palladium
mittee (ssd09018). We appreciate Prof. Xiyan Lu, Prof. Vy
phile and attacks the copper coordinated alkyne 8 to
give the indole-containing copper intermediate 9. Pro-
tonolysis of 9 can provide the corresponding indole
(or benzo[b]furan) product.
M. Dong, Prof. Zhaoguo Zhang, Prof. Xiaobing Wan, Mr.
Peter K. Dornan and Dr. Yang Li for their proofreading and
valuable discussion.
In conclusion, we have demonstrated a concise and
practical method for the synthesis of indoles and ben-
zo[b]furans. Both heterocycles could be obtained in References
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or 1,4-dioxane without using a phosphine ligand. It is
worth noting that simple aliphatic substituted termi-
nal alkynes could be tolerated to smoothly produce
indole and benzo[b]furan derivatives. Therefore, these
methods are complementary to those of the previous-
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tions and an atmosphere of dry nitrogen. EtOH and dioxane
were freshly distilled and stored with 4 ꢃ molecular sieves
under a nitrogen atmosphere. Reactions were monitored
using thin-layer chromatography (TLC). All copper catalysts
were purified prior to use according to literature methods.
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detector. Infrared spectra were recorded on an AVATAR
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Synthesis of 1-(Methanesulfonyl)-2-phenyl-1H-indole
(3a) as an Example
Under nitrogen, a mixture of N-mesyl-2-iodoaniline (74 mg,
0.25 mmol), CuI (4.8 mg, 10 mol%), and DBU (177 mL,
1.25 mmol) was dissolved in EtOH (1 mL), and ethynylben-
zene (65 mL, 0.5 mmol) was added dropwise with stirring
into the reaction. The reaction system was stirred at reflux
and monitored by TLC. Upon completion, the mixture was
diluted with H2O and extracted with EtOAc (3ꢄ15 mL).
The extract was washed with brine (2ꢄ15 mL) and dried
over Na2SO4. After evaporation, the residue was purified
via flash column chromatography on silica gel with petrole-
um ether/ethyl acetate [50/1–15/1 (v/v)] as the eluent to
afford the white solid 3a in 90% yield and 4a in 10% yield
resulting from the cleavage of the Ms group.
Acknowledgements
This work was supported by the National Natural Sciences
Foundation of China (20852004, 20902058), Shanghai Pu-
jiang Program (09J1408100) and Shanghai Education Com-
Adv. Synth. Catal. 2011, 353, 713 – 718
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ruiping Wang et al.
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