An efficient route to 2,3-disubstituted indoles via reductive alkylation using H2 as reductant

Article abstract of DOI:10.1016/j.tetlet.2011.03.099

An efficient route to 2,3-disubstituted indoles was developed via reductive alkylation of 2-substituted indoles using hydrogen as a clean and atom economic reductant under ambient pressure.

Full text of DOI:10.1016/j.tetlet.2011.03.099

Tetrahedron Letters 52 (2011) 2837–2839
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient route to 2,3-disubstituted indoles via reductive alkylation using
H2 as reductant
Liang-Liang Cao a, Duo-Sheng Wang b, Guo-Fang Jiang a, , Yong-Gui Zhou b,
⇑
⇑
a College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
b State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route to 2,3-disubstituted indoles was developed via reductive alkylation of 2-substituted
indoles using hydrogen as a clean and atom economic reductant under ambient pressure.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 January 2011
Revised 12 March 2011
Accepted 22 March 2011
Available online 30 March 2011
Keywords:
2,3-Disubstituted indoles
Reductive alkylation
Pd/C–H2
Substituted indoles are important structures due to their wide
distribution in nature products and biologically active molecules.1
Among them, 2,3-disubstituted indole, bearing substitutes at both
C-2 and C-3 positions, is a particular subclass of substituted in-
doles, which are the core nucleus of many promising therapeutic
agents.2 Considering the significance of this kind of compounds, a
variety of synthetic methods have been developed over the past
hundred years. For example, the venerable Fischer indole synthesis
was discovered as early as 1883,3 and recently various transition-
metal-catalyzed transformations were developed.4 Despite the
progress achieved, continual emergence of novel biologically active
indole-containing natural products promotes the development of
new and convenient access to 2,3-disubstituted indoles.5
ployed this method to get the desired compounds using triethylsi-
lane as the reductant. Though triethylsilane is efficient, its atom
economy is low and the further purification is relatively complex.
Meanwhile, hydrogen gas is considered as a clean reductant and
its application in indoles’ reductive alkylation has not been re-
ported up to now despite the operational simplicity and atom
economy. Herein, we described an efficient route to 2,3-disubsti-
tuted indoles via reductive alkylation of simple 2-substituted in-
doles with aldehydes or ketones using H2 as a clean and atom
economy reductant under ambient pressure.
As we know, benzylic alcohol can be conveniently reduced by
Pd/C–H2 system in the presence of acid.11 We envisaged that the
dehydration reduction of Friedel–Crafts reaction products, 3-(
hydroxyalkyl) indoles 4, might be feasible under Pd/C–H2 system.
So, dehydration reduction of 3-( -hydroxyalkyl) indoles 4 was
a-
Among the numerous methods developed, the most direct and
divergent method to 2,3-disubstituted indoles is via C-3 Friedel–
Crafts alkylation reaction of simple and commercially available
2-substituted indoles with aldehydes or ketones.6 Nevertheless,
a
investigated using Pd/C as a catalyst in the presence of a weak acid
(PhCO2H) with H2 (1 atm). To our delight, the desired products 2
were obtained in excellent yields (Scheme 2). Encouraged by these
results, direct reductive alkylation of 2-substituted indoles with
aldehydes or ketones in one pot was investigated using hydrogen
gas as reductant in the presence of Brønsted acid.
Initial studies were conducted using 2-methylindole and benz-
aldehyde (1.1 equiv) as a model reaction with H2 (1 atm) as the
reductant (Table 1). Firstly, the reaction was carried out in THF
using PhCO2H as the acid under room temperature. The mixture
was stirred for 4 h and to our disappointment no desirable reaction
occurred (Table 1, entry 1). In principle, strong acid and low tem-
perature facilitate the Friedel–Crafts reaction,7–10 but poor results
were still obtained when the reaction was carried out in THF (Table
1, entries 2 and 3). Then, the effect of solvent on the reactivity was
the products are 3-(a-hydroxyalkyl) indoles and an extra step of
reduction has to be performed to obtain 3-alkyl substituted in-
doles. Reductive alkylation that is based on tandem Friedel–Crafts
alkylation and removing of hydroxyl could occur under mild condi-
tion, thus C-3 alkyl substituted indoles can be attained in one pot
(Scheme 1). Due to its high efficiency in the synthesis of C-3 substi-
tuted indoles, reductive alkylation has been studied by several
groups. Steele,7 Mahadevan,8 Campbell,9 and Zhang10 have em-
⇑
Corresponding authors. Tel./fax: +86 411 84379220 (Y.-G.Z.); tel.: +86 731
88821861; fax: +86 731 88713642 (G.-F.J.).
E-mail addresses: guofangjiang@yahoo.com.cn (G.-F. Jiang), ygzhou@dicp.ac.cn
(Y.-G. Zhou).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.099

2838
L.-L. Cao et al. / Tetrahedron Letters 52 (2011) 2837–2839
Table 1
R2
R2
Optimization of reaction condition of reductive alkylationa
R3
R4
Ph
Pd/C, H2 (1 atm), Acid
NH
O
HN
+
PhCHO
R1
Solvent, T
R1
N
H
N
H
7
1a
3a
2a
R2
R1
R3
R4
N
H
Entry
Solvent
Temp (°C)
Acidb (1.5 equiv)
Yieldc (%)
Acid
1
R4
1
2
3
4
5
6
7
8
THF
THF
THF
Toluene
DCM
DCM
DCM
DCM
25
25
0
0
0
0
0
0
PhCO2H
TFA
TFA
TFA
TFA
<5
<5
<5
29
95
62
83
<5
R3
R3
O
R4
OH
R3
R4
3
R2
R1
R2
R1
Acid
R2
R1
Acid
N
H
N
N
TsOHÁH2O
H
H
1
4
5
CSA
PhCO2H
Previous Work: Et3SiH
a
Conditions: 1a (1.0 mmol), 3a (1.1 mmol), acid (1.5 mmol), 5% Pd/C (15 mg).
TFA: trifluoroacetic acid; TsOHÁH2O: p-toluenesulfonic acid monohydrate; CSA:
b
camphorsulfonic acid.
This Work: Pd/C, H2 (1 atm)
c
Isolated yields based on 1a.
R4
R3
Table 2
R2
R1
Reductive alkylation of indoles with various aldehydes and ketonesa
N
H
R4
2
R3
R1
O
Pd/C, H2 (1 atm)
R2
R1
+
R3
R4
Scheme 1. Reductive alkylation of indoles.
R2
N
H
CF3CO2H, CH2Cl2
N
3
1
H
2
HO
R
R
Pd/C, H2 (1 atm),PhCO2H
Entry13
R1
R2
R3
R4
Yieldb (%)
N
H
THF, rt
N
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
H
H
5-F
H
H
H
H
H
Ph
i-Pr
Cy
H
H
H
H
H
H
H
H
H
H
H
H
95 (2a)
96 (2b)
89 (2c)
81 (2e)
95 (2f)
92 (2g)
99 (2h)
93 (2i)
83 (2j)
68 (2k)
72 (2l)
94 (2m)
62 (2n)
95 (2o)
29 (2p)
82 (2p)
H
4
2
n-Pentyl
2-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-FC6H4
Ph
i-Pr
2b
Cy
2c
R
Ph
2a
Et
2d
)
Yield(%)
75 (
)
97 (
)
93 (
)
91 (
Scheme 2. The reduction of 2-methyl-3-(a-hydroxyalkyl)indoles 4 under Pd/C–H2
9
system.12
10
11
12
13
14
15c
16d
Ph
H
–(CH2)5–
–(CH2)5–
Ph
examined. CH2Cl2 was found to be the most effective among the
solvents tested, this may attribute to CH2Cl2 facilitated Friedel–
Crafts reaction, and the yield of the desired product was sharply in-
creased to 95% (Table 1, entry 5). In addition to TFA, we compared
the effect of several other Brønsted acids such as TsOH, CSA, and
PhCO2H. PhCO2H failed to deliver the product (Table 1, entry 6),
TFA showed the best catalytic reactivity. Thus, the optimized con-
dition was established as: Pd/C–H2 (1 atm)/CH2Cl2/TFA/0 °C.
With the optimized conditions in hand, we turned our attention
to an investigation of the scope of this transformation. The results
are summarized in Table 2. As expected, various aldehydes worked
well under the standard reaction conditions. Particularly, aliphatic
aldehydes were also good reaction partners, moderate to excellent
yields were obtained (Table 2, entries 2–4). Remarkably, the trans-
formation is also tolerant of ortho-substitution in aromatic alde-
hydes, and the steric hindrance had no effect on the reaction
(Table 2, entries 5 and 7). The effect of the electronic properties
of the substituents on the phenyl ring of the aryl aldehydes was
also investigated. Generally, substrate bearing electron-donating
substituents showed high reactivity and 2-methoxy-benzaldehyde
gave the highest yield (Table 2, entry 7), whereas an electron-with-
drawing group decreased the efficiency. Take 4-fluoro-benzalde-
hyde for example, the yield was dramatically decreased to 68%
Me
Me
Me
Me
Me
Ph
a
Conditions: 1 (2.0 mmol), 3 (2.2 mmol), 5% Pd/C (30 mg), CF3CO2H (3.0 mmol),
0 °C.
b
Isolated yields based on 1.
The reaction was carried out at 0 °C.
The reaction was carried out at 40 °C.
c
d
(Table 2, entry 10). Various substituted indoles reacted smoothly,
affording the products in moderate to excellent yields. The elec-
tron-withdrawing group (5-F) of the indole core gave a slight de-
creased yield, and steric hindrance (2-Ph) had no obvious
influence on the outcome of the reaction (Table 2, entries 11 and
12). Notably, ketones were also compatible in this reaction. When
cyclohexanone was employed, 95% yield was obtained (Table 2, en-
try 14). However, when acetophenone reacted with 2-methylin-
dole, only 29% conversion was obtained. Fortunately, increasing
the reaction temperature to 40 °C, yield of 2p was increased to
82% (Table 2, entries 15 and 16).
It is noted that the reductive alkylation of indole 1a also could
be carried out in an enlarged scale with Pd/C–H2 (1 atm) system.

L.-L. Cao et al. / Tetrahedron Letters 52 (2011) 2837–2839
2839
2. (a) Jacotot, B.; Banga, J. D.; Pfister, P.; Mehra, M. Br. J. Clin. Pharmacol. 1994, 38,
257; (b) Walsh, T. F.; Toupence, R. B.; Ujjainwalla, F.; Young, J. R.; Goulet, M. T.
Tetrahedron 2001, 57, 5233.
Ph
Pd/C, H2 (1 atm)
+
PhCHO
3. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.
4. For recent some reviews on synthesis of indoles and substituted indoles, see:
(a) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449; (b)
Gil, C.; Brase, S. J. Comb. Chem. 2009, 11, 175; (c) Barluenga, J.; Rodriguez, F.;
Fananas, F. J. Chem. Asian J. 2009, 4, 1036; (d) Bandini, M.; Eichholzer, A. Angew.
Chem., Int. Ed. 2009, 48, 9608; (e) Metwally, M. A.; Shaaban, S.; Abdel-Wahab, B.
F.; El-Hiti, G. A. Curr. Org. Chem. 2009, 13, 1475; (f) Hajicek, J. Collect. Czech.
Chem. Commun. 2007, 72, 821; (g) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875; (h) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (i)
Agarwal, S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl, M. P.; Reddy, K.
R.; Knolker, H. J. Curr. Org. Chem. 2005, 9, 160.
N
H
CF3CO2H, CH2Cl2
N
H
1a
2a
1a
2a
50.0 mmol
10.0 mmol
2.04 g, 92% yield 10.78 g, 97% yield
Scheme 3. Scale up of reductive alkylation of indole 1a.
5. Selected examples of synthesis of indoles and substituted indoles, see: (a)
Arcadi, A.; Cianci, R.; Ferrara, G.; Marinelli, F. Tetrahedron 2010, 66, 2378; (b)
Boyer, A.; Isono, N.; Lackner, S.; Lautens, M. Tetrahedron 2010, 66, 6468; (c)
Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile, P. Org.
Lett. 2010, 12, 3279; (d) Chiba, S.; Zhang, L.; Sanjaya, S.; Ang, G. Y. Tetrahedron
2010, 66, 5692; (e) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett.
2010, 12, 3736; (f) Monguchi, Y.; Mori, S.; Aoyagi, S.; Tsutsui, A.; Maegawa, T.;
Sajiki, H. Org. Biomol. Chem. 2010, 8, 3338; (g) Oh, C. H.; Karmakar, S.; Park, H.;
Ahn, Y.; Kim, J. W. J. Am. Chem. Soc. 2010, 132, 1792.
6. Bandini, M.; Umani-Ronchi, A. Catalytic Asymmetric Friedel–Crafts Alkylations;
Wiley-WCH, 2009.
7. Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. Tetrahedron Lett. 1993, 34,
1529.
As illustrated in Scheme 3, the desired product 2a was obtained in
92% yield at 10 mmol scale and in 97% yield at 50 mmol scale,
respectively.
In summary, we have developed an efficient and facile approach
to 2,3-disubstituted indoles via reductive alkylation of simple 2-
substituted indoles with aldehydes or ketones using hydrogen as
a clean and atom economic reductant under ambient pressure.
The main advantages of this route are excellent yields, simple
operation, and purification procedures.
8. Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C. Tetrahedron Lett. 2003, 44,
4589.
Acknowledgment
9. Campbell, J. A.; Bordunov, V.; Broka, C. A.; Dankwardt, J.; Hendricks, R. T.; Kress,
J. M.; Walker, K. A. M.; Wang, J.-H. Tetrahedron Lett. 2004, 45, 3793.
10. Rizzo, J. R.; Alt, C. A.; Zhang, T. Y. Tetrahedron Lett. 2008, 49, 6749.
11. (a) Rylander, P. N. Hydrogenation Methods; Academic: New York, 1985; (b)
Hudlicky, M. Reductions in Organic Chemistry, second ed; ACS: Washington, DC,
1996.
We are grateful to financial support from National Natural Sci-
ence Foundation of China (J0830415 & 21032003).
Supplementary data
12. General procedure from 2-methyl-3-(
a
-hydroxyalkyl)-indoles
4
to 2,3-
disubstituted indoles 2: compound 4 (2.0 mmol) was dissolved in 10 mL THF,
and PhCO2H (0.2 mmol), 5% Pd/C (30 mg) was added. The mixture was stirred
at room temperature under H2 (1 atm, hydrogen balloon) atmosphere for 12 h,
then the product was purified by flash chromatography on silica gel using
EtOAc/hexanes (1:5) as eluent.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.099.
13. General procedure from 2-substituted indole 1 to 2,3-disubstituted indoles 2: a
solution of 2-substituted indole 1 (2 mmol) and the aldehyde or ketone 3
References and notes
(2.2 mmol) in CH2Cl2 (10 mL) was added dropwise to
a stirred, ice-cold
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt,
J. J. Med. Chem. 1988, 31, 2235; (b) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A.
J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939; (c)
Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances,
fourth ed; Thieme: New York, 2001.
solution of TFA (3.0 mmol) and 5% Pd/C (30 mg) in CH2Cl2 (5 mL) under H2
(1 atm, hydrogen balloon) atmosphere. The mixture was stirred at 0 °C and
monitored by TLC until completed (4–8 h). After evaporation of the solvent
under reduced pressure, the product was purified by flash chromatography on
silica gel using EtOAc/hexanes (1:5) as eluent.