Bronsted acid-catalyzed decarboxylative redox amination: Formation of N-alkylindoles from azomethine ylides by isomerization

Article abstract of DOI:10.1021/jo102218v

A Bronsted acid-catalyzed decarboxylative redox amination involving aldehydes with 2-carboxyindoline for the synthesis of N-alkylindoles is described. The decarboxylative condensations of aldehydes with 2-carboxyindoline produce azomethine ylides in situ,

Full text of DOI:10.1021/jo102218v

pubs.acs.org/joc
ylides (eq 3).5 When we investigated the azomethine ylide
Brønsted Acid-Catalyzed Decarboxylative Redox
Amination: Formation of N-Alkylindoles from
Azomethine Ylides by Isomerization
generated from aldehyde with 2-carboxyindoline, it was
interesting to find that it was bound to form N-alkylindole
4 by isomerization rather than react with nucleophiles (eq 4).
N-Alkylindoles are very important building blocks not
only in biologically active natural products, but also in phar-
maceutical compounds.6 Traditionally, treatment of alkyl
halides with indole was a straight method.7 The requirement
of equivalent base and low atom-efficiency restricted the
application of this methodology. Recently, transition metal-
catalyzed reactions also have become a very powerful tool in
this area.8 Herein, we report a Brønsted acid-catalyzed
decarboxylative redox amination for the synthesis of N-
alkylindoles.
Hui Mao,† Sichang Wang,† Peng Yu,‡ Huiqing Lv,§
Runsheng Xu,† and Yuanjiang Pan*,†
†Department of Chemistry, Zhejiang University,
Hangzhou, 310027, China,
‡Department of Chemistry, Zhejiang Normal University,
Jinhua, 321004, China, and §College of Pharmaceutical
Science, Zhejiang Chinese Medical University,
Hangzhou 310053, China
panyuanjiang@zju.edu.cn
Received November 12, 2010
A Brønsted acid-catalyzed decarboxylative redox amina-
tion involving aldehydes with 2-carboxyindoline for the
synthesis of N-alkylindoles is described. The decarbox-
ylative condensations of aldehydes with 2-carboxyindo-
line produce azomethine ylides in situ, which then
transform into N-alkylindoles by isomerization.
Initially, we were interested in performing a three-compo-
nent reaction described by Seidel.5 However, instead of
the expected product, the N-alkylindole 4a was isolated
with 43% yield (eq 5). Obviously, the reaction between
aldehyde with 2-carboxyindoline gave the product 4a
while the nucleophile 2-methylindole did not participate
in this process. Since such a decarboxylative redox amina-
tion is a potential synthetic method for the formation of
N-alkylindoles, we tried to further investigate this amina-
tion under different conditions.
Decarboxylation of R-amino acids with carbonyl com-
pounds, known as the Strecker degradation, has been ex-
tensively studied since it was proposed in 1862.1 Azomethine
ylide was supposed to act as the key intermediate in the
process and Grigg had demonstrated this idea exhaus-
tively.2 In 1979, Cohen reported a reaction involving pro-
line and 2-hydroxyacetophenones to afford 1 (eq 1).3 Banner
designed a MCR of proline, aldehyde, and maleimide for the
synthesis of 2 by using an intermolecular [3 þ 2] cycloaddi-
tions of azomethine ylides with alkene (eq 2).4 Recently,
Seidel described a three-component decarboxylative of ami-
no acids involving a new reaction pathway for azomethine
(1) Schonberg, A.; Moubasher, R. Chem. Rev. 1952, 50, 261.
(2) (a) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc., Chem.
Commun. 1987, 49. (b) Grigg, R.; Thianpatanagul, S. J. Chem. Soc., Chem.
Commun. 1984, 180.
(3) Cohen, N.; Blount, J. F.; Lopresti, R. J.; Trullinger, D. P. J. Org.
Chem. 1979, 44, 4005.
(5) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798.
(6) (a) Sundberg, R. J., The Chemistry of Indoles; Academic Press: New
York, 1970. (b) Sundberg, R. J. Indoles; Academic Press: London, UK, 1966.
(c) Sexton, J. E. Indoles; Wiley: New York, 1983. (d) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045.
(4) Schrer, K.; Morgenthaler, M.; Paulini, R.; Obst, U.; Banner, D. W.;
Schlatter, D.; Benz, J.; Stihle, M.; Diederich, F. Angew. Chem., Int. Ed. 2005,
44, 4400.
(7) (a) Barbero, N.; SanMartin, R.; Domınguez, E. Tetrahedron Lett.
2009, 50, 2129. (b) Knaack, M.; Emig, P.; Bats, J. W. Eur. J. Org. Chem. 2001,
3843.
DOI: 10.1021/jo102218v
r
Published on Web 01/18/2011
J. Org. Chem. 2011, 76, 1167–1169 1167
2011 American Chemical Society

Mao et al.
JOCNote
TABLE 1. Evaluation of Potential Catalyst and Solventa
TABLE 2. Decarboxylative Amination of 2-Carboxyindoline with
Various Aldehydesa
entry
R
4
yield (%)b
entry
catalyst
b
solvent
toluene
toluene
EtOH
water
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
time (h)
4a yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20c
4-MeOC6H4
4-MeC6H4
4-N(Me)2C6H4
2-MeOC6H4
2-MOMOC6H4
C6H5
4-FC6H4
2-FC6H4
4-ClC6H4
2-ClC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
74
70
64
72
62
78
75
72
78
75
76
73
82
80
69
81
79
80
69
65
1
2
3
4
5
6
7
8
-
24
24
24
30
24
24
24
24
24
24
trace
45
20
trace
trace
67
55
60
50
74
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
AcOH
TFA
p-TsOH
PhCOOH
9
4j
4k
4l
10d
4-BrC6H4
2-BrC6H4
aAll the reactions were conducted with 2-carboxyindoline (1.5 equiv,
0.75 mmol), p-anisaldehyde (1 equiv, 0.5 mmol), and catalyst (0.2 equiv,
0.1 mmol) in 3 mL of solvent under reflux in nitrogen atmosphere. bNo
catalyst was used. cIsolated yield of the corresponding product. d4 A MS
(20 mg) was added.
4-NO2C6H4
3-NO2C6H4
4-CF3C6H4
2-pyridinyl
2-furanyl
2-thiophenyl
1-naphthylc
9-anthracenylc
4m
4n
4o
4p
4q
4r
4s
4t
Treatment of a mixture of 2-carboxyindoline9 and p-
anisaldehyde in toluene under reflux in the absence of
catalyst afforded little product (Table 1, entry 1). Addition
of benzoic acid (0.2 eqiv) to the reaction led to formation of
the desired product with 45% yield (Table 1, entry 2). Since
the result did not seem so satisfactory, we then began to study
the solvent effect, and 1,4-dioxane was found to be the best
medium compared with toluene, EtOH, water, and THF
(Table 1, entries 2-6). In addition, different Brønsted acids
were also evaluated as catalysts for the reaction and benzoic
acid was shown to be the optimal catalyst (Table 1, entries
6-9). It was interesting to find that addition of 4 A MS gave
a higher yield (Table 1, entry 10).
aAll the reactions were conducted with 2-carboxyindoline (1.5 equiv,
0.75 mmol), aldehyde (1 equiv, 0.5 mmol), PhCOOH (0.2 equiv,
0.1 mmol), and 4 A MS (20 mg) in 3 mL of 1,4-dioxane under reflux
in nitrogen atmosphere. bIsolated yield of the corresponding product.
c2-Carboxyindoline (0.9 mmol) was added.
SCHEME 1. Decarboxylative Redox Amination of Phthalal-
dehydes
With the optimal conditions in hand, we then began to
explore the substrate scope of this reaction. As shown in
Table 2, a variety of aromatic aldehydes bearing various
types of substituents were employed in the reaction to give
the corresponding products with moderate to good yields
(Table 2, entries 1-15). Notably, the aldehyde substrates
with electron-donating groups on the aromatic ring af-
forded a little lower yields (Table 2, entries 1-5). The
benzaldehyde formed N-benzylindole with 78% yield
(Table 2, enrtry 6). Moveover, the heteroaromatic alde-
hydes also could react with 2-carboxyindoline with satis-
factory yields (Table 2, entries 16-18). Finally, we focused
on the reaction of 1-naphthaldehyde and 9-anthraldehyde.
To our delight, 69% and 65% yield were obtained, respec-
tively (Table 2, entries 19 and 20). While aliphatic aldehydes
were employed, no desired product was observed.
Having established the scope of this reaction, we then
turned our attention to the decarboxylative redox amination
of phthalaldehydes. It was satisfying to find that p-phthal-
aldehyde and o-phthalaldehyde reacted with 2-carboxyindo-
line (3 equiv) smoothly to afford the corresponding prod-
ucts, albeit with longer time and lower yields (Scheme 1).
According to the reaction results and related research,2,5
we proposed a mechanism for the decarboxylative redox
amination based on the formation of azomethine ylide. As
shown in Scheme 2, in the presence of an acid, direct
condensation of aldehyde 6 with 2-carboxyindoline 5 pro-
duces oxazolidin-5-one A,5 which is subsequently converted
to azomethine ylide B by releasing one molecular CO2.
Protonation of azomethine ylide results in the formation
of the iminium ion pair C and D. Deprotonation of the
(8) (a) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmesb, I. P. Adv.
Synth. Catal. 2006, 348, 851. (b) Ackermann, L. Org. Lett. 2005, 7, 439.
(c) Barluenga, J.; Aquino, A. J.; Aznar, F.; Valdes, C. J. Am. Chem. Soc.
2009, 131, 4031. (d) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem.
2005, 117, 407. (e) Bahn, S.; Imm, S.; Mevius, K.; Neubert, L.; Tillack, A.;
Williams, J. M. J.; Beller, M. Chem.;Eur. J. 2010, 16, 3590.
(9) For the synthesis of 2-carboxyindolines, see: (a) Viswanathan, R.;
Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003,
125, 163. (b) Gademann, K.; Bethuel, Y.; Locher, H. H.; Hubschwerle, C. J.
Org. Chem. 2007, 72, 8361. (c) Liu, J.; Qian, C.; Chen, X. Synthesis 2010, 3,
403.
1168 J. Org. Chem. Vol. 76, No. 4, 2011

Mao et al.
JOCNote
SCHEME 2. Proposed Mechanism for Decarboxylative Redox
Amination
by isomerization. Further studies are in progress in our
laboratory.
Experimental Section
General Procedure for the Synthesis of 4a-t. To a solution of
p-anisaldehyde (0.5 mmol) and 2-carboxyindoline (0.75 mmol)
in 1,4-dioxane (3 mL) were added PhCOOH (0.1 mmol) and 4 A
MS (20 mg) under nitrogen atmosphere. The mixture was stirred
at room temperature for 0.1 h and then refluxed for another
24 h. Then the mixture was cooled and purified by flash column
chromatography to give the product 4a as as colorless oil with
74% yield. 1HNMR (DMSO, 500 MHz) δ 7.55 (d, J = 7.8 Hz,
1H), 7.46 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H), 7.10 (t, J = 7.2 Hz,
1H), 7.02 (t, J = 7.1 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.46 (d,
J = 3.1 Hz), 5.32 (s, 2H), 3.73 (s, 3H). 13C NMR (DMSO, 125
MHz) δ 159.7, 136.7, 131.3,130.0, 129.6, 129.5, 122.2, 121.5,
120.1, 115.0, 111.3, 101.9, 56.1, 49.7. HRMS m/z 238.1229 ([M þ
H]þ), calcd for ([C16H15NO þ H]þ) 238.1226.
General Procedure for the Synthesis of 4u,v. To a solution
of p-phthalaldehyde (0.5 mmol) and 2-carboxylindoline
(1.5 mmol) in 1,4-dioxane (3 mL) were added PhCOOH
(0.1 mmol) and 4 A MS (20 mg) under nitrogen atmosphere.
The mixture was stirred at room temperature for 0.1 h and then
heated at reflux for another 36 h. Then the mixture was cooled
and purified by flash column chromatography to give the
product 4u as a white solid with 55% yield. Mp 120-122 °C.
1H NMR (DMSO, 500 MHz) δ 7.56 (d, J = 7.7 Hz, 2H), 7.44 (d,
J = 3.0 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.11 (m, 6H), 7.02 (t,
intermediate C at C-3 directly leads to the formation of
final product 4 (path a).10 Alternatively, hydrolysis of the
intermediate D produces indoline and regenerates the
starting aldehyde (path b). The aromatization is considered
to be the orginal motivation of this decarboxylative redox
process.
In conclusion, a Brønsted acid-catalyzed decarboxylative
redox amination has been developed for the synthesis of N-
alkylindoles from aldehydes with 2-carboxyindoline. Be-
sides, we also have disclosed a novel mode of reactivity for
azomethine ylides, which transform into N-alkylindoles
J = 7.5, 7.1 Hz, 2H), 6.47 (d, J = 3.0 Hz, 2H), 5.34 (s, 4H). 13
C
NMR (DMSO, 125 MHz) δ 138.5, 136.8, 130.1, 129.4, 128.3,
122.3, 121.6, 120.2, 111.2, 102.1, 49.9. HRMS m/z 337.1694
([M þ H]þ), calcd for ([C24H20N2 þ H]þ) 337.1699.
Acknowledgment. Financial support from Natural Science
Foundation of China (Nos. 21025207 and 20975092) is
greatly acknowledged.
Supporting Information Available: Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) An isotopic labeling reaction also was carried out to support our
proposed mechanism. For the detailed information about the isotopic
labeling reaction, see the Supporting Information.
J. Org. Chem. Vol. 76, No. 4, 2011 1169