Construction of nitrogen heterocycles bearing an aminomethyl group by copper-catalyzed domino three-component coupling-cyclization

Article abstract of DOI:10.1021/jo901328q

(Chemical Equation Presented) A direct approach to 2-(aminomethyl)indoles by copper-catalyzed domino three-component coupling-cyclization of 2-ethynylanilines with a secondary amine and aldehyde has been developed. By use of a cyclic or acyclic secondary

Full text of DOI:10.1021/jo901328q

pubs.acs.org/joc
Construction of Nitrogen Heterocycles Bearing an Aminomethyl Group
by Copper-Catalyzed Domino Three-Component Coupling-Cyclization
Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received June 25, 2009
A direct approach to 2-(aminomethyl)indoles by copper-catalyzed domino three-component
coupling-cyclization of 2-ethynylanilines with a secondary amine and aldehyde has been developed.
By use of a cyclic or acyclic secondary amine and aldehyde (paraformaldehyde, aliphatic or aromatic
aldehydes) in the presence of 1 mol % of CuBr, 2-ethynylanilines were converted to a variety of
substituted 2-(aminomethyl)indoles in good to excellent yields. Utilizing this domino reaction and
C-H functionalization at the indole C-3 position, polycyclic indoles were readily synthesized.
Construction of benzo[e][1,2]thiazine and indene motifs by the reaction of sulfonamide and malonate
congeners is also presented.
Introduction
biological activities.4 Particularly, the 2-(aminomethyl)-
indole motif represents the key structures that exist in several
biologically active indole alkaloids5 as well as synthetic
compounds6 including calindol.7 Most of the existing
synthetic routes to 2-(aminomethyl)indoles start from the
functionalized indoles such as indole-2-carboxylic acid or its
derivatives, which limit the structural diversity of the target
molecules that can be readily synthesized.8
Development of efficient and practical methods that mini-
mize requisite reagents, cost, byproducts, time, andseparation
processes1 for the desired transformation is of growing inter-
est in modern organic chemistry. For diversity-oriented synth-
esis of structurally complex molecules, it is desirable to
convert easily available materials to the target compounds
by multibond forming processes with simple operation. While
considerable attention has been focused on the multicompo-
nent reaction (MCR),2 a catalytic cascade reaction3 including
MCR would be more valuable to accomplish these tasks.
The indole nucleus is a prominent structural motif found
in numerous natural and unnatural products with vital
During the course of our efforts directed toward
the development of useful transformations of allenic
ꢀ
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Published on Web 08/12/2009
DOI: 10.1021/jo901328q
r
2009 American Chemical Society

Ohta et al.
JOCArticle
SCHEME 1. Domino Three-Component Coupling-Cyclization
SCHEME 2. Indole Formation from the Proposed Intermediate 8
formation, and synthesis of benzo[e][1,2]thiazine derivatives
and indene-1,1-dicarboxylate are also presented.
Result and Discussion
Synthesis of 2-(Aminomethyl)indoles with Use of Several
Amines and Aldehydes. To improve the original reaction
conditions using a stoichiometric amount of CuBr and 3
equiv of (i-Pr)2NH (Scheme 1), our initial attempt was made
by reacting N-tosyl-2-ethynylaniline 1a, paraformaldehyde
2a (2 equiv), piperidine 3b (1.1 equiv), and CuBr (100 mol %)
in the presence of Et3N (2 equiv), which would decrease the
loading of piperidine (Table 1, entry 1).17 The reaction
proceeded rapidly to give the desired 2-(aminomethyl)indole
7b in 71% yield. While use of a catalytic amount of CuBr (10
or 1 mol %) with respect to 1a increased the yield of 7b
(entries 2 and 3), the reaction without CuBr led to the
recovery of 1a. The reaction in the absence of Et3N also
showed efficient conversion into 7b (entry 4). This result can
be explained by the plausible reaction mechanism depicted in
Scheme 1, in which the sulfonamide proton is presumably
transferred to the 3-position of indole. This step could be
mediated by piperidine or the basic substituent in the pro-
duct and/or intermediate. The decreased use of 2a also
produced the desired indole 7b, although a prolonged reac-
tion time (1-12 h) was necessary (entries 5 and 6). Use of
CuBr2, CuCl, or CuI as the catalyst was also tolerated in this
three-component indole formation (entries 7-9).
Next, we examined the scope of the 2-(aminomethyl)-
indole formation with various symmetrical secondary
amines (Table 2) under the optimized conditions (Table 1,
entry 4). The reaction of 2-ethynylaniline 1a with bulky
diisopropylamine 3a (1.1 equiv) and paraformaldehyde 2a
(2 equiv) in the presence of CuBr (1 mol %) gave the expected
indole derivatives 7a in 81% yield (entry 1). Pyrrolidine 3c
also showed efficient conversion into the corresponding
indoles 7c (entry 3). The use of volatile diethylamine 3d
successfully afforded 7d, although 2 equiv of Et2NH was
needed (entry 4). Secondary amines containing removable
allyl and benzyl groups 3e and 3f, respectively, were also
acceptable as amine components when the reactions were
conducted with a prolonged reaction time (entries 5 and 6).18
We also investigated the three-component synthesis of
2-(aminomethyl)indoles using various aldehyde components
compounds,9,10 we found that the reaction of N-tosylated
2-ethynylaniline 1a with paraformaldehyde 2a and diisopro-
pylamine 3a in dioxane in the presence of copper(I) bromide
11
ꢀ
(Crabbe conditions) afforded a 2-(aminomethyl)indole
derivative 7a in 92% yield (Scheme 1) without forming the
expected [2-(N-tosylamino)phenyl]allene. This reaction can
be rationalized by Mannich-type MCR followed by indole
formation through intramolecular hydroamination toward
the activated alkyne moiety of a plausible intermediate 6.
Actually, the reaction of the identically prepared propargyl
amine 812 with CuBr (5 mol %) gave the expected indole 7b in
quantitative yield (Scheme 2).
To develop an atom-economical, direct synthetic method
to 2-(aminomethyl)indoles without producing any salts as
byproducts,13-15 we conducted a careful survey of the above
indole formation. Herein we report full details of our in-
vestigation into the copper(I)-catalyzed domino three-
component coupling-cyclization reaction of 2-ethynylani-
line derivatives.16 Two-step construction of polycyclic
indoles by combination with palladium-catalyzed C-H
functionalization at the indole C-3 position, scope
and limitation of the asymmetric three-component indole
(9) For our recent studies on allene chemistry, see: (a) Ohno, H.;
Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42,
1749–1753. (b) Ohno, H.; Miyamura, K.; Takeoka, Y.; Tanaka, T. Angew.
Chem., Int. Ed. 2003, 42, 2647–2650. (c) Ohno, H.; Hamaguchi, H.; Ohata,
M.; Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744–8754.
(d) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T. Angew. Chem., Int.
Ed. 2005, 44, 1513–1517. (e) Ohno, H.; Mizutani, T.; Kadoh, Y.; Miyamura,
K.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5113–5115. (f) Ohno, H.;
Kadoh, Y.; Fujii, N.; Tanaka, T. Org. Lett. 2006, 8, 947–950. (g) Ohno, H.;
Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T. Angew. Chem., Int. Ed. 2007, 46,
6325–6328. (h) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007,
9, 4821–4824. (i) Okano, A.; Mizutani, T.; Oishi, S.; Tanaka, T.; Ohno, H.;
Fujii, N. Chem. Commun. 2008, 3534–3536. (j) Inuki, S.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2008, 10, 5239–5242.
(10) For recent reviews, see: (a) Ohno, H. Chem. Pharm. Bull. 2005, 53,
1211–1226. (b) Ohno, H. Yakugaku Zasshi 2005, 125, 899–925.
ꢀ
(11) Searles, S.; Nassim, Y.; Li, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe,
P. J. Chem. Soc., Perkin Trans. 1 1984, 747–751.
(12) For the preparation of 8, see the Supporting Information.
(13) For indole synthesis with dihaloarenes, see: (a) Ackermann, L. Org.
Lett. 2005, 7, 439–442. (b) Kaspar, L. T.; Ackermann, L. Tetrahedron 2005,
61, 11311–11316.
(14) For indole synthesis with haloanilines, see: (a) Olivi, N.; Spruyt, P.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2004, 45, 2607–2610.
(b) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour, M.; Farina, V.; Senanayake, C.
(17) We consider decreasing the amount of amine component is impor-
tant and economical especially when using more valuable amines such as 11
(Scheme 4).
(18) When benzylamine was used instead of a secondary amine, dimeric
compound 18 was produced in 82% yield (100 °C, 3 h, then reflux, 1 h).
ꢀ
H. Org. Lett. 2006, 8, 3271–3274. (c) Sanz, R.; Guilarte, V.; Perez, A.
Tetrahedron Lett. 2009, 50, 4423–4426.
(15) For two-component indole synthesis via a Sonogashira-type reac-
tion, see: (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843–
3846. (b) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3307–3310.
(16) A portion of this study (several reactions in Tables 1, 2, and 5, and
Scheme 3) was already reported in a preliminary communication: Ohno, H.;
Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295–2298.
J. Org. Chem. Vol. 74, No. 18, 2009 7053

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TABLE 1. Optimization of Reaction Conditions with Use of Ethynyl-
aniline 1a and Piperidine 3ba
TABLE 3. Reactions with Various Aldehydesa
entry
1
aldehyde 2
conditions
product (%yield)b
(HCHO)n
equiv
additive
(equiv)
entry CuX (mol %)
time (h) yieldb (%)
n-PrCHO (2b)
80 °C for
0.25 h
reflux for 3 h
7g [R=n-Pr] (quant.)
1
2
3c
4
5
6
7
8
9
CuBr (100)
CuBr (10)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr2 (1)
CuCl (1)
CuI (1)
2.0
2.0
2.0
2.0
1.5
1.1
2.0
2.0
2.0
Et3N (2)
Et3N (2)
Et3N (2)
0.25
0.25
0.25
0.25
1
71
84
92
87
75
70
79
87
83
2
3
4
i-PrCHO (2c)
PhCHO (2d)
(4-CO2Me)
C6H4CHO (2e)
(4-Me)
C6H4CHO (2f)
(2-Br)
C6H4CHO (2g)
7h [R=i-Pr] (77)
reflux for 10 h 7i [R=Ph] (70)
reflux for 3 h
reflux for 3 h
reflux for 4 h
7j [R=(4-CO2Me)C6H4]
(76)
7k [R=(4-Me)C6H4] (85)
5
6
12
0.25
0.25
0.25
7l [R=(2-Br)C6H4] (65)
aReactions were carried out with 1a (0.18 mmol), 2 (2.0 equiv), amine
3b (1.1 equiv), and CuBr (1 mol %) in 1,4-dioxane (1.5 mL) at 80 °C.
bYields of isolated products.
aUnless otherwise stated, reaction was carried out with 1a (0.18
mmol, 1 equiv), 2a (equivalents shown), 3b (1.1 equiv), and a copper
salt (catalyst amount shown) in 1,4-dioxane (3 mL) at 80 °C. bYields of
isolated products. cThe reaction was conducted on 1.25 mmol scale.
TABLE 4. Asymmetric Synthesis of 2-(Aminomethyl)indolesa
TABLE 2. Reactions with Various Aminesa
entry
amine 3
time (h)
product
yieldc (%)
1
2
3
4
5
6
(i-Pr)2NH (3a)
piperidine (3b)
pyrrolidine (3c)
Et2NH (3d)b
(allyl)2NH (3e)
Bn2NH (3f)
0.25
0.25
0.25
0.25
0.5
7a
7b
7c
7d
7e
7f
81
87
89
89
78
78
2
aUnless otherwise stated, reactions were carried out with 1a (0.18
mmol), 2a (2.0 equiv), amine 3 (1.1 equiv), and CuBr (1 mol %) in 1,4-
dioxane (3 mL) at 80 °C. b2 equiv of amine 3d was used. cYields of
isolated products.
entry
ligand
(R)-QUINAP dioxane rt, 24 h
(R)-QUINAP THF rt, 72 h
(R)-QUINAP benzene rt, 72 h
(R)-QUINAP toluene rt, 72 h
solvent conditions yieldb (%) product (% ee)c
1
2
3
4
5
6
7
quant.
86
86
(þ)-7g (47)
(þ)-7g (30)
(þ)-7g (43)
(þ)-7g (22)
(-)-7g (59)
(-)-7g (56)
(-)-7g (63)
94
(Table 3). The reaction of 2-ethynylaniline 1a with n-butyral-
dehyde 2b and piperidine 3b in the presence of CuBr effi-
ciently gave the indole 7g bearing a branched substituent in
excellent yield (quant., entry 1). The bulky isobutyraldehyde
2c required an elevated reaction temperature and prolonged
reaction time leading to a slightly decreased yield of 7h (77%,
entry 2). Benzaldehyde 2d was tolerated for this indole
formation (entry 3). Similarly, use of a variety of substituted
aryl aldehydes afforded the desired indoles 7j-l in good
yields (entries 4-6).19
(S)-PINAP
(S)-PINAP
(S)-PINAP
dioxane rt, 10 h
toluene rt, 120 h
benzene rt, 120 h
quant.
93
quant.
aReactions were carried out with 2-ethynylaniline 1a, CuBr (5 mol %),
and ligand (5.5 mol %) in solvent (2 mL). bYields of isolated products.
cDetermined by chiral HPLC (CHIRALCEL OD-H).
novel asymmetric synthesis of chiral propargylic amines with
excellent ee values through a copper-catalyzed asymmetric
Mannich-type reaction of alkynes with an aldehyde and a
secondary amine using QUINAP as a chiral ligand (up to
98% ee).20 Carreira reported the similar synthesis of pro-
pargylic amine in up to 99% ee with PINAP.21 We initially
examined the asymmetric three-component construction of
We expected that a reaction with a chiral ligand that
coordinates to a copper atom could produce optically active
2-(aminomethyl)indoles. Knochel recently developed a
(19) When acetone was used instead of an aldehyde, Mannich-type
reaction did not proceed and compound 19 was produced.
(20) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763–5766. (b) Gommerman, N.; Knochel,
P. Chem. Commun. 2004, 2324–2325. (c) Gommerman, N.; Knochel, P.
Chem. Commun. 2005, 4175–4177.
€
(21) (a) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971–5973. (b) Aschwan-
den, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437–2440.
7054 J. Org. Chem. Vol. 74, No. 18, 2009

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TABLE 5. Synthesis of Variously Substituted 2-(Aminomethyl)indolesa
aUnless otherwise stated, reactions were carried out with 2-ethynylaniline (0.18 mmol), 2a (2.0 equiv), amine (1.1 equiv), and CuBr (1 mol %) in 1,4-
dioxane (3 mL). b0.37 mmol scale. c4 equiv of Et3N was added before reflux. dYields of isolated products.
the 2-(aminomethyl)indole motif with n-butyraldehyde 2b in
dioxane in the presence of CuBr (5 mol %) and QUINAP (5.5
mol %) (Table 4). The reaction proceeded smoothly even at
room temperature to give the desired 7g in a quantitative yield
but with only 47% ee (entry 1).22 Screening of the reaction
solvent did not improve the asymmetric induction (entries 2-4).
When the reaction was carried out with PINAP in dioxane, 7b
was obtained with a slightly higher ee (59%, ee, entry 5). Use of
PINAP in benzene gave the most promising result (63% ee),
although a prolonged reaction time was necessary (entry 7).
These results suggest that 2-ethynylaniline 1a is a less effective
alkyne component for an asymmetric Mannich reaction.23
Synthesis of Substituted 2-(Aminomethyl)indoles with Use
of Various Ethynylanilines and Secondary Amines. Various
substituted 2-ethynylanilines and asymmetrical secondary
amines were then applied to the domino three-component
coupling-cyclization (Table 5). 2-Ethynylanilines 1b and 1c
substituted by an electron-withdrawing trifluoromethyl or
methoxycarbonyl group at the para position to the amino group
werereactedwithparaformaldehyde2a and dibenzylamine 3f in
the presence of CuBr (1 mol %) to yield indoles 7m (90% yield)
and 7n (91% yield), respectively (entries 1 and 2). Ethynylaniline
1d bearing an electron-donating methyl group at the para
position to the amino group also showed efficient compatibility
leading to the corresponding indole 7o. The reactions with 2-
ethynylanilines 1e and 1f containing an electron-withdrawing
group such as a trifluoromethyl or methoxycarbonyl group at
the meta position were similarly converted into the correspond-
ing indoles 7p (61% yield) and 7q (79% yield), respectively
(entries 4 and 5). The asymmetrical 2-bromoallylamine 3g and
2-bromobenzylamine 3h were also applicable to this indole
formation with use of various 2-ethynylanilines (entries 6-
12), although Et3N was necessary for the cyclization step when
using 2-ethynylanilines 1a and 1d (entries 6 and 9).
Construction of Polycyclic Indoles by Palladium-Catalyzed
C-H Functionalization. A polycyclic indole motif is an
important core framework that is widely found in biologi-
cally active compounds.24 Therefore, development of a
(24) For biologically active polycyclic indoles having a 2-(aminomethyl)
ꢀ
moiety, see: (a) Espada, A.; Jimenez, C.; Debitus, C.; Riguera, R. Tetrahedron
Lett. 1993, 34, 7773–7776. (b) Rashid, M. A.; Gustafson, K. R.; Boyd, M. R.
J. Nat. Chem. 2001, 64, 1454–1456. (c) Glennon, R. A.; Grella, B.; Tyacke,
R. J.; Lau, A.; Westaway, J.; Hudson, A. L. Bioorg. Med. Chem. Lett. 2004, 14,
999–1002. (d) Liu, C.; Masuno, M. N.; MacMillan, J. B.; Molinski, T. F.
Angew. Chem., Int. Ed. 2004, 43, 5941–5945. (e) Sonnenschein, R. N.; Farias,
J. J.; Tenney, K.; Mooberry, S. L.; Lobkovsky, E.; Clardy, J.; Crews, P. Org.
Lett. 2004, 6, 779–782.
(22) It was reported that the copper-catalyzed Mannich reaction of alkynes
in the presence of (R)-QUINAP gave (S)-propargylamines, while the reaction
with (S)-PINAP gave the corresponding (R)-isomers, see refs 20 and 21.
(23) Knochel and Carreira reported that phenylacetylene is a good
component for enantioselective synthesis of propargylic amine with QUI-
NAP or PINAP, see refs 20 and 21.
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TABLE 6. Palladium-Catalyzed C-H Olefinationa
TABLE 7. Palladium-Catalyzed C-H Olefination with Use of
Substituted 2-Ethynylanilinesa
entry
catalyst
ligand
base
solvent
yieldb (%)
entry
R1
CF3
CO2Me
CH3
H
R2
indole
product
yieldb (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
CsOAc
CsOAc
CsOAc
KOAc
CsOAc
DMF
DMA
DMA
DMA
DMA
47
65
7
35
32
1
2
3
4
5
H
H
H
7s
7t
7u
7v
7w
9b
9c
9d
9e
9f
64
54
62
62
77
PPh3
dppm
CF3
CO2Me
H
aReactions were carried out with 2-(aminomethyl)indole 7r, palla-
dium catalyst (10 mol %), ligand (20 mol %), and base (2 equiv) in
solvent (2 mL) at 100 °C for 0.5 h. bYields of isolated products.
aReactions were carried out with 2-(aminomethyl)indole 7, Pd(OAc)2
(10 mol %), PPh3 (20 mol %), and CsOAc (2 equiv) in DMA (2 mL) at
100 °C for 0.5 h. bYields of isolated products.
2a and 1-(1-naphthyl)ethylamine 1126 in the presence of
CuBr directly produced a protected calindol 12. The allyl
and tosyl groups on the nitrogen atoms of 12 were easily
removed by successive treatment with Pd(PPh3)4 (2 mol %)/
NDMBA and TBAF to give calindol 13 in 90% yield over
two steps.
We next envisioned the preparation of benzothiazine-1,1-
dioxide derivatives 15 through domino MCR and cycliza-
tion. Since benzo[e][1,2]thiazine-1,1-dioxides are widely
found in biologically active compounds including non-
steroidal anti-inflammatory drugs (NSAIDs),27 various ap-
proaches to construct this structure have been reported.28
We expected that the use of such a sulfonamide as 14, an
aldehyde, and a secondary amine in the presence of a copper
catalyst would bring about a Mannich-type reaction followed
by 6-endo-dig cyclization29 to afford a benzo[e][1,2]thiazine 15.
The reaction of N-methyl- and N-ethylsulfonamides 14a and
convenient and reliable method for the construction of these
frameworks is strongly required.25 We expected that the
present synthesis of 2-(aminomethyl)indoles via domino
three-component coupling-cyclization would bring about
an extremely useful synthetic route to this class of com-
pounds. Thus, we surveyed the construction of polycyclic
indole skeletons by three-component indole formation fol-
lowed by palladium-catalyzed C-H functionalization at the
C-3 position of indoles. First, 2-(aminomethyl)indole 7r
synthesized by the three-component indole formation
(Table 5, entry 6) was subjected to Pd(OAc)2 (10 mol %),
PPh3 (20 mol %), and CsOAc (2 equiv) in DMF (Table 6,
entry 1). The reaction proceeded cleanly to afford tetra-
hydropyridine-fused indole 9a in 47% yield. When DMA
was used as the reaction solvent, a higher yield of 9a was
observed (65%, entry 2). Further investigation of the palla-
dium catalyst, ligand, and base (entries 3-5) revealed that
the conditions shown in entry 2 were most effective. Encour-
aged by this result, we investigated the reaction with several
2-(aminomethyl)indoles containing an electron-withdraw-
ing and -donating group to obtain variously substituted
tetrahydropyridine-fused indoles 9b-f in moderate to good
yields (Table 7).
We next examined construction of polycyclic indoles by
palladium-catalyzed C-H arylation using 2-(aminomethyl)-
indole 7x, which was prepared from ethynylaniline 1a and
amine 3h (Table 5, entry 12). By treatment with 20 mol % of
Pd(OAc)2 and 40 mol % of PPh3, dihydrobenzazepine-fused
indole 10 was efficiently obtained in 80% yield over 2 steps
(Scheme 3). One-pot three-component indole formation/Pd-
catalyzed C-H arylation also provided polycyclic indole 10
in 84% yield from 1a.
Synthetic Application to Calindol, Benzo[e][1,2]thiazines,
and Indene. Calindol (13), which contains a 2-(aminomethyl)-
indole motif, is a positive modulator of the human Ca2þ
receptor showing a calcimimetic activity.4 This compound
could be easily synthesized by using our domino three-
component indole formation (Scheme 4). As we expected,
the reaction of 2-ethynylaniline 1a with paraformaldehyde
(26) For the preparation of 11, see the Supporting Information.
(27) (a) Lombardino, J. G.; Wiesman, E. H. J. Med. Chem. 1971, 14, 973–
977. (b) Lombardino, J. G.; Wiesman, E. H.; McLamore, W. M. J. Med.
Chem. 1971, 14, 1171–1175. (c) Lombardino, J. G.; Wiesman, E. H. J. Med.
Chem. 1972, 15, 848–849. (d) Zinnes, H.; Lindo, N. A.; Sircar, J. C.;
Schwartz, M. L.; Shavel, J., Jr. J. Med. Chem. 1973, 16, 44–48. (e) Zinnes,
H.; Sircar, J. C.; Lindo, N.; Schwartz, M. L.; Fabian, A. C.; Shavel, J., Jr.;
Kasulanis, C. F.; Genzer, J. D.; Lutomski, C.; DiPasquale, G. J. Med. Chem.
1982, 25, 12–18. (f) Kwon, S.-K.; Park, M.-S. Arch. Pharm. Res. 1992, 15,
251–255. (g) Lazer, E. S.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-
C.; Meng, Z.; Potocki, I.; Hoermann, M.; Snow, R. J.; Tschantz, M. A.;
Kelly, T. A.; McNeil, D. W.; Coutts, S. J.; Churchill, L.; Graham, A. G.;
David, E.; Grob, P. M.; Engel, W.; Meier, H.; Trummlitz, G. J. Med. Chem.
1997, 40, 980–989. (h) Lee, E. B.; Kwon, S. K.; Kim, S. G. Arch. Pharm. Res.
1999, 22, 44–47.
(28) (a) Watanabe, H.; Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J. Org.
Chem. 1969, 34, 919–926. (b) Lombardino, J. G.; Kuhla, D. E. Adv.
Heterocycl. Chem. 1981, 28, 73–126. (c) Motherwell, W. B.; Pennell, A. M.
K. J. Chem. Soc., Chem. Commun. 1991, 877–879. (d) Nemazanyi, A. G.;
Volovenko, Y. M.; Neshchadimenko, V. V.; Babichev, F. S. Chem. Hetero-
ꢀ
cycl. Compd. 1992, 28, 220–222. (e) Manjarrez, N.; Perez, H. I.; Sorıs, A.;
´
Luna, H. Synth. Commun. 1996, 26, 585–591. (f) Manjarrez, N.; Perez, H. I.;
ꢀ
Sorıs, A.; Luna, H. Synth. Commun. 1996, 26, 1405–1410. (g) Takahashi, M.;
´
Morimoto, T.; Isogai, K.; Tsuchiya, S.; Mizumoto, K. Heterocycles 2001, 55,
1759–1769. (h) Layman, W. J.; Greenwood, T. D.; Downey, A. L.; Wolfe, J.
F. J. Org. Chem. 2005, 70, 9147–9155. (i) Vidal, A.; Madelmont, J.-C.;
Mounetou, E. Synthesis 2006, 591–593. (j) Aliyenne, A. O.; Kraiem, J.;
Kacem, Y.; Hassine, B. B. Tetrahedron Lett. 2008, 49, 1473–1475. (k) Zia-ur-
Rehman, M.; Choudary, J. A.; Elsegood, M. R. J.; Siddiqui, H. L.; Khan, K.
M. Eur. J. Med. Chem. 2009, 44, 1311–1316.
(25) For recent synthesis of polycyclic indoles, see: (a) Kusama, H.;
Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 11592–11593. (b)
Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-
Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–1425. (c) Kuroda, N.;
Takahashi, Y.; Yoshinaga, K.; Mukai, C. Org. Lett. 2006, 8, 1843–1845.
(29) Related synthesis of thiazines already has been reported, see:
(a) Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.; Tatini,
L. K.; Babu, J. M.; Pal, M. Tetrahedron 2007, 63, 1775–1789. (b) Barange, D.
K.; Nishad, T. C.; Swamy, N. K.; Bandameedi, V.; Kumar, D.; Sreekanth, B.
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7056 J. Org. Chem. Vol. 74, No. 18, 2009

Ohta et al.
JOCArticle
SCHEME 3. Palladium-Catalyzed C-H Arylation and
One-Pot Formation of Polycyclic Indoles from Ethynylaniline
TABLE 9. Synthesis of 2-(Aminomethyl)indene 17a
entry
solvent
additiveb
temp (°C)
time (h)
yieldc (%)
1
2
3
dioxane
DMF
DMF
80
150
110
2
5
10
0
39
70
(i-Pr)2NEt
aReactions were carried out with 2a (2.0 equiv) and 3a (1.2 equiv) in
solvent (2 mL) in the presence of CuBr (5 mol %). bAdded after
completion of the Mannich type reaction (ca. 30 min, monitored by
TLC). cYields of isolated products.
SCHEME 4. Synthesis of Calindola
reaction/cyclization strategy (Table 9). Disappointingly, the
reaction of malonate derivative 16 with (HCHO)n 2a and
(i-Pr)2NH 3a in dioxane in the presence of CuBr (5 mol %) did
not afford the desired indene 17, only giving the Mannich
adduct in 90% yield (entry 1). A careful evaluation of the
reaction conditions revealed that the use of more polar DMF
as the solvent converted 16 into the desired 2-(aminomethyl)
indene 17 in 39% yield. Addition of (i-Pr)2NEt after comple-
tion of the Mannich reaction efficiently promoted the indene
formation leading to 17 in 70% yield.
Conclusions
aNDMBA=N,N0-dimethylbarbituric acid.
We have developed a novel synthesis of 2-(aminomethyl)-
indoles through a copper-catalyzed domino three-compo-
nent coupling-cyclization. This domino reaction forming
two carbon-nitrogen bonds and one carbon-carbon bond
is the first catalytic multicomponent indole construction
producing water as the only theoretical waste. The use of
the chiral ligand PINAP in the reaction with alkyl aldehydes
produced the corresponding indole bearing a branched sub-
stituent 7g with moderate ee values. This reaction is synthe-
tically useful for diversity-oriented synthesis of not only
2-(aminomethyl)indoles but also tetrahydropyridine- and
benzazepine-fused indoles, using readily available reaction
components. The benzo[e][1,2]thiazine and indene motif can
also be constructed by using a similar domino three-compo-
nent coupling and cyclization strategy.
TABLE 8. Synthesis of Benzo[e][1,2]thiazine-1,1-dioxide Motif by
Three-Component Coupling and Cyclizationa
entry
R
time (h)
product
yieldb (%)
1
2
3
4
5
6
Me (14a)
Et (14b)
(4-CH3)C6H4 (14c)
Ph (14d)
(4-MeO)C6H4 (14e)
(4-Cl)C6H4 (14f)
16
22
3.5
4
3.5
3
15a
15b
15c
15d
15e
15f
34
37
90
92
89
95
Experimental Section
aReactions were carried out with 2a (2.0 equiv) and 3a (1.2 equiv) in
the presence of CuBr (5 mol %) in 1,4-dioxane (3 mL) at 100 °C. bYields
of isolated products.
General Procedure for Synthesis of 2-(Aminomethyl)indole:
Synthesis of 2-[(N,N-Diisopropylamino)methyl]-1-tosylindole
(7a). To a stirred mixture of 2-ethynylaniline 1a (50.0 mg, 0.18
mmol), (HCHO)n (11.1 mg, 0.37 mmol), and CuBr (0.3 mg,
0.0018 mmol) in dioxane (3.0 mL) was added diisopropylamine
3a (28.6 μL, 0.20 mmol) at room temperature under argon, and
the reaction mixture was stirred at 80 °C for 15 min. Concentra-
tion under reduced pressure followed by column chromatogra-
phy purification over silica gel with hexane-EtOAc (10:1)
afforded the indole 7a (57.3 mg, 81%) as a colorless solid: mp
105 °C; 1H NMR (400 MHz, CDCl3) δ 0.98 (d, J=6.6 Hz, 12H,
4 ꢀ CHCH3), 2.33 (s, 3H, ArCH3), 3.01-3.11 (m, 2H, 2 ꢀ CH),
3.92 (d, J=1.5 Hz, 2H, CH2), 6.79 (s, 1H, 3-H), 7.18-7.25 (m,
4H, Ar), 7.41-7.43 (m, 1H, Ar), 7.64-7.67 (m, 2H, Ar), 8.16 (d,
J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8 (4C), 21.5,
44.4, 49.3 (2C), 110.1, 114.4, 120.2, 123.3, 123.5, 126.3 (2C),
14b under standard conditions gave the desired benzothiazines
15a and 15b, respectively, but in low yields (34% and 37%,
respectively, entries 1 and 2, Table 8). Considering that acidity
of the amide proton in 14a and 14b would be insufficient for the
cyclization step, we next examined the reaction of sulfonanilide
derivatives bearing a related structure to 2-ethynylanilines 1.
As we expected, the reaction of sulfonanilide 14c gave the
benzothiazine 15c in high yield (90%, entry 3). Other sufona-
nilides 14d-f were also good reactants in this three-component
thiazine synthesis (entries 4-6).
Finally, we investigated the synthesis of 2-(aminomethyl)-
indene-1,1-dicarboxylate 17 using this domino Mannich-type
J. Org. Chem. Vol. 74, No. 18, 2009 7057

Ohta et al.
JOCArticle
129.8 (2C), 129.9, 136.4, 137.8, 144.4, 144.6; MS (FAB) m/z (%)
385 (MHþ, 100), 284 (75); HRMS (FAB) calcd for
C22H29N2O2S (MHþ) 385.1950, found 385.1953.
132.9, 143.5. Anal. Calcd for C16H24N2O2S: C, 62.30; H, 7.84;
N, 9.08. Found: C, 62.09; H, 7.57; N, 8.88.
Dimethyl 2-[(N,N-Diisopropylamino)methyl]indene-1,1-dicar-
boxylate (17). To a stirred mixture of 16 (51.0 mg, 0.22 mmol),
(HCHO)n 2a (13.2 mg, 0.44 mmol), and CuBr (1.58 mg, 0.011
mmol) in DMF (2 mL) was added diisopropylamine 3a (34.0 μL,
0.24 mmol) at room temperature under argon. After the reaction
mixture was stirred at 110 °C for 30 min, diisopropylethylamine
(77.0 μL, 0.44 mmol) was added to the mixture. The mixture was
additionally stirred at 110 °C for 9.5 h. Concentration under
reduced pressure followed by column chromatography purifica-
tion over alumina with hexane-EtOAc (20:1) gave 17 (52.8 mg,
70%) as a brown oil: IR (neat) 1732 (CdO) cm-1; 1H NMR (500
MHz, CDCl3) δ 1.02 (d, J=14.0 Hz, 12H, 4ꢀCCH3), 3.06-3.11
(m, 2H, 2 ꢀ NCH), 3.50 (d, J=1.1 Hz, 2H, NCH2), 3.73 (s, 6H,
2 ꢀ OCH3), 7.00 (s, 1H, 3-H), 7.15-7.18 (m, 1H, Ar), 7.24-7.31
(m, 2H, Ar), 7.57 (d, J=7.4 Hz, 1H, Ar); 13C NMR (125 MHz,
CDCl3) δ 20.7 (4C), 43.8, 48.7, 53.0 (2C), 70.3, 120.8, 124.8,
125.1, 128.7, 131.6, 141.0, 144.3, 149.4, 168.9 (2C); MS (FAB)
m/z 346 (MHþ, 100), 286 (35), 245 (60); HRMS (FAB) calcd for
C20H28NO4 (MHþ) 346.2018, found 346.2008.
General Procedure for Synthesis of Tetrahydropyridine-Fused
Indole: Synthesis of 2-Butyl-4-methylene-9-tosyl-2,3,4,9-tetra-
hydro-1H-pyrido[3,4-b]indole (9a). The mixture of indole 7r
(50.0 mg, 0.11 mol), Pd(OAc)2 (2.4 mg, 0.011 mmol), PPh3 (5.5
mg, 0.021 mmol), and CsOAc (40.4 mg, 0.021 mmol) in DMA
(2 mL) was stirred at 100 °C for 0.5 h under argon. Concentration
under reduced pressure followed by column chromatography
purification over silica gel with hexane-AcOEt (4:1) gave 9a
(26.8 mg, 65%) as an yellow oil: 1H NMR (500 MHz, CDCl3) δ
0.94 (t, J=7.4 Hz, 3H, CH2CH3), 1.30-1.38 (m, 2H, CH2CH3),
1.53-1.59 (m, 2H, NCH2CH2), 2.33 (s, 3H, ArCH3), 2.53-2.56
(m, 2H, NCH2CH2), 3.38 (s, 2H, NCH2), 4.16 (s, 2H, NCH2), 5.10
(s, 1H, CdCHH), 5.59 (s, 1H, CdCHH), 7.20 (d, J=8.6 Hz, 2H,
Ar), 7.26-7.33 (m, 2H, Ar), 7.67 (d, J=8.6 Hz, 2H, Ar), 7.76-7.78
(m, 1H, Ar), 8.18 (d, J=8.1 Hz, 1H, Ar); 13C NMR (125 MHz,
CDCl3) δ 14.0, 20.6, 21.5, 29.6, 51.5, 55.8, 57.7, 108.6, 114.4, 116.5,
120.4, 124.0, 124.4, 126.4 (2C), 127.3, 130.0 (2C), 135.5, 135.7,
136.1, 136.6, 145.1; MS (FAB) m/z (%) 395 (MHþ, 100); HRMS
(FAB) calcd for C23H27N2O2S (MHþ) 395.1793, found 395.1804.
General Procedure for Synthesis of Benzo[e][1,2]thiazine-1,1-
dioxide: 3-[(N,N-Diisopropylamino)methyl]-2-methyl-2H-benzo-
[e][1,2]thiazine-1,1-dioxide (15a). To a stirred mixture of 14a
(50.0 mg, 0.26 mmol), (HCHO)n (15.4 mg, 0.51 mmol), and
CuBr (1.8 mg, 0.013 mmol) in dioxane (3 mL) was added
diisopropylamine (43.1 μL, 0.31 mmol) at room temperature
under argon. The reaction mixture was stirred at 100 °C for 16 h.
Concentration under reduced pressure followed by column
chromatography purification over silica gel with hexane-
EtOAc (8:1) gave 15a as a pale yellow solid (27.2 mg, 34%):
mp 94.5-98.5 °C; 1H NMR (500 MHz, CDCl3) δ 1.06 (d, J=6.9
Hz, 12H, 4 ꢀ CHCH3), 3.11-3.19 (m, 2H, 2 ꢀ CH), 3.40 (s, 3H,
NCH3), 3.50 (s, 2H, NCH2), 6.51 (s, 1H, 4-H), 7.32 (d, J=8.0
Hz, 1H, Ar), 7.39-7.42 (m, 1H, Ar), 7.52-7.55 (m, 1H, Ar), 7.84
(d, J=8.0 Hz, 1H Ar); 13C NMR (125 MHz, CDCl3) δ 20.4 (4C),
30.9, 47.5 (2C), 48.4, 109.0, 121.5, 126.3, 126.8, 130.5, 131.7,
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, the program for the Promotion of
Fundamental Studies in Health Sciences of the National
Institute of Biomedical Innovation (NIBIO), and the Tar-
geted Proteins Research Program. Y.O. is grateful to Re-
search Fellowships of the Japan Society for the Promotion of
Science (JSPS) for Young Scientists.
Supporting Information Available: Experimental proce-
dure, full characterization, 1H and 13C NMR spectra of all
new compounds, and COSY spectra of 7a, 9a, 15a, and 17. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7058 J. Org. Chem. Vol. 74, No. 18, 2009