Domino heck-aza-michael reactions: efficient access to 1-substituted tetrahydro-β-carbolines

Article abstract of DOI:10.1021/jo902652h

"Chemical Equation Presentation" A simple and efficient palladium-catalyzed domino reaction for the synthesis of a series of C1-substituted tetrahydro-β-carbolines is described. This domino process involves a Heck reaction at the indole 2-position of a ha

Full text of DOI:10.1021/jo902652h

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Domino Heck-Aza-Michael Reactions: Efficient
Access to 1-Substituted Tetrahydro-β-carbolines
Daniel L. Priebbenow,† Luke C. Henderson,†
Frederick M. Pfeffer,*,† and Scott G. Stewart*,‡
†School of Life and Environmental Science, Deakin
University, Geelong 3217, Victoria, Australia, and ‡School of
Biomedical, Biomolecular and Chemical Sciences, University
of Western Australia, Crawley 6009, Western Australia,
Australia
fred.pfeffer@deakin.edu.au; sgs@cyllene.uwa.edu.au
Received December 20, 2009
FIGURE 1. Natural products (1-3) containing the tetrahydro-β-
carboline heterocyclic core.
Domino reactions are an attractive proposition for the
modern synthetic chemist, generating a high level of mole-
cular complexity in one efficient step.4 A domino reaction is
defined as “the execution of two or more bond-forming
transformations under identical reaction conditions, in
which the latter transformations take place at the function-
alities formed by the preceding transformation.”4,5
These reactions are appealing to industry and research
laboratories because of their potential to minimize the use of
solvents, reagents, time, and energy.4 The more conceivable
domino reactions are those where all transformations occur
under similar reaction conditions, for example, where each of
the steps are palladium-catalyzed.5,6 The range of single-step
reactions involving palladium catalysis has grown to the
extent where palladium-mediated reactions are common-
place in most synthetic laboratories. Consequently, the
number of palladium-mediated domino reactions has also
increased over the past decade.7 In spite of this increase,
domino Heck-Michael methodology remains relatively
underutilized, with limited examples in the literature.8 Of
those reported, only one details a domino Heck-aza-Michael
process, used in the synthesis of benzo-fused sultams.8c
Due to their biological relevance, it is important that
molecularly diverse THβCs are prepared containing multiple
sites for further functionalization. Traditionally, C1-substi-
tuted THβCs are accessed through the acid-catalyzed Pictet-
Spengler reaction between tryptamine and an appropriate
aldehyde.9 Alternatively, a four-step process involving a
A simple and efficient palladium-catalyzed domino reac-
tion for the synthesis of a series of C1-substituted tetra-
hydro-β-carbolines is described. This domino process
involves a Heck reaction at the indole 2-position of a
halogenated tryptamine precursor, followed by intramo-
lecular aza-Michael addition.
Tetrahydro-β-carbolines (THβCs or tryptolines) substi-
tuted at the 1-position are central to a number of pharma-
ceutical targets with potential for the treatment of medical
conditions including breast cancer, type-2 diabetes, and
bacterial infections.1 This ring system is prevalent in several
more structurally complex natural products, including the
secologanin-type terpenoid indole alkaloid ajmalicine (1)
(Figure 1) and the antihypertensive agent reserpine (2).1a,2
Biosynthetically, attaching a 3-(l-Δ0-pyrroliniumyl)propanal
to this carboline ring system accesses the alkaloid elaeo-
carpidine (3) containing an additional indolizidine ring
fragment.3
(4) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(5) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; 1st ed.; Wiley-VCH: Weinheim, Germany, 2006.
(6) (a) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456–9459. (b)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Masiocchi, N.; Sottocornola, S.
Org. Lett. 2006, 8, 4521–4524.
(1) (a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14,
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2000, 43, 1577–1585. (c) Jenkins, P. R.; Wilson, J.; Emmerson, D.; Garcia,
M. D.; Smith, M. R.; Gray, S. J.; Britton, R. G.; Mahale, S.; Chaudhuri, B.
Bioorg. Med. Chem. 2008, 16, 7728–7739. (d) Gul, W.; Hamann, M. T. Life
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J. Ethnopharmacol. 2004, 92, 1–21.
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5179–5182. (b) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122,
10220–10221. (c) Gruber, M.; Chouzier, S.; Koehler, K.; Djakovitch, L. Appl.
Catal., A 2004, 265, 161–169. (d) Sugihara, T.; Coperet, C.; Owczarczyk, Z.;
Harring, L. S.; Negishi, E. J. Am. Chem. Soc. 1994, 116, 7923–7924. (e) Tietze,
L. F.; Redert, T.; Bell, H. P.; Hellkamp, S.; Levy, L. M. Chem.;Eur. J. 2008,
14, 2527–2535.
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Wahab Khan, M.; Masud Reza, A. F. G. Tetrahedron 2005, 61, 11204–
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DOI: 10.1021/jo902652h
r
Published on Web 02/04/2010
J. Org. Chem. 2010, 75, 1787–1790 1787
2010 American Chemical Society

Priebbenow et al.
JOCNote
SCHEME 1. Single Step versus a Domino Process To Access
THβCs
SCHEME 2. Initial Attempts of the Domino Heck-Aza-Michael
Reaction in the Synthesis of the Tetrahydro-β-carboline 11
highly likely as both aza-Michael addition13 and the Heck
reaction14 take place under mildly basic conditions. In this
domino process, a new C-C and C-N bond would be created
in sequence, at the same carbon atom.
Initially, several protecting groups (at R1, Scheme 1) including
tert-butoxycarbonyl, trifluoroacetate, tosyl, benzenesulfonyl,
and 2-nitrobenzenesulfonyl were trialed to influence the acidity
of the proton on the protected amine, tuning nucleophilicity at
the tryptamine N10 nitrogen. During these preliminary investi-
gations, the tosyl group was quickly identified as most suited to
our domino system.6b
Bischler-Napieralski reaction to afford the dihydro-β-carbo-
line and subsequent reduction is effective in producing specific
THβCs.10
More recently, due to difficulties in the preparation and
handling of the requisite aldehydes (for example, β-formyl
esters11), modified Pictet-Spengler reactions have been
developed using alternatives such as alkynoates2a and per-
hydro-1,3-heterocycles.2c To complement these existing
methodologies, a domino Heck-aza-Michael reaction of a
tryptamine derivative (such as compound 4, Scheme 1) was
foreseen as an efficient method for introducing molecular
diversity at C1 of the THβC scaffold. Using cheap and
readily available acrylates under mild conditions, an ortho-
gonally protected THβC scaffold containing multiple sites
for further functionalization would be readily accessible.
The indole C2-position of tryptamine was considered ideal
for further functionalization using a domino Heck-aza-
Michael reaction (Scheme 1). Palladium-catalyzed cross-
coupling of C2-halogenated indole compounds, namely,
the Heck, Sonogashira, and Suzuki reactions, has been
reported by our group and others.12 As the Heck reaction
regenerates the olefin functionality following syn-elimina-
tion and is reliably efficient with electron-deficient terminal
alkenes, the potential exists for a second nucleophilic addi-
tion reaction. In this case, a 1,4-Michael addition should be
suitable, depending on the nature of the tethered amine and if
it reacts before or after the Heck reaction (an intra- vs
intermolecular aza-Michael reaction; see Scheme 1).
The tosyl protection of the primary amine within tryptamine
(8) proceeded in quantitative yields to afford sulfonamide 9.
Similarly, bromination of the C2 position proceeded readily to
give 2-bromoindole 10 in excellent yields (90%). Following
preliminary treatment of the precursor 10 with Pd(PPh3)4,
K2CO3 and butyl acrylate, the target tetrahydro-β-carboline
11 was isolated in a promising yield of 30% (Scheme 2).
The synthesis of carboline 11 from tryptamine (8) was
achieved in three steps in a moderate overall yield of 27%.
More importantly, this encouraging result confirmed that the
domino Heck-aza-Michael reaction was applicable to this
particular ring system. To improve the yield, three features of
the domino Heck-aza-Michael reaction were identified for
further optimization, namely, the Heck reaction, the nucleophi-
licity of the sulfonamide, and the degree of electron deficiency of
the Michael acceptor. The Heck reaction, the initial step of this
domino process, was optimized first, with the roles of the
palladium catalyst, base, and the solvent investigated (Table 1).
The results from this investigation were consistent with
previous reports of the Heck reaction at the indole 2-posi-
tion,12c,15 with Pd(PPh3)4 (10 mol %) providing the highest
yields. Interestingly, the use of Na2CO3 (Table 1, entry 5)
produced only the Heck adduct 12 in excellent yields,
whereas K2CO3 facilitated the formation of the desired
tetrahydro-β-carboline 11 (Scheme 2). Unfortunately, the
highly reactive catalytic system pioneered by Fu16 afforded
only a moderate yield for the Heck product (Table 1, entry 3).
Assuch, a dominoHeck-aza-Michael transformation with
an appropriately functionalized tryptamine was considered
(10) da Silva, W. A.; Rodrigues, M. T.; Shankaraiah, N.; Ferreira, R. B.;
Andrade, C. K. Z.; Pilli, R. A.; Santos, L. S. Org. Lett. 2009, 11, 3238–3241.
(11) Dinh, M. T.; Bouzbouz, S.; Peglion, J. L.; Cossy, J. Tetrahedron
2008, 64, 5703–5710.
(12) (a) Luo, S.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709–4712.
(b) Uno, T.; Beausoleil, E.; Goldsmith, R. A.; Levine, B. H.; Zuckermann,
R. N. Tetrahedron Lett. 1999, 40, 1475–1478. (c) Stewart, S. G.; Heath, C. H.;
Ghisalberti, E. L. Eur. J. Org. Chem. 2009, 1934-1943.
(13) (a) Chandrasekhar, S.; Ramakrishna Reddy, N.; Srinivasa Rao,
Y. Tetrahedron 2006, 62, 12098–12107. (b) Rayabarapu, D. K.; Zhou, A.; Jeon,
K. O.; Samarakoon, T.; Rolfe, A.; Siddiqui, H.; Hanson, P. R. Tetrahedron
2009, 65, 3180–3188. (c) Ihara, M.; Ishida, Y.; Tokunaga, Y.; Kabuto, C.;
Fukumoto, K. J. Chem. Soc., Chem Commun. 1995, 2085–2086.
(14) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–
3066. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442–4489.
(15) Jain, H. D.; Zhang, C.; Zhou, S.; Zhou, H.; Ma, J.; Liu, X.; Liao, X.;
Deveau, A. M.; Dieckhaus, C. M.; Johnson, M. A.; Smith, K. S.; Macdonald,
T. L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16,
4626–4651.
(16) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989–7000.
1788 J. Org. Chem. Vol. 75, No. 5, 2010

Priebbenow et al.
JOCNote
TABLE 1. Optimization of the Heck Transformation of Arylbromide 10
TABLE 2. Optimization of the Domino Heck-Aza-Michael Reaction
of Arylbromides
entry
catalyst (10 mol %)
a
Pd(OAc)2/PPh3
Pd2(dba)3/P(tBu)3a
Pd2(dba)3/P(tBu)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
base
NEt3
NEt3
Cy2NMe
NEt3
Na2CO3
K2CO3
K2CO3
K2CO3
CH3CO2Na
solvent
yield (%)
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
DMF
MeCN
dioxane
toluene
22
43
65
39
a
substrate,
entry product
catalyst
(10 mol %)
yield
(%)
base
solvent
99
1
2
3
4
5
6
7
8
9
10, 11
10, 11
10, 11
10, 11
10, 11
10, 11
10, 11
10, 11
10, 11
Pd(PPh3)4
Cs2CO3 toluene
NEt3
DBU
0
trace b
trace b
32
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
toluene tracea
toluene tracea
toluene 30
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene 30b
75
MeCN tracea
aCatalyst and ligand used in a 1:1 ratio. bTrace is <10% as deter-
tracea
0
mined by 1H NMR.
DMF
dioxane
toluene 14c
With the Heck reaction proceeding in excellent yields, the
second step in the domino sequence, the aza-Michael addi-
tion, was explored (Table 2).17 A range of organic amines
(i.e., NEt3, DBU) and inorganic bases (i.e., Na2CO3, K2CO3,
Cs2CO3) did not improve the domino transformation.
A range of solvents were also trialed to improve the Pd-
(PPh3)4, K2CO3 catalytic system; however, solvents more polar
thantoluene(MeCN, DMF, anddioxane, Table2, entries6-8)
failed to increase the yield of the domino process with many of
these increasing the propensity for the sulfonamide to undergo
an initial 1,4-addition (to compound 5, Scheme 1). In such
cases, the relatively slow rate of the Heck reaction is secondary
to the more reactive intermolecular aza-Michael addition.
The addition of the phase transfer agent TBAC to improve
the rate of key steps in the catalytic cycle (Table 2, entries 10
and 11) also failed to increase the yield of the domino process
beyond 30%.14,18 Alternatively, a change in the reactivity of
the R,β-unsaturated moiety in the initial Heck adduct was
envisaged through protection of the indole nitrogen. To our
delight, this approach proved successful and the domino
reaction using N-Boc indole 13a produced the desired carbo-
line 14a in an excellent yield of 83% (Table 2, entry 14).
To further investigate the role of indole N-substitution on
the domino process, two additional protecting groups were
trialed (Table 2, entries 18 and 19). These substrates were
reacted according to the previously identified conditions for
the domino process, and a marked improvement in the yield
of the desired tetrahydro-β-carbolines was observed.
10 10, 11
11 10, 11
12 10, 11
13 10, 11
14 13a, 14a
15 13a, 14a
16 13a, 14a
17 13a, 14a
18 13b, 14b
19 13c, 14c
toluene tracea,d
Na2CO3 toluene 17d
toluene tracea
f
Pd2(dba)3/P(tBu)3 f NEt3
Pd2(dba)3/P(tBu)3 Cy2NMe toluene
0
toluene 83
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3
K2CO3
MeCN tracea
Na2CO3 toluene 27
Na2CO3 toluene 86e
K2CO3
K2CO3
toluene 54
toluene 54
aTrace is <10% as determined by 1H NMR. bUsing 2 equiv of butyl
acrylate. cUsing 3 equiv of butyl acrylate also resulted in a large
formation of only the aza-Michael product 5. dTetra-n-butylammonium
chloride added to initial reaction mixture. eA one-pot process where
tetra-n-butylammonium chloride was added to reaction mixture after 12
h at 120 °C, with stirring at 120 °C continued for 4 h. fCatalyst and ligand
used in a 1:1 ratio.
number of terminal alkenes, each possessing a suitably
conjugated Michael-type acceptor (Table 3). This domino
process allowed access to a series of tetrahydro-β-carboline
scaffolds, containing a variety of sites available for further
functionalization.
The two-step domino process performed well for all
alkenes employed (except in the case of acrylic acid) with
isolated yields ranging from 64 to 83% (Table 3).
In conclusion, a novel domino Heck-aza-Michael reac-
tion has been developed. This methodology has been
applied to the synthesis of a series of C1-substituted tetra-
hydro-β-carbolines. Using mild conditions, this domino
process affords indole-based heterocyclic scaffolds, highly
amenable to larger total syntheses. Furthermore, the dom-
ino Heck-aza-Michael conditions reported by Hanson
et al. failed for those systems in which the sulfonyl moiety
was not contained within the heterocyclic ring formed.8c
The domino Heck-aza-Michael process reported herein
proved successful in the synthesis of tetrahydro-β-carbo-
lines with the sulfonyl group external to the newly con-
structed heterocycle. To the best of our knowledge, this
is the first example of a domino Heck-aza-Michael reac-
tion for the synthesis of a carbon-nitrogen heterocycle.
Complementing existing methodology, this domino process
The highest yields (up to 83%) for the domino process
were obtained following the addition of Pd(PPh3)4 (10mol%),
alkene (1.1 equiv), and K2CO3 (3.0 equiv) to a sealed tube
containing 2-bromoindole (1.0 equiv) in toluene (5 mL)
that was subsequently stirred at 120 °C for 16 h. A simple
purification protocol, including column chromatography,
furnished the desired tetrahydro-β-carbolines. Reproducible
yields for this domino process were obtained on various
scales (ranging from 0.1 to 1.1 mmol).
To illustrate the versatility of this methodology, the
domino Heck-aza-Michael reaction was repeated using a
(17) Our attention turned to the optimal conditions to bring about a
simple 1,4-addition. In this case, the tosylamine tether was reactive enough
for aza-Michael addition to occur under mild basic conditions.
(18) The phase transfer agent used in an attempt to improve the solubility
of K2CO3 failed to significantly increase the yield.
J. Org. Chem. Vol. 75, No. 5, 2010 1789

Priebbenow et al.
JOCNote
TABLE 3. Preparation of Diverse 1-Substituted THβCs
Experimental Section
Typical Procedure for the Preparation of 1-Substituted THβCs
14a, 15-19 (Butyl Acetate THβC 14a as Example). A sealed tube
containing a 2-bromoindole 13a (100 mg, 0.20 mmol), Pd(PPh3)4
(23 mg, 10 mol %), K2CO3 (84 mg, 0.61 mmol), and butyl
acrylate (29 mg, 0.22 mmol) in toluene (4 mL) was heated at
120 °C for 16 h. The reaction mixture was cooled to room
temperature, the solvent removedinvacuo, and the crudeproduct
purified by column chromatography (1:4 EtOAc/Pet Sp) to
afford the tetrahydro-β-carboline 14a (91 mg, 0.17 mmol, 83%)
as a pale yellow oil: FT-IR (ν, cm-1, KBr) 1730vs, 1457, 1374,
1324, 1159, 747; 1H NMR (400 MHz, CDCl3, δ) 8.10 (d,
J = 8.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.14-7.28 (m, 3H),
7.03 (d, J = 8.6 Hz, 1H), 6.12 (dd, J = 3.6 and 10.6 Hz, 1H), 4.05
(m, 3H), 3.50 (m, 1H), 3.00 (dd, J = 3.7 and 14.3 Hz, 1H), 2.70
(dd, J = 10.6 and 14.3 Hz, 1H), 2.39-2.60 (m, 2H), 2.18 (s, 3H),
1.75 (s, 9H), 1.60 (m, J = 7.8 Hz, 2H), 1.34 (m, J = 7.6 Hz, 1H),
0.92 (t, J = 7.5 Hz, 3H); 13C NMR (67.5 MHz, CDCl3, δ) 169.8,
149.9, 143.4, 137.5, 135.9, 133.0, 129.2, 128.6, 127.1, 124.8, 122.9,
118.0, 115.7, 114.9, 85.0, 64.9, 51.1, 40.3, 37.9, 30.6, 28.4, 21.4,
19.7, 19.2, 13.8; HRMS-ESI (m/z) [C29H36N2O6S - H]- calcd
539.22213, found 539.22187.
entry
alkene
R
product yield (%)
1
2
3
4
5
6
7
butyl acrylate
CO2(CH2)3CH3
CO2CH3
2-hydroxyethyl acrylate CO2(CH)2OH
14a
15
16
17
18
19
20
83
79
64
64
80a
67
0
methyl acrylate
acrolein
CHO
CONH2
CN
acrylamide
acrylonitrile
acrylic acid
CO2H
aConversion calculated for desired product; however, partial Boc
deprotection during synthesis resulted in an inseparable mixture of
indole N-Boc and indole N-H tetrahydro-β-carbolines. See Supporting
Information.
allows synthetic flexibility when access to a specific C1-sub-
stituted tetrahydro-β-carboline is required.
Current work within this group is focused on variations of
this domino process, including the use of more highly sub-
stituted alkenes and the introduction of chirality through the
use of tryptophan-derived starting materials.
Supporting Information Available: Experimental proce-
dures, characterization, copies of 1H and 13C NMR spectra for
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1790 J. Org. Chem. Vol. 75, No. 5, 2010