The synthesis of N-heterocycles via copper/TEMPO catalysed aerobic oxidation of amino alcohols

Article abstract of DOI:10.1039/c2gc35062a

N-Heterocycles can be prepared using alcohol oxidation as a key synthetic step. Herein we report studies exploring the potential of Cu/TEMPO as an aerobic oxidation catalyst for the synthesis of substituted indoles and quinolines.

Full text of DOI:10.1039/c2gc35062a

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 1281
www.rsc.org/greenchem
COMMUNICATION
The synthesis of N-heterocycles via copper/TEMPO catalysed aerobic
oxidation of amino alcohols†
James C. A. Flanagan, Laura M. Dornan, Mark G. McLaughlin, Niall G. McCreanor, Matthew J. Cook*
and Mark J. Muldoon*
Received 13th January 2012, Accepted 24th February 2012
DOI: 10.1039/c2gc35062a
loxyl), a base and dioxygen as the terminal oxidant. Along with
the fact that it employs copper, this system was appealing
because it is known to operate under mild conditions and is
selective for the oxidation of primary alcohols to aldehydes.9
This feature would increase the scope of this oxidative intramole-
cular oxidative cyclization and allow us to prepare N-hetero-
cycles using substrates containing secondary alcohol
functionality. Furthermore, because it is an aerobic approach we
envisaged that this would allow us to obtain quinolines as
opposed to tetrahydroquinolines7 and lactams8 which were
obtained using the Ir and Rh catalysts mentioned earlier. While
there have been numerous studies exploring Cu/TEMPO for cat-
alytic alcohol oxidation, these studies have primarily focused on
simple model substrates;9 the catalyst had not been exploited for
the synthesis of N-heterocycles.10
N-Heterocycles can be prepared using alcohol oxidation as a
key synthetic step. Herein we report studies exploring the
potential of Cu/TEMPO as an aerobic oxidation catalyst for
the synthesis of substituted indoles and quinolines.
N-Heterocycles are important scaffolds for many drugs and
natural products, and substituted quinolines and indoles are the
basis of many top selling pharmaceuticals; for example, Singu-
lair® and Maxalt®. The synthesis of such substituted N-hetero-
cycles can be challenging with many traditional approaches
requiring harsh conditions and delivering poor selectivity.1–3
An attractive route for the synthesis of N-heterocycles is to
utilize alcohols as substrates as they are readily available and
easy to handle. There are numerous examples where catalytic
transfer hydrogenations or “hydrogen borrowing” methods have
been used to prepare N-heterocycles from alcohols.4 A particu-
larly desirable route for the selective synthesis of substituted N-
heterocycles is the intramolecular oxidative cyclization of amino
alcohols. Watanabe and co-workers previously employed this
route for the synthesis of indoles, using a RuCl2(PPh3)3 catalyst.5
More recently, heterogeneous ruthenium catalysts (Ru/CeO2 and
Ru/ZrO2) were used to prepare indole using the same route.6
Fujita et al. reported the use of a [Cp*IrCl2]2 catalyst for the syn-
thesis of indoles, 1,2,3,4-tetrahydroquinolines and 2,3,4,5-tetra-
hydro-1-benzazepine.7 For the same starting materials, it was
found that when the catalyst was switched to [Cp*RhCl2]2 it pro-
duced the corresponding five-, six-, and seven-membered ring
lactams.8
Indole synthesis
We began by exploring the synthesis of indole from the commer-
cially available starting material 2-aminophenethyl alcohol. We
explored a range of different reaction conditions and Table 1
highlights some selected examples.
Table 1 Selected examples from studies aimed at optimising the
oxidation of 2-aminophenethyl alcohol
This approach would be greatly improved if we could move
away from expensive precious metals and employ more earth
abundant metals. Given that oxidation of an alcohol to an alde-
hyde is the key step in this route, the Cu/TEMPO/O2 system is
an attractive alternative.9 This biomimetic system employs a
Cu(II) or Cu(I)9e salt complexed by a ligand such as 2,2-bipyri-
dine, the stable free radical TEMPO (2,2,6,6-tetramethylpiperidiny-
Cu source
Entry (mol%)
Co-catalyst
(mol%)
Temperature
(time, h)
Yield
(%)
1a
2a
3a
4b
5c
Cu(OTf)2 (3) TEMPO (3)
Cu(OTf)2 (3) TEMPO (3)
Cu(OTf)2 (9) TEMPO (9)
Cu(OTf)2 (3) HO-TEMPO (3) 90 °C (18)
CuCl (5) DBAD (5) 90 °C (4)
60 °C (4)
60 °C (24)
60 °C (4)
46
30
90
39
33
School of Chemistry and Chemical Engineering, Queen’s University
Belfast, David Keir Building, Stranmillis Road, Belfast, BT9 5AG,
Northern Ireland. E-mail: m.cook@qub.ac.uk; Tel: +44 (0) 28 9097
4682; E-mail: m.j.muldoon@qub.ac.uk; Tel: +44 (0) 28 9097 4420
†Electronic supplementary information (ESI) available: Further details
of experiments and synthesis of starting materials. See DOI: 10.1039/
c2gc35062a
a Ligand = 2′2-bipyridine, base = 3 mol% NMI and 3 mol% DBU,
solvent = acetonitrile, 3 Å molecular sieves present. b Aqueous biphasic
system with decalin as the organic solvent, ligand = 2′2-bipyridine,
base = 3 mol% NMI and 3 mol% DBU. c Ligand = 1,10-phenanthroline,
base = 2 equivalent K2CO3, solvent = toluene.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1281–1283 | 1281

View Online
Table 2 Synthesis of substituted indoles
case, we could only recover and isolate 26% of the original 3-
methylindole, with many unidentified by-products produced. We
believe this greater reactivity can be rationalised by the fact that
3-methylindole is more nucleophilic at the 3-position than
indole.
The fact that we can obtain a 90% isolated yield for the syn-
thesis of indole (entry 3 in Table 1) indicates that the catalyst
will preferentially oxidize the substrate over this unwanted reac-
tion with the product. As shown in Fig. 1, when we monitored
1
the reaction by H NMR of 1a, we observed smooth kinetics
over the course of the reaction (until we obtained a yield of
∼80%).
The results indicate that if we had a method of removing the
product this could lead to greater efficiency and catalyst stability.
We attempted to address the product inhibition problem by
exploring the use of aqueous biphasic systems. In these cases,
we employed either 4-hydroxy-TEMPO or 4-carboxy-TEMPO
to ensure that both the copper complex and TEMPO were
retained in the aqueous phase.† It was hoped that if the product
was extracted into the upper organic phase (we explored the use
of toluene, xylene, decalin and nonane) it would reduce product
decomposition. Unfortunately, it was found that the reactions
were very slow and the highest yield obtained was 39% (entry 3
in Table 1). As part of our optimisation studies we also investi-
gated the use of copper(I)/di-tert-butyl-azodicarboxylate
(DBAD) or its corresponding hydrazine (DBADH2) for the syn-
thesis of indole. This catalyst system was reported by Markó as
an effective method for alcohol oxidation,12 however we found
that it was not as effective as Cu/TEMPO and a maximum yield
of 33% was obtained for these catalysts (entry 4 in Table 1).
Taking our optimised conditions that allowed us to obtain
90% isolated yield of indole, we then applied these conditions
for the synthesis of some substituted indoles. As can be seen in
Table 2, these could be obtained in moderate to good (isolated)
yields.
The catalyst system which we mainly used was previously
optimised for alcohol oxidation by Kumpulainen and Koskinen9d
and consisted of Cu(OTf)2/2,2′-bipyridine/TEMPO, 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU), N-methylimidazole (NMI), 3 Å
molecular sieves and acetonitrile. In our studies, it was found
that longer reaction times led to lower yields (cf. entries 1 and 2
in Table 1), suggesting that the product is undergoing decompo-
sition. This was further confirmed by subjecting pure indole to
our reaction conditions, resulting in the recovery of 82% of
indole (isolated yield). Additionally, we followed this product
inhibition by 1H NMR using methyl benzoate as an internal stan-
dard and we clearly observed the disappearance of indole over
time. So far we have been unable to identify the by-products
from the reaction between the catalyst and indole, but one poss-
ible explanation is that indole is reacting with the Cu(II) via the
nucleophilic C3-position. Work by Gaunt and co-workers has
demonstrated that Cu(OTf)2 can be used to catalyse the arylation
of indoles at this position.11 Further evidence that the product is
reacting with the catalyst in this manner was obtained when we
subjected 3-methylindole to standard reaction conditions. In this
The oxidation of 3 to 4 is an impressive illustration of the
ability of the Cu/TEMPO system to selectively oxidize the
primary alcohol to an aldehyde whilst leaving the secondary
alcohol unaffected (eqn (1)). The carbonyl group formed is
attacked by the N atom of the amino group to afford the indole
in 58% isolated yield with a secondary alcohol still intact.
ð1Þ
Quinoline synthesis
We began studying the synthesis of quinolines by once again
looking at the simplest product, quinoline itself. The results of
optimisation experiments for this procedure once again
suggested some mechanistic details. Firstly, the issues of product
inhibition experienced with the indole experiments do not seem
to exist (at least to the same extent) for quinoline synthesis.
Fig. 1 Kinetic study for the oxidation of 1a, monitored by 1H NMR
using PhCO2Me as an internal standard in CD3CN.
1282 | Green Chem., 2012, 14, 1281–1283
This journal is © The Royal Society of Chemistry 2012

View Online
Table 3 Synthesis of quinolines
undec-7-ene (DBU) (3 mol%) N-methylimidazole (NMI)
(3 mol%), and 3 Å molecular sieves (0.5 g) were then successively
added. The solution was stirred at 60 °C in a round-bottomed
flask with a reflux condenser attached. The reflux condenser had a
drying tube fitted to the top and was open to the air. In case of
indoles reactions were stopped after 4 h while 24 h were required
for quinolines. The mixture was then placed in a separating
funnel and extracted three times with 15 ml diethyl ether and 15 ml
water. The organic layers were then combined, dried with anhy-
drous magnesium sulfate, filtered, evaporated in vacuo and purified
by flash column chromatography (EtOAc–hexane).†
Acknowledgements
We are grateful to the RCUK, the Nuffield Foundation and
Almac Discovery for funding. We also gratefully acknowledge
GlaxoSmithKline for the donation of laboratory equipment.
However, it was found that a significant amount of 1,2,3,4-tetra-
hydroquinolin-2-one was produced in each experiment. The
amount of this minor product increased further if less rigorously
anhydrous conditions were used. This observation leads to the
suggestion that once aldehyde oxidation is complete there are
two competing slow steps: a dehydration to give the 3,4-dihydro-
quinoline and a further alcohol oxidation to give a 1,2,3,4-tetra-
hydroquinoline. The removal of water (by sieves and drying
tube) clearly helps to drive the reaction towards quinoline
production.
Notes and references
1 Reviews of indole synthesis: R. B. Van Order and H. G. Lindwall, Chem.
Rev., 1942, 30, 69; G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000,
1045; G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875;
S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873.
2 Reviews of quinoline synthesis: V. V. Kouznetsov, L. Y. Vargas Méndez
and C. M. Meléndez Gómez, Curr. Org. Chem., 2005, 9, 141;
S. Madapa, Z. Tusi and S. Batra, Curr. Org. Chem., 2008, 12, 1116.
3 J. A. Joule and K. Mills, Heterocyclic Chemistry, Wiley-Blackwell,
5th edn, 2010, ch. 9 and ch.20.
4 Reviews: A. C. Marr, Catal. Sci. Technol., 2012, 2, 279;
M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv. Synth.
Catal., 2007, 349, 1555.
5 Y. Tsuji, S. Kotachi, K. Huh and Y. Watanabe, J. Org. Chem., 1990, 55,
580.
Conclusions
6 S. Shimura, H. Miura, K. Wada, S. Hosokawa, S. Yamazoe and M. Inoue,
Catal. Sci. Technol., 2011, 1, 1340.
7 K. Fujita, K. Yamamoto and R. Yamaguchi, Org. Lett., 2002, 4, 2691.
8 K. Fujita, Y. Takahashi, M. Owaki, K. Yamamoto and R. Yamaguchi,
Org. Lett., 2004, 6, 2785.
The study indicates that the Cu/TEMPO oxidation catalyst has
potential for the synthesis of N-heterocycles. In the case of
indole synthesis, the issue of product inhibition needs to be
further resolved. The kinetics suggest that formation of the
product is faster than the inhibition reaction that leads to catalyst
deactivation. If it was possible to immobilise the catalyst, con-
tinuous flow operation could allow the product to be removed
and improve the efficiency of the reaction. There is much room
for expanding the substrate scope, especially with those contain-
ing both primary and secondary alcohols. We also aim to explore
the use of Cu/TEMPO for synthesis of other N-heterocycles.
9 Examples of key papers: (a) M. F. Semmelhack, C. R. Schmid,
D. A. Cortes and C. S. Chou, J. Am. Chem. Soc., 1984, 106, 3374;
(b) P. Gamez, I. W. C. E. Arends, J. Reedijk and R. A. Sheldon, Chem.
Commun., 2003, 2414; (c) P. Gamez, I. W. C. E. Arends, R. A. Sheldon
and J. Reedijk, Adv. Synth. Catal., 2004, 346, 805; (d) E. T. Kumpulainen
and A. M. Koskinen, Chem.–Eur. J., 2009, 15, 10901; (e) J. M. Hoover
and S. S. Stahl, J. Am. Chem. Soc., 2011, 133, 16901.
10 During the preparation of this manuscript a report describing the use of
copper/4-HO-TEMPO for the synthesis of 2-substituted quinazolines and
4H-3,1-benzoxazines was published. In this case the catalyst does not
perform an alcohol oxidation but oxidises in-situ prepared aminals and
hemi-aminals. B. Han, X.-Y. Long, C. Wang, Y.-W. Bai, T.-C. Pan,
X. Chen and W. Yu, J. Org. Chem., 2012, 77, 1136.
Experimental
11 R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc., 2008,
130, 8172.
General (optimised) procedure: Copper(II) trifluoromethanesulfo-
nate (Cu(OTf)2) (9 mol%), 2,2′-bipyridyl (2,2′-bipy) (9 mol%)
and 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) (9 mol%) were
added to acetonitrile (1.5 cm3) in an oven-dried round-bottomed
flask to give a green solution. The starting amino alcohol
(1 equivalent, typically 0.5–1 mmol), 1,8-diazabicyclo[5.4.0]
12 (a) I. E. Markó, P. R. Giles, M. Tsukazaki, S. M. Brown and C. J. Urch,
Science, 1996, 274, 2044; (b) I. E. Markó, A. Gautier, I. Chellé-Regnaut,
P. R. Giles, M. Tsukazaki, C. J. Urch and S. M. Brown, J. Org. Chem.,
1998, 63, 7576; (c) I. E. Markó, A. Gautier, R. Dumeunierl, K. Dodal,
F. Philippart, S. M. Brown and C. J. Urch, Angew. Chem., Int. Ed., 2004,
43, 1588.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1281–1283 | 1283