TEMPO oxoammonium salt-mediated dehydrogenative Povarov/oxidation tandem reaction of N-alkyl anilines

Article abstract of DOI:10.1021/ol202552y

The synthesis of a variety of substituted quinolines from N-alkyl anilines by a one-pot dehydrogenative Povarov/oxidation tandem reaction with mono- and 1,2-disubstituted aryl and alkyl olefins was developed. A simple protocol using cheap and benign iron(

Full text of DOI:10.1021/ol202552y

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6066–6069
TEMPO Oxoammonium Salt-Mediated
Dehydrogenative Povarov/Oxidation
Tandem Reaction of N-Alkyl Anilines
~
Heinrich Richter and Olga Garcıa Mancheno*
´
Organisch-Chemisches Institut, Mu€nster University, Corrensstrasse 40, 48149 Mu€nster,
Germany
olga.garcia@uni-muenster.de
Received September 21, 2011
ABSTRACT
The synthesis of a variety of substituted quinolines from N-alkyl anilines by a one-pot dehydrogenative Povarov/oxidation tandem reaction with
mono- and 1,2-disubstituted aryl and alkyl olefins was developed. A simple protocol using cheap and benign iron(III)chloride as the Lewis acid
catalyst and a TEMPO oxoammonium salt as a nontoxic, mild, efficient oxidant is reported.
In the past few years, Cross Dehydrogenative Coupling
reactions (CDCs)1 have been established as powerful
synthetic tools, allowing the direct generation of a new
CꢀC bond from two CꢀH bonds. This approach has
started to revolutionize the way of tackling organic syn-
thesis, since prefunctionalization in the reaction partners is
not required and CꢀH bonds are ubiquitous in organic
molecules. Consequently, the use of simpler starting ma-
terials, as well as the development of more atom-economic
processes and the less waste generation constitute its major
advance. However, one of the main issues in CDC is still
the limited substrate scope, being basically restricted to
more or less activated diarylmethanes or benzylic CꢀH
bonds alpha to a heteroatom such as in tetrahydroisoqui-
nolines or isochromanes. Recently, it has been shown that
glycine derivatives2 and N-alkyl anilines3 are also good
substrates in CDC reactions with malonates, ketones,
heteroaromatic compounds, and alkynes astypical nucleo-
philes. However, it would be of added synthetic value to
extend their use to the synthesis of more interesting
N-containing compounds, such as bioactive heterocycles
by employing less usual nucleophiles in CDC such as simple
olefins.4 Although the use of olefins is still scarce in this
chemistry, they are widely available reagents, making them
very interesting for developing general CDC reactions.
On the other hand, substituted quinolines are important
scaffolds present in many biologically active compounds,
including natural products and synthetic drugs.5 As a
consequence of their proven interesting bioactivity, many
different strategies for the preparation of quinolines have
been developed.6 Among them, the Povarov reaction
followed by oxidation is widely recognized.6a,b,7 Never-
theless, the last oxidation step, which involves a formal
removal of four hydrogens from the tetrahydroquinoline
intermediate, is still challenging. Typically, harsh condi-
tions or large amounts (e.g., MnO2), expensive (e.g., Pd-
based), or toxic oxidants (e.g., DDQ, nitrobenzene, etc.)
(1) Selected reviews: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b)
Scheuermann, C. J. Chem. Asian J. 2009, 5, 436. (c) Klussmann, M.;
Sureshkumar, D. Synthesis 2011, 353. (d) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780. (e) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215.
(2) (a) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075. (b)
Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010, 49, 10181.
(3) See, for example: (a) Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li,
Z. Org. Lett. 2009, 11, 4176. (b) Han, W.; Ofial, A. R. Chem. Commun.
2009, 40, 6023. (c) Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal.
2010, 352, 1667. (d) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett.
2010, 12, 5214.
(4) (a) Song, C.-X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z.-P.; Li, H.;
Gan, L.-B.; Shi, Z.-J. Chem. Commun. 2009, 6002. (b) Li, H.; Li, W.; He,
Z.; Li, Z. Angew. Chem., Int. Ed. 2011, 50, 2975. (c) Nishino, M.; Hirano,
K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 6447.
(5) See, for example: (a) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, 2003; p 316. (b) Musiol, R.;
Serda, M.; Hensel-Bielowka, S.; Polanski, J. Curr. Med. Chem. 2010, 17,
1960.
r
10.1021/ol202552y
Published on Web 10/18/2011
2011 American Chemical Society

are employed. Therefore, the identification of more effi-
cient and environmentally benign oxidants for this trans-
formation is highly desirable.
and Fe(III)chloride salts as catalysts.10 Although both
complexes were active, we were pleased to find out that
cheap and commercially available FeCl3 was the most
active catalyst, leading to quinoline 3a in an excellent
93% yield (entry 4).11
We herein report on an alternative one-pot method for
the synthesis of quinolines from N-alkyl anilines and
olefins by a one-pot dehydrogenative couplingꢀaromatic
substitutionꢀoxidation sequence reaction using a TEMPO
ꢀ 8,9
salt (TþBF4
)
as a highly efficient, mild and nontoxic
Table 1. Optimization of the Reaction of 1a with Styrenea
oxidant. This oxidant will be then involved in two dehy-
drogenative processes (Scheme 1): (i) the formation of an
iminium ion intermediate 4, which will undergo the CDC
reaction inthepresenceof anolefin2 asnucleophile and (ii)
the final aromatization step of the intermediate 5 to form
the quinoline unit 3.
entry
catalyst
oxidant (equiv) time (h) yield of 3 (%)b
Scheme 1. One-pot Dehydrogenative Approach
1
Cu(OTf)2
Fe(OTf)2
TþBF4ꢀ (2)
TþBF4ꢀ (2)
24
24
64
55
2
3
FeCl3 6H2O TþBF4ꢀ (2)
24
91
3
4
5
FeCl3
TþBF4- (2)
TþBF4ꢀ (2)/aird
TþBF4ꢀ (2)
DDQ (2)
16 (20)
18
93 (93)c
86
FeCl3
6
16
51e
7
7
FeCl3
FeCl3
FeCl3
FeCl3
24
8
(t-BuO)2 (2)
aird
24
30
9
24
3
41e,f
10
O2 (1 atm)
16
a 1a (0.1 mmol), catalyst (10 mol %), 2a (0.2 mmol) and oxidant in
DCM (1 mL). b Isolated yield. c 0.5 mmol scale reaction in brackets.
d Reaction under air atmosphere. e Reaction stopped after 16 h. f Higher
temperatures (e110 °C) or O2 pressure (3 atm) gave no improvements.
Initially, the reaction betweenglycine1aand styrene (2a)
was chosen as a model reaction and several Lewis acid
metal catalysts and oxidants were tested (Table 1). Under
slightly modified conditions of our recently reported CDC
reaction with R,β-unsaturated aldehydes:9b 1a (1 equiv), 2
equivalents of 2a, 10 mol % of metal catalyst and 2
The reaction was not sensitive to moisture or aerobic
conditions, permitting the use of FeCl3 6H2O or nondry
ꢀ
equivalents of TþBF4 as oxidant in DCM at 60 °C, the
3
clean formation of quinoline 3a was observed.
solvents (91% yield, entry 3) and conducting the reaction
under air atmosphere (86% yield, entry 5) maintaining the
same level of efficiency. Moreover, the reaction also pro-
ceeded in the absence of iron catalyst, probably by an acid-
mediated reaction. Nevertheless, 3a was obtained in a
significantly lower 51% yield (entry 6). For that reason,
we decided to continue the study using FeCl3 as a catalyst.
Subsequently, other typical oxidants for CDC reactions
were tested; however, the TEMPO oxoamonium salt
TþBF4ꢀ turned out to be the most efficient. Thus, DDQ,
peroxides such as (t-BuO)2, and air were not competent
oxidants for this reaction, leading to quinoline 3a in only 7,
30 and 3%, respectively (entries 7ꢀ9). On the other hand,
the use of oxygen (1ꢀ3 atm) permitted the formation of 3a
in a decent 41% yield (entry 10).12
The use of Cu(OTf)2 as catalyst provided the desired
quinoline 3a in a promising 64% yield (entry 1). Consider-
ing that the more environmentally friendly iron species are
well-known to promote electrophilic aromatic substitution
reactions we next explored the corresponding Fe(II)triflate
(6) For reviews on quinoline synthesis, see: (a) Jones, G. In Compre-
hensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., McKillop, A., Eds.; Pergamon Press: Oxford, 1996; Vol. 5, p 167. (b)
Larsen, R. D. In Science of Synthesis; Black, D. S., Ed.; Thieme: Stuttgart,
ꢀ
2005; Vol. 15, pp 389 and 551. (c) Kouznetsov, V. V.; Vargas Mendez,
ꢀ
ꢀ
L. Y.; Melendez Gomez, C. M. Curr. Org. Chem. 2005, 9, 141. (d)
Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12, 1116. (e)
ꢀ
Marco-Contelles, J.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M. D.;
Soriano, E. Chem. Rev. 2009, 109, 2652.
(7) For recent examples with alkynes: (a) Huang, H.; Jiang, H.; Chen,
K.; Liu, H. J. Org. Chem. 2009, 74, 5476. (b) Cao, K.; Zhang, F.-M.; Tu,
Y.-Q.; Zhuo, X.-T.; Fan, C.-A. Chem.;Eur. J. 2009, 15, 6332. (c)
Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728. (d) Kulkarni,
(10) For recent reviews and highlights on iron catalysis, see: (a) Iron
Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH: Weinheim,
2008. (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104,
€ €
A.; Torok, B. Green Chem. 2010, 12, 875 and references cited therein.
Povarov’s initial work:(e) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(8) TþBF4- preparation, see for example: (a) Yonekuta, Y.; Oyaizu,
K.; Nishide, H. Chem. Lett. 2007, 36, 866. For comprehensive reviews
~
´
6217. (c) Correa, A.; Garcıa Mancheno, O.; Bolm, C. Chem. Soc. Rev.
2008, 37, 1108. (d) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int.
€
Ed. 2008, 47, 3317. (e) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008,
€
on oxoammonium chemistry:(b) Bobbitt, J. M.; Bruckner, C.; Merbouh,
€
41, 1500. (f) Furstner, A. Angew. Chem., Int. Ed. 2009, 48, 1364. (g)
N. Oxoammonium- and nitroxide-catalyzed oxidations of alcohols. In
Organic Reactions; Denmark, S. E., Ed.; Wiley: New York, 2009; Vol. 74, p
103. (c) Tebben, L.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 5034.
(9) For our previous works on CDC using TþBF4ꢀ as oxidant, see:
Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061. (h) Garcı
´
a
~
Mancheno, O. Angew. Chem., Int. Ed. 2011, 50, 2216.
(11) The reaction in DCE gave a slightly lower yield of 80%.
~
(a) Richter, H.; Garcı
´
Richter, H.; Rohlmann, R.; Garcı
17, 11622.
a Mancheno, O. Eur. J. Org. Chem. 2010, 4460. (b)
(12) The reaction with 10 mol % TEMPO salt and NaOCl (2 equiv) as
co-oxidant at 60 °C gave as major product the corresponding ortho-
chlorinated aniline (29%), along with 17% of 1a recovered.
~
´
a Mancheno, O. Chem.;Eur. J. 2011,
Org. Lett., Vol. 13, No. 22, 2011
6067

investigated (Figure 1). The ester function was then chan-
ged to another electron withdrawing group such as ketone
(72%, 6) and phosphonate(42%, 7) ortoanaryl(Ph, 40%,
8) or alkyl group (Me, traces, 9).13 In general, lower yields
or no desired reactivity was observed, indicating the ester
substitution is optimal.
The scope of the reaction with ethyl glycine 1 was then
explored (Table 2). The substitution at the aniline ring was
studied first (entries 1ꢀ8). Para (93%), ortho (38%) and
meta (42%, 1.6:1 regioisomers) substituents were tolerated
(entries 1ꢀ3, respectively), although the para substitution
gave the best results in terms of reactivity and selectivity.
Both electron donating (entries 4ꢀ5) and electron with-
drawing groups (entries 6ꢀ8) were compatible, providing
the corresponding quinolines 3 in good yields (73ꢀ84%).
Interestingly, functional moieties such as chloro, bromo or
an acetyl group behave well under these oxidative condi-
tions. Next, a variety of substituted olefins 2 were applied
Figure 1. Effect of the substitution at the N-alkyl group.
Having identifiedtheoptimal reaction cꢀonditions(FeCl3
as catalyst and 2 equivalents of TþBF4 at 60 °C), the
substitution of the N-alkyl group at the aniline was next
Table 2. Scope of the Reaction of Glycines 1 with Olefins 2a
a 1 (1 equiv), olefin 2 (2 equiv), FeCl3 (10 mol %), and TþBF4ꢀ (2 equiv) in DCM (0.1 M) at 60 °C. b Isolated yield. c 4 equiv of olefin were used.
d Methylene bis-quinoline 10 was also formed in 23% (see Scheme 2). e 2.5 equiv. of TþBF4ꢀ at 70 °C. f Isolated yields of 3o and 3p in brackets.
6068
Org. Lett., Vol. 13, No. 22, 2011

in the reaction with 1a (entries 9ꢀ18). The electronic
nature of the substituents at the aromatic ring of different
styrenes did not have a significant impact on the reaction,
leading to the corresponding quinolines in similar good
yields of 76ꢀ86% (electron donating: entries 9ꢀ10; and
electron withdrawing: entries 17ꢀ18).
be followed by GC-MS, which might indicate certain
evolution of H2. Further investigations aiming the eluci-
dation of the dehydrogenative nature of this TEMPO
salt-mediated reaction are currently undergoing in our
laboratory.
Olefins with linear aliphatic chains such as n-hexyl
reacted well, providing quinoline 3k in 66% yield (entry
11). Interestingly, 1,2-disubstituted olefins were also sui-
table. Thus, β-ethyl styrene lead to 2,3,4-trisubstituted
quinoline 3l in a remarkable 58% yield (entry 12). On the
other hand, 1,2-aryl alkenyl and 1,2-diaryl substituted
olefins such as 1,4-diphenyl butadiene and stilbene turned
to be less reactive providing 3m and 3n in 44% and 29%
yield, respectively (entries 13ꢀ14). Finally, the reaction
with n-butyl and ethyl vinyl ethers was also explored
(entries 15 and 16). Then, C-4 unsubstituted quinolines
were exclusively obtained by elimination of the corre-
sponding alcohol. This was confirmed by the formation
in good overall yield (82%) of a mixture of quinolines with
ethyl (3o, 47%) and n-butyl (3p, 35%) esters when using n-
butyl vinyl ether as nucleophile (entry 15).
Scheme 2. Mechanistic Insights
To get some insights into the mechaniꢀsm of this one-pot
sequential process, the role of TþBF4 as oxidant was
studied. As expected, the reaction of 1a with only 1.2
equivanlents of TþBF4 was notably less efficient (51%)
ꢀ
showing the need of at least 2 equiv of this oxidant for
achieving high performance in both key steps: the iminium
ion formation and the oxidation of the tetrahydroquino-
line intermediate. Additionally, the reaction proceeded
relatively slower at room temperature, making it possible
to isolate after 13 h the tetrahydroquinoline 5a in a 33%
yield along with 48% of 3a. However, 5a could be then
converted to the corresponding quinoline 3a upon treat-
ment with an extra equivalent of oxidant.14 Furthermore,
we could prove the dehydrogenative coupling nature of the
transformation by the formation of diarylmethane deriva-
tive 10 by a double CDC arylation followed by double
dehydrogenativePovarov-type reaction in the reaction with
2-methyl substituted aniline derivative 1b (Scheme 2, eq 1;
Table 2, entry 2).14 Consequently, a mechanism implying a
multistep sequence is proposed (Scheme 2, eq 2). After the
first in situ generation of an iminium ion 4 mediated by the
TEMPO salt, a nucleophilic attack of the olefin to form a
carbocation 11 occurs. This highly reactive intermediate
undergoes an intramolecular electrophilic aromatic substi-
tution reaction to form a tetrahydroquinoline 5, which then
is finally further dehydrogenated to form the corresponding
quinoline 3. Interestingly, someoverpressurein thereaction
vessel was observed after the reaction and the conversion
with the time of N-hydroxy TEMPO 12 to amine 13 could
In summary, we have developed a one-pot dehydro-
genative synthesis of quinolines using a TEMPO oxoam-
monium salt as highly efficient, mild and nontoxic oxidant.
The combinꢀation of cheap and available FeCl3 catalyst
with TþBF4 as formal hydrogen acceptor was success-
fully employed. This approach allows the direct reaction of
simple N-alkyl anilines, such as ethyl glycines, with a
variety of mono- and 1,2-disubstituted aryl and alkyl
olefins. A mechanism implying a multistep sequence in
which the TEMPO oxoammonium salt participates in
both the first and the last stage is proposed. This oxidant
seems to be crucial for both the in situ generation of a
reactive iminium ion and the final dehydrogenation of the
tetrahydroquinoline to form the corresponding heteroaro-
matic compound.
Acknowledgment. Financial support from the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization and NMR spectra of compounds
and further mechanistic aspects. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Although the reaction with p-toluidine and ethyl glyoxalate to
form the Schiff base in situ is possible (71%, 3a), the advantage of
starting from 1 is to be able to introduce groups such as phosphonates
(7), etc., which not accessible by the in situ approach.
(14) For more details, see Supporting Information.
Org. Lett., Vol. 13, No. 22, 2011
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