Acetic acid promoted metal-free aerobic carbon-carbon bond forming reactions at α-position of tertiary amines

Article abstract of DOI:10.1021/ol5018883

The oxidative functionalization of the benzylic C-H bonds in tetrahydroisoquinolines and tetrahydro-β-carboline derivatives was investigated. C-C bond forming reactions proceeded with a range of nucleophiles (nitroalkane, enol silyl ether, indole, allylstannane, and tetrabutylammonium cyanide) under metal-free conditions and an oxygen atmosphere. Acetic acid caused a significant acceleration effect.

Full text of DOI:10.1021/ol5018883

Letter
pubs.acs.org/OrgLett
Acetic Acid Promoted Metal-Free Aerobic Carbon−Carbon Bond
Forming Reactions at α‑Position of Tertiary Amines
Hirofumi Ueda, Kei Yoshida, and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: The oxidative functionalization of the benzylic C−H bonds in
tetrahydroisoquinolines and tetrahydro-β-carboline derivatives was investigated. C−C
bond forming reactions proceeded with a range of nucleophiles (nitroalkane, enol silyl
ether, indole, allylstannane, and tetrabutylammonium cyanide) under metal-free
conditions and an oxygen atmosphere. Acetic acid caused a significant acceleration
effect.
he development of a novel C−C bond-forming reaction is
one of the most important topics in the field of organic
atmosphere.19 This prompted us to examine the wider
applicability of this aerobic catalytic oxidation reaction using an
oxidative aza-Henry reaction with N-phenyltetrahydro-
isoquinoline 1a as a model reaction (Table 1). As expected,
T
chemistry because C−C bond formation is a fundamental
organic reaction. Most of the reactions require the special
activation of a substrate as a nucleophile, an electrophile, or a
precursor of a reactive species (such as a radical), which causes
unnecessary waste, costs, and laborious experimental operations.
In addition, cross-coupling reactions generally need transition
metal catalysts and special ligands.1 Recently, cross-dehydrogen-
ative coupling (CDC) reactions,2 which can introduce a
substituent through the cleavage of a C−H bond under redox
conditions without the introduction of a leaving group,3 have
received considerable attention because they are more environ-
mentally friendly than other available reactions. If molecular
oxygen can be used as an oxidant, the reaction only produces
hydrogen peroxide, which decomposes to form water. These
advantages inspired the synthetic community to develop aerobic
CDC reactions.2 A number of CDC reactions at C(sp3)−H
bonds adjacent to tertiary amines have been developed, including
Murahashi’s seminal contribution using Ru catalysts.4 Most of
these reactions involve strong oxidants, such as DDQ,5 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) salt,6 (diacetoxy-
iodo)benzene,7 iodine,8 or sulfuryl chloride;9 transition metal
catalysts, such as Ru,4 Cu,10 Fe,11 Rh,12 Au,13 Pt,14 V,15 or Mo;16
or photocatalysts, such16 as Ir(ppy)2(dtbbpy)+17a−e or eosin Y.17f
Tremendous efforts have been made to develop novel CDC
reactions, but few metal-free aerobic CDC reactions with broad
scopes have been reported. One such example is the recently
disclosed Klussmann’s aerobic oxidative C−C bond-forming
reaction at the benzylic methylene in xanthenes, acridines, and
tetrahydroisoquinoline derivatives with an acid catalyst and no
metal catalyst or oxidant.18 Stephenson reported that a quite slow
aerobic oxidative aza-Henry reaction proceeded without a
catalyst or oxidant.17b Here, we describe the versatile metal-
free oxidative C−C bond-forming reactions of tetrahydroiso-
quinoline and tetrahydro-β-carboline derivatives that proceed at
atmospheric pressure under oxygen and in the presence of acetic
acid.
Table 1. Preliminary Experiments on Oxidative Aza-Henry
Reaction
additive
(equiv)
time
(h)
yield
a
entry
1
catalyst (mol %)
(%)
b
Hoveyda−Grubbs second catalyst
−
30
24
(5)
2
Hoveyda−Grubbs second catalyst AcOH (10)
3.5
84
(5)
3
−
AcOH (10)
3.5
71
a
b
Isolated yield. The starting compound 1a was recovered in 62%
yield.
heating a mixture of 1a and a Hoveyda−Grubbs second
generation catalyst in a 1:1 (v/v) mixture of nitromethane 2
and 1,2-dichloroethane under an oxygen atmosphere provided
the aza-Henry product 3a in low yield (Table 1, entry 1). After
further investigation, we found that the conversion rate was
dramatically increased in the presence of 10 equiv of acetic acid
and the starting material 1a was completely consumed after only
3.5 h to give 3a in 84% yield (Table 1, entry 2). Surprisingly, a
control experiment in the absence of the catalyst provided 3a
with a comparable yield and conversion rate. These results
contrasted with those in Klussmann’s seminal report on aerobic
metal-free oxidative C−C bond formation, the coupling
reactions between 1a and ketones in that work giving low to
modest yields using catalytic trifluoromethanesulfonic acid or
methanesulfonic acid under a pressurized oxygen atmosphere.18
We recently found that Grubbs’ catalyst works as a precatalyst
for the catalytic oxidation of tertiary amines under an oxygen
Received: June 30, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Intrigued by these unexpected results, we performed a detailed
optimization study on the acetic acid promoted oxidative aza-
Henry reaction (Table 2). First, 1a was treated with 10 equiv of
which we believe eliminated the possibility that these metals were
involved in this oxidative process.20
Next, we investigated the substituent effect of the N-aryl
moiety in the tetrahydroisoquinoline derivatives on the aza-
Henry reaction and found that a variety of substituents, including
electron-donating and electron-withdrawing groups, were
compatible with the reaction conditions (Table 3). Substrates
Table 2. Optimization of Reaction Conditions and Control
Experiments
Table 3. Substituent Effects of N-Aryl Moiety of
Tetrahydroisoquinoline
AcOH
entry (equiv)
MeNO2
(equiv)
temp time
yield
a
solvent
(°C)
(h)
(%)
1
2
3
4
10
10
10
10
−
−
−
−
MeNO2/(CH2Cl)2
90
3.5
71
80
81
72
b
(1:1 v/v)
MeNO2/(CH2Cl)2
70
50
rt
3
a
entry
substrate
X
product
time (h)
yield (%)
b
(1:1 v/v)
1
2
3
4
5
6
1a
1b
1c
1d
1e
H
3a
3b
3c
3d
3e
3f
18
2
92
56
47
90
95
MeNO2/(CH2Cl)2
7
b
(1:1 v/v)
CH3
MeNO2/(CH2Cl)2
160
OCH3
Br
2.5
18
18
120
b
(1:1 v/v)
5
6
7
8
9
10
5
10
10
10
10
10
10
10
10
10
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
AcOH
70
70
70
70
70
70
70
70
70
6
67
92
86
53
CO2CH3
NO2
18
b
1f
30
c
5
20
a
b
Isolated yield. Starting material 1f was recovered in 70% yield.
d
e
5
144
168
70
f
5
2
10
11
12
13
1
63
1b and 1c, which bear an electron-donating methyl group and
methoxy group, respectively, on the para position of the N-
phenyl group had high conversion rates and provided the desired
products 3b and 3c in moderate yields (Table 3, entries 2 and 3).
Introducing a bromo or methoxycarbonyl group also allowed the
reaction to proceed, resulting in products 3d and 3e, respectively,
in high yields (Table 3, entries 4 and 5). Substrate 1f, which has a
powerful electron-withdrawing nitro group, was poorly reactive,
and the desired product 3f was obtained in only 30% yield even
after 120 h (Table 3, entry 6).
g
0
168
24
14
−
5
54
57
none
42
a
b
c
Isolated yield. The initial concentration of 1a was 0.1 M. Gram
scale reaction. Reaction was conducted under air. Reaction was
conducted under argon after degassing by performing freeze−pump−
thaw cycles. The starting 1a was recovered in 98% yield. The starting
1a was recovered in 70% yield.
d
e
f
g
Having obtained the basic information on the acetic acid
promoted aerobic metal-free oxidative aza-Henry reaction, we
focused our attention on the applicability of this metal-free
oxidative process to other C−C bond forming reactions. A wide
range of nucleophiles were found to be suitable for this oxidative
coupling process (Table 4). Nitroethane could be used in the
oxidative aza-Henry reaction, giving products 9a and 9e in good
yields as diastereomeric mixtures (Table 4, entries 1 and 2). An
aza-Mannich-type reaction proceeded smoothly with enol silyl
ether 5 to provide product 10e in a moderate yield (Table 4,
entry 3). In addition, the indole derivative 6 proved to be a
suitable nucleophile for an oxidative Friedel−Crafts reaction,
giving products 11a−c in 71−79% yields (Table 4, entries 4−6).
We were also able to apply the reaction to an oxidative allylation
reaction, the reaction with allyltributylstannane 7, giving
products 12a−c in moderate to good yields (Table 4, entries
7−9). Furthermore, the oxidative coupling took place smoothly
using tetrabutylammonium cyanide 8 to give Strecker products
13a and 13e in good yields (Table 4, entries 10 and 11).
Further investigations were conducted to expand the scope of
the substrates. First, tetrahydro-β-carboline 14 was found to be a
suitable substrate for the reaction. The allylation reaction using
allyltributylstannane 7 proceeded with 20 equiv of acetic acid to
afford product 15 in a modest yield (Scheme 1). The oxidative
Strecker reaction with tetrabutylammonium cyanide 8 pro-
ceeded well to provide 16 in good yield. In addition, a simple N-
heterocyclic compound, pyrrolidine derivative 17, gave the
corresponding oxidative Strecker product 18 in a modest yield.
acetic acid in a mixture of nitromethane and 1,2-dichloroethane
at different temperatures (Table 2, entries 1−4). The yield of
product 3a was slightly better (80%) when the reaction was
conducted at 70 °C (Table 2, entry 2). The reaction required a
long reaction time at 50 °C and rt (Table 2, entries 3 and 4). The
amount of nitromethane could be decreased to 10 equiv (Table
2, entry 5). The best yield of product 3a (92%) was obtained
when a mixture of 1a, 10 equiv of nitromethane, and 5 equiv of
acetic acid in 1,2-dichloroethane was heated to 70 °C (Table 2,
entry 6). These optimal conditions were also applicable in a gram
scale reaction (Table 2, entry 7).
We then conducted control experiments (Table 2, entries 8−
13) to investigate the importance of oxygen and acetic acid. The
conversion rate became much lower under an air atmosphere,
and 6 days were required to consume all of 1a (Table 2, entry 8).
The reaction gave product 3a in only 2% yield under an argon
atmosphere, and 98% of 1a was recovered even after a week
(Table 2, entry 9). We also found that the conversion rate was
strongly dependent on the amount of acetic acid present (Table
2, entries 5, 6, 10, and 11). However, the use of acetic acid as the
solvent was not effective (Table 2, entry 12). Finally, we analyzed
the metals that were present as contaminants in the reaction
mixture by inductively coupled plasma optical emission
spectrometry, to determine the possibility that redox-active
metallic impurities acted as catalysts. Redox-active transition
metals, including V, Mn, Fe, Cu, Ru, and Pd, were not detected in
our quantitative analyses (the detection limit was 0.05 ppm),
B
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Letter
Table 4. Oxidative Coupling of N-Aryltetrahydroisoquinoline
with Various Nucleophiles
Scheme 2. Proposed Mechanisms for Oxidative Coupling in
the Presence of Acetic Acid and Molecular Oxygen
abstraction from the benzylic CH2 in another molecule of 1, and
elimination of hydrogen peroxide would provide the iminium ion
species D,22,23 which should form a C−C bond with various
nucleophiles. The involvement of the intermediate radical
species A was proven by a control experiment in the presence
of a radical inhibitor, 2,6-di-tert-butyl-4-methylphenol 21
(Scheme 3). The conversion rate was substantially lower in
Scheme 3. Effects of a Radical Inhibitor on the Aza-Henry
Reaction
this reaction than in the reaction without 21, and product 3a was
obtained in only 8% yield after the standard reaction time, while
the starting material 1 was recovered in 86% yield.
a
b
c
Isolated yield. AcOH (5 equiv) was used. The diastereomeric ratio
d
e
(dr) was 2:1. The dr was 3:2. The initial concentration of 1e was 0.3
M. The dr was 1:1. The reaction was performed in CH2Cl2 at 50 °C.
There would be two processes in the proposed reaction
mechanism (Scheme 2) in which acetic acid might participate to
accelerate the reaction. One is the formation of iminium ion D by
protonation of the peroxide C (Scheme 2). A similar explanation
was proposed by Klussmann et al. for the acid-catalyzed metal-
free aerobic coupling of xanthenes. Our results were very
different from the results reported by Klussmann et al. when they
used stronger acids, and we found that using methanesulfonic
acid instead of acetic acid did not allow the oxidative aza-Henry
reaction to occur effectively in a reaction with an excess or a
catalytic amount of methanesulfonic acid (Scheme 4).24,25 The
f
g
Scheme 1. Oxidative Coupling of Tertiary Amines
Scheme 4. Oxidative Aza-Henry Reaction in the Presence of a
Strong Acid
other process involved would be the generation of the benzylic
radical A during the autoxidation step. Given the facts that
neither peroxide C nor the corresponding hemiaminal was
detected and that 70% of starting material 1a remained even after
a week under conditions without acetic acid (Table 1, entry 11),
it seems likely that the process in which the benzylic radical A is
generated is the rate-determining process and that acetic acid
either accelerates this process or accelerates both steps (1 to A
and C to D)(Scheme 2). In analogy to the acetic acid promoted
acceleration of the oxidation of phenol with peroxyl radicals that
was recently disclosed by Pratt et al.,26 we wonder whether the
acetic acid might work in a way that acetic acid could protonate a
Significantly, N,N-dimethylaniline derivative 19 was feasible to
the oxidative allylation and the reaction gave N-homoallylaniline
derivative 20.
A plausible mechanism for the acetic acid promoted metal-free
aerobic C−C bond-forming reaction has not yet been fully
elucidated, but the reaction may proceed through a benzylic
radical species A generated by the autoxidation of 1 (Scheme
2).21 A reaction of the product with molecular oxygen, H-
C
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Organic Letters
Letter
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́
acid than with a stronger acid because a weaker acid should have a
reasonably basic conjugated base that could be involved in the
deprotonation of H to generate radical species A.24,25
In summary, we have established an oxidative C−C bond-
forming reaction that occurs at a benzylic C−H bond adjacent to
a tertiary amine. The utility of the reaction was fully
demonstrated by applying it to a wide range of C−C bond-
forming reactions with various nucleophiles and substrates.
Significantly, the reaction proceeds in the presence of only acetic
acid and molecular oxygen, and no metal catalyst or external
oxidant is required. Further investigations are currently in
progress, which are aimed at expanding the scope of this
environmentally friendly reaction and elucidating the mecha-
nisms involved.
ASSOCIATED CONTENT
* Supporting Information
(15) Jones, K. M.; Karier, P.; Klussmann, M. ChemCatChem 2012, 4,
51.
■
S
(16) (a) Alagiri, K.; Prabhu, K. R. Org. Biomol. Chem. 2012, 10, 835.
(b) Wang, F.; Ueda, W. Chem.Eur. J. 2009, 15, 742.
Experimental details and procedures, compound characterization
data, copies of 1H and 13C NMR spectra for all new compounds.
This materials is available free of charge via the Internet at http://
pubs.acs.org.
(17) For examples, see: (a) McNally, A.; Prier, C. K.; MacMillan, D. W.
́ ́
C. Science 2011, 334, 1114. (b) Condie, A. G.; Gonzalez-Gomez, J. C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. (c) Freeman, D.
B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org. Lett. 2012, 14, 94.
(d) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O. Org. Lett. 2012, 14, 672.
(e) Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem.
AUTHOR INFORMATION
Corresponding Author
■
2013, 9, 1977. (f) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852.
̈
*E-mail: tokuyama@mail.pharm.tohoku.ac.jp.
Notes
́
́
, A.; Sud, A.; Sureshkumar, D.; Klussmann, M. Angew.
(18) (a) Pinter
Chem., Int. Ed. 2010, 49, 5004. (b) Schweitzer-Chaput, B.; Sud, A.;
́
́
Pinter, A.; Dehn, S.; Schulze, P.; Klussmann, M. Angew. Chem., Int. Ed.
The authors declare no competing financial interest.
2013, 52, 13228.
(19) Komatsu, Y.; Yoshida, K.; Ueda, H.; Tokuyama, H. Tetrahedron
Lett. 2013, 54, 377.
(20) See the Supporting Information (SI).
ACKNOWLEDGMENTS
■
This work was financially supported by the Cabinet Office,
Government of Japan through its “Funding Program for Next
Generation World-Leading Researchers (LS008), and the JSPS
through a Grant-in-aid for Scientific Research (A) (26253001)
and Young Scientists (B) (26860004). We thank reviewers for
their valuable suggestions.
(21) Rieche, A.; Hoft, E.; Schultze, H. Chem. Ber. 1964, 97, 195.
̈
(22) Peracetic acid mediated oxidation may be excluded by a control
experiment on an oxidative aza-Henry reaction with peracetic acid
instead of oxygen and acetic acid, which did not give the desired product,
but provided the corresponding N-oxide in 45% yield; see the SI.
(23) Another possibility that D might be formed by direct 1e oxidation
of A could not be excluded because an attempt to detect hydrogen
peroxide by starch-iodine testing was unsuccessful (see the SI).
(24) For a series of experiments using various Brønsted acids including
acid−base conditions, see the SI.
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