Molecular-iodine-catalyzed aerobic photooxidative C-C bond formation between tertiary amines and carbon nucleophiles

Article abstract of DOI:10.1039/c3ra41850b

This paper reports a useful method for molecular-iodine-catalyzed aerobic photooxidative C-C bond formation between tertiary amines and carbon nucleophiles. This reaction provides a practical method for C-C bond formation through the use of molecular iodi

Full text of DOI:10.1039/c3ra41850b

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Molecular-iodine-catalyzed aerobic photooxidative C–
C bond formation between tertiary amines and carbon
nucleophiles3
Cite this: RSC Advances, 2013, 3, 10189
Received 16th March 2013,
Accepted 30th April 2013
Tomoya Nobuta, Akitoshi Fujiya, Tomoaki Yamaguchi, Norihiro Tada,
Tsuyoshi Miura and Akichika Itoh*
DOI: 10.1039/c3ra41850b
www.rsc.org/advances
This paper reports a useful method for molecular-iodine-catalyzed
aerobic photooxidative C–C bond formation between tertiary
amines and carbon nucleophiles. This reaction provides a practical
method for C–C bond formation through the use of molecular
iodine, harmless visible light irradiation, and molecular oxygen as
the terminal oxidant.
Scheme 1 Molecular-iodine-catalyzed CDC reaction with molecular oxygen under
visible light irradiation.
As compared to classical cross-coupling reactions, C–C bond
formation through cross-dehydrogenative coupling (CDC) reac-
tions is a powerful method because it does not require the
preactivation of two precursors required, and hence, various CDC
reactions have been developed in recent years.1 In particular,
oxidation of C–H bonds adjacent to the nitrogen atom of tertiary
amines to form iminium ions has attracted great interest because
synthetically and biologically useful Mannich-type products are
obtained from simple precursors. Recently, various methods,
which include reactions using transition metal catalysts, such as
Ru,2 Cu,3 Fe,4 V,5 Rh,6 Au,7 and Pt,8 or a stoichiometric amount of
an oxidant, such as PhI(OAc)2,9 DDQ,10 and tropylium ion have
been reported.11 We also recently reported a metal-free, catalytic
CDC reaction between tertiary amines and carbon nucleophiles
using catalytic molecular iodine and aq H2O2 as the terminal
oxidant.12 Iodine-source-catalyzed C–H oxidation with various
stoichiometric oxidants has attracted great interest because iodine
sources have low toxicity and are inexpensive reagents compared
to transition metal catalysts and terminal oxidants such as
mCPBA,13 Oxone,14 aq H2O2, or TBHP.15 On the other hand, we
have developed various oxidation methods using catalytic iodine
sources with molecular oxygen as the terminal oxidant under
visible light irradiation.16 Molecular oxygen is photosynthesized by
plants and is an effective oxidant with atom efficiency greater than
that of other oxidants such as toxic heavy metals or complex
organic reagents. Through our study of aerobic photooxidation
with iodine sources, we found that tertiary amines can be oxidized
by catalytic molecular iodine under aerobic photooxidative
Table 1 Study of reaction conditionsa
Entry
lodine source
Solvent
3aa (%)b
1
2
I2
I2
THF
EtOAc
DMF
1
5
3
4
I2
I2
14
25
50
66
93 (84)
89
3
MeOH
CH2Cl2
Hexane
MeCN
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
6
I2
I2
7
I2
I2
—
8c
9
10d
11e
12f
13
14
15
16
17
18
I2
I2
I2
CaI2
Bu4NI
KI
MgI2
LiI
NaI
3
11
10
89
84
83
82
75
74
a
Reaction conditions: 1a (0.3 mmol), MeNO2 (5 equiv.), iodine
source (0.05 equiv.), and AcOH (5 equiv.) in solvent (3 mL), purged
with an O2 balloon, was stirred and irradiated externally with a 22 W
fluorescent lamp for 12 h. b 1H NMR yields. Number in parenthesis
c
d
is isolated yield. Nitromethane (3 mL) was used as solvent. The
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
E-mail: itoha@gifu-pu.ac.jp; Fax: +81-58-230-8108; Tel: +81-58-230-8108
reaction was performed without AcOH. 1a was recovered in 14%
e
f
yield. The reaction was performed under N2. The reaction was
performed in the dark.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra41850b
3
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Table 2 CDC reaction of amines with carbon nucleophilesa
Entry
1
Substrate
NuH (equiv.)
Time (h)
12
Product
Yield (%)b
84
MeNO2 (5)
2a
2
3
4
5
6
7
8
MeNO2 (5)
2a
12
22
5
75
MeNO2 (5)
2a
84
MeNO2 (5)
2a
73
EtNO2 (5)
2b
20
20
12
12
74c
64d
53e
76
EtNO2 (5)
2b
EtNO2 (5)
2b
Dimethylmalonate (2)
2c
9
Diethylmalonate (2)
2d
12
12
75
32
10f
Acetone (5)
2e
a
Reaction conditions: 1 (0.3 mmol), 2, I2 (0.05 equiv.), and AcOH (5 equiv.) in MeCN (3 mL), purged with an O2 balloon, was stirred and
b
c
d
e
f
externally irradiated with a 22 W fluorescent lamps. Isolated yields. dr = 63 : 37. dr = 66 : 34. dr = 65 : 35. L-Proline (0.1 equiv.) was
used instead of AcOH.
conditions. CDC reactions between tertiary amines and carbon
nucleophiles using a photocatalyst such as Ir(ppy)2(dtbbpy)+,17
functionalization catalyzed by iodine without photo-irradiation.20
However, when nitroalkanes were used as nucleophile, addition of
silica gel was required, and when ketones and 1,3-diesters were
used, TBHP was required as oxidant instead molecular oxygen.
Herein, we report molecular-iodine-catalyzed aerobic photooxida-
Ru(bpy)3 ,
2+ 18 and eosin Y19 were reported; however, their methods
require transition metal photocatalysts and an excess amount of
carbon nucleophiles as a solvent. During the course of preparing
this manuscript, Prabhu have reported impressive aerobic C–H
10190 | RSC Adv., 2013, 3, 10189–10192
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tive C–C bond formation between tertiary amines and carbon
nucleophiles (Scheme 1).
Table 1 shows results from a study of the reaction conditions
for aerobic photooxidative C–C bond formation using N-phenyl
tetrahydroisoquinoline (1a) as a test substrate with 5 equivalents
of nitromethane (2a) in the presence of 5 equivalents of AcOH.
Among the solvents and iodine sources examined, MeCN and
I2 were found to afford the desired product 3aa most efficiently
(entries 1–7 and 13–18). Although nitromethane was used as
solvent, the yield of 3aa was not improved (entries 7 and 8). A
background reaction performed in the absence of molecular
iodine proceeded scarcely (entry 9). Furthermore, the fact that 3aa
was obtained in low yields without AcOH, irradiation, and
molecular oxygen shows the necessity of these reagents to perform
this reaction (entries 10–12).
Table 2 presents the scope and limitations of CDC reactions
between N-aryl tetrahydroisoquinolines (1) and carbon nucleo-
philes (2) under optimized reaction conditions.{ In general, the
corresponding aza-Henry products were obtained in good to high
yields using nitromethane (2a) and nitroethane (2b) regardless of
whether an electron-donating or electron-withdrawing group was
present on the aromatic ring of the N-aryl moiety (entries 1–7).
Unfortunately other tertiary amines, such as N,N-dimethyl-
p-toluidine and N-benzyl-N-methylaniline, were poor substrates.
In addition to oxidative aza-Henry reactions, we applied our
method to oxidative Mannich reactions. The corresponding
Mannich products were obtained in good yields using 2
equivalents of activated methylene compounds such as dimethyl
malonate (2c) and diethyl malonate (2d) (entries 8 and 9).
Furthermore, we attempted oxidative couplings between tertiary
amines and unactivated ketones. Under the optimized conditions
described in Table 1, the corresponding oxidative Mannich
product was not obtained with acetone (2e); however, in the
presence of 0.1 equivalents of L-proline instead of AcOH, C–C
bond formation proceeded to afford the corresponding Mannich
product in modest yield (entry 10).
Scheme 3 Plausible path.
molecular oxygen, and irradiation. Furthermore, the CDC reaction
was not suppressed in the presence of 1 equivalent of BHT, which
is a radical inhibitor (Scheme 2, eqn (2)).
Scheme 3 shows a plausible path for this oxidation, which is
postulated by considering all of the results mentioned above. It is
known that molecular iodine is converted to the more reactive I+
species with an oxidizing reagent.23 Active species in our reaction
have not yet been clarified; however, we speculate that hypoiodous
acid24 or acetyl hypoiodite is generated from I2 in situ under
aerobic photooxidative conditions in the presence of H2O or
AcOH.25 Tertiary amines (1) are oxidized to iminium ions (4) by
ROI or its protonated species (protonated by AcOH and/or HI)
generated in situ from I2. Intermediate 4 undergoes an acid-
promoted addition of the carbon nucleophile to form the desired
product (3). HI, generated by the combination of 4 and a
nucleophile, is reoxidized to I2 under the aerobic photooxidative
conditions.
Conclusions
In conclusion, we report molecular-iodine-catalyzed oxidative C–C
bond formation through CDC reactions between tertiary amines
and carbon nucleophiles. This novel reaction is interesting as it
uses catalytic molecular iodine, molecular oxygen as the terminal
oxidant, and visible light from a general-purpose fluorescent lamp.
Further application of this photooxidation to other reactions is
now in progress in our laboratory.
To resolve the reaction mechanism, several control experi-
ments were examined. It is known that tetrahydroisoquinolines
can be oxidized to 3,4-dihydroisoquinolines with molecular iodine
in ethanol;21,22 however, when 1 equivalent of molecular iodine
was used in the absence of molecular oxygen and visible light
irradiation, only a trace amount of 3aa was obtained and 76% of
1a was recovered (Scheme 2, eqn (1)). This result suggests that
amine oxidation requires all three components: molecular iodine,
Notes and references
{ General procedure: a solution of N-phenyl-1,2,3,4-tetrahydroisoquinoline
(1a, 0.3 mmol), I2 (0.015 mmol), MeNO2 (2a, 1.5 mmol), and AcOH (1.5
mmol) in MeCN (3 mL) in a pyrex test tube, purged with an O2 balloon, was
stirred and externally irradiated with a 22 W fluorescent lamps for 12 h.
The reaction mixture was washed with aq. NaHCO3, and aq. Na2S2O3, dried
over Na2SO4, and concentrated in vacuo. Purification of the crude product
by flash chromatography on silica gel (hexane : ethylacetate = 10 : 1)
provided 1-(nitromethyl)-N-phenyl-1,2,3,4-tetrahydroisoquinoline (3aa)
(67.9 mg, 84%).
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Scheme 2 Study of reaction mechanisms.
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