Friedel-Crafts amidoalkylation via thermolysis and oxidative photocatalysis

Article abstract of DOI:10.1021/jo300162c

Friedel-Crafts amidoalkylation was achieved by oxidation of dialkylamides using persulfate (S₂O₈^2-) in the presence of the visible light catalyst, Ru(bpy)₃Cl₂, at room temperature, via a reactive N-acyliminium intermediate. Alternatively, mild heating of the dialkylamides and persulfate afforded a metal and Lewis acid-free Friedel-Crafts amidoalkylation. Alcohols and electron-rich arenes served as effective nucleophiles, forming new C-O or C-C bonds. In general, photocatalysis provided higher yields and better selectivities.

Full text of DOI:10.1021/jo300162c

Note
pubs.acs.org/joc
Friedel−Crafts Amidoalkylation via Thermolysis and Oxidative
Photocatalysis
Chunhui Dai, Francesco Meschini, Jagan M. R. Narayanam, and Corey R. J. Stephenson*
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Friedel−Crafts amidoalkylation was achieved by oxidation
of dialkylamides using persulfate (S2O82−) in the presence of the visible
light catalyst, Ru(bpy)3Cl2, at room temperature, via a reactive N-
acyliminium intermediate. Alternatively, mild heating of the dialkylamides
and persulfate afforded a metal and Lewis acid-free Friedel−Crafts
amidoalkylation. Alcohols and electron-rich arenes served as effective nucleophiles, forming new C−O or C−C bonds. In general,
photocatalysis provided higher yields and better selectivities.
hotoredox catalysis has emerged as a powerful tool for
organic synthesis.1 Extensive studies demonstrated that
significantly more positive reduction potential (2.0 V for
primary amides, 1.8 V for secondary amides, and 1.2−1.5 V (vs
SCE) for tertiary amides)9 than the corresponding amines,
making them far less susceptible to direct oxidation, including
photocatalyst-mediated oxidation.
P
photocatalysts, such as Ru(bpy)3Cl2 (1), can initiate single
electron transfer (SET) processes under visible light irradiation,
providing a new means to selectively activate molecules and
promote chemical transformations.2 For instance, by harnessing
the reductive quenching cycle of Ru(bpy)3Cl2, we have recently
demonstrated the oxidative functionalization of N-arylamines.3,4
Key to this process was the mild and efficient visible light
promoted generation of iminium ion intermediates, using
Ru(bpy)3Cl2 and BrCCl3 as the terminal oxidant. The amino
radical cation was generated through oxidation of N-
aryltetrahydroisoquinoline by Ru2+* (Ered = +0.84 V vs SCE).
A subsequent H-atom abstraction, or deprotonation followed
by oxidation, provided the electrophilic iminium ion
intermediate (Scheme 1, top).
However, this difficulty in oxidation can be circumvented by
reordering the steps, that is, C−H abstraction followed by
oxidation. The α-amine C−H bond has been shown to be
prone to H-atom abstraction under a number of reaction
conditions, normally requiring a combination of metal complex
catalyst/peroxide and sometimes elevated temperatures are
needed.10,11 The α-amino radical thus generated is strongly
reducing, potentially allowing for the generation of N-
acyliminium ions by a photocatalyzed oxidation (Scheme 1,
bottom). Meanwhile, one of the hallmarks of visible light
photocatalysis is the mild reaction condition and outstanding
functional group tolerance, which would provide some
advantages over the current methods. It is well precedented
that persulfate (S2O82−) is an effective oxidative quencher of
Ru(bpy)32+*,12 and the generated sulfate radical anion (SO4·−)
is a reactive intermediate known to abstract activated hydrogen
atoms and also to be a strong oxidant.13 Herein, we report a
visible light enabled Friedel−Crafts amidoalkylation using
persulfate at room temperature via the oxidative quenching
cycle of Ru(bpy)3Cl2. In addition, a metal-free thermal
decomposition of persulfate was observed upon heating the
reaction to 55 °C, leading to the same amide oxidation
products albeit with attenuated yields and selectivities.
In line with our investigative pursuit into α-amine
functionalization via visible light mediated photoredox catalysis,
we decided to explore the formation of N-acyliminium ions. N-
Acyliminium ions are known to be more reactive than the
simple N-alkyliminium or N-aryliminium ions and thus open to
a broader range of functionalization.5 The importance of N-
acyliminium ions in organic synthesis has been well
documented, especially in the synthesis of alkaloid natural
products.6 In general, these highly reactive N-acyliminium ions
historically are generated in situ from α-oxyalkylated amides by
Lewis acid- or Brønsted acid-promoted elimination,7 or through
direct anodic oxidation of amides.8 However, amides have a
When 3-phenyl-1-propanol (2a) or 3-(4-methoxyphenyl)-1-
propanol (2b) was treated with Ru(bpy)3Cl2 (1.0 mol %),
Na2S2O8 (5.0 equiv) and 2,6-lutidine (2.0 equiv) in DMF, upon
visible light irradiation for 12 h at room temperature, formation
of the N,O-aminal product (3a or 3b), presumably resulting for
DMF oxidation followed by nucleophilic trapping, was
observed (Scheme 2).14 Despite complete consumption of
Received: January 24, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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Note
Scheme 1. α-C−H Functionalization of Amines and Amides via Visible Light-Mediated Photocatalysis
Scheme 2. Formation of N,O-Aminals
the starting material, the isolated yields were relatively low
(30−66%) because of the lability of the N,O-aminals during the
aqueous workup and chromatographic purification. However,
these results demonstrated that N-acyliminium ions could be
generated via the visible light-mediated reduction of persulfate
at room temperature.
Table 1. Optimization and Control Experiments
conversion
We next explored the use of electron-rich aromatics as
nucleophiles to form more stable C−C bonds via a Friedel−
Crafts reaction. At the onset, 1,3,5-trimethoxybenzene (4a) was
chosen as the nucleophile in DMF. Full consumption of 4a was
observed when treated with Ru(bpy)3Cl2, and 5.0 equiv of
persulfate after 12 h of visible light irradiation at room
temperature (Table 1, entry 1). Little or no conversion was
observed in the absence of catalyst or light (Table 1, entries 2−
4), and rigorous degassing was required to achieve optimal
results, presumably a consequence of undesired and unpro-
ductive excited state energy transfer with oxygen. Persulfate was
found to be essential for the transformation, requiring 5.0 equiv
for optimal results (Table 1, entries 5−6). Interestingly, we
discovered that reactivity was observed in the absence of
photocatalyst (Table 1, entry 7); however, the reaction required
elevated temperature (55 °C). This result verified that Friedel−
Crafts amidoalkylation can be achieved in a metal- and Lewis
acid-free condition via the thermolysis of persulfate.
a
b
entry
conditions
(%)
1
2
3
4
5
6
catalyst, persulfate (5.0 equiv), 25 °C
99
<5
0
no catalyst, persulfate (5.0 equiv), 25 °C
catalyst, persulfate (5.0 equiv), 25 °C, no blue LEDs
catalyst, persulfate (5.0 equiv), 25 °C, no degassing
catalyst, no persulfate, 25 °C
catalyst, persulfate (4.0 equiv), 25 °C
no catalyst, persulfate (5.0 equiv), 55 °C
59
0
86
99
c
7
a
Except for entries 4 and 7, the reactions were rigorously degassed.
Determined by crude H NMR. Reaction was complete in 2 h.
b
c
1
catalytic conditions afforded monosubstituted product 6aa
exclusively, in contrast to thermolytic conditions, which gave
both monosubstituted (6aa) and disubstituted products (7aa,
Table 2, entry 1). Switching to DMA (5b), both photocatalysis
and thermolysis provided monosubstituted (6ab) and disub-
stituted products (7ab, Table 2, entry 2) in a 3.9:1 ratio, but
better yields were observed under photocatalytic reaction
conditions. A differentiated dialkylamide, such as 1-methyl-2-
pyrrolidinone (5c), afforded a mixture of regioisomeric,
monosubstituted products 6ac and 6ac′ (Table 2, entry 3)
under both reaction conditions, but higher selectivities were
observed with photocatalysis. Surprisingly, when 1,2,3-trime-
With the optimized conditions in hand, we then examined
various electron-rich aromatic and heteroaromatic substrates
with dialkylamides in the presence of ammonium persulfate,
under both photocatalytic and thermolytic conditions (Table
2). Treatment of 1,3,5-trimethoxybenzene (4a) with Ru-
(bpy)3Cl2 in DMF (5a) at room temperature under photo-
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Note
Table 2. Oxidation of Dialkylamides and Coupling with Electron-Rich Aromatics
a
The reaction was degassed (freeze−pump−thaw) and carried out under argon atmosphere using a nucleophile (4, 0.5 mmol) and ammonium
b
persulfate (2.5 mmol) in the presence of Ru(bpy)3Cl2 (1.0 mol %) in dialkylamides (5, 5.0 mL). The reaction was carried out under argon
atmosphere using a nucleophile (4, 0.5 mmol) and ammonium persulfate (2.5 mmol) in dialkylamides (5, 5.0 mL). Isolated yields . Determined by
crude H NMR. Yields are based on recovered starting material.
c
d
e
1
thoxybenzene (4b) was treated with the same conditions in the
presence of 5a or 5b, the reaction failed to provide either of the
desired products. Prolonged reaction time or higher temper-
ature did not improve the conversion (Table 2, entry 4). Less
nucleophilic substrates, such as 4c and 4d, needed higher
temperatures and longer reaction times under photocatalytic
conditions, although under thermolytic conditions, higher
temperatures did not show obvious improvement (Table 2,
entries 5−8). Substrates that have multiple nucleophilic sites,
such as 4d, generated mixtures of regioisomers. Furthermore,
1,4-dimethoxybenzene (4e) failed to provide the desired
products (Table 2, entry 9). Highly reactive substrates, such
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Note
as indole (4f, Table 2, entry 10) and N-methylindole (4g, Table
2, entry 11), performed poorly for this oxidative coupling
reaction. We speculate that the low yield was due to the
oxidative decomposition of the highly electron-rich substrate
itself or the loss of the product 4fa and 4ga by oxidation at the
methylene carbon adjacent to the amide nitrogen.15 When
switching to indoles known to be less prone to oxidation, such
as N-phenyl indole (4h, Table 2, entry 12) and N-benzyl indole
(4i, Table 2, entry 13), the reactions gave moderate yields of
the desired products. In all cases, substitution at the C-2
position of the indoles was not observed. As a general
observation, photocatalysis provided higher yields and better
selectivities than thermolysis.
also occurred. This might be the result of a reversible oxidation
of trimethoxybenzene during the course of the reaction
(Scheme 3, eq 1).
In conclusion, utilizing the oxidative quenching cycle of
Ru(bpy)3Cl2 and a mechanistically distinct reaction design
compared to previous studies in photoredox catalysis, we have
developed a protocol for the oxidative functionalization of
dialkyl amides. Persulfate was found to be an inexpensive and
efficient reagent for this transformation and is operative under
either thermal or photochemical reaction conditions. Electron-
rich species, such as alcohols and arenes, served as suitable
nucleophiles. In most cases, photocatalysis provided higher
yields and better selectivities for the Friedel−Crafts reactions
compared with the thermolytic reaction conditions. This
method is highlighted by its operational simplicity and mild
reaction conditions. Further studies on substrate expansion are
now in progress.
Plausible mechanisms for the oxidation of dialkylamides,
using DMF as an example, are shown in Scheme 3. Under the
Scheme 3. Plausible Reaction Mechanism
EXPERIMENTAL SECTION
■
General Remarks. Glassware was dried in a 170 °C oven or flame-
dried under vacuum and cooled under inert atmosphere before use.
Chemicals were either used as received or purified according to the
procedures outlined in Purification of Common Laboratory Chemicals.
All reactions were performed using common dry, inert atmosphere
techniques. 1H and 13C NMR spectra were recorded on Varian
Mercury 300, Varian Unity Plus 400, or Varian 500 spectrometers,
using an internal deuterium lock.
General Procedure for the Oxidation of Alkylamides Using
Ru(bpy)3Cl2 Catalyst (Table 2). A flame-dried 10 mL Schlenk flask
with a rubber septum and magnetic stir bar was charged with tris(2,2′-
bipyridyl)ruthenium(II) chloride hexahydrate (5.0 μmol), the
corresponding substrate (0.5 mmol), and ammonium persulfate (2.5
mmol). Then, 5.0 mL of dry dimethylformamide (DMF),
dimethylacetamide (DMA), or 1-methyl-2-pyrrolidinone (DMP) was
added via syringe. The mixture was degassed by the freeze−pump−
thaw procedure (3×), and placed in a 250 mL beaker with blue LEDs
wrapped inside. The reaction mixture was stirred at room temperature
(or 30 °C using a 100 mL beaker) under argon atmosphere for the
time specified in Table 2. Then, the mixture was poured into a
separatory funnel containing 100 mL of ethyl acetate and 50 mL of
saturated NaHCO3 solution. The layers were separated, and the
aqueous layer was extracted with ethyl acetate (50 mL). The combined
organic layers were washed with H2O (2 × 50 mL) and brine and
dried over Na2SO4. Solvent was evaporated under reduced pressure,
and the residue was purified by chromatography on silica gel to afford
the desired product.
General Procedure for the Oxidation of Alkylamides Under
Thermolysis (Table 2). To a solution of substrate (0.5 mmol) in 5.0
mL of dimethylformamide (DMF), dimethylacetamide (DMA), or 1-
methyl-2-pyrrolidinone (DMP) in a 10 mL round-bottom flask was
added ammonium persulfate (2.5 mmol). The mixture was then
heated to 55 °C and stirred at that temperature for the time specified
in Table 2. Then, the reaction mixture was poured into a separatory
funnel containing 100 mL of ethyl acetate and 50 mL of saturated
NaHCO3 solution. The layers were separated, and the aqueous layer
was extracted with ethyl acetate (50 mL). The combined organic layers
were washed with H2O (2 × 50 mL) and brine and dried over Na2SO4.
Solvent was evaporated under reduced pressure, and the residue was
purified by chromatography on silica gel to afford the desired product.
N-Methyl-N-((3-phenylpropoxy)methyl)formamide (3a). A
photocatalytic conditions, persulfate16 is reduced by Ru-
(bpy)32+* to give sulfate and sulfate radical anion 8.
Alternatively, under thermal conditions, persulfate may
decompose to generate 2 equiv of 8. The alkyl amide (DMF
in this case) can then undergo H-atom abstraction by 8 to give
α-amido radical 9. Direct oxidation of 9 by Ru3+ (+1.27 V vs
SCE)17 or via electron-transfer of persulfate can lead to N-
acyliminium ion 10 (pathway A), which can also be achieved
via a radical chain process (pathway B) to give oxyalkylamide
11 followed by elimination of sulfate. Either way, the generated
acyliminium ion 10 is susceptible to nucleophilic trapping by
various electron-rich arenes to afford the desired product 6.
Intermolecular H-atom abstraction was supported by an
isotopic labeling experiment using 1:1 mixture of DMF/
DMF-d7 as solvent with 4a, which provided the product with a
H/D ratio of 2.3:1. Surprisingly, a very small amount (7%) of
deuterium incorporation on the aromatic ring of the product
1
colorless oil: observed as two rotamers of 82/18 ratio in H NMR
(500 MHz, CDCl3) δ 8.15/8.15 (s, 1 H), 7.31−7.27 (m, 2 H), 7.21−
7.16 (m, 2 H), 4.82/4.66 (s, 2 H), 3.45/3.34 (t, J = 6.4 Hz, 2 H), 2.98/
2.93 (s, 3 H), 2.71−2.66 (m, 2 H), 1.94−1.87 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 163.4, 162.8, 141.7, 141.3, 128.4 (two overlapping
signals 128.41, 128.37), 128.3, 126.0, 125.8, 80.3, 73.6, 67.7, 66.6, 33.0,
32.3, 32.2, 31.1, 30.9, 29.0; HRMS (ESI) m/z calcd for C12H18NO2 [M
+ H]+ 208.1338, found 208.1345.
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Note
N-((3-(4-Methoxyphenyl)propoxy)methyl)-N-methylforma-
mide (3b). A colorless oil: observed as two rotamers of 81/19 ratio in
1H NMR (400 MHz, CDCl3) δ 8.16/8.16 (s, 1 H), 7.10−7.06 (m, 2
H), 6.85−6.81 (m, 2 H), 4.82/4.65 (s, 2 H), 3.79/3.79 (s, 3 H), 3.44/
3.33 (t, J = 6.4 Hz, 2 H), 2.98/2.93 (s, 3 H), 2.65−2.59 (m, 2 H),
1.90−1.83 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 163.4, 162.7,
157.8 (two overlapping signals 157.85, 157.76), 133.7, 133.4, 129.2,
113.8, 113.7, 80.3, 73.6, 67.7, 66.5, 55.2, 33.0, 31.3 (two overlapping
signals 31.32, 31.29), 31.2, 31.1, 28.9; HRMS (ESI) m/z calcd for
C13H20NO3 [M + H]+ 238.1443, found 238.1453.
N-(2,4-Dimethoxy-5-methylbenzyl)-N-methylacetamide
1
(6cb). A colorless oil: observed as two rotamers of 62/38 ratio in H
NMR (400 MHz, CDCl3) δ 6.98/6.79 (s, 1 H), 6.43/6.41 (s, 1 H),
4.53/4.40 (s, 2 H), 3.84/3.83/3.82 (s, 6 H), 2.91/2.88 (s, 3 H), 2.16/
2.13/2.12 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 171.1, 170.5,
157.8, 157.6, 156.5, 156.1, 131.5, 129.4, 118.2, 117.9, 116.7, 115.4,
94.8, 94.7, 55.6, 55.4 (two overlapping signals 55.44, 55.37), 55.3, 49.2,
44.1, 35.5, 33.1, 21.8, 21.2, 15.2, 15.1; HRMS (ESI) m/z calcd for
C13H19NO3Na [M + Na]+ 260.1263, found 260.1251.
N-(2,4-Dimethoxybenzyl)-N-methylformamide (6da). A col-
orless solid: observed as two rotamers of 75/25 ratio in 1H NMR (400
MHz, CDCl3) δ 8.24/8.10 (s, 1 H), 7.13/7.03 (d, J = 8.8 Hz, 1 H),
6.46−6.43 (m, 2 H), 4.48/4.29 (s, 2 H), 3.80/3.79 (s, 6 H), 2.83/2.73
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.3, 162.6, 161.0, 160.4,
158.8, 158.6, 130.7, 130.4, 116.6, 116.1, 104.2, 103.8, 98.7, 98.4, 55.4,
55.3 (two overlapping signals 55.35, 55.29), 48.6, 41.7, 34.2, 29.0;
HRMS (ESI) m/z calcd for C11H16NO3 [M + H]+ 210.1130, found
210.1138.
N-Methyl-N-(2,4,6-trimethoxybenzyl)formamide (6aa). A
1
colorless solid: observed as two rotamers of 92/8 ratio in H NMR
(400 MHz, CDCl3) δ 8.25/8.03 (s, 1 H), 6.11/6.11 (s, 2 H), 4.56/4.35
(s, 2 H), 3.81/3.81 (s, 3 H), 3.80/3.80 (s, 6 H), 2.72/2.66 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 163.6, 162.0, 161.3, 161.1, 160.0, 159.6,
104.4, 103.8, 90.3, 90.2, 55.6, 55.5, 55.3, 41.3, 35.3, 33.0, 28.7; HRMS
(ESI) m/z calcd for C12H17NO4Na [M + Na]+ 262.1055, found
262.1055.
N-(2,6-Dimethoxybenzyl)-N-methylformamide (6da′). A col-
orless solid. This product could not be isolated in a pure form, being
contaminated with 6da. The following data were obtained from a pure
form by an alternative synthetic route, which resemble the spectra of
the mixture: observed as two rotamers of 91/9 ratio in 1H NMR (400
MHz, CDCl3) δ 8.29/8.05 (s, 1 H), 7.25 (t, J = 8.4 Hz, 1 H), 6.55/
6.55 (d, J = 8.4 Hz, 2 H), 4.65/4.43 (s, 2 H), 3.82/3.81 (s, 6 H), 2.74/
2.67 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.7, 162.1, 159.3,
158.9, 129.6, 129.3, 111.7, 111.2, 103.5, 55.7, 55.6, 41.4, 35.5, 33.1,
28.8; HRMS (ESI) m/z calcd for C11H15NO3Na [M + Na]+ 232.0950,
found 232.0943.
N,N′-((2,4,6-Trimethoxy-1,3-phenylene)bis(methylene))bis-
(N-methylformamide) (7aa). A colorless solid. Each component was
observed as a set of 2−4 peaks due to existence of three rotamers: 1H
NMR (400 MHz, CDCl3) δ 8.25/8.06 (s, 2 H), 6.28/6.28 (s, 1 H),
4.60/4.36 (s, 4 H), 3.84/3.84 (s, 6 H), 3.72/3.71 (s, 3 H), 2.70/2.69/
2.67/2.66 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 163.4, 163.3,
162.3, 160.3, 160.1, 159.9, 159.8, 159.7, 109.4, 109.2, 108.9, 91.5, 91.2,
63.2, 62.8, 55.8, 55.7, 55.6, 42.2 (two overlapping signals 42.22, 42.20),
36.0, 33.1, 28.8, 28.7; HRMS (ESI) m/z calcd for C15H22N2O5Na [M
+ Na]+ 333.1426, found 333.1439.
N-Methyl-N-(2,4,6-trimethoxybenzyl)acetamide (6ab). A col-
orless solid: observed as two rotamers of 80/20 ratio in 1H NMR (400
MHz, CDCl3) δ 6.12/6.12 (s, 2 H), 4.62/4.45 (s, 2 H), 3.82/3.82 (s, 3
H), 3.80/3.79 (s, 6 H), 2.71/2.71 (s, 3 H), 2.28/2.07 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 170.7, 170.0, 161.1, 160.8, 160.0, 159.6,
105.2, 104.8, 90.2, 90.1, 55.6, 55.4, 55.2 (two overlapping signals 55.25,
55.23), 42.1, 37.9, 33.7, 31.1, 22.1, 21.4; HRMS (ESI) m/z calcd for
C13H19NO4Na [M + Na]+ 276.1212, found 276.1208.
N,N′-((2,4,6-Trimethoxy-1,3-phenylene)bis(methylene))bis-
(N-methylacetamide) (7ab). A colorless solid. Each component was
observed as a set of 2−4 peaks due to existence of three rotamers: 1H
NMR (400 MHz, CDCl3) δ 6.29/6.28 (s, 1 H), 4.67/4.65/4.47/4.46
(s, 4 H), 3.84/3.83 (s, 6 H), 3.67/3.65 (s, 3 H), 2.71/2.69 (s, 6 H),
2.28/2.08 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.6,
170.2, 170.1, 160.6, 160.2, 159.8, 159.7, 159.6, 159.5, 159.3, 110.3,
110.2, 109.9, 109.7, 91.4, 91.2, 63.0, 62.5, 62.1, 55.7, 55.6, 55.5, 55.4,
42.9, 38.5, 38.4, 33.7, 33.6, 31.1, 22.0 (two overlapping signals 21.99,
21.96), 21.4; HRMS (ESI) m/z calcd for C17H26N2O5Na [M + Na]+
361.1739, found 361.1729.
N-(2,4-Dimethoxybenzyl)-N-methylacetamide (6db). A color-
1
less solid: observed as two rotamers of 62/38 ratio in H NMR (400
MHz, CDCl3) δ 7.14/6.96 (d, J = 8.8 Hz, 1 H), 6.47−6.43 (m, 2 H),
4.54/4.42 (s, 2 H), 3.81/3.80/3.79 (s, 6 H), 2.93/2.89 (s, 3 H), 2.15/
2.12 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 171.4, 170.8, 160.5,
160.1, 158.5, 158.2, 130.4, 128.2, 117.9, 116.8, 104.2, 103.8, 98.6, 98.3,
55.4, 55.3 (two overlapping signals 55.33, 55.30), 55.2, 49.5, 44.7, 35.8,
33.3, 21.8, 21.2; HRMS (ESI) m/z calcd for C12H17NO3Na [M + Na]+
246.1106, found 246.1113.
N-(2,6-Dimethoxybenzyl)-N-methylacetamide (6db′). A col-
orless solid. This product could not be isolated in a pure form, being
contaminated with 6db. The following data were obtained from a pure
form by an alternative synthetic route, which resemble the spectra of
the mixture: observed as two rotamers of 80/20 ratio in 1H NMR (400
MHz, CDCl3) δ 7.25/7.23 (t, J = 8.0 Hz, 1 H), 6.56/6.55 (d, J = 8.0
Hz, 2 H), 4.71/4.53 (s, 2 H), 3.82/3.81 (s, 6 H), 2.73/2.73 (s, 3 H),
2.31/2.08 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.1,
159.3, 158.9, 129.4, 129.0, 112.7, 112.2, 103.5 (two overlapping signals
103.54, 103.51), 55.7, 55.5, 42.3, 38.2, 33.8, 31.2, 22.0, 21.3; HRMS
(ESI) m/z calcd for C12H17NO3Na [M + Na]+ 246.1106, found
246.1099.
1-Methyl-5-(2,4,6-trimethoxyphenyl)pyrrolidin-2-one (6ac).
A colorless solid. This product could not be isolated in a pure form,
being contaminated with 6ac′ (6ac:6ac′ = 94:6): 1H NMR (400 MHz,
CDCl3) δ 6.12 (s, 2 H), 5.23 (dd, J = 9.6, 4.6 Hz, 1 H), 3.81 (s, 3 H),
3.77 (s, 6 H), 2.63−2.53 (m, 1 H), 2.53 (s, 3 H), 2.47−2.38 (m, 1 H),
2.36−2.25 (m, 1 H), 2.06−1.97 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 175.3, 160.8, 159.8 (broad), 108.4, 90.5 (broad), 55.7, 55.2,
53.9, 31.1, 27.3, 23.6; HRMS (ESI) m/z calcd for C14H20NO4 [M +
H]+ 266.1392, found 266.1392.
N-((1H-Indol-3-yl)methyl)-N-methylformamide (6fa). A yellow
1
oil: observed as two rotamers of 54:46 ratio in H NMR (400 MHz,
CDCl3) δ 8.42/8.12 (s, 1 H), 8.30−8.17 (br s, 1 H), 7.71/7.54 (d, J =
7.6 Hz, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 7.24−7.17 (m, 3 H), 4.71/4.59
(s, 2 H), 2.83/2.82 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 162.6,
162.3, 136.6, 136.3, 126.6, 126.3, 124.2, 123.6, 122.5, 122.3, 120.0,
119.8, 119.1, 118.3, 111.5, 111.2, 110.5, 110.1, 45.4, 38.8, 33.9, 29.2;
HRMS (ESI) m/z calcd for C22H25N4O2 [2M + H]+ 377.1978,
found377.1965.
Key peaks for compound 6ac′: 1H NMR (400 MHz, CDCl3) δ 4.48
(s, 2 H), 3.13 (t, J = 7.0 Hz, 2 H), 1.90−1.82 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 174.1, 161.0, 159.8, 104.6, 90.2, 55.7, 55.2, 46.0,
34.4, 31.2, 17.6.
N-Methyl-N-((1-methyl-1H-indol-3-yl)methyl)formamide
1
(6ga). A yellow oil: observed as two rotamers of 54:46 ratio in H
N-(2,4-Dimethoxy-5-methylbenzyl)-N-methylformamide
1
(6ca). A colorless oil: observed as two rotamers of 75/25 ratio in H
NMR (400 MHz, CDCl3) δ 8.41/8.10 (s, 1 H), 7.69/7.52 (d, J = 8.0
Hz, 1 H), 7.35−7.22 (m, 2 H), 7.17−7.11 (m, 1 H), 7.05/7.00 (s, 1
H), 4.68/4.57 (s, 2 H), 3.79/3.77 (s, 3 H), 2.83/2.81 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 162.3, 162.0, 137.1, 136.9, 128.6, 128.0,
127.1, 126.7, 122.0, 121.8, 119.5, 119.3, 119.2, 118.4, 109.4, 109.1 (two
overlapping signals 109.13, 109.08), 108.7, 45.1, 38.4, 33.7, 32.6, 32.5,
29.0; HRMS (ESI) m/z calcd for C12H14N2ONa [M + Na]+ 225.1004,
found 225.1006.
NMR (400 MHz, CDCl3) δ 8.26/8.11 (s, 1 H), 6.97/6.87 (s, 1 H),
6.42/6.42 (s, 1 H), 4.48/4.28 (s, 2 H), 3.84/3.84/3.83/3.82 (s, 6 H),
2.82/2.74 (s, 3 H), 2.13/2.11 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 163.2, 162.5, 158.3, 157.9, 156.8, 156.7, 131.8, 131.5, 118.3, 117.8,
115.3, 114.7, 94.8, 94.7, 55.6, 55.4, 48.4, 41.3, 34.1, 28.9, 15.1; HRMS
(ESI) m/z calcd for C12H17NO3Na [M + Na]+ 246.1106, found
246.1104.
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The Journal of Organic Chemistry
Note
N-Methyl-N-((1-phenyl-1H-indol-3-yl)methyl)formamide
(k) Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem.,
Int. Ed. 2011, 50, 9655−9659.
1
(6ha). A yellow oil: observed as two rotamers of 54:46 ratio in H
NMR (400 MHz, DMSO-d6) δ 8.48/8.11 (s, 1 H), 7.73−7.53 (m, 7
H), 7.43−7.38 (m, 1 H), 7.25−7.11 (m, 2 H), 4.66/4.63 (s, 2 H),
2.84/2.70 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 162.5, 162.2,
139.4, 139.2, 136.5, 136.2, 129.7, 129.6, 128.0, 127.7, 127.6, 127.0,
126.8, 126.5, 124.3, 124.2, 123.0, 122.9, 120.7, 120.5, 119.7, 118.8,
111.9, 111.5, 110.9, 110.5, 45.2, 38.6, 33.9, 29.3; HRMS (ESI) m/z
calcd for C17H16N2ONa [M + Na]+ 287.1160, found 287.1165.
N-((1-Benzyl-1H-indol-3-yl)methyl)-N-methylformamide
(3) (a) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J.
Org. Lett. 2012, 14, 94−97. (b) For a previous study using
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Gom
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ez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464−
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(4) For selected recent examples of the oxidative functionalization of
tertiary amines using photoredox catalysis, see: (a) Rueping, M.; Vila,
C.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011,
1
(6ia). A yellow oil: observed as two rotamers of 55:45 ratio in H
47, 2360−2362. (b) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852−
̈
NMR (400 MHz, DMSO-d6) δ 8.42/8.07 (s, 1 H), 7.59−7.53 (m, 1
H), 7.54/7.50 (s, 1 H), 7.45−7.40 (m, 1 H), 7.30−7.17 (m, 5 H),
7.14−7.08 (m, 1 H), 7.06−6.98 (m, 1 H), 5.40/5.39 (s, 2 H), 4.60/
4.57 (s, 2 H), 2.77/2.64 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ
162.4, 162.0, 138.2, 138.1, 136.3, 136.2, 128.9, 128.7, 128.5 (two
overlapping signals 128.53, 128.51), 127.3 (two overlapping signals
127.32, 127.30), 127.0, 126.9, 121.6, 121.5, 119.2, 119.1, 119.0, 118.6,
110.4, 110.2, 109.4 (two overlapping signals 109.41, 109.39), 49.0
(two overlapping signals 48.98, 48.94), 43.8, 37.7, 33.1, 28.4; HRMS
(ESI) m/z calcd for C18H18N2ONa [M + Na]+ 301.1317, found
301.1316.
3855. (c) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-
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ASSOCIATED CONTENT
■
S
* Supporting Information
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1H and 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: crjsteph@bu.edu.
Notes
(9) Steckhan, E. In Organic Electrochemistry, 4th ed.; Henning, L.,
Baizer, M., Eds.; Marcel Dekker Inc: New York, 2001; pp 570 and
references therein.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(10) For an example of amide oxidation using Co, Mn with tert-butyl
hydroperoxide or peracetic acid, see: Doumaux, A. R.; McKeon, J. E.;
Trecker, D. J. J. Am. Chem. Soc. 1969, 91, 3992−3993. For a review on
Ru catalyzed oxidation of amides, see: Murahashi, S.-I.; Zhang, D.
Chem. Soc. Rev. 2008, 37, 1490−1501. For a review on Cu catalyzed
oxidation of amides, see: Rawlinson, D. J.; Sosnovsky, G. Synthesis
1972, 1−28. For a recent example of Fe catalyzed Friedel-Crafts
aminoalkylation via oxidation of alkylamides, see: ref 15. For an
example of oxidation of amides using persulfate, see: Needles, H. L.;
Whitfield, R. E. J. Org. Chem. 1966, 31, 341−342.
■
Financial support for this research from the NIH-NIGMS
(R01-GM096129), NSF (CHE-1056568), the Alfred P. Sloan
Foundation, Amgen, Boehringer Ingelheim, and Boston
University is gratefully acknowledged. C.D. thanks AstraZeneca
for a graduate fellowship. J.M.R.N. thanks the Swiss National
Science Foundation for a postdoctoral fellowship. NMR (CHE-
0619339) and MS (CHE-0443618) facilities at BU are
supported by the NSF.
(11) For selected recent examples of α-amino C−H activation using
metals and peroxides, see: (a) Sud, A.; Sureshkumar, D.; Klussmann,
M. Chem. Commun. 2009, 3169−3171. (b) Murahashi, S.-I.; Nakae, T.;
Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005−11012.
(c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672−3673.
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H. D.; Formosinho, S. J. J. Phys. Chem. 1994, 98, 2883−2888.
(c) Fancy, D. A.; Kodadek, T. Proc. Nat. Acad. Sci. U. S. A. 1999, 96,
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The Journal of Organic Chemistry
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