Oxidative Mannich Reactions of Tertiary Amines Using a Cu(II) 2-Quinoxalinol Salen Catalyst

Article abstract of DOI:10.1021/acs.joc.9b01409

Oxidative Mannich reactions can be catalyzed using a Cu(II) 2-quinoxalinol salen catalyst and with tert-butyl hydroperoxide (TBHP). Under mild conditions, a range of both cyclic and open chain tertiary amines was tested as substrates, resulting in yields up to 98%.

Full text of DOI:10.1021/acs.joc.9b01409

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Note
Oxidative Mannich Reactions of Tertiary Amines
Using a Cu(II) 2-Quinoxalinol Salen Catalyst
Clayton C Black, and Anne Elizabeth Vivian Gorden
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01409 • Publication Date (Web): 16 Jul 2019
Downloaded from pubs.acs.org on July 17, 2019
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The Journal of Organic Chemistry
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Oxidative Mannich Reactions of Tertiary Amines Using a Cu(II) 2-
Quinoxalinol Salen Catalyst
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Clayton C. Black, Anne E.V. Gorden*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA
*anne.gorden@auburn.edu
Ar
R2
1
Complex (1 mol %)
N
Ar
O
N
N
O
O
N
Cu(II)
N
O
+
R1
OTIPS
TBHP, MeOH
60 °C
O
R1
OH
N
o
o
o
C(sp3)-H Functionalization
Up to 98 % yield
1
Complex
Mild Catalyst from Earth Abundant Starting Materials
ABSTRACT: Oxidative Mannich reactions can be catalyzed using a Cu(II) 2-quinoxalinol salen catalyst and with tert-butyl
hydroperoxide (TBHP). Under mild conditions, a range of both cyclic and open chain tertiary amines were tested as
substrates resulting in yields up to 98%.
The Mannich reaction is a very useful tool in the
formation of carbon-carbon bonds. Historical syntheses of
note compounds such as, the synthesis of sarain by Larry
Overman1, luciduline by David Evans2, and strychnine by
Robert Woodward3, require a key Mannich transformation.
Despite these illustrious examples, several challenges arise
when forming the iminium ion intermediate necessary for
Mannich coupling reactions. Often this can require harsh
reaction conditions, long reaction times, expensive
transition metal catalysts, or high catalyst loading.4–11
However, C-H oxidation could provide one direct route to
forming the iminium ion using only catalytic amounts of
transition metal.
Here, we describe the use of a Cu(II) 2-quinoxaminol
salen (Salqu) complex as a catalyst in these oxidative
Mannich type reactions. These reactions can be carried out
in mild conditions, using only 1 mol % of the Cu(II) catalyst
heated to 60 °C for 4 hours. Salqu can be easily prepared in
5
synthetic steps starting from 1,5-difluro-2,4-
dinitrobenzene and L-leucine methyl ester.14 Previously, we
have had good results with this catalyst and TBHP for the
oxidation of various activated C-H and OH bonds producing
yields up to 99%.14–16
Scheme 1. Oxidative Mannich reactions using N,N-
dimethylaniline
In 2006, a dirhodium caprolactamate catalyst was used
for the oxidation of tertiary amines to iminium ions (as
shown in scheme 1a).10 Yields up to 95% could be obtained
when using 2-triisopropoxysilylfuran as the nucleophile;
however, these reactions required the expensive rhodium
complex as the catalyst. In 2010, the simple copper salt
CuBr (5 mol %) was used by Huang and coworkers for
oxidative Mannich reactions, producing modest yields from
52-78% with indole as the nucleophile in the Mannich
coupling reaction (scheme 1b).12 Recently, a sequence of 2
oxidative Mannich reactions were used for the construction
of nortropane containing compounds.13 In an effort to make
reactions like these more efficient and accessible, we
envisioned using a ligand supported copper catalyst for the
oxidation of tertiary amines.
Doyle's work
a)
Rh2(cap)4
+
N
OTIPS
O
N
O
O
TBHP
3-16 h
up to 95%
Huang's work
b)
CuBr
NH
N
+
N
H
N
TBHP
3-12 h
up to 78%
this work
c)
Cu(II)-Salqu
+
O
N
N
OTIPS
O
O
TBHP
3-4 h
up to 98%
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Table 1. Optimization of Reaction Conditions
Page 2 of 6
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cat.
O
+
solvent
TBHP
OTIPS
N
N
O
O
3
2
4
entry
1
catalyst
variationa
solvent
time (h)
yieldb (%)
64c
81c
92c
98
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
Cu(OAc)2 (5 mol %)
CuCl2 (5 mol %)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeOH
MeOH
MeOH
EtOH
1
2
3
4
4
4
4
4
4
4
4
4
2
3
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60
4
5
3 (1 equiv)
82
6
K2CO3
trace
52
7
8
62
9
60
10
11
12
complex 1 (1 mol %)
complex 1 (1 mol %)
complex 1 (1 mol %)
H2O2
51
74
DCM
52
aReactions were done using 2 (1 mmol), 3 (0.5 mmol), TBHP (1.2 equiv), solvent (1 mL) at 60 °C. b Isolated yield after column
chromatography. cGC yield using internal standard.
To test this hypothesis, studies using N,N-dimethylaniline
as the model substrate and 2-triisopropoxysilylfuran as the
nucleophile (Table 1). These two reactants were chosen for
ease of comparison to previous methods as well as the
abundance of γ-butyrolactones found in natural products.17
were tested including EtOH and DCM (11-12), both of which
gave lower overall yields for under these conditions. The
optimal yield was achieved with 1 mol % of Cu(II)-Salqu, in
MeOH for 4 hours (entry 4).
Optimized conditions in hand the scope of these reactions
was examined (Scheme 2). First, several aniline derivatives
were characterized. The presence of a methyl group in the
para position gave a slightly lower yield of 82% (4b). We
then investigated a p-formyl electron withdrawing group,
which gave a substantially lower yield of only 54% (4c).
This could be because of the oxidizability of the aldehyde
under these conditions leading to an ester. However, these
reaction conditions seem to be accelerated by the presences
of electron donating groups (such as seen in 4h) leading to
a very good isolated yield of 94%. We also demonstrated the
incorporation of halide functional groups (4f) for these
reactions.
푦
Surprisingly, the desired product, containing a coupled
-
butyrolactone, was obtained in a 64% yield in only one hour
using 1 mol% of catalyst 1 (entry 1). Knowing that Cu(II)-
Salqu was a capable catalyst for these types of reactions,
investigations continued with the goal of further optimizing
the yield.
Lengthening the reaction time in this same reaction up to
4 hours produced an isolated yield of 98% (entries 2-4).
Base was added to see if the addition would accelerate the
reaction;18 however, this yielded only a trace amount of
product after 4 hours (entry 6). from the next reactions
compared the Cu(II)-Salqu complex as catalyst to some
simple copper salts. Reactions with Cu(OAc)2 and CuCl2
were found to produce the desired product, but in lower
overall yields even with higher catalyst loading (entries 8-
9). Although these catalysts would be ideal due to ease of
availability, the Cu(II)-Salqu still gives a higher overall yield
and is easily prepared while also utilizing lower catalyst
loading. It can also be readily isolated from products. This
would be particularly important on large scale reactions. To
demonstrate the importance of TBHP as the oxidant in this
Next, we looked at the regioselectivity for the formation
of the iminium ion when the disubstituted N-methyl, N-
ethyl aniline is used as the substrate.10 The coupling was
found to happen exclusively on the methyl carbon giving
rise to 4g in a 62% yield. These results are consistent with
the reported acidity values by Mariano and coworkers in
reactions with aniline derivatives.20 Steric hindrance could
also play a role in the regioselectivity of this reaction. To
explore the utility of larger aromatic containing substrates,
reaction,
the analogous experiment was performed
2-(N,N-dimethylamino)naphthalene was tested as
a
replacing TBHP with H2O2 as the oxidant, which
subsequently resulted in a more modest yield of 51% (entry
10). This is likely due to the fact that TBHP has a higher
solubility in organic solvents and forms a more stable
radical compared to H2O2.19 Next, the use of different
solvents for the reaction was tested. Using acetonitrile led
to a lower overall yield of 52% (entry 7). Other solvents also
substrate resulting in an isolated yield of 89% of 4i. Not only
do open chain amines work well, but reactions with
pyrrolidine and tetrahydroquinoline, two examples of cyclic
amine heterocycles, were also found to be high yielding (80-
87%) under these conditions (4j-4k).
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The Journal of Organic Chemistry
deficient intermediate throughout the reaction mechanism
Scheme 2. Substrate Scopea
1
which is stabilized by the donating groups.
2
3
4
1
(1 mol %)
R
+
OTIPS
N
O
MeOH
60 °C
N
O
O
4
2
3
tBuOH
tBuO
R
5
6
7
8
O
H
N
R
N
Ar
Ar
2
OH
O
O
N
tBuOOH
O
N
O
O
N
tBuO
O
Cu(III)Salqu
4a
, 98%
tBuOO + H2O
4b
, 82%
tBuOO
4c
, 54%
9
tBuOOH
Br
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Cu(II)Salqu
R
R
N
OOtBu
N
OMe
O
O
N
O
O
N
N
O
O
Ar
Ar
5
6
MeOH
tBuOOH
4e
4f
, 71%
, 80%
4d
, 91%
MeO
R
R
N
Nu
N
O
Ar
Ar
O
O
N
O
Nu
N
O
4
N
4h
, 94%
Figure 2. Proposed catalytic cycle.
Ph
4g
, 62%
O
O
O
O
N
Ph
Preliminary studies were done to obtain some
mechanistic information for this reaction. First, we
conducted EPR experiments and see a loss of signal when
using Cu(II)-Salqu and TBHP. While Cu(II) is EPR active,
both Cu(I) and Cu(III) are EPR silent. We believe that Cu(II)-
Salqu is oxidized by TBHP to form a Cu(III) species and a
tert-butoxy radical. The formation of Cu(III) is stabilized by
our noninnocent salen type ligand system.21 Also, previous
DFT calculations done at the B3LYP/6-311+G(d,p) level
with reactions using Cu(II)-Salqu show an enhanced spin
density dispersion with the heterocyclic backbone as
compared to simple salen.15 This further explains the
stabilization of Cu(III) by extended conjugation of the
ligand. From here, reductive elimination is carried out with
TBHP giving a t-butoxy radical and Cu(II)-Salqu. The t-
butoxy radical then removes a hydrogen radical α to the
amine forming t-butanol. Coupling of the α-amino radical
and t-butylperoxy radical forms intermediate 5 which can
be isolated and identified by NMR using a non-nucleophilic
solvent such as DCM.10 However, when MeOH is used, it
displaces the t-butylperoxy group to form 6. This then leads
to the formation of the electrophilic iminium ion upon
elimination of MeOH. The iminium ion is then intercepted
by 2-trisoporpoxysilyfuran to form the coupled product 4.
O
N
4j
, 80%
4
k, 87%
4i
, 89%
aReaction conditions: N,N dimethylaniline 2a (1.0 mmol), 2-
triisopropoxysilylfuran (0.5 mmol), MeOH (1 mL), Cu(II)-Salqu
(1 mol%), TBHP (1.2 equiv), 60 °C, 3-4 h. bYields of isolated
products.
0.6
OMe
0.3
H
Br
0
Me
-0.3
-0.6
CN
CHO
-0.9
-1.2
-0.3
-0.1
0.1
0.3
0.5
0.7
σp
Figure 1. Correlation between log(kx/kH) and para position
Hammett constants. Reaction rates were monitored by NMR at
room temperature in d4-MeOD.
In conclusion, we have developed a new method for
oxidative Mannich reactions using only 1 mol% of an earth
abundant transition metal catalyst with the Cu(II)-Salqu
complex. These reactions proceed under mild conditions
with mild heating in as little as 3 hours. We have tested a
range of different substrates including dimethylaniline
derivatives as well as cyclic amines all producing good
yields of the corresponding coupled product up to 98%.
Further investigation of the reaction scope and to better
understand the reaction mechanism are currently being
explored in our laboratory.
To consider the electronic effects of various substituents
on the reaction, kinetics studies were conducted on the para
substituted aniline derivatives using MeOD as the
nucleophile and solvent.
A correlation of Hammett
constants for the p-methoxy, p-methyl, p-formyl, p-bromo,
and p-cyano anilines were plotted against log(kx/kH) (figure
1). The reaction rates were monitored by NMR and the
linear free energy relationship was found to demonstrate a
good linear fit (R2 0.968). The ρ value of -1.41 indicates the
acceleration of oxidative Mannich reactions by electron
donating groups which is consistent with our reaction
yields. Also, this could indicate the buildup of an electron
EXPERIMENTAL SECTION
General Methods. 1H NMR and 13C NMR spectra were
recorded in CDCl3 using a 600 or 400 MHz instrument;
chemical shifts (δ) were reported in parts per million (ppm)
relative to Me4Si. Chromatographic purifications were
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performed using Fisher (60 Å, 70-230 mesh) silica gel.
39.9; HRMS (ES) calcd. for C13H13NO3Na 254.0793, found
254.0779 (M+Na)+.
1
2
3
4
5
6
7
8
HRMS data were collected with electron spray ionization
using a TOF analyzer. Commercially available reagents were
obtained and used as received without additional further
purification.
4d
5-[[[4-(1,1-
dimethylethyl)phenyl]methylamino]methyl]-2(5H)-
furanone: Purified by flash column chromatography on
silica gel to afford a clear oil, 91% yield (118 mg). TLC Rf=
0.25 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ:
7.51 (d, J=5.6 Hz, 1H), 7.28 (d, J=8.9 Hz, 2H), 6.68 (d, J=8.7
Hz, 2H), 6.14 (d, J=4.0 Hz, 1H), 5.27 (m, 1H), 3.65 (d, J=4.9
Hz, 2H), 2.99 (s, 3H), 1.28 (s, 9H);13C NMR (150 MHz, CDCl3)
δ:171.9, 153.8, 144.9, 138.9, 125.2, 121.1, 110.9, 81.0, 54.2,
38.5, 32.7, 30.4; HRMS (ES) calcd. for C16H22NO2 260.1651,
found 260.1647 (M+H)+.
Synthesis of Cu(II) Salqu Complex 1: The Cu(II) salqu
complex
1 was synthesized following a previously
published procedure by these authors.22
Representative Procedure for Oxidative Mannich
Reaction: The 2-triisopropoxysilylfuran nucleophile (0.5
mmol) was added to a round bottom flask (25 mL) and
dissolved in MeOH (1 mL). To this, the required amine (1
mmol), T-HYDRO (1.2 equiv), Cu-Salqu (1 mol%) were
added. The reaction was heated, using an oil bath, to 60 °C
and stirred using a stir bar for 3-4 hr. The solvent was then
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4e
5-[[methyl(2,4,6-trimethylphenyl)amino]methyl]-
2(5H)-furanone: Purified by flash column chromatography
on silica gel to afford a clear oil, 71% yield (87 mg). TLC Rf=
0.4 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ: 7.49
(dd, J=4.8, 1.2 Hz, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.13 (dd,
J=5.5, 1.8 Hz, 1H), 5.08 (m, 1H), 3.38 (dd, J=13.9, 5.8 Hz, 1H),
3.28 (dd, J=13.9, 5.8 Hz, 1H), 2.81 (s, 3H), 2.28 (s, 3H), 2.23
(s, 6H); 13C NMR (150 MHz, CDCl3) δ: 173.4, 155.9, 146.1,
136.7, 136.6, 135.2, 129.9, 129.7, 122.0, 83.9, 59.1, 42.1,
20.8, 19.1, 19.0; HRMS (ES) calcd. for C15H20NO2 246.1494,
found 246.1475 (M+H)+.
evaporated under reduced pressure using
a rotary
evaporator, and the resulting product was purified by flash
column chromatography on silica gel as indicated below.
Representative Procedure for Oxidative Mannich
Reaction on 2 mmol scale: The 2-triisopropoxysilylfuran
(2.0 mmol) was added to a round bottom flask (25 mL) and
dissolved in MeOH (4 mL). To this, N,N-dimethylaniline (4.0
mmol), T-HYDRO (1.2 equiv), Cu-Salqu (1 mol%) were
added. The reaction was heated, using an oil bath, to 60 °C
and stirred using a stir bar for 4 hr. The solvent was then
4f
5-[[(4-Bromophenyl)methylamino]methyl]-2(5H)-
evaporated under reduced pressure using
a
rotary
furanone: Purified by flash column chromatography on
silica gel to afford a yellow oil, 80% yield (113 mg). TLC Rf=
0.23 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ:
7.48 (dd, J=5.2, 1.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 6.58 (d,
J=8.8 Hz, 2H), 6.14 (dd, J=6.0, 2.0 Hz, 1H), 5.27-5.23 (m, 1H),
3.71 (dd, J=15.2, 5.6 Hz, 1H), 3.62 (dd, J=15.4, 6.1 Hz, 1H),
2.99 (s, 3H); 13C NMR (150 MHz, CDCl3) δ: 172.7, 154.3,
147.3, 132.1, 122.5, 113.9, 109.3, 82.0, 54.8, 39.8; HRMS
(ES) calcd. for C12H13NO2Br 282.0130, found 282.0117
(M+H)+.
evaporator, and 5-[(Methylphenylamino)methyl]-2(5H)-
furanone was purified by flash column chromatography on
silica gel (2:1 hex/EtOAc) to afford an orange oil, 94% yield
(227 mg).
4a
5-[(Methylphenylamino)methyl]-2(5H)-furanone:
Purified by flash column chromatography on silica gel (2:1
hex/EtOAc) to afford an orange oil, 98% yield (99 mg). TLC
Rf= 0.3 (1:1 hex/EtOAc);1H NMR (600 MHz, CDCl3) δ: 7.50
(dd, J=5.6, 1.5 Hz, 1H), 7.28 (t, J=8.0 Hz, 2H), 6.79 (t, J=7.3
Hz, 1H), 6.75 (d, J=8.0 Hz, 2H), 6.16 (dd, J=5.6, 1.6 Hz, 1H),
5.29 (tt, J=5.6, 1.6 Hz, 1H), 3.70 (t, J=5.6 Hz, 2H), 3.04 (s, 3H);
13C NMR (150 MHz, CDCl3) δ: 172.7, 154.5, 148.3, 129.4,
122.4, 117.4, 112.3, 82.0, 54.0, 39.5; HRMS (ES) calcd. for
C12H14NO2 204.1025, found 204.1022 (M+H)+.
4g
5-[(Ethylphenylamino)methyl]-2(5H)-furanone:
Purified by flash column chromatography on silica gel to
afford a clear oil, 62% yield (67 mg). TLC Rf= 0.25 (3:1
hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ: 7.51 (d, J=5.6
Hz, 1H), 7.26-7.24 (m, 2H), 6.74-6.70 (m, 3H), 6.16 (d, J=5.6
Hz, 1H), 5.28-5.24 (m, 1H), 3.69 (dd, J=15.2, 6.0 Hz, 1H), 3.5
(dd, J=15.2, 6.0 Hz, 1H), 3.52-3.35 (m, 2H), 1.17 (t, J=7.0 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ: 172.9, 155.0, 146.9,
129.6, 122.2, 117.0, 112.3, 81.9, 52.9, 45.8, 11.9; HRMS (ES)
calcd. for C13H16NO2 218.1181, found 218.1178 (M+H)+.
4b 5-[[Methyl(4-methylphenyl)amino]methyl]-2(5H)-
furanone: Purified by flash column chromatography on
silica gel to afford an orange oil, 82% yield (89.5 mg). TLC
1
Rf= 0.5 (1:1 hexanes/EtOAc); H NMR (600 MHz, CDCl3) δ:
4h 5-[[(4-methoxyphenyl)methylamino]methyl]- 2(5H)-
furanone: Purified by flash column chromatography on
silica gel to afford a clear oil, 94% yield (109 mg). TLC Rf=
0.30 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ:
7.48 (dd, J=5.8, 2.0 Hz, 1H), 6.85 (d, J=9.4 Hz, 2H), 6.71 (d,
J=9.4 Hz, 2H), 6.14 (dd, J=5.8, 2.0 Hz, 1H), 5.27-5.24 (m, 1H),
3.77 (s, 3H), 3.62 (d, J=5.8 Hz, 2H), 2.97 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ: 172.9, 154.8, 152.2, 143.0, 122.1, 114.9,
114.4, 82.1, 56.2, 55.8, 40.2; HRMS (ES) calcd. for C13H16NO3
234.1130, found 234.1135 (M+H)+.
7.48 (d, J=5.6, 1.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 6.64 (d,
J=8.8 Hz, 2H), 6.13 (dd, J=6.0, 2.0 Hz, 1H), 5.26-5.24 (m, 1H),
3.65 (d, J=6.0 Hz, 2H), 2.99 (s, 3H), 2.26 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ: 172.7, 154.6, 146.2, 130.0, 126.8, 122.1,
112.7, 82.0, 55.4, 39.7, 20.2; HRMS (ES) calcd. for C13H16NO2
218.1181, found 218.1161 (M+H)+.
4c
4-[[(2,5-dihydro-5-oxo-2-
furanyl)methyl]methylamino]benzaldehyde: Purified by
flash column chromatography on silica gel to afford a yellow
oil, 54% yield (62.4 mg). TLC Rf= 0.25 (1:2 hexanes/EtOAc);
1H NMR (600 MHz, CDCl3) δ: 9.76 (s, 1H), 7.75 (d, J=8.8 Hz,
2H), 6.75 (d, J=8.8 Hz, 2H), 6.18 (dd, J=5.6, 2.0 Hz, 1H), 5.33-
5.28 (m, 1H), 3.89 (dd, J=15.6, 4.8 Hz, 1H), 3.73 (dd, J=15.3,
5.9 Hz, 1H), 3.14 (s, 3H);13C NMR (150 MHz, CDCl3) δ: 190.4,
172.2, 153.5, 152.8, 132.1, 126.2, 122.9, 111.4, 81.8, 54.3,
4i
5-[[(Methyl(2-naphthyl)amino]methyl]-2(5H)-
furanone: Purified by flash column chromatography on
silica gel to afford a yellow oil, 89% yield (113 mg). TLC Rf=
0.22 (3:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ:
7.70 (t, J=9.3 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.44 (d, J= 4.6
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The Journal of Organic Chemistry
Hz, 1H), 7.38 (t, J=7.1 Hz, 1H), 7.24-7.22 (m, 1H), 7.01 (d,
ORCID
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J=8.6 Hz, 1H), 6.90 (s, 1H), 6.09 (d, J=4.1 Hz, 1H), 5.28-5.24
(m, 1H), 3.75 (dd, J=15.7, 5.3 Hz, 2H), 3.09 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ:172.9, 154.6, 146.1, 134.8, 129.3, 127.5,
127.0, 126.6, 126.3, 122.6, 122.2, 115.5, 106.6, 82.3, 55.0,
39.9;; HRMS (ES) calcd. for C16H16NO2 254.1188, found
254.1181 (M+H)+.
Anne E. V. Gorden 0000-0001-6623-9880
Clayton C. Black 0000-0001-9993-0694
Notes
The authors declare no competing financial interest.
Present Addresses
4j
5-(1,2,3,4-Tetrahydro-2-phenyl-1-isoquinolinyl)-
2(5H)-furanone: Purified by flash column chromatography
on silica gel to afford a yellow oil, 80% yield (114 mg). TLC
Rf= 0.18 (3:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ:
7.53 (d, J=5.6 Hz, 1H), 7.39 (d, J=5.6 Hz, 1H), 7.34-7.19 (m,
6H), 6.99 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.87-6.80
(m, 1H), 6.15-6.12 (m, 1H), 5.95-5.92 (m, 1H), 5.46-5.44 (m,
1H), 5.38-5.34 (m, 1H), 5.18 (d, J=4.4 Hz, 1H), 4.19 (d, J=4.4
Hz, 1H), 3.82-3.75 (m, 1H), 3.67-3.55 (m, 2H), 3.48-3.41
(m,1H), 3.20-2.90 (m, 4H); 13C NMR (150 MHz, CDCl3) δ:
172.7, 172.6, 154.8, 153.7, 149.0, 149.0, 135.8, 135.4, 132.5,
131.8, 129.7, 129.6, 128.7, 128.5, 128.2, 127.9, 127.9, 127.7,
126.5, 126.1, 124. 4, 122.7, 122.4, 118.9, 118.8, 114.6, 114.5,
86.0, 85.4, 61.8, 60.7, 44.1, 43.5, 28.5, 27.3; HRMS (ES)
calcd. for C19H18NO2 292.1338, found 292.1336 (M+H)+.
† Department of Chemistry and Biochemistry
Auburn University, Auburn, Alabama 36849
United States of America
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ACKNOWLEDGMENT
This work was funded by Auburn University and by an
Auburn University Mallon-Zallen graduate research
award to CCB.
REFERENCES
(1)
Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.; Garg,
N. K.; Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J.
A.; Ng, F. W.; Overman, L. W.; Total Synthesis of (−)-Sarain
A. J. Am. Chem. Soc. 2007, 129 (39), 11987–12002.
https://doi.org/10.1021/ja074300t.
Scott, W. L.; Evans, D. A. Total Synthesis of (+-)-Luciduline.
J. Am. Chem. Soc. 1972, 94 (13), 4779–4780.
https://doi.org/10.1021/ja00768a083.
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. THE TOTAL SYNTHESIS OF
STRYCHNINE. J. Am. Chem. Soc. 1954, 76 (18), 4749–4751.
https://doi.org/10.1021/ja01647a088.
Huo, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y.; Tang, J. Aerobic
Oxidative Mannich Reaction Promoted by Catalytic
Amounts of Stable Radical Cation Salt. J. Org. Chem. 2014,
4k 5-(1-Phenyl-2-pyrrolidinyl)-2(5H)-furanone: Purified
by flash column chromatography on silica gel to afford a
clear oil, 87% yield (99.7 mg). TLC Rf= 0.25 (2:1
hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ: 7.48-7.42 (m,
2H), 7.30-7.24 (m, 4H), 6.80-6.73 (m, 4H), 6.57 (d, J=8.2 Hz,
2H), 6.19 (m, 2H), 5.40 (s, 1H), 5.02 (m, 1H), 4.37 (m, 1H),
3.85 (t, J=7.2 Hz, 1H), 3.63-3.57 (m, 2H), 3.20-3.16 (m, 1H),
2.15-1.60 (m, 8H); 13C NMR (150 MHz, CDCl3) δ: 173.2,
173.1, 156.3, 153.9, 147.1, 129.6, 122.9, 121.7, 117.3, 112.7,
112.4, 84.2, 82.4, 60.7, 59.2, 49.5, 49.3, 28.1, 25.2, 24.2, 23.3;
HRMS (ES) calcd. for C14H16NO2 230.1181, found 230.1184
(M+H)+.
(2)
(3)
(4)
(5)
(6)
(7)
79
(20),
9860–9864.
Representative Procedure for Determining the Initial
Reaction Rates. A solution of N,N-dimethylaniline (0.15
mmol), with Cu(II)-Salqu (1 mol %), was prepared in d4-
MeOD (1.5 mL), and 1,3,5-trichlorobenzene (0.15 mmol)
was added as the internal standard. These were mixed in a
2 dram vial. An aliquot of 500 µL of the solution was then
added to an NMR tube. TBHP in water (28 µL) was then
added to the tube and inserted immediately into the NMR at
https://doi.org/10.1021/jo5017822.
Shen, Y.; Li, M.; Wang, S.; Zhan, T.; Tan, Z.; Guo, C.-C. An
Efficient Copper-Catalyzed Oxidative Mannich Reaction
between Tertiary Amines and Methyl Ketones. Chem.
Commun.
2009,
No.
8,
953–955.
https://doi.org/10.1039/B819657E.
Wu, K.; Huang, Z.; Qi, X.; Li, Y.; Zhang, G.; Liu, C.; Yi, H.;
Meng, L.; Bunel, E. E.; Miller, J. T.; Pao, C.-W; Lee, J.-F.; Lan,
Y.; Le, A.; Copper-Catalyzed Aerobic Oxidative Coupling:
From Ketone and Diamine to Pyrazine. Sci. Adv. 2015, 1
(9), e1500656. https://doi.org/10.1126/sciadv.1500656.
Ratnikov, M. O.; Doyle, M. P. Mechanistic Investigation of
1
room temperature. H scans were taken every 60 seconds
for 20 minutes. The rate of oxidation was measured by the
decrease in the integration values corresponding to the 4-
substituted anilines with respect to the internal standard,
using the program Bruker Dynamic Center 2.5.6.
Oxidative
Hydroperoxide. The Role of Transition Metal Salt. J. Am.
Chem. Soc. 2013, 135 (4), 1549–1557.
https://doi.org/10.1021/ja3113559.
Mannich
Reaction
with
Tert-Butyl
ASSOCIATED CONTENT
(8)
Matsuo, J.; Tanaki, Y.; Ishibashi, H. Oxidative Mannich
Reaction of N-Carbobenzyloxy Amines with 1,3-
Dicarbonyl Compounds. Org. Lett. 2006, 8 (19), 4371–
4374. https://doi.org/10.1021/ol0618095.
Ratnikov, M. O.; Xu, X.; Doyle, M. P. Simple and Sustainable
Iron-Catalyzed Aerobic C–H Functionalization of N,N-
Dialkylanilines. J. Am. Chem. Soc. 2013, 135 (25), 9475–
9479. https://doi.org/10.1021/ja402479r.
Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. The
Oxidative Mannich Reaction Catalyzed by Dirhodium
Caprolactamate. J. Am. Chem. Soc. 2006, 128 (17), 5648–
5649. https://doi.org/10.1021/ja061146m.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
(9)
Copies of 1H and 13C spectra for all products and table of
results from kinetics NMR experiments
(10)
AUTHOR INFORMATION
Corresponding Author
* Email: anne.gorden@auburn.edu
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The Journal of Organic Chemistry
Page 6 of 6
(11)
(12)
(13)
Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J.
like Compounds. Curr. Opin. Chem. Biol. 2005, 9 (3), 285–
292. https://doi.org/10.1016/j.cbpa.2005.03.005.
Yu, J.-Q.; Corey, E. J. A Mild, Catalytic, and Highly Selective
Method for the Oxidation of α,β-Enones to 1,4-Enediones.
J. Am. Chem. Soc. 2003, 125 (11), 3232–3233.
https://doi.org/10.1021/ja0340735.
Das, T. N.; Dhanasekaran, T.; Alfassi, Z. B.; Neta, P.
Reduction Potential of the Tert-Butylperoxyl Radical in
Aqueous Solutions. J. Phys. Chem. A 1998, 102 (1), 280–
284. https://doi.org/10.1021/jp972903t.
Zhang, X.; Yeh, S.-R.; Hong, S.; Freccero, M.; Albini, A.;
Falvey, D. E.; Mariano, P. S. Dynamics of .Alpha.-CH
Deprotonation and .Alpha.-Desilylation Reactions of
Tertiary Amine Cation Radicals. J. Am. Chem. Soc. 1994,
Visible-Light Photoredox Catalysis: Aza-Henry Reactions
via C−H Functionalization. J. Am. Chem. Soc. 2010, 132 (5),
1464–1465. https://doi.org/10.1021/ja909145y.
Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Copper-Catalyzed Cross
Dehydrogenative Coupling Reactions of Tertiary Amines
with Ketones or Indoles. Org. Lett. 2010, 12 (22), 5214–
5217. https://doi.org/10.1021/ol102252n.
Jo, H.; Hassan, A. H. E.; Jung, S. Y.; Lee, J. K.; Cho, Y. S.; Min,
S.-J. Construction of 8-Azabicyclo[3.2.1]Octanes via
Sequential DDQ-Mediated Oxidative Mannich Reactions of
N-Aryl Pyrrolidines. Org. Lett. 2018, 20 (4), 1175–1178.
https://doi.org/10.1021/acs.orglett.8b00098.
Wu, X.; Gorden, A. E. V. 2-Quinoxalinol Salen Copper
Complexes for Oxidation of Aryl Methylenes. Eur. J. Org.
1
2
3
4
5
6
7
8
(18)
(19)
(20)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14)
(15)
(16)
(17)
116
(10),
4211–4220.
Chem.
2009,
2009
(4),
503–509.
https://doi.org/10.1021/ja00089a010.
https://doi.org/10.1002/ejoc.200800928.
(21)
(22)
Storr, T.; Verma, P.; Pratt, R. C.; Wasinger, E. C.; Shimazaki,
Y.; Stack, T. D. P. Defining the Electronic and Geometric
Structure of One-Electron Oxidized Copper−Bis-
Phenoxide Complexes. J. Am. Chem. Soc. 2008, 130 (46),
15448–15459. https://doi.org/10.1021/ja804339m.
Wu, X.; Gorden, A. E. V. An Efficient Method for Solution-
Phase Parallel Synthesis of 2-Quinoxalinol Salen Schiff-
Base Ligands. J. Comb. Chem. 2007, 9 (4), 601–608.
https://doi.org/10.1021/cc070021q.
Li, Y.; Lee, T. B.; Wang, T.; Gamble, A. V.; Gorden, A. E. V.
Allylic C–H Activations Using Cu(II) 2-Quinoxalinol Salen
and Tert-Butyl Hydroperoxide. J. Org. Chem. 2012, 77 (10),
4628–4633. https://doi.org/10.1021/jo300372q.
Black, C. C.; Gorden, A. E. V. Propargylic CH Activation
Using a Cu(II) 2-Quinoxalinol Salen Catalyst and Tert-
Butyl Hydroperoxide. Tetrahedron Lett. 2018, 59 (9),
803–806. https://doi.org/10.1016/j.tetlet.2018.01.030.
Seitz, M.; Reiser, O. Synthetic Approaches towards
Structurally Diverse γ-Butyrolactone Natural-Product-
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