Aerobic oxidative Mannich reaction promoted by catalytic amounts of stable radical cation salt

Article abstract of DOI:10.1021/jo5017822

A catalytic amount of triarylaminium salt is demonstrated to be an efficient initiator for oxidative Mannich reaction of tertiary amines and nonactivated ketones under mild neutral conditions. Air is essential for this reaction and acts as a terminal oxid

Full text of DOI:10.1021/jo5017822

Note
pubs.acs.org/joc
Aerobic Oxidative Mannich Reaction Promoted by Catalytic Amounts
of Stable Radical Cation Salt
Congde Huo,* Mingxia Wu, Xiaodong Jia, Haisheng Xie, Yong Yuan, and Jing Tang
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
S
* Supporting Information
ABSTRACT: A catalytic amount of triarylaminium salt is
demonstrated to be an efficient initiator for oxidative Mannich
reaction of tertiary amines and nonactivated ketones under
mild neutral conditions. Air is essential for this reaction and
acts as a terminal oxidant. Metal catalysts, acid or base
additives, and stoichiometric amounts of chemical oxidants are
all avoided in this methodology. Six examples of intramolecular
cyclized products are also delivered.
annich reaction involves the condensation of enolizable
As part of our ongoing interest in stable radical cation salt
Maldehydes or ketones with imine or iminium species to initiated aerobic oxidative reactions of amines,6 herein, we
report a catalytic amounts of triarylaminium salt induced sp3−
afford substituted β-amino carbonyl compounds. It is a
sp3 C−C bond formation protocol between tertiary amines and
fundamentally important carbon−carbon bond construction
unmodified ketones with air as a sustainable and efficient
oxidant under mild conditions. The additional advantage of this
method is that it does not require the activation of ketones. Six
examples of intramolecular cyclized products are delivered too.
In our preliminary investigation, as shown in Table 1, we
chose N-phenyl-1,2,3,4-tetrahydroisoquinoline (1a) and ace-
tone (2a) as model substrates. A 0.5 mmol portion of 1a was
treated with 10 mmol % tris(4-bromophenyl)-aminium hexa-
method in organic synthesis and has been widely utilized in the
syntheses of natural products and pharmaceuticals.1 During the
past few years, the oxidative coupling of amines has gained
significant attention since the pioneering study of Murahashi2
and Li.3 In these reactions, the secondary amines or tertiary
amines are oxidized to generate highly reactive imine or
iminium intermediates that can be used for further function-
alization.4 Until now, various kinds of nucleophiles have been
utilized to intercept the imine or iminium intermediates
generated in situ to construct new C−C bonds under
Mannich-type processes.4 However, the utilization of the
nonactivated ketones as the nucleophiles to carry out the
classic Mannich reaction under oxidizing conditions is relatively
scarce.5 Although a few successful processes have been achieved
in this area, these methods generally have some serious
7
chloroantimonate (TBPA•+SbCl6 , a well-known stable radical
cation salt; see Table 1 for its structure) in 10 equiv of acetone
under an air atmosphere. The reaction was carried out at
ambient temperature, and acetone was used as both reactant
and solvent. To our delight, the reaction worked smoothly and
the desired β-amino ketone 3aa was isolated in good yield
(66%, Table 1, entry 1) after 12 h. We then optimized the
reaction conditions by changing initiator loadings. The best
yield (92%, Table 1, entry 2) was achieved with 20 mol %
−
drawbacks: (1) Extra Bronsted acids or secondary amines are
̈
always required as additives to activate ketones to their enolate
form;5a−c,e−n (2) light or heating sources are usually needed to
run the reactions;5a,c−o,q (3) costly and toxic transition metal
reagents or photoredox complexes often act as catalysts;5a−n
(4) stoichiometric amounts of dangerous oxidants5b,p,q or pure
oxygen are frequently necessary; and (5) no more than three
successful ketone examples are reported in most of the so far
published papers.5c,d,f,h,j−q Therefore, due to the increasing
demand for sustainable methods in organic synthesis, the
development of a metal free, additive free, chemical oxidant
free, and energy source free methodology under aerobic
conditions for the oxidative Mannich reaction is highly
desirable. Our group has had a long-standing interest in radical
cation mediated transformations and their synthetic potential.6
TBPA•+SbCl6 . No appreciable differences of the trans-
−
formation were observed when pure oxygen gas was used
instead of an air atmosphere (Table 1, entry 5). Subsequently,
we chose acetophenone (2k, 2 equiv) as a high boiling point
ketone to screen the solvents. The highest yield (76%, Table 1,
entry 6) was observed when acetonitrile was used as solvent.
The reaction of 1a with acetone in the absence of molecular
oxygen (in argon atmosphere) afforded no product (Table 1,
entry 11), indicating that dioxygen is definitely crucial for the
reaction.
Received: August 2, 2014
Published: September 22, 2014
© 2014 American Chemical Society
9860
dx.doi.org/10.1021/jo5017822 | J. Org. Chem. 2014, 79, 9860−9864

The Journal of Organic Chemistry
Note
Table 1. Screening of Reaction Conditions
Table 2. Scope of TBPA Radical Cation Salt Induced
a b
,
Intermolecular Aerobic Oxidative Mannich Reaction
a
entry
R1
conditions
10 mol % catalyst,
yield (%)
1
2
Me
Me
Me
Me
Me
Ph
neat, air, rt, 12 h
neat, air, rt, 12 h
neat, air, rt, 12 h
neat, air, rt, 12 h
neat, O2, rt, 12 h
MeCN, air, rt, 48 h
CHCI3, air, rt, 48 h
CH2CI2, air, rt, 48 h
(CHCI)2, air, rt, 48 h
THF, air, rt, 48 h
neat, Ar, rt, 12 h
66
92
38
87
92
76
60
65
48
51
trace
20 mol % catalyst,
5 mol % catalyst,
30 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
20 mol % catalyst,
3
4
5
6
7
Ph
8
Ph
9
Ph
10
11
Ph
Me
a
Isolated yields of the isolated products.
Under the optimized conditions, we probed the generality
and scope of both ketones and tetrahydroisoquinolines for this
TBPA radical cation induced aerobic oxidative Mannich
reaction (Table 2). Initially, we investigated different
unmodified ketones. Methyl alkyl ketones gave the correspond-
ing products in high yields (Table 2, 3ab−3ag). The bulky
methyl ketones 2e−g still effectively gave good results in this
method. Methyl aryl ketones were transformed into the
corresponding β-amino products smoothly (Table 2, 3ak−
3am). Notably, the methyl heteroaryl ketone 2m could also be
coupled with 1a to give 3am in satisfactory yield. Besides the
methyl alkyl and aryl ketones, cycloketones and pentan-3-one
could also be used to construct sp3−sp3 C−C bonds (Table 2,
3ah−3aj). Furthermore, we explored the variety of tetrahy-
droisoquinolines. For both electron-donating and electron-
withdrawing groups, the desired products were achieved in high
yields (Table 2, 3ba−3da). The reaction can also be performed
successfully in CH3CN with a significantly reduced amount of
ketone (see Table 2, 3ak−3am), but it runs most conveniently
in neat ketones if liquid and inexpensive ketones are employed.
The reaction of tetrahydroisoquinoline (1a) with acetone had
been performed on a 10 mmol scale to evaluate the
practicability of this protocol, and no loss of yield was observed
(Scheme 1). It indicates that our method can be conveniently
scaled up. Moreover, as shown in Scheme 1, the TBPA can be
efficiently recovered after the reaction by column chromato-
a
Standard reaction conditions: For aliphatic ketones: tetrahydroiso-
−
quinolines 1 (0.5 mmol), ketones 2 (10 equiv), TBPA•+SbCl6 (0.1
mmol), ambient air, rt. For aromatic ketones: tetrahydroisoquinolines
1 (0.5 mmol), ketones 2 (2 equiv), TBPA•+SbCl6 (0.1 mmol),
−
b
MeCN (5 mL), ambient air, rt. Isolated yields of the isolated
products.
Scheme 1. Scale-Up Experiment and Recycle of the Initiator
in this method too. The thiophene derived substrate also
provided the product 5e in good yield. To extend the scope of
our method, we also presented here an example of a
triarylaminium salt promoted intramolecular C−N bond-
forming reaction, as shown in Scheme 2.
graphic separation and can be recycled back to TBPA•+SbCl6
−
easily in perfect yield.
The success of intermolecular aerobic oxidative Mannich
reaction of tertiary amines by using catalytic amounts of
triarylaminium salt encouraged us to investigate the analogous
intramolecular dehydrogenative coupling reaction to deliver
ring-fused tetrahydroquinoline derivatives. Ring-fused tetrahy-
droquinolines are valuable precursors of a lot of bioactive
molecules and are widely used building blocks in organic
synthesis.8 As summarized in Table 3, three tetrahydro-
isoquinoline derivatives were first examined. For both
electron-donating and electron-withdrawing groups, the desired
products were achieved in high yields (Table 3, 5a−5c). The
piperidine derived substrate is applicable to giving product 5d
A plausible mechanism for this catalytic amounts of
triarylaminium salt induced aerobic oxidative transformation
is illustrated in Scheme 3. In this transformation, the Ar3N
radical cation plays two roles in generating iminium ion A: (1)
generating the radical cation of substrate 1 as a one electron
oxidant and (2) abstracting α-H of substrate 1 as a molecular
oxygen activator. The iminium species A can then be trapped
with nucleophiles such as ketones to afford the desired product
3.
In conclusion, we have reported a novel triarylaminium salt
promoted method that is highly efficient and simple for the
oxidative coupling of tertiary amines with various kinds of
9861
dx.doi.org/10.1021/jo5017822 | J. Org. Chem. 2014, 79, 9860−9864

The Journal of Organic Chemistry
Note
GF254 plates, and the products were visualized by UV detection. Flash
Table 3. Scope of TBPA Radical Cation Salt Induced
Intramolecular Aerobic Oxidative Mannich Reaction
1
a b
,
chromatography was carried out using silica gel 200−300. HNMR
(400 MHz) and 13CNMR (100 MHz) spectra were measured with
CDCl3 as solvent. HRMS were carried out on an Orbitrap analyzer.
−
General Procedure for TBPA•+SbCl6 Induced Intermolecu-
lar Aerobic Oxidative Mannich Reaction. Method I. N-Aryl
tetrahydroisoquinolines (1, 0.5 mmol) were dissolved in ketones (2, 5
−
mmol) at ambient temperature; TBPA•+SbCl6 (0.1 mmol) was then
added in one portion under stirring. The reactions were performed
under an air atmosphere at room temperature and completed as
monitored by TLC. The products were separated by silica gel column
chromatography using petroleum ether/ethyl acetate (v/v 40:1 to
20:1) to afford the products.
Method II. N-Aryl tetrahydroisoquinolines (1, 0.5 mmol) and
ketones (2, 1 mmol) were dissolved in MeCN (5 mL) at ambient
−
temperature; TBPA•+SbCl6 (0.1 mmol) was then added in one
portion under stirring. The reactions were performed under an air
atmosphere at room temperature and completed as monitored by
TLC. The products were separated by silica gel column chromatog-
raphy using petroleum ether/ethyl acetate (v/v 40:1 to 20:1) to afford
the products.
−
General Procedure for TBPA•+SbCl6 Induced Intramolecu-
a
lar Aerobic Oxidative Mannich Reaction. Substrates (4 or 6, 0.5
Standard reaction conditions: tetrahydroisoquinolines 1 (0.5 mmol),
b
−
TBPA•+SbCl6 (0.1 mmol), MeCN (5 mL), ambient air, rt. Isolated
yields of the isolated products.
mmol) were dissolved in MeCN (5 mL) at ambient temperature;
−
TBPA•+SbCl6 (0.1 mmol) was then added in one portion under
stirring. The reactions were performed under an air atmosphere at
room temperature and completed as monitored by TLC. The products
were separated by silica gel column chromatography using petroleum
ether/ethyl acetate (v/v 20:1) to afford the products.
Scheme 2. TBPA Radical Cation Salt Induced
Intramolecular C−N Bond-Forming Reaction
Characterization of the Products. 1-(2-Phenyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)propan-2-one (3aa).5a The desired pure
product was obtained in 92% yield (122 mg) as a white solid, mp 82−
1
84 °C. H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.4 Hz, 2H), 7.16
(m, 4H), 6.93 (d, J = 8.1 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 5.40 (t, J =
6.2 Hz, 1H), 3.64−3.46 (m, 2H), 3.11−2.97 (m, 2H), 2.89−2.74 (m,
2H), 2.07 (s, 3H).
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one
unmodified ketones. The highlight of the method is that it
requires only catalytic amounts of TBPA radical cation salt as
initiator under mild neutral aerobic conditions. The normally
used metal catalysts, acid or base additives, and stoichiometric
amounts of chemical oxidants are all avoided. Furthermore, six
examples of intramolecular cyclized products are delivered too.
(3ab).5a The desired pure product was obtained in 87% yield (121
1
mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.26−7.21
(m, 2H), 7.19−7.09 (m, 4H), 6.94 (d, J = 8.2 Hz, 2H), 6.77 (t, J = 7.2
Hz, 1H), 5.42 (t, J = 6.3 Hz, 1H), 3.71−3.47 (m, 2H), 3.11−2.98 (m,
2H), 2.88−2.72 (m, 2H), 2.43−2.19 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-2-one
(3ac).5a The desired pure product was obtained in 80% yield (117
1
EXPERIMENTAL SECTION
mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.33−7.12
■
(m, 6H), 7.02−6.92 (m, 2H), 6.79 (t, J = 7.2 Hz, 1H), 5.44 (t, J = 6.2
Hz, 1H), 3.81−3.44 (m, 2H), 3.20−2.98 (m, 2H), 2.94−2.71 (m, 2H),
2.43−2.15 (m, 2H), 1.64−1.47 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).
General Information. The starting materials, reagents, and
solvents, purchased from commercial suppliers, were used without
further purification. Analytical TLC was performed with silica gel
Scheme 3. Proposed Reaction Mechanism
9862
dx.doi.org/10.1021/jo5017822 | J. Org. Chem. 2014, 79, 9860−9864

The Journal of Organic Chemistry
Note
3-Methyl-1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-
CDCl3) δ 7.73 (s, 1H), 7.62−7.12 (m, 7H), 5.46 (t, J = 6.2 Hz, 1H),
3.75−3.56 (m, 2H), 3.17−3.01 (m, 2H), 2.99−2.83 (m, 2H), 2.12 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 206.4, 149.5, 149.3, 137.5, 134.0,
129.9, 128.6, 127.2, 126.8, 126.6, 119.4, 112.1, 107.7, 54.6, 50.2, 42.2,
31.1, 27.0. HRMS (ESI) exact mass calcd for C18H19N2O3 [M + H]
m/z 311.1396, found 311.1401.
2-one (3ad). The desired pure product was obtained in 77% yield
1
(113 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.29−
7.20 (m, 2H), 7.19−7.08 (m, 4H), 6.94 (d, J = 8.1 Hz, 2H), 6.75 (t, J =
7.2 Hz, 1H), 5.43 (t, J = 6.2 Hz, 1H), 3.68−3.43 (m, 2H), 3.15−2.99
(m, 2H), 2.91−2.76 (m, 2H), 2.48−2.31 (m, 1H), 1.06−0.88 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 212.8, 148.7, 138.5, 134.3, 129.3,
6,7,11b,12-Tetrahydro-13H-isoquinolino[2,1-a]quinolin-13-one
(5a).8a The desired pure product was obtained in 85% yield (106 mg)
128.5, 126.8, 126.7, 126.1, 117.9, 114.3, 54.8, 47.0, 42.0, 41.7, 27.4,
17.6, 17.5. HRMS (ESI) exact mass calcd for C20H24NO [M + H] m/z
294.1858, found 294.1853.
1
as a yellow solid, mp 122−124 °C. H NMR (400 MHz, CDCl3) δ
7.99 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.31−7.13 (m, 4H),
7.00 (d, J = 8.6 Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 4.74 (d, J = 13.7 Hz,
1H), 4.18−4.04 (m, 1H), 3.28−3.02 (m, 3H), 2.99−2.87 (m, 1H),
2.85−2.71 (m, 1H).
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)hexan-2-one
(3ae).5a The desired pure product was obtained in 74% yield (114
1
mg) as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.25−7.20 (m,
3-Methoxy-6,7,11b,12-tetrahydro-13H-isoquinolino[2,1-a]quino-
lin-13-one (5b).8a The desired pure product was obtained in 77%
yield (108 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d,
J = 9.1 Hz, 1H), 7.30−7.06 (m, 4H), 6.49−6.33 (m, 2H), 4.72 (d, J =
13.3 Hz, 1H), 4.11−3.98 (m, 1H), 3.87 (s, 3H), 3.26−2.83 (m, 4H),
2.82−2.67 (m, 1H).
2H), 7.19−7.09 (m, 4H), 6.94 (d, J = 8.3 Hz, 2H), 6.76 (t, J = 7.2 Hz,
1H), 5.42 (t, J = 6.2 Hz, 1H), 3.71−3.46 (m, 2H), 3.12−2.97 (m, 2H),
2.88−2.72 (m, 2H), 2.38−2.17 (m, 2H), 1.52−1.42 (m, 2H), 1.28−
1.16 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H).
4-Methyl-1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-
2-one (3af).5b The desired pure product was obtained in 73% yield
1
3-(Trifluoromethyl)-6,7,11b,12-tetrahydro-13H-isoquinolino[2,1-
a]quinolin-13-one (5c). The desired pure product was obtained in
64% yield (102 mg) as a yellow solid, mp 150−152 °C. 1H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 7.33−7.15 (m, 5H), 7.03 (d,
J = 7.9 Hz, 1H), 4.80 (d, J = 13.7 Hz, 1H), 4.24−4.04 (m, 1H), 3.32−
3.04 (m, 3H), 3.04−2.90 (m, 1H), 2.89−2.74 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 193.1, 151.9, 134.9, 133.8, 129.3, 128.8, 127.1,
126.9, 125.6, 122.5, 113.9, 113.9, 110.4, 110.4, 57.6, 46.6, 42.7, 29.3.
HRMS (ESI) exact mass calcd for C18H15F3NO [M + H] m/z
318.1106, found 318.1111.
(112 mg) as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.31−7.08
(m, 6H), 6.95 (d, J = 14.4 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 5.43 (t, J
= 6.2 Hz, 1H), 3.69−3.46 (m, 1H), 3.17−2.94 (m, 2H), 2.91−2.69 (m,
2H), 2.27−1.98 (m, 3H), 0.85 (d, J = 6.3 Hz, 6H).
1-Cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
ethan-1-one (3ag). The desired pure product was obtained in 84%
1
yield (122 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.33−7.23 (m, 2H), 7.23−7.10 (m, 4H), 6.98 (d, J = 8.2 Hz, 2H), 6.80
(t, J = 7.3 Hz, 1H), 5.48 (m, 1H), 3.73−3.53 (m, 2H), 3.25−2.83 (m,
4H), 1.90−1.79 (m, 1H), 1.07−0.97 (m, 2H), 0.89−0.76 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 209.3, 148.8, 138.5, 134.5, 129.4, 128.6,
127.0, 126.8, 126.2, 118.0, 114.5, 54.8, 49.9, 42.0, 27.5, 21.6, 11.1, 11.0.
HRMS (ESI) exact mass calcd for C20H22NO [M + H] m/z 292.1701,
found 292.1707.
1,2,3,4,4a,5-Hexahydro-6H-pyrido[1,2-a]quinolin-6-one (5d).8b
The desired pure product was obtained in 55% yield (55 mg) as a
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.3 Hz, 1H),
7.40 (t, J = 7.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.79 (t, J = 7.4 Hz,
1H), 3.98 (d, J = 11.3 Hz, 1H), 3.30 (m, 1H), 2.76−2.50 (m, 3H),
1.94−1.20 (m, 6H).
3b,4,11,12-Tetrahydro-5H-thieno[3′,2′:3,4]pyrido[1,2-a]quinolin-
5-one (5e). The desired pure product was obtained in 52% yield (66
mg) as a yellow solid, mp 146−148 °C. 1H NMR (400 MHz, CDCl3)
δ 7.99 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.18 (d, J = 5.0 Hz,
1H), 7.05 (d, J = 8.4 Hz, 1H), 6.95−6.78 (m, 2H), 4.65 (d, J = 13.2
Hz, 1H), 4.34−4.20 (m, 1H), 3.19−2.94 (m, 4H), 2.82−2.69 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 193.5, 152.2, 135.5, 135.0, 133.5,
128.4, 124.2, 123.8, 121.1, 118.2, 113.6, 57.2, 45.4, 43.3, 24.9. HRMS
(ESI) exact mass calcd for C15H14NOS [M + H] m/z 256.0796, found
256.0790.
5-Phenyl-4b,5,12,13-tetrahydro-6H-isoquinolino[2,1-a]quinazo-
lin-6-one (7).8c The desired pure product was obtained in 72% yield
(118 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J
= 7.8, 1.5 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.44−7.33 (m, 4H),
7.23−7.05 (m, 4H), 7.01 (d, J = 8.2 Hz, 1H), 6.94−6.87 (m, 1H), 6.19
(s, 1H), 4.26 (m, 1H), 3.81−3.69 (m, 1H), 3.32 (m, 1H), 2.88 (m,
1H).
1-Phenyl-2-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethan-1-
one (3ak).5a The desired pure product was obtained in 76% yield
1
(124 mg) as a pale yellow solid, mp 105−107 °C. H NMR (400
MHz, CDCl3) δ 7.85 (d, J = 7.3 Hz, 2H), 7.57−7.48 (m, 1H), 7.47−
7.35 (m, 2H), 7.34−7.19 (m, 4H), 7.19−7.08 (m, 1H), 6.96 (d, J = 7.8
Hz, 2H), 6.82−6.70 (m, 1H), 5.73−5.63 (m, 1H), 3.73−3.51 (m, 3H),
3.47−3.33 (m, 1H), 3.18−3.04 (m, 1H), 3.01−2.86 (m, 1H).
2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-(p-tolyl)ethan-
1-one (3al).5a The desired pure product was obtained in 80% yield
1
(136 mg) as a white solid, mp 113−115 °C. H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8.1 Hz, 2H), 7.28−7.17−7.06 (m, 8H), 6.97 (d,
J = 8.1 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 5.69−5.60 (m, 1H), 3.75−
3.49 (m, 3H), 3.45−3.28 (m, 1H), 3.19−3.01 (m, 1H), 3.01−2.84 (m,
1H), 2.38 (s, 3H).
2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-(thiophen-2-yl)-
ethan-1-one (3am). The desired pure product was obtained in 75%
1
yield (125 mg) as a yellow solid, mp 131−133 °C. H NMR (400
MHz, CDCl3) δ 7.63 (d, J = 4.9 Hz, 1H), 7.57 (d, J = 3.7 Hz, 1H),
7.32−7.01 (m, 9H), 6.79 (t, J = 7.2 Hz, 1H), 5.64 (t, 1H), 3.74−3.52
(m, 3H), 3.31 (dd, J = 15.8, 7.2 Hz, 1H), 3.22−3.08 (m, 1H), 3.00−
2.88 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 191.3, 148.7, 144.6,
138.1, 134.5, 134.0, 132.1, 129.4, 128.6, 128.1, 127.2, 126.9, 126.3,
118.0, 114.4, 55.6, 46.0, 42.0, 27.5. HRMS (ESI) exact mass calcd for
C21H20NOS [M + H] m/z 334.1266, found 334.1273.
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
1-(2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-
propan-2-one (3ba).5e The desired pure product was obtained in 93%
1
yield (137 mg) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ
AUTHOR INFORMATION
Corresponding Author
*E-mail: huocongde1978@hotmail.com (C.H.).
■
7.22−7.07 (m, 4H), 6.91 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H),
5.24 (t, J = 6.3 Hz, 1H), 3.75 (s, 3H), 3.63−3.38 (m, 2H), 3.09−2.93
(m, 2H), 2.82−2.66 (m, 2H), 2.06 (s, 3H).
Notes
1-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-
2-one (3ca).5e The desired pure product was obtained in 89% yield
The authors declare no competing financial interest.
1
(133 mg) as a red oil. H NMR (400 MHz, CDCl3) δ 7.23−7.11 (m,
6H), 6.85 (d, J = 9.0 Hz, 2H), 5.34 (t, J = 6.2 Hz, 1H), 3.68−3.43 (m,
2H), 3.10−2.96 (m, 2H), 2.90−2.76 (m, 2H), 2.09 (s, 3H).
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21262029) and the Fok Ying Tong Education Foundation
(141116) for financially supporting this work.
1-(2-(3-Nitrophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-
2-one (3da). The desired pure product was obtained in 77% yield
(119 mg) as a red solid, mp 101−102 °C. 1H NMR (400 MHz,
9863
dx.doi.org/10.1021/jo5017822 | J. Org. Chem. 2014, 79, 9860−9864

The Journal of Organic Chemistry
Note
REFERENCES
■
(1) For reviews about Mannich reactions, see: (a) Kleinman, E. D. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 2, p 893. (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069. (d) Ting, A.; Schaus, S. E. Eur.
J. Org. Chem. 2007, 5797. (e) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29−
41.
(2) Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc.
2003, 125, 15312.
(3) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.;
Li, C.-J. Org. Lett. 2004, 6, 4997.
(4) For reviews, see: (a) Murahashi, S.; Zhang, D. Chem. Soc. Rev.
2008, 37, 1490. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Klussmann, M.;
Sureshkumar, D. Synthesis 2011, 3, 353. (e) Girard, S. A.; Knauber, T.;
Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74.
(5) (a) Shen, Y.; Li, M.; Wang, S.; Zhan, T.; Tan, Z.; Guo, C. Chem.
Commun. 2009, 953. (b) Sud, A.; Sureshkumar, D.; Klussmann, M.
Chem. Commun. 2009, 3169. (c) Shu, X.; Yang, Y.; Xia, X.; Ji, K.; Liu,
X.; Liang, Y. Org. Biomol. Chem. 2010, 8, 4077. (d) Zeng, T.; Song, G.;
Moores, A.; Li, C. Synlett. 2010, 13, 2002. (e) Xie, J.; Li, H.; Zhou, J.;
Cheng, Y.; Zhu, C. Angew. Chem., Int. Ed. 2012, 51, 1252. (f) Rueping,
M.; Vila, C.; Koenigs, R.; Poscharny, K.; Fabry, D. Chem. Commun.
2011, 47, 2360. (g) Cherevatskaya, M.; Neumann, M.; Fuldner, S.;
Harlander, C.; Kummel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.;
Kcņ ig, B. Angew. Chem., Int. Ed. 2012, 51, 4062. (h) Rueping, M.;
Zoller, J.; Fabry, D.; Poscharny, K.; Koenigs, M.; Mayer, E. W.
Chem.Eur. J. 2012, 18, 3478. (i) Xue, Q.; Xie, J.; Jin, H.; Cheng, Y.;
Zhu, C. Org. Biomol. Chem. 2013, 11, 1606. (j) To, W.; Liu, Y.; Lau,
T.; Che, C. Chem.Eur. J. 2013, 19, 5654. (k) Pan, Y.; Kee, C.; Chen,
L.; Tan, C. Green Chem. 2011, 13, 2682. (l) Liu, Q.; Li, Y.; Zhang, H.;
Chen, B.; Tung, C.; Wu, L. Chem.Eur. J. 2012, 18, 620.
(m) Mohlmann, L.; Baar, M.; Rie, J.; Antonietti, M.; Wang, X.;
Blechert, S. Adv. Synth. Catal. 2012, 354, 1909. (n) Wang, S.; Nai, C.;
Jiang, X.; Pan, Y.; Tan, C.; Nesladek, M.; Xu, Q.; Loh, K. P. J. Phys.
Chem. Lett. 2012, 3, 2332. (o) Alagiri, K.; Devadig, P.; Prabhu, R.
Chem.Eur. J. 2012, 18, 5160. (p) Dhineshkumar, J.; Lamani, M.;
Alagiri, K.; Prabhu, R. Org. Lett. 2013, 15, 1092. (q) Nobuta, T.; Tada,
N.; Fujiya, A.; Kariya, A.; Miura, T.; Itoh, A. Org. Lett. 2013, 15, 574.
(6) (a) Huo, C.; Xu, X.; An, J.; Jia, X.; Wang, X.; Wang, C. J. Org.
Chem. 2012, 77, 8310. (b) Huo, C.; Kang, L.; Xu, X.; Jia, X.; Wang, X.;
Yuan, Y.; Xie, H. Tetrahedron. 2014, 70, 1055. (c) Huo, C.; Wang, C.;
Wu, M.; Jia, X.; Xie, H.; Yuan, Y. Adv. Synth. Catal. 2014, 356, 411.
(d) Huo, C.; Wang, C.; Sun, C.; Jia, X.; Wang, X.; Chang, W.; Wu, M.
Adv. Synth. Catal. 2013, 355, 1911. (e) Huo, C.; Wang, C.; Wu, M.; Jia,
X.; Wang, X.; Yuan, Y.; Xie, H. Org. Biomol. Chem. 2014, 12, 3123.
(7) (a) Nelsen, S. F. Acc. Chem. Res. 1987, 20, 269. (b) Bauld, N. L.
Tetrahedron 1989, 45, 5307. (c) Schmittel, M.; Burghart, A. Angew.
Chem., Int. Ed. 1997, 36, 2550.
(8) (a) Zhang, G.; Wang, S.; Ma, Y.; Kong, W.; Wang, R. Adv. Synth.
Catal. 2013, 355, 874. (b) Nie, S.-Z.; Sun, X.; Wei, W.-T.; Zhang, X.-J.;
Yan, M.; Xiao, J.-L. Org. Lett. 2013, 15, 2394. (c) Neel, A. J.; Hehn, J.
P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14044.
(d) Barton, D. H.; Nakanishi, K.; Meth-Cohn, O. Comprehensive
Natural Chemistry; Elsevier: Oxford, U.K., 1999; Vols. 1−9.
9864
dx.doi.org/10.1021/jo5017822 | J. Org. Chem. 2014, 79, 9860−9864