Transition-metal-free oxidative α-C-H amination of ketones via a radical mechanism: Mild synthesis of α-amino ketones

Article abstract of DOI:10.1021/jo5015855

A transition-metal-free direct α-C.H amination of ketones has been developed using commercially available ammonium iodide as the catalyst and sodium percarbonate as the co-oxidant. A wide range of ketone ((hetero)aromatic or nonaromatic ketones) and amine (primary/secondary amines, anilines, or amides) substrates undergo cross-coupling to generate synthetically useful α-amino ketones. The mechanistic studies indicated that a radical pathway might be involved in the reaction process. The utility of the method is highlighted through a concise one-step synthesis of the pharmaceutical agent amfepramone.

Full text of DOI:10.1021/jo5015855

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Article
Transition-Metal-Free Oxidative alpha-C-H Amination of Ketones
via a Radical Mechanism: Mild Synthesis of alpha-Amino Ketones
Qing Jiang, Bin Xu, An Zhao, Jing Jia, Tian Liu, and Cancheng Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5015855 • Publication Date (Web): 25 Aug 2014
Downloaded from http://pubs.acs.org on August 26, 2014
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TransitionꢀMetalꢀFree Oxidative αꢀC−H Amination of Ketones via
a Radical Mechanism: Mild Synthesis of αꢀAmino Ketones
Qing Jiang, Bin Xu, An Zhao, Jing Jia, Tian Liu, and Cancheng Guo*
College of Chemistry and Chemical Engineering, Advanced Catalytic Engineering Research
Center of the Ministry of Education, Hunan University, Changsha 410082, China
ccguo@hnu.edu.cn
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O
H
N
NH4I (15 mol%)
O
R2
R1
Na2CO3 1.5 H2O2 (2.0 equiv)
R2
+
R1
CH3CN, 50 o
C
N
H
Ketone: (hetero)aromatic or nonaromatic ketones
Amine: cyclic/acyclic dialkyl amines, aliphatic primary
amines, anilines or amides
27 examples
up to 94% yield
ABSTRACT: A transitionꢀmetalꢀfree direct αꢀC−H amination of ketones has been developed
using commercially available ammonium iodide as the catalyst and sodium percarbonate as the
coꢀoxidant. A wide range of ketone ((hetero)aromatic or nonaromatic ketones) and amine
(primary/secondary amines, anilines or amides) substrates undergo crossꢀcoupling to generate
synthetically useful αꢀamino ketones. The mechanistic studies indicated that a radical pathway
might be involved in the reaction process. The utility of the method is highlighted through a
concise oneꢀstep synthesis of the pharmaceutical agent amfepramone.
INTRODUCTION
Direct functionalization of C−H bonds to build C−C and C−heteroatom bonds is of great
significance and a fundamental challenge in organic chemistry and it offers substantial benefits
owing to their remarkable potential for atomꢀeconomy and environmental sustainability.1 Over the
past decade, construction of carbon−carbon (C−C) bonds via the oxidative crossꢀdehydrogenative
couplings between two C−H centers has become a field of intense interest because such couplings
avoid the tedious and timeꢀconsuming prefunctionalization of both substrates, and a plethora of
new synthetic methods have been developed toward the synthesis of complex structures.2 In
parallel, the development of C−N bond formation reactions has recently also captured the attention
of organic chemists since a wide array of important compounds (such as pharmaceuticals, natural
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products, and functional polymers/materials) contain nitrogen.3 However, despite the success of
C−H amination methods based on tandem C(sp2)−H/N−H functionalization,4 C(sp3)−H/N−H
coupling reactions is more limited; existing reports suffered from one or more limitations such as
use of expensive and/or toxic transition metal or reagents, harsh reaction conditions, and/or
narrow substrate scope.5 Consequently, the development of new and improved methods for
C(sp3)−H amination with N−H bonds is a worthwhile objective and remains an important
challenge in organic synthesis. As part of our continuous interest in transitionꢀmetalꢀfree
transformations,6 we herein disclose a transitionꢀmetalꢀfree oxidative αꢀC−H amination of ketones
with amines using NH4I as the catalyst in the presence of sodium percarbonate as the oxidant. This
transitionꢀmetalꢀfree oxidative amination method extends amine compounds to cyclic or acyclic
dialkyl amines, aliphatic primary amines, anilines and amides, thus allowing introduction of an
amino group into the αꢀposition of ketone. Most importantly, αꢀamino ketones are common
structural motifs in pharmaceutical agents and natural products7 as well as versatile intermediates
in organic synthesis.8
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RESULTS AND DISCUSSION
We started our investigations with propiophenone (1a) and morpholine (2a) as the model
substrates. By optimizing various reaction parameters, the combination of NH4I (15 mol%) and
o
sodium percarbonate (2.0 equiv) in CH3CN at 50 C was found to be the best reaction conditions
for this transformation, which provided the desired product 3a in 97% yield along with byproduct
2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone 4a in 2% yield (Table 1, entry 1). Control reactions confirmed that
no reaction occurred in the absence of NH4I or sodium percarbonate (Table 1, entries 2 and 3).
When NH4I was replaced by NaI or KI, a relatively low yield of corresponding product was
obtained (Table 1, entries 4 and 5), while using a catalytic amount of NH4Br led to no conversion
(Table 1, entry 6). Moreover, using I2 as catalyst provided the desired 3a in 94% yield (Table 1,
entry 7). Further optimization with sodium percarbonate showed that only a trace amount of
desired amination product was detected at room temperature (Table 1, entry 8). Increasing the
o
temperature to 80 C resulted in a significantly lower yield (54 %; Table 1, entry 9). Thus, the
optimal temperature was established to be 50 oC. A screening of solvents revealed that essentially
no conversion was observed in DMSO (Table 1, entry 10), while CH3CN, DMF and DCE
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performed with comparable efficiency (Table 1, entries 1, 11 and 12). Various oxidants such as
TBHP, PIDA, K2S2O8 and DTBP were then screened in the presence of NH4I (Table 1, entries 13ꢀ
16). TBHP was found to be as effective as sodium percarbonate. Using slightly lower amount of
sodium percarbonate resulted in a decrease in the yield (Table 1, entry 17). To our delight, the
reaction could be carried out at a relatively lower loading of NH4I (2 mol%) which furnished the
desired product 3a in 62% yield (Table 1, entry 18).
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Table 1. Optimization of the reaction conditionsa
Catalyst
(mol %)
Yieldb
(%)
Entry
Oxidant (equiv)
Solvent T (oC)
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2
3
4
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7
8
9
NH4I (15) Na2CO3·1.5 H2O2 (2.0) CH3CN 50
97
0
0
none
NH4I (15) none
Na2CO3·1.5 H2O2 (2.0)
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 25
CH3CN 80
NaI (15)
KI (15)
Na2CO3·1.5 H2O2 (2.0)
Na2CO3·1.5 H2O2 (2.0)
92
90
0
94
trace
54
NH4Br (15) Na2CO3·1.5 H2O2 (2.0)
I2 (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (2.0)
NH4I (15) TBHP (2.0)
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18
DMSO
DMF
DCE
50
50
50
trace
93
95
92
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
CH3CN 50
NH4I (15) PIDA (2.0)
trace
trace
trace
84
NH4I (15) K2S2O8 (2.0)
NH4I (15) DTBP (2.0)
NH4I (15) Na2CO3·1.5 H2O2 (1.5)
NH4I (2.0) Na2CO3·1.5 H2O2 (2.0)
62
a
Reaction conditions: propiophenone (1.0 mmol), morpholine (3.0 mmol),
b
solvent (1.0 mL), 18h. GC yields. The entry hightlighted in bold marks
optimized reaction conditions.
With the establishment of the optimal conditions, the scope and limitation of the reaction of
different ketones with morpholine was next examined. As shown in Table 2, electronꢀrich, ꢀneutral
and ꢀpoor aryl propiophenones could all be coupled with morpholine in good to excellent yields
(entries 1ꢀ6, 78%ꢀ94% yield). Notably, halo substituents including Br, Cl and F are compatible
with the reaction conditions, providing more chance for further functionalization or modification
of these molecules.9 Moreover, Substituents at the carbonyl βꢀposition did not hinder the reaction,
providing the corresponding amination products in high yields (entries 7 and 8, 82% and 74%
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yield). Heteroaromatic ketones are also suitable reaction substrates, which delivered the desired αꢀ
amination products in good yield (entries 9 and 10, 66% and 75% yield). In addition, the
methodology could be extended to nonaromatic ketones as well, although in moderate yield
(entries 11 and 12, 63% and 57% yield). However, dialkylꢀsubstituted ketone such as 3ꢀpentanone
did not afford the desired amination product and almost all of the 3ꢀpentanone remained intact.
Table 2. αꢀAmination of ketones: Scope of the ketone coupling componenta,c
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Table 3. αꢀAmination of ketones: Scope of the amine coupling componenta,e
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Considering the great importance of direct functionalization of different amines, we further
investigated the applicability of propiophenone with various simple amine derivatives in this
transformation. As demonstrated in Table 3, a range of amines is viable in this transformation.
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Cyclic amines coupled smoothly with propiophenone 1a, affording the corresponding α–amination
products in 64–92% yield (entries 1–5). Differentially protected acyclic dialkyl amines such as Nꢀ
methylbenzylamine and Nꢀethylbenzylamine were also compatible reaction partners in this
protocol, thus affording the corresponding desired products 3q and 3r in 87% and 85% yield,
respectively (entries 6 and 7). Moreover, Nꢀmethylallylamine was allowed to react with
propiophenone to give the corresponding product 3s in 74% yield, wherein carbonꢀcarbon double
bond could be well tolerated in the reaction process (entry 8). In addition, the present protocol
could be further extended to primary amines. For instance, tertꢀbutylamine and 4ꢀ
bromobenzylamine could afford the corresponding amination products 3t and 3u in 62% and 32%
yield, respectively (entries 9 and 10). To our delight, amides such as phthalimide and benzamide
also coupled with 1a, but in moderate or low yield (entries 11 and 12, 56% and 36% yield).
Notably, anilines are also applicable, albeit with relatively low conversion and yield (entries 13ꢀ15,
24%ꢀ42% yield).
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To demonstrate the practicality of this transitionꢀmetalꢀfree reaction, we carried out the αꢀ
amination reaction of propiophenone with morpholine on a gram scale (Eq. 1). Reaction of 1.34 g
(10 mmol) of propiophenone with 3.0 equiv morpholine in the presence of 15 mol% NH4I in
acetonitrile gave 2a (1.84 g) in 84% isolated yield. Finally, given the generality and operational
simplicity of this transformation, the synthetic utility of this new catalytic protocol has been
demonstrated. As shown in eq 2, the reaction of propiophenone 1a with diethylamine using our
catalysis protocol yielded the desired amfepramone 5 in 72% yield, which is a highꢀprofile
appetite suppressant.10
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In order to better understand the reaction mechanism and to determine the active intermediates
involved, several control experiments were conducted. The reaction of 1a and 2a was studied in
CH3CN at 50 oC using iodized salts of different oxidation states (Table 4). The use of a mixture of
molecular iodine (I2) and two equivalents of potassium hydroxide or sodium iodate (NaIO4) only
resulted in trace formation of the desired product 3a (Table 4, entries 2 and 4). No product was
detected when sodium periodate (NaIO3) was used (Table 4, entry 3). In contrast, when molecular
iodine was employed in this reaction, the desired product was obtained in a good yield of 72 %
(Table 4, entry 1). As a result, an in situ generated molecular iodine (I2) was suggested to be the
active intermediate. This proposal was also supported by the result obtained from entry 7 in Table
1. When radical inhibitors, such as 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and 2,6ꢀdiꢀtertꢀ
butylꢀ4ꢀmethylphenol (BHT), were employed in the standard reaction, and the reaction was
obviously inhibited (Scheme 1a). This observation implied that the reaction presumably
underwent a radical pathway, and also indicated that the present reaction mechanism is different
from those developed by Prabhu5b and MacMillan.5a Moreover, the 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone
4a was utilized for this reaction, which provided only a trace amount of the desired product 3a
(Schemes 1b, 1c and 1d). These results suggested that the 4a is not possible intermediate in this
transformation, and that a nucleophilic substitution might not be involved in the reaction process.
Subsequently we wanted to verify whether in situ generation of an activated Nꢀiodamine is likely.
Thus Nꢀiodomorpholine hydroiodide 6 was synthesized and further investigated. The reaction of 6
with propiophenone 1a only gave a trace amount of 3a no matter the existence of the NH4I
(Schemes 1e), which suggested that 6 as intermediate is also unlikely.
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Table 4. Control experiments: use of iodized salts at different oxidations statesa
Entry
Additive (equiv)
I2 (1.0)
Yieldb (%)
1
2
3
4
72
trace
0
I2 (1.0) + KOH (2.0)
NaIO3 (1.0)
NaIO4 (1.0)
trace
a Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), additive (1.0 equiv),
CH3CN (1.0 mL), 50 oC, 18 h. b GC yields.
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Scheme 1. Mechanistic studies and control experiments
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On the basis of the above results and previous reports,11 a tentative mechanism for this
transitionꢀmetalꢀfree oxidative amination is proposed and shown in Scheme 2 (using
propiophenone 1a and morpholine 2a as the model). Initially, oxidation of iodide (Iꢀ) by hydrogen
peroxide generates molecular iodine, which is further decomposed into iodine radical. Then, the
iodine radical abstracts the αꢀhydrogen of the propiophenone to form a carbon radical intermediate
A, accompanied by the liberation of one molecule of HI, which is trapped by the base to
regenerate iodide (Iꢀ). Moreover, the HI can also be reoxidized into molecular iodide by hydrogen
peroxide. Through further single electron oxidation, this carbon radical A would be converted to
intermediate cation B. This proposal is supported by the isolation of byproduct 2ꢀiodoꢀ1ꢀ
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phenylpropanꢀ1ꢀone 4a. Finally, the nucleophilic substitution of 2a to B gives the desired product
3a. Moreover, under the standard conditions, the possibility of a nitrogenꢀcentered radical process
can not be completely ruled out at present.
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Scheme 2. Proposed mechanism
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CONCLUSION
In conclusion, we have discovered a highly efficient αꢀamination of various ketones catalyzed
by in situ generated molecular iodine. This process offers an expedient approaches to the
introduction of an amine functionality at the carbonyl αꢀposition of ketones. This reaction has
apparent advantages, such as mild reaction conditions, nonꢀtoxicity, broad substrate scope, and
easy handling, and sodium percarbonate is used as an environmentally benign coꢀoxidant.
Furthermore, this simple method, which exhibits a broad substrate scope and good functional
group tolerance, has been applied to concise oneꢀstep synthesis of one prominent pharmaceutical
agent. Further studies on the synthetic applications and relevant transitionꢀmetalꢀfree
transformations are currently ongoing in our laboratory.
EXPERIMENTAL SECTION
General Comments. All reagents and solvents used were purchased from commercial suppliers
and used without further purification unless otherwise noted. 1H NMR and 13C NMR spectra were
recorded on 400 MHz in CDCl3 using TMS as internal standard. Column chromatography was
performed on silica gel. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet),
and m (multiplet), and coupling constants (J) are reported in Hertz. Mass spectra were obtained on
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a mass instrument using the EI technique.
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General procedure for the transitionꢀmetalꢀfree oxidative αꢀamination of ketones with
amines. NH4I (21.7 mg, 0.15 mmol, 0.15 equiv) was added to a mixture of sodium percarbonate
or TBHP (2 mmol, 2 equiv), ketones (1 mmol, 1 equiv), and amines (3 mmol, 3 equiv) in
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o
acetonitrile or DMF(1 mL) at room temperature. The reaction was stirred at 50 C for the time
indicated. The reaction mixture was then allowed to cool to room temperature, after which the
crude reaction mixture was loaded directly onto a column of silica gel and purified by column
chromatography to give the desired αꢀamino ketones.
2ꢀMorpholinoꢀ1ꢀphenylpropanꢀ1ꢀone (3a). Following the general procedure, the product was
isolated as a yellow oil, 201.5 mg (92%); Flash chromatography (petroleum ether/ ethyl acetate,
3/1); 1H NMR (CDCl3, 400 MHz) δ 1.30 (d, J = 6.8 Hz, 3 H), 2.56ꢀ2.66 (m, 4 H), 3.66ꢀ3.73 (m, 4
H), 4.08 (q, J = 6.8 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H), 8.09 (d, J = 7.6
Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 11.7, 50.1, 64.8, 67.2, 128.5, 128.8, 133.1, 136.2, 208.2
ppm; LRMS: m/z calcd for C13H17NO2 (M+H): 219, found: 219.
2ꢀMorpholinoꢀ1ꢀ(4ꢀ(methyl)phenyl)propanꢀ1ꢀone (3b). Following the general procedure, the
product was isolated as a colorless solid, 219.0 mg (94%), mp = 83.2ꢀ85.5 oC; Flash
1
chromatography (petroleum ether/ ethyl acetate, 2/1); H NMR (CDCl3, 400 MHz) δ 1.29 (d, J =
6.4 Hz, 3 H), 2.42 (s, 3 H), 2.57ꢀ2.62 (m, 4 H), 3.69 (m, 4 H), 4.04 (q, J = 6.4 Hz, 1 H), 7.25 (d, J
= 7.6 Hz, 2 H), 8.00 (d, J = 7.6 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 12.0, 21.7, 50.2, 64.7,
67.1, 129.0, 129.2, 133.6, 143.9, 199.9 ppm; Anal.Calcd for C14H19NO2 Elemental Analysis: C,
72.07; H, 8.21; N, 6.00; Found: C, 72.01; H, 8.28; N, 5.91.
2ꢀMorpholinoꢀ1ꢀ(4ꢀ(methoxyl)phenyl)propanꢀ1ꢀone (3c). Following the general procedure, the
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product was isolated as a pale yellow solid, 199.2 mg (80%), mp = 66.4ꢀ68.5 C; Flash
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chromatography (petroleum ether/ ethyl acetate, 1/1); H NMR (CDCl3, 400 MHz) δ 1.20 (d, J =
5.6 Hz, 3 H), 2.47ꢀ2.52 (m, 4 H), 3.60ꢀ3.64 (m, 4 H), 3.78 (s, 3 H), 3.92 (q, J = 5.6 Hz, 1 H), 6.84
(d, J = 8.0 Hz, 2 H), 8.02 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 12.1, 50.2, 55.4,
64.8, 67.1, 113.6, 129.0, 131.2, 163.4, 198.8 ppm; Anal.Calcd for C14H19NO3 Elemental Analysis:
C, 67.45; H, 7.68; N, 5.62; Found: C, 67.38; H, 7.78; N, 5.54.
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2ꢀMorpholinoꢀ1ꢀ(4ꢀ(fluoro)phenyl)propanꢀ1ꢀone (3d). Following the general procedure, the
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product was isolated as a colorless solid, 201.5 mg (85%), mp = 68.6ꢀ70.8 oC; Flash
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chromatography (petroleum ether/ ethyl acetate, 3/1); H NMR (CDCl3, 400 MHz) δ 1.25 (d, J =
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6.8 Hz, 3 H), 2.49ꢀ2.60 (m, 4 H), 3.61ꢀ3.68 (m, 4 H), 3.97 (q, J = 6.8 Hz, 1 H), 7.08 (t, J = 8.8 Hz,
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2 H), 8.11ꢀ8.15 (m, 2 H); 13C NMR (CDCl3, 101 MHz) δ 11.1, 49.9, 65.1, 67.0, 115.3 (d, JCꢀF
=
22.0 Hz), 131.5 (d, JCꢀF = 29.0 Hz), 132.2 (d, JCꢀF = 3.0 Hz), 165.5 (d, JCꢀF = 253.0 Hz), 198.5 ppm;
Anal.Calcd for C13H16FNO2 Elemental Analysis: C, 65.81; H, 6.80; N, 5.90; Found: C, 65.72; H,
6.88; N, 5.78.
2ꢀMorpholinoꢀ1ꢀ(4ꢀ(chloro)phenyl)propanꢀ1ꢀone (3e). Following the general procedure, the
o
product was isolated as a pale yellow solid, 197.3 mg (78%), mp = 84.2ꢀ86.1 C; Flash
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chromatography (petroleum ether/ ethyl acetate, 2/1); H NMR (CDCl3, 400 MHz) δ 1.28 (d, J =
6.0 Hz, 3 H), 2.56ꢀ2.59 (m, 4 H), 3.68 (m, 4 H), 4.10 (q, J = 6.0 Hz, 1 H), 7.42 (d, J = 7.6 Hz, 2 H),
8.07 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 11.0, 49.9, 65.2, 67.1, 128.7, 130.4,
134.2, 139.4, 199.0 ppm; Anal.Calcd for C13H16ClNO2 Elemental Analysis: C, 61.54; H, 6.36; N,
5.52; Found: C, 61.46; H, 6.42; N, 5.43.
2ꢀMorpholinoꢀ1ꢀ(4ꢀ(bromo)phenyl)propanꢀ1ꢀone (3f). Following the general procedure, the
product was isolated as a colorless solid, 247.3 mg (83%), mp = 98.2ꢀ100.5 oC; Flash
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chromatography (petroleum ether/ ethyl acetate, 3/1); H NMR (CDCl3, 400 MHz) δ 1.26 (d, J =
6.8 Hz, 3 H), 2.50ꢀ2.61 (m, 4 H), 3.62ꢀ3.70 (m, 4 H), 3.98 (q, J = 6.8 Hz, 1 H), 7.57 (d, J = 8.4 Hz,
2 H), 7.97 (d, J = 8.8 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 10.9, 49.8, 65.1, 67.0, 128.1, 130.4,
131.6, 134.5, 199.0 ppm; Anal.Calcd for C13H16BrNO2 Elemental Analysis: C, 52.36; H, 5.41; N,
4.70; Found: C, 52.25; H, 5.50; N, 4.58.
1ꢀPhenylꢀ2ꢀmorpholinopentanꢀ1ꢀone (3g). Following the general procedure, the product was
isolated as a yellow oil, 202.5 mg (82%); Flash chromatography (petroleum ether/ ethyl acetate,
5/1); 1H NMR (CDCl3, 400 MHz) δ 0.88 (d, J = 8.0 Hz, 3 H), 1.21ꢀ1.27 (m, 2 H), 1.64ꢀ1.66 (m, 1
H), 1.82ꢀ1.87 (m, 1 H), 2.53ꢀ2.58 (m, 2 H), 2.62ꢀ2.67 (m, 2 H), 3.62ꢀ3.64 (m, 4 H), 3.98 (dd, J =
8.0, 4.0 Hz, 1 H), 7.42ꢀ7.52 (m, 2 H), 7.52ꢀ7.56 (m, 1 H), 8.02ꢀ8.04 (m, 2 H); 13C NMR (CDCl3,
101 MHz) δ 14.2, 19.8, 28.5, 50.2, 67.3, 68.4, 128.4, 128.5, 133.0, 137.2, 199.8 ppm; LRMS: m/z
calcd for C15H24NO2 (M+H): 247, found: 247.
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1,2ꢀDiphenylꢀ2ꢀmorpholinoethanꢀ1ꢀone (3h). Following the general procedure, the product was
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isolated as a yellow oil, 207.9 mg (74%); Flash chromatography (petroleum ether/ ethyl acetate,
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2/1); H NMR (CDCl3, 400 MHz) δ 2.46ꢀ2.53 (m, 4 H), 3.70ꢀ3.80 (m, 4 H), 4.93 (s, 1 H), 7.23ꢀ
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7.49 (m, 8 H), 8.00 (d, J = 8.0, 2 H); 13C NMR (CDCl3, 101 MHz) δ 52.2, 66.8, 76.4, 128.4, 128.5,
128.7, 128.9, 129.7, 133.2, 134.6, 136.3, 197.2 ppm; LRMS: m/z calcd for C18H19NO2 (M+H):
281, found: 281.
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1ꢀ(Furanꢀ2ꢀyl)ꢀ2ꢀmorpholinobutanꢀ1ꢀone (3i). Following the general procedure, the product was
isolated as a yellow oil, 147.2 mg (66%); Flash chromatography (petroleum ether/ ethyl acetate,
3/1); 1H NMR (CDCl3, 400 MHz) δ 0.89 (t, J = 8.0 Hz, 3 H), 1.73ꢀ1.90 (m, 2 H), 2.58ꢀ2.69 (m, 4
H), 3.67 (m, 4 H), 3.76 (t, J = 8.0, 1 H ), 6.57 (m, 1 H), 7.34 (s, 1 H), 7.85 (s, 1 H); 13C NMR
(CDCl3, 101 MHz) δ 10.6, 20.6, 50.4, 67.3, 70.1, 112.3, 118.1, 146.8, 152.9, 189.3 ppm; LRMS:
m/z calcd for C12H17NO3 (M+H): 223, found: 223.
1ꢀ(Thiophenꢀ2ꢀyl)ꢀ2ꢀmorpholinobutanꢀ1ꢀone (3j). Following the general procedure, the product
was isolated as a yellow oil, 179.3 mg (75%); Flash chromatography (petroleum ether/ ethyl
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acetate, 3/1); H NMR (CDCl3, 400 MHz) δ 0.85 (t, J = 8.0 Hz, 3 H), 1.73ꢀ1.85 (m, 2 H), 2.50ꢀ
2.56 (m, 2 H), 2.61ꢀ2.67 (m, 2 H), 2.53 (dd, J = 8.0, 4.0 Hz, 1 H ), 3.65ꢀ3.67 (m, 4 H), 7.08ꢀ7.10
(m, 1 H), 7.57ꢀ7.60 (m, 1 H), 7.89ꢀ7.90 (m, 1 H); 13C NMR (CDCl3, 101 MHz) δ 10.9, 20.5, 50.6,
67.1, 73.1, 127.8, 132.9, 134.0, 142.7, 193.3 ppm; LRMS: m/z calcd for C12H17NO2S (M+H): 239,
found: 239.
3ꢀMorpholinoꢀ3ꢀ(4ꢀ(methoxyl)phenyl)propanꢀ2ꢀone (3k). Following the general procedure, the
product was isolated as a pale yellow oil, 156.9 mg (63%); Flash chromatography (petroleum
ether/ ethyl acetate, 3/1); 1H NMR (CDCl3, 400 MHz) δ 2.10 (s, 3 H), 2.39 (m, 4 H), 3.74 (m, 4 H),
3.80 (s, 3 H), 3.87 (s, 3 H), 6.89 (d, J = 7.6 Hz, 2 H), 7.30 (d, J = 7.6 Hz, 2 H); 13C NMR (CDCl3,
101 MHz) δ 26.5, 52.0, 55.3, 66.8, 81.4, 114.3, 126.4, 130.2, 159.8, 206.7 ppm; LRMS: m/z calcd
for C14H19NO3 (M+H): 249, found: 249.
3ꢀMorpholinoꢀ3ꢀ(4ꢀ(fluoro)phenyl)propanꢀ2ꢀone (3l). Following the general procedure, the
product was isolated as a yellow oil, 135.1 mg (57%); Flash chromatography (nꢀhexane/ acetone,
5/1); 1H NMR (CDCl3, 400 MHz) δ 2.05 (s, 3 H), 2.32ꢀ2.34 (m, 4 H), 3.67ꢀ3.69 (m, 4 H), 3.85 (s,
1 H), 7.00 (t, J = 8.0 Hz, 2 H), 7.31ꢀ7.34 (m, 2 H); 13C NMR (CDCl3, 101 MHz) δ 26.4, 51.9, 66.7,
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81.2, 115.9 (d, JCꢀF = 21.0 Hz), 130.3 (d, JCꢀF = 3.0 Hz), 130.5 (d, JCꢀF = 8.0 Hz), 162.7 (d, JCꢀF
=
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246.0 Hz), 206.4 ppm; LRMS: m/z calcd for C13H16FNO2 (M+H): 237, found: 237.
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1ꢀPhenylꢀ2ꢀ(piperidinꢀ1ꢀyl)propanꢀ1ꢀone (3m). Following the general procedure, the product
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was isolated as a brown oil, 180.1 mg (83%); Flash chromatography (petroleum ether/ ethyl
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acetate, 1/1); H NMR (CDCl3, 400 MHz) δ 1.17 (d, J = 8.0 Hz, 3 H), 1.28ꢀ1.34 (m, 2 H), 1.39ꢀ
1.48 (m, 4 H), 2.39ꢀ2.50 (m, 4 H), 4.00 (q, J = 8.0 Hz, 1 H), 7.33ꢀ7.43 (m, 2 H), 7.44ꢀ7.47 (m, 1
H), 8.01ꢀ8.03 (m, 2 H); 13C NMR (CDCl3, 101 MHz) δ 11.1, 24.5, 26.2, 50.6, 64.9, 128.1, 128.8,
132.6, 136.4, 201.0 ppm; LRMS: m/z calcd for C14H19NO (M+H): 217, found: 217.
1ꢀPhenylꢀ2ꢀ(4ꢀmethylpiperidinꢀ1ꢀyl)propanꢀ1ꢀone (3n). Following the general procedure, the
product was isolated as a yellow oil, 189.4 mg (82%); Flash chromatography (petroleum ether/
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ethyl acetate, 5/1); H NMR (CDCl3, 400 MHz) δ 0.81 (d, J = 6.8 Hz, 3 H), 1.01ꢀ1.20 (m, 6 H),
1.46ꢀ1.55 (m, 2 H), 2.06 (t, J = 12.0 Hz, 1 H), 2.33 (t, J = 12.0 Hz, 1 H), 2.68 (d, J = 8.0 Hz, 1 H),
2.83 (d, J = 8.0 Hz, 1 H),4.03 (q, J = 8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.46 (t, J = 8.0 Hz, 1
H), 8.03 (d, J = 8.0, 2 H); 13C NMR (CDCl3, 101 MHz) δ 11.5, 21.9, 30.8, 34.4, 34.8, 48.7, 51.7,
64.8, 128.3, 128.9, 132.8, 136.5, 201.1 ppm; LRMS: m/z calcd for C15H21NO (M+H): 231, found:
231.
2ꢀThiomorpholinoꢀ1ꢀphenylpropanꢀ1ꢀone (3o). Following the general procedure, the product
was isolated as a brown oil, 152.8 mg (65%); Flash chromatography (petroleum ether/ ethyl
acetate, 3/1); 1H NMR (CDCl3, 400 MHz) δ 1.25 (d, J = 8.0 Hz, 3 H), 2.55ꢀ2.65 (m, 4 H), 2.87 (m,
4 H), 4.15 (q, J = 8.0 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.0
Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 9.9, 28.4, 51.6, 65.2, 128.3, 128.9, 133.0, 136.2, 200.1
ppm; LRMS: m/z calcd for C13H17NOS (M+H): 235, found: 235.
2ꢀ(3,4ꢀDihydroisoquinolinꢀ2(1H)ꢀyl)ꢀ1ꢀphenylpropanꢀ1ꢀone (3p). Following the general
procedure, the product was isolated as a yellow oil, 169.6 mg (64%); Flash chromatography
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(petroleum ether/ ethyl acetate, 10/1); H NMR (CDCl3, 400 MHz) δ 1.40 (d, J = 6.8 Hz, 3 H),
2.83ꢀ2.89 (m, 4 H), 3.83 (d, J = 16.0 Hz, 1 H), 3.92 (d, J = 12.0 Hz, 1 H), 4.35 (q, J = 8.0 Hz, 1
H),7.02ꢀ7.14 (m, 4 H), 7.42ꢀ7.46 (m, 2 H), 7.52ꢀ7.56 (m, 1 H), 8.14ꢀ8.16 (m, 2 H); 13C NMR
(CDCl3, 101 MHz) δ 11.3, 29.5, 47.0, 51.9, 64.0, 125.5, 125.9, 126.5, 128.3, 128.6, 128.8, 132.9,
134.3, 134.7, 136.1, 200.5 ppm; LRMS: m/z calcd for C18H19NO (M+H): 265, found: 265.
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2ꢀ(Benzylmethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3q). Following the general procedure, the
product was isolated as a yellow oil, 220.1 mg (87%); Flash chromatography (petroleum ether/
ethyl acetate, 10/1); 1H NMR (CDCl3, 400 MHz) δ 1.32 (d, J = 8.0 Hz, 3 H), 2.23 (s, 3 H), 3.65 (s,
2 H), 4.31 (q, J = 8.0 Hz, 1 H),7.21ꢀ7.27 (m, 5 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 1
H), 7.98 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 9.8, 37.6, 58.4, 62.2, 127.1, 128.2,
128.3, 128.9, 129.0, 132.8, 136.5, 139.0, 200.9 ppm; LRMS: m/z calcd for C17H19NO (M+H): 253,
found: 253.
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2ꢀ(Benzylethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3r). Following the general procedure, the product
was isolated as a yellow oil, 226.9 mg (85%); Flash chromatography (petroleum ether/ ethyl
acetate, 15/1); 1H NMR (CDCl3, 400 MHz) δ 1.03 (t, J = 8.0 Hz, 3 H), 1.29 (d, J = 8.0 Hz, 3 H),
2.53ꢀ2.60 (m, 2 H), 3.53 (d, J = 16.0 Hz, 1 H), 3.71 (d, J = 12.0 Hz, 1 H), 4.41 (q, J = 8.0 Hz, 1
H),7.16ꢀ7.18 (m, 2 H), 7.21ꢀ7.274 (m, 3 H), 7.38ꢀ7.42 (m, 2 H), 7.50ꢀ7.54 (m, 1 H), 7.90ꢀ7.92 (m,
2 H); 13C NMR (CDCl3, 101 MHz) δ 8.7, 13.5, 41.2, 54.5, 58.6, 126.8, 127.9, 128.0 128.8, 128.9,
132.4, 136.7, 139.6, 201.8 ppm; LRMS: m/z calcd for C18H21NO (M+H): 267, found: 267.
2ꢀ(Allylmethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3s). Following the general procedure, the product
was isolated as a yellow oil, 150.2 mg (74%); Flash chromatography (petroleum ether/ ethyl
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acetate, 8/1); H NMR (CDCl3, 400 MHz) δ 1.25 (d, J = 8.0 Hz, 3 H), 2.25 (s, 3 H), 3.15 (d, J =
6.8 Hz, 3 H), 4.30 (q, J = 8.0 Hz, 1 H), 5.11ꢀ5.19 (m, 2 H), 5.80ꢀ5.90 (m, 1 H), 7.44 (t, J = 8.0, 2
H), 7.53 (t, J = 8.0, 1 H), 8.05 (d, J = 8.0, 2 H); 13C NMR (CDCl3, 101 MHz) δ 9.9, 37.6, 57.6,
61.9, 117.6, 128.4, 128.8, 132.8, 135.9, 136.5, 201.0 ppm; LRMS: m/z calcd for C13H17NO
(M+H): 203, found: 203.
2ꢀTertꢀbutylaminoꢀ1ꢀphenylpropanꢀ1ꢀone (3t). Following the general procedure, the product
was isolated as a yellow oil, 127.1 mg (62%); Flash chromatography (petroleum ether/ ethyl
acetate, 2/1); 1H NMR (CDCl3, 400 MHz) δ 1.06 (s, 9 H), 1.28 (d, J = 8.0 Hz, 3 H), 2.74 (brs, 1 H),
4.39 (q, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.0 Hz, 2 H), 7.60 (t, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0, 2 H);
13C NMR (CDCl3, 101 MHz) δ 22.6, 29.7, 50.9, 51.9, 128.3, 128.8, 133.3, 134.9, 204.9 ppm;
LRMS: m/z calcd for C13H19NO (M+H): 205, found: 205.
2ꢀ((4ꢀBromobenzyl)amino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3u). Following the general procedure, the
o
product was isolated as a pale yellow solid, 101.8 mg (32%), mp = 50.3ꢀ52.4 C; Flash
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chromatography (hexane/acetone, 8/1); 1H NMR (CDCl3, 400 MHz) δ 1.33 (d, J = 8.0 Hz, 3 H),
3.60 (d, J = 16.0 Hz, 1 H), 3.79 (d, J = 12.0 Hz, 1 H), 4.32 (q, J = 8.0 Hz, 1 H), 7.24 (t, J = 8.0 Hz,
2 H), 7.43ꢀ7.50 (m, 4 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3,
101 MHz) δ 20.0, 51.2, 57.0, 120.9, 128.3, 128.8, 130.1, 131.5, 133.5, 135.5, 138.8, 203.4 ppm;
Anal.Calcd for C16H16BrNO Elemental Analysis: C, 60.39; H, 5.07; N, 4.40; Found: C, 60.28; H,
5.16; N, 4.29.
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2ꢀ(1ꢀOxoꢀ1ꢀphenylpropanꢀ2ꢀyl)isoindolineꢀ1,3ꢀdione (3v). Following the general procedure, the
o
product was isolated as a pale yellow solid, 156.2 mg (56%), mp = 84.1ꢀ86.2 C; Flash
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chromatography (petroleum ether/ ethyl acetate, 4/1); H NMR (CDCl3, 400 MHz) δ 1.73 (d, J =
8.0 Hz, 3 H), 5.67 (q, J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 2 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.69ꢀ
7.71 (m, 2 H), 7.80ꢀ7.83 (m, 4 H); 13C NMR (CDCl3, 101 MHz) δ 14.9, 50.9, 123.5, 128.0, 128.7,
131.8, 133.1, 134.2, 135.2, 167.5, 196.2 ppm; Anal.Calcd for C17H13NO3 Elemental Analysis: C,
73.11; H, 4.69; N, 5.02; Found: C, 73.01; H, 4.80; N, 4.90.
Nꢀ(1ꢀOxoꢀ1ꢀphenylpropanꢀ2ꢀyl)benzamide (3w). Following the general procedure, the product
o
was isolated as a colorless solid, 91.1 mg (36%), mp = 108.2ꢀ110.4 C; Flash chromatography
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(petroleum ether/ ethyl acetate, 10/1); H NMR (CDCl3, 400 MHz) δ 1.67 (d, J = 8.0 Hz, 3 H),
6.21 (q, J = 8.0 Hz, 1 H), 7.43ꢀ7.50 (m, 4 H), 7.55ꢀ7.61 (m, 2 H), 8.00 (d, J = 8.0 Hz, 2 H), 8.09 (d,
J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 17.2, 71.9, 128.4, 128.6, 128.8, 129.5, 129.9,
133.3, 133.6, 134.5, 166.0, 196.8 ppm; Anal.Calcd for C16H15NO2 Elemental Analysis: C, 75.87;
H, 5.97; N, 5.53; Found: C, 75.77; H, 6.04; N, 5.42.
2ꢀ(pꢀTolylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3x). Following the general procedure, the product was
o
isolated as a violet black solid, 83.7 mg (35%), mp = 86.6ꢀ88.9 C; Flash chromatography
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(petroleum ether/ ethyl acetate, 10/1); H NMR (CDCl3, 400 MHz) δ 1.46 (d, J = 8.0 Hz, 3 H),
2.22 (s, 3 H), 4.55 (brs, 1 H), 5.11 (q, J = 8.0 Hz, 1 H), 6.61 (d, J = 6.8 Hz, 2 H), 6.98 (d, J = 8.0
Hz, 2 H), 7.50 (t, J = 8.0 Hz, 2 H), 7.60 (t, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 2 H); 13C NMR
(CDCl3, 101 MHz) δ 19.6, 20.4, 53.8, 113.8, 127.2, 128.5, 128.9, 129.9, 133.6, 134.8, 144.3,
201.0 ppm; Anal.Calcd for C16H17NO Elemental Analysis: C, 80.30; H,7.16; N, 5.85; Found: C,
80.22; H, 7.28; N, 5.75.
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2ꢀ((4ꢀMethoxyphenyl)amino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3y). Following the general procedure, the
product was isolated as a red oil, 107.1 mg (42%); Flash chromatography (petroleum ether/ ethyl
acetate, 10/1); 1H NMR (CDCl3, 400 MHz) δ 1.47 (d, J = 6.8 Hz, 3 H), 3.73 (s, 3 H), 5.06 (q, J =
8.0 Hz, 1 H), 6.67 (d, J = 6.8 Hz, 2 H), 6.77 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 8.0 Hz, 2 H), 7.61 (t,
J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 19.7, 54.6, 55.8, 115.0,
115.4, 128.4, 128.9, 133.6, 134.8, 140.7, 152.6, 201.2 ppm; LRMS: m/z calcd for C16H17NO2
(M+H): 255, found: 255.
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2ꢀ((4ꢀChlorophenyl)amino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3z). Following the general procedure, the
product was isolated as a red oil, 62.2 mg (24%); Flash chromatography (petroleum ether/ ethyl
acetate, 10/1); 1H NMR (CDCl3, 400 MHz) δ 1.47 (d, J = 6.8 Hz, 3 H), 4.75 (brs, 1 H), 5.08 (q, J
= 8.0 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.63
(t, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 101 MHz) δ 19.5, 53.5, 114.6,
122.5, 128.5, 129.0, 129.2, 133.8, 134.5, 145.1, 200.3 ppm; LRMS: m/z calcd for C15H14ClNO2
(M+H): 259, found: 259.
2ꢀDiethylaminoꢀ1ꢀphenylpropanꢀ1ꢀone (5). Following the general procedure, the product was
isolated as a brown oil, 147.6 mg (72%); Flash chromatography (petroleum ether/ ethyl acetate,
2/1); 1H NMR (CDCl3, 400 MHz) δ 0.94 (t, J = 8.0 Hz, 6 H), 1.16 (d, J = 8.0 Hz, 3 H), 2.44ꢀ2.61
(m, 4 H), 4.31 (q, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 1 H), 8.02 (d, J =
8.0, 2 H); 13C NMR (CDCl3, 101 MHz) δ 10.1, 13.6, 44.3, 128.1, 128.9, 132.6, 136.8, 202.0 ppm;
LRMS: m/z calcd for C13H19NO (M+H): 205, found: 205.
2ꢀIodoꢀ1ꢀphenylpropanꢀ1ꢀone (4a). Following the general procedure, the product was isolated as
a yellow oil, 5.2 mg (2% GC yield); Flash chromatography (petroleum ether/ ethyl acetate, 3/1);
1H NMR (CDCl3, 400 MHz) δ 1.46 (d, J = 8.0 Hz, 3 H), 5.18 (q, J = 8.0 Hz, 1 H), 7.51 (t, J = 8.0
Hz, 2 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.94 (d, J = 6.8, 2 H); 13C NMR (CDCl3, 101 MHz) δ 22.3,
69.3, 128.7, 128.9, 133.3, 134.0, 202.4 ppm; LRMS: m/z calcd for C9H9IO (M+H): 260, found:
260.
General procedure for the gramꢀscale reaction of propiophenone with morpholine (Eq. 1).
NH4I (217 mg, 1.5 mmol, 0.15 equiv) was added to a mixture of sodium percarbonate (3.14 g, 20
mmol, 2 equiv), propiophenone (1.34 g, 10 mmol, 1 equiv), and morpholine (2.61 g, 30 mmol, 3
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equiv) in acetonitrile (10 mL) at room temperature. The reaction was stirred at 50 oC for 24 h. The
reaction mixture was then allowed to cool to room temperature, after which the crude reaction
mixture was loaded directly onto a column of silica gel and purified by column chromatography to
give the tertiary amine 3a (1.84 g, 84%).
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ACKNOWLEDGEMENTS
We are grateful for the financial support from the National Natural Science Foundation of China
(21372068, J1210040, J1103312).
Supporting Information. Copies of H and13C NMR spectra for the products. This material is
1
available free of charge via the Internet athttp://pubs.acs.org.
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