Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl Iodides with Amines to α-Ketoamides under Atmospheric Pressure of Carbon Monoxide and at Room Temperature

Article abstract of DOI:10.1021/acs.joc.5b01249

A general Pd-catalyzed double carbonylation of aryl iodides with secondary or primary amines to produce α-ketoamides at atmospheric CO pressure has been developed. This transformation proceeds successfully even at room temperature and in the absence of any ligand and additive. A wide range of aryl iodides and amines can be coupled to the desired α-ketoamides in high yields with excellent chemoselectivities. Importantly, the current methodology has been demonstrated to be applied in the synthesis of bioactive molecules and chiral α-ketoamides.

Full text of DOI:10.1021/acs.joc.5b01249

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Note
Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl
Iodides with Amines to alpha-Ketoamides under Atmospheric
Pressure of Carbon Monoxide and at Room Temperature
Hongyan Du, Qing Ruan, Minghao Qi, and Wei Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01249 • Publication Date (Web): 03 Jul 2015
Downloaded from http://pubs.acs.org on July 6, 2015
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LigandꢀFree PdꢀCatalyzed Double Carbonylation of Aryl
Iodides with Amines to αꢀKetoamides under Atmospheric
Pressure of Carbon Monoxide and at Room Temperature
Hongyan Du,† Qing Ruan,† Minghao Qi,† and Wei Han*,†,‡
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†Jiangsu Key Laboratory of Biofunctional Materials, Key Laboratory of Applied
Photochemistry, School of Chemistry and Materials Science, Nanjing Normal University,
Wenyuan Road NO.1, Nanjing 210023, China
‡Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing
210023, China
*Corresponding author’s email address: hanwei@njnu.edu.cn; whhanwei@gmail.com
ABSTRACT: A general Pdꢀcatalyzed double carbonylation of aryl iodides with
secondary or primary amines to produce αꢀketoamides at atmospheric CO pressure has
been developed. This transformation proceeds successfully even at room temperature and
in the absence of any ligand and additive. A wide range of aryl iodides and amines can be
coupled to the desired αꢀketoamides in high yields with excellent chemoselectivities.
Importantly, the current methodology has been demonstrated to be applied in the
synthesis of bioactive molecules and chiral αꢀketoamides.
αꢀKetoamides are important fragments in biologically active molecules, synthetic
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drugs, and pharmaceutically interesting compounds.1 Moreover, they frequently serve as
useful building blocks for an array of functional group transformations.2 As a
consequence, establishing a general, practical, and efficient approach to αꢀketoamides
having polyfunctional groups, is of significance.
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Palladiumꢀcatalyzed double carbonylation of aryl halides with amines is well known
as a direct and efficient protocol for the synthesis of αꢀketoamides.3,4 Generally, this
transformation undergoes efficiently at a high pressure of carbon monoxide(≥10 bar)
o
and/or an elevated temperature (≥80 C).4,5 Moreover, the palladium catalysts are
required to be modified by cost of ligands (often with phosphine ligands).2d,3b,5,6 These
drawbacks have blocked the transfer of the advances to widespread applications,
particularly in complex organic syntheses.
In contrast, double carbonylation for αꢀketoamides under ambient pressure of CO
gas has been scarcely reported, likely due to inertness of CO and poor
chemoselectivity.6,7 However, in these cases, the necessity to employ extra additives,
such as a copper coꢀcatalyst, a nucleophilic amine base, an airꢀsensitive phosphine, or
Auꢀsupported material. Most disadvantageous of all, aryl halide bearing a deactivating
group such as halo, cyano, trifluoro, or an ester group in the aryl ring leads to a large
amount of monocarbonylated side products.6,7 To the best of our knowledge, there is no
report of general, ligandꢀ and additiveꢀfree double carbonylations of aryl iodides under
ambient conditions thus far.
Recently, we demonstrated in situ generation of palladium nanoparticles in
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polyethylene glycol (PEG) without any additional ligand and additive. And this catalytic
system achieved outstanding performance in carbonylative Suzuki coupling8 and
hydrocarboxylation9 of aryl halides with CO gas under ambient conditions. In
continuation of our research to employ this in situ generation of palladium nanoparticles
system for other carbonylation, herein we disclose a ligandꢀfree palladiumꢀcatalyzed
double carbonylation for the synthesis of αꢀketoamides by direct threeꢀcomponent
coupling of various aryl iodides (including electronꢀdeprived aryl iodides) and amines
with CO gas at ambient pressure and temperature. The generality of this protocol is
demonstrated here by synthesizing a typical set of αꢀketoamide compounds (44
examples) with high yields and excellent selectivities.
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We commenced our studies by investigating the reaction between
1ꢀchloroꢀ4ꢀiodobenzene 1a and cyclohexylamine 2a (1.0 equiv) employing Pd(OAc)2
as a catalyst and Na2CO3 as a base in PEGꢀ400 at room temperature and atmospheric
pressure of CO gas (Table 1). The reaction resulted in double carbonylated product
3aa in 74% yield with excellent selectivity (>95%) (entry 1). A screening of
palladium sources revealed that Pd(OAc)2 is much better than PdCl2 (entry 2), and
Pd/C is complete ineffective for the reaction (entry 3). Replacing PEGꢀ400 with
glycol, NHDꢀ250 (polyethylene glycol dimethyl ether with an average molecular
weight of 250 Da) , DMF, toluene, or 1,4ꢀdioxane as the solvent resulted in poorer
results (entries 4−8). Evaluation of several bases indicated that Na2CO3 was the
optimal choice, albeit Na3PO4, and NEt3 were also efficient bases for this
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Table 1. Optimization of reaction conditions a
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Ent
ꢀry
[Pd]
Base
Solvent
Yield of
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3aa/%
1
2
3
Pd(OAc)2
PdCl2
Na2CO3
Na2CO3
Na2CO3
PEGꢀ400
PEGꢀ400
74
61
ꢀ
PEGꢀ400
Ethylene
glycol
Pd/C
4
Pd(OAc)2
Na2CO3
<5
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NHDꢀ250
40
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6
DMF
7
Toluene
Dioxane
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25
9
NaHCO3 PEGꢀ400
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Na3PO4
NaF
PEGꢀ400
PEGꢀ400
PEGꢀ400
PEGꢀ400
PEGꢀ400
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67
DBU
Et3N
<5
73
DIEA
52
Bu4NOH PEGꢀ400
Na2CO3 PEGꢀ400
DABCO PEGꢀ400
Na2CO3 PEGꢀ400
Trace
Trace
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16b Pd(OAc)2
17 Pd(OAc)2
18c NanoꢀPd
a Reaction conditions (unless otherwise stated): 1a (0.5 mmol), 2a (0.5
mmol), [Pd] (0.01 mmol), CO (balloon), base (1.0 mmol), solvent
(2.0 mL), RT, and 6 h. b With addtion of Hg (1.0 mmol). b Preꢀprepared
nanopalladium.
69
transformation (entries 10 and 13); other bases, like NaHCO3, NaF, and DIEA
(N,NꢀDiisopropylethylamine), gave rise to lower yields (entries 9, 11, and 14), but
DBU (1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene) and Bu4NOH were totally ineffective
(entries 12 and 15). DABCO (1,4ꢀDiazabicyclo[2.2.2]octane) known as a base
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promoting double carbonylation6b was also effective and gave a comparable result to
Na2CO3 (entry 17). Considering that DABCO is more expensive and can readily
contaminate products, we chose Na2CO3 as the base. TEM (transmission electron
microscopy) analyzed the reaction mixture and indicated palladium nanoparticles
were formed (see ESI, Figure S1). And the size distribution of Pd nanoparticles was
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Reaction conditions(unless otherwise stated): 1 (0.5 mmol), 2b (0.5 mmol),
CO (balloon), Na2CO3 (1.0 mmol), Pd(OAc)2 (2 mol %), PEGꢀ400 (2.0 mL),
and RT.
Scheme 1. Pdꢀcatalyzed double carbonylation of 2b with various aryl iodides
about 3.0 ± 0.6 nm. An enlarged TEM image indicated that the shape of nanoparticles
was spherical [see ESI, Figure S1 (b)]. Furthermore, under the optimal conditions, Hg
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(100 equiv to Pd) was added to the system and led to complelely inhibit the reaction
(entry 16), suggesting that the real active catalyst is likely to be nanopalladium.
Moreover, recently, we reported Pd(OAc)2 readily formed palladium nanoparticles in
PEG.10 According to our previous study, preꢀprepared palladium nanoparticles had an
average size of 3.6 nm,10b bigger than that of the present in situ generated palladium
nanoparticles (3.0 nm), and exhibited lower activity (entry 18).
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Having the optimized conditions in hand, a series of aryl iodides 1 as coupling
partners to morpholine 2b were explored (Scheme 1). This protocol was efficient with
diverse aryl iodides bearing electronꢀdonating substitutes, such as methyl and
methoxy, to give the corresponding coupling products in high yields. To our delight,
the orthoꢀsubstituted substrate 1c wasn’t affected by the steric hindrance of methyl
group and provided 3cb in excellent yield. A free amino group (1u) proved to be
compatible in the system, albeit a moderate conversion was obtained. The inductive
electronꢀdeprived chloro, fluoro, and trifluoro groups were also well tolerated, and the
desired products 3ab and 3gb−3jb were generated in high yields. Electronꢀpoor
cyanoꢀ and esterꢀsubstituted iodides that readily directed the reactions towards
monocarbonylation6,7 reacted slowly but still afforded the desired double carbonylated
products in 89% (3lb) and 80% (3mb) yields, along with yielding 8% and 6% of
amides, respectively. Gratifyingly, a reactive and useful carboxyl group (1t) was intact
under the present conditions, which had never been demonstrated in double
carbonylation process. The new protocol was also applicable to 1ꢀiodonaphthalene
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(1n) and 4ꢀiodoꢀ1,1'ꢀbiphenyl (1s) as illustrated by the synthesis of 3nb (90%) and 3sb
(66%), the latter accompanied by the formation of amide side product in 15% yield. In
addition, heterocyclic iodides such as 3ꢀiodothiophene (1o), 2ꢀiodothiophene (1p), and
4ꢀiodoꢀ3,5ꢀdimethylisoxazole (1q) were readily converted to the corresponding
αꢀketoamides in 86%, 66%, and 96% yields. It should also be noted that the reaction
between 1ꢀ(bromomethyl)ꢀ4ꢀiodobenzene (1r) and morpholine 2b (2.0 equiv) under
ambient conditions underwent oneꢀpot amination/double carbonylation to yield 3rb in
84%. However, bromobenzene and chlorobenzene derivatives when tested failed to
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o
give desired products even at 100 C. And 1,4ꢀdiiodobenzene as aryl iodide resulted in
a complex mixture.
Encouraged by the above results, various amines 2 were subjected to the double
carbonylation conditions to further evaluate the scope of the transformation (Scheme
2). Generally, cyclic or acyclic primary and secondary amines (2a−2l) furnished the
corresponding αꢀketoamides in satisfactory yields with excellent selectivities (>95%).
For instance, NꢀBocꢀprotected amine 2d worked well to give the double carbonylated
product 3ad in 86% yield. Amines bearing a strain ring (2g), a pyridyl group (2h), and
an allylic substituent (2k) were also applied succesfully to the double carbonylation
protocol, affording the corresponding products in 65%, 81%, and 75% yields,
respectively. Additionally, the double carbonylation of bulky amantadine (3i) or
tꢀbutyl amine (3j) with 1ꢀchloroꢀ4ꢀiodobenzene (1a) proceeded smoothly. To our
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Reaction conditions (unless otherwise stated): 1 (0.5 mmol), 2 (0.5
mmol), CO (balloon), Na2CO3 (1.0 mmol), Pd(OAc)2 (2 mol %),
o
PEGꢀ400 (2.0 mL), and RT. a Withou the use of a base. b50 C.
Scheme 2. Pdꢀcatalyzed double carbonylation of aryl iodides with various amines
delight, a longꢀalkylꢀchain lauryl amine (2l) gave access to the desired αꢀketoamide in
o
73% at an elevated temperature (50 C). When piperazine (2m) bearing two identical
reactive sites was subjected to the nomal conditions, mono αꢀketoamide 3am, a
versatile intermediate for further synthetic manipulations, was obtained in 75% yield
with high selectivity.
To demonstrate the transformation’s practical utility, a gramꢀscale reaction was
performed by using 1a and 2b under ambient conditions, which provided the
αꢀketoamide 3ab in 77% yield (Scheme 3). Moreover, the same reaction was used to
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test the recycling uses of the catalytic system. Gratifyingly, the in situ nanocatalyst
can be recycled up to five times to provide the corresponding product in 80, 80, 77, 77,
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Scheme 3 A gramꢀscale synthesis of 3ab
and 72 % yield, respectively. To our delight, when optically active amines 2n and 2o,
were treated with 1a, the desired products 3an and 3ao were obtained in satisfactory
yields without racemization (eq 1 and 2).11 And the latter proceeded smoothly even in
the absence of a base. To further test the applicability of this protocol to bioactive or
drugꢀlike molecules, a HIVꢀ1 inhibitor 3vp12 and an acetylated glucoꢀketoamine 3wb
could be directly synthesized via the present double carbonylation approach and were
obtained in 65% (eq 3) and 68% (eq 4) yields, respectively.
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In summary, we have developed the first general, ligandless, and nonꢀadditive
palladiumꢀcatalyzed double carbonylation of aryl iodides and amines giving
αꢀketoamides in high yields. Notably, the in situ generated catalyst system devoid of a
tedious process for the preparation of nanopalladium enables the transformation to
proceed efficiently even at atmospheric pressure of carbon monoxide and room
temperature with excellent chemoselectivities. Moreover, a series of reactive groups
are compatible with the reaction conditions. This protocol has also been successfully
demonstrated to be adaptable to chiral amines as substrates and to be applicable to the
synthesis of a HIVꢀ1 inhibitor and an acetylated glucoꢀketoamine.
Experiment Section
1
13
General Information. PEGꢀ400 was preꢀdried (toluene azeotrope). H and C NMR
spectra of solutions in CDCl3 or DMSOꢀd6 were recorded on a 400 MHz instrument.
Chemical shifts were expressed in parts per million (ppm) downfield from
tetramethylsilane and refer to the solvent signals (CDCl3: H 7.24 and C 77.0 ppm;
DMSOꢀd6: H 2.50 and C 39.5 ppm). The signals of water were observed at about 1.58
ppm in CDCl3 and 3.42 ppm in DMSOꢀd6, respectively.
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General Procedures for PdꢀCatalyzed Double Carbonylation of Aryl Iodide with
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Amine:
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General Procedure A: A 25 mL Schlenk flask was charged with Pd(OAc)2 (0.01 mmol,
2.3 mg), sodium carbonate (1.0 mmol, 106.5 mg), and PEGꢀ400 (2.0 mL) before standard
cycles of evacuation and backꢀfilling with dry and pure carbon monoxide. Corresponding
aryl iodide (0.5 mmol) and amine (0.5 mmol) were added successively. The mixture was
stirred at room temperature for the indicated time. At the end of the reaction, the reaction
mixture was poured into a saturated aqueous NaCl solution (15 mL) and extracted with
ethyl acetate (3 × 15 mL). The organic phases were combined, and the volatile
components were evaporated in a rotary evaporator. The crude product was purified by
column chromatography on silica gel (petroleum ether: diethyl ether = 10 : 1–10 : 6).
In the recycling experiment, the residue was subjected to a second run of the double
carbonylation by charging it with the same materials (1a, 2b, and Na2CO3) without further
addition of Pd(OAc)2 except addition of another 0.5 mL PEGꢀ400 to the reaction mixture.
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General Procedure B: A 25 mL Schlenk flask was charged with Pd(OAc)2 (0.01 mmol,
2.3 mg), sodium carbonate (1.0 mmol, 106.5 mg), and PEGꢀ400 (2.0 mL) before standard
cycles of evacuation and backꢀfilling with dry and pure carbon monoxide. Corresponding
aryl iodide (0.5 mmol) and amine (0.5 mmol) were added successively. The mixture was
stirred at 50 oC for the indicated time. At the end of the reaction, the reaction mixture was
poured into a saturated aqueous NaCl solution (15 mL) and extracted with ethyl acetate (3
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× 15 mL). The organic phases were combined, and the volatile components were
evaporated in a rotary evaporator. The crude product was purified by column
chromatography on silica gel (petroleum ether: diethyl ether = 10 : 1−10 : 6).
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General Procedure C: A 25 mL Schlenk flask was charged with Pd(OAc)2 (0.01 mmol,
2.3 mg), and PEGꢀ400 (2.0 mL) before standard cycles of evacuation and backꢀfilling
with dry and pure carbon monoxide. Corresponding aryl iodide (0.5 mmol) and amine
(0.5 mmol) were added successively. The mixture was stirred at room temperature for the
indicated time. At the end of the reaction, the reaction mixture was poured into a saturated
aqueous NaCl solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic
phases were combined, and the volatile components were evaporated in a rotary
evaporator. The crude product was purified by column chromatography on silica gel
(petroleum ether: diethyl ether = 10 : 1−10 : 6).
2ꢀ(4ꢀChlorophenyl)ꢀNꢀcyclohexylꢀ2ꢀoxoacetamide
(3aa).
Following
general
procedure A, 3aa was isolated as a white solid (98 mg, 74%). Known compound (CAS:
24914ꢀ10ꢀ1). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8 Hz, 2 H), 7.42 (d, J = 8 Hz, 2
H), 6.98 (s, 1 H), 3.86ꢀ3.76 (m, 1 H), 1.97–1.71 (m, 2 H), 1.65–1.23 (m, 4 H), 1.29–1.20
13
(m, 2 H); C NMR (100 MHz, CDCl3) δ 186.7, 160.4, 141.0, 132.7, 131.8, 128.8, 48.5,
32.7, 25.4, 24.7 ppm; mp 100.5–100.9 °C.
1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione(3ab).13
Following
general
1
procedure A, 3ab was isolated as a white solid (102 mg, 80%). H NMR (400 MHz,
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CDCl3) δ 7.89 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8 Hz, 2 H), 3.79–3.73 (m, 4 H), 3.64 (t, J
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= 4 Hz, 2 H), 3.36 ppm (t, J = 4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 189.7, 164.9,
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141.6, 131.5, 131.1, 129.5, 66.7, 66.6, 46.3, 41.7 ppm; mp 116.0–116.5 °C.
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1ꢀMorpholinoꢀ2ꢀ(pꢀtolyl)ethaneꢀ1,2ꢀdione (3bb).13 Following general procedure A,
3bb was isolated as a yellow oil (93 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J =
8 Hz, 2 H), 7.30 (d, J = 8 Hz, 2 H), 3.79–3.74 (m, 4 H), 3.63 (t, J = 8 Hz, 2 H), 3.35 (t, J =
8 Hz, 2 H), 2.42 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 190.9, 165.7, 146.3, 130.7,
129.8, 129.8, 66.8, 66.7, 46.3, 41.6, 21.9 ppm.
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1ꢀMorpholinoꢀ2ꢀ(oꢀtolyl)ethaneꢀ1,2ꢀdione (3cb).13 Following general procedure A,
3cb was isolated as a yellow solid (108 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d,
J = 8 Hz, 1 H), 7.47 (td, J = 8, 1.2 Hz, 1 H), 7.33–7.28(m, 2 H), 3.78–3.74(m, 4 H), 3.65(t,
13
J = 8 Hz, 2 H), 3.37(t, J = 8 Hz, 2 H), 2.64 ppm (s, 3 H); C NMR (100 MHz, CDCl3) δ
193.1, 166.2, 141.6, 133.9, 132.7, 132.7, 131.5, 126.2, 66.7, 66.6, 46.3, 41.6, 21.8 ppm;
mp 80.5–81.2 °C.
1ꢀMorpholinoꢀ2ꢀ(mꢀtolyl)ethaneꢀ1,2ꢀdione (3db).14 Following general procedure A,
3db was isolated as a yellow oil (115 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1
H), 7.71 (d, J = 8 Hz, 1 H), 7.44 (d, J = 8 Hz, 1 H), 7.40–7.36 (m, 1 H) 3.79–3.75 (m, 4
H), 3.63 (t, J = 4 Hz, 2 H), 3.35 (t, J = 4 Hz, 2 H), 2.40 ppm (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 191.4, 165.6, 139.1, 135.8, 133.0, 129.9, 129.0, 127.0, 66.7, 66.6, 46.2, 41.6,
21.2 ppm.
1ꢀ(3,5ꢀDimethylphenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3eb). Following general
1
procedure A, 3eb was isolated as a white solid (104 mg, 84%). H NMR (400 MHz,
CDCl3) δ 7.53 (s, 2 H), 7.26 (s, 1 H), 3.79–3.74 (m, 4 H), 3.63 (t, J = 4.8 Hz, 2 H), 3.34 (t,
13
J = 4.8 Hz, 2 H), 2.35 ppm (d, J = 0.5 Hz, 6 H). C NMR (100 MHz, CDCl3) δ 191.6,
165.7, 138.9, 136.8, 133.1, 127.3, 66.7, 66.7, 46.2, 41.6, 21.1 ppm. HRMS (ESI) m/z: [M
+ Na]+ calcd for C14H17NO3Na 270.1100; found 270.1113; IR νmax (KBr)/ cmꢀ1 3458,
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2965, 2921,2893, 2850, 1755, 1675, 1653, 1592, 1444, 1289, 1179,1115, 843, 803,761,
746, 665; mp 93.0–93.7 °C.
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1ꢀMorpholinoꢀ2ꢀphenylethaneꢀ1,2ꢀdione (3fb).13 Following general procedure A, 3fb
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was isolated as a brown oil (103 mg, 94%). H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8
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Hz, 2 H), 7.64 (tt, J = 4, 1.2 Hz, 1 H), 7.52–7.48 (m, 2 H), 3.79–3.76 (m, 4 H), 3.63 (t, J =
4.8 Hz, 2 H), 3.36 ppm (t, J = 4.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 191.1, 165.4,
134.9, 133.0, 129.7, 129.1, 66.7, 66.7, 46.3, 41.6 ppm.
1ꢀ(4ꢀFluorophenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3gb).15 Following general
procedure A, 3gb was isolated as a gray solid (101 mg, 85%). 1H NMR (400 MHz, CDCl3)
δ 7.98 (dd, J = 8, 4 Hz, 2 H), 7.17 (dd, J = 8, 4 Hz, 2 H), 3.79–3.73 (m, 4 H), 3.64 (t, J = 4
Hz, 2 H), 3.36 ppm (t, J = 4 Hz, 2 H ); 13C NMR (100 MHz, CDCl3) δ 189.3, 165.1, 166.8
(d, J = 256 Hz), 132.5 (d, J = 10 Hz), 129.6 (d, J = 2.8 Hz),116.4 (d, J = 22 Hz), 66.7,
66.6, 46.3, 41.7 ppm; mp 86.1–86.3 °C.
1ꢀ(3ꢀFluorophenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3hb). Following general
1
procedure A, 3hb was isolated as a yellow liquid (114 mg, 96%). H NMR (400 MHz,
CDCl3) δ 7.71 (dt, J = 8, 0.3 Hz, 1 H), 7.65–7.62 (m, 1 H), 7.48 (td, J = 7.6, 5.6 Hz, 1 H),
7.32 (tdd, J = 16.4, 2.4, 0.8 Hz, 1 H), 3.77–3.75 (m, 4 H), 3.64(t, J = 4 Hz, 2 H), 3.35 ppm
13
(t, J = 8 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 189.6, 164.7, 162.9 (d, J = 248 Hz),
135.1 (d, J = 6 Hz), 130.8 (d, J = 7 Hz), 125.7 (d, J = 3 Hz), 122.0 (d, J = 21 Hz), 115.9
(d, J = 23 Hz), 66.7, 66.6, 46.2, 41.7 ppm. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H12FNO3Na 260.0693; found 260.0692; IR νmax (KBr)/ cmꢀ1 3092, 2972, 2920, 2859,
1682, 1647, 1606, 1584, 1482, 1369, 1167, 1150, 1066, 797, 772, 762.
1ꢀMorpholinoꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)ethaneꢀ1,2ꢀdione (3ib).14 Following
1
general procedure A, 3ib was isolated as a violet solid (109 mg, 76%). H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8 Hz, 2H), 7.75 (d, J = 8 Hz, 2 H), 3.79–3.75 (m, 4 H), 3.64
13
(t, J = 4 Hz, 2 H), 3.37(t, J = 4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 189.6, 164.5,
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135.9(q, J = 31 Hz), 130.0, 126.1(q, J = 4 Hz), 123.3(q, J = 271 Hz), 66.7, 66.6, 46.3,
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41.8 ppm; mp 127.3–127.5 °C.
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1ꢀ(3ꢀFluoroꢀ4ꢀmethylphenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione
(3jb).
Following
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general procedure A, 3jb was isolated as a white solid (112 mg, 89%). H NMR (400
MHz, CDCl3) δ 7.61 – 7.56 (m, 2 H), 7.31 (t, J = 8 Hz, 1 H), 3.78–3.73 (m, 4 H), 3.62 (t,
J = 4 Hz, 2 H), 3.34 (t, J = 4 Hz, 2 H), 2.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 189.7,
165.0, 161.3 (d, J = 247 Hz), 133.3 (d, J = 18 Hz), 132.8 (d, J = 7 Hz), 132.1 (d, J = 5 Hz),
125.5 (d, J = 3 Hz), 115.5 (d, J = 25 Hz), 66.7, 66.6, 46.2, 41.6, 15.1 (d, J = 4 Hz); mp
84.0–84.5 °C; HRMS (ESI) m/z: [M + H]+ calcd for C13H15FNO3 252.1030; found
252.1043; IR νmax (KBr)/ cmꢀ1 3076, 2966, 2927, 2854, 2854, 1755, 1677, 1656, 1645,
1614, 1164, 1114, 1066, 1577, 1502, 880, 812, 764.
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1ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3kb).13 Following general
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procedure A, 3kb was isolated as a white solid (101 mg, 81%). H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 8.0 Hz, 2 H), 6.96 (d, J = 8 Hz, 2 H), 3.86 (s, 3 H), 3.78–3.73 (m, 4
13
H), 3.62 (t, J = 4 Hz, 2 H), 3.35 ppm (t, J = 4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ
189.8, 165.8, 165.0, 132.1, 126.1, 114.4, 66.9, 66.7, 55.6, 46.3, 41.5 ppm; mp
113.1–113.3 °C.
4ꢀ(2ꢀMorpholinoꢀ2ꢀoxoacetyl)benzonitrile (3lb).16 Following general procedure A,
3lb was isolated as a white solid (109 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.04(d, J
= 8 Hz, 2 H), 7.79 (d, J = 8 Hz, 2 H), 3.79–3.74 (m, 4 H), 3.64 (t, J = 4.8 Hz, 2 H), 3.37
ppm (t, J = 4.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 189.0, 164.1, 136.0, 132.7, 130.0,
117.8, 117.5, 66.7, 66.5, 46.3, 41.8 ppm; mp 118.3–118.5 °C.
Methyl 4ꢀ(2ꢀmorpholinoꢀ2ꢀoxoacetyl)benzoate (3mb). Following general procedure
A, 3mb was isolated as a gray solid (111 mg, 80%). Known compound
(CAS:1616527ꢀ07ꢀ1). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 2 H), 7.99 (d, J
= 8.7 Hz, 2 H), 3.93 (s, 3 H), 3.79–3.75 (m, 4 H), 3.63 (t, J = 4 Hz, 2 H), 3.36 ppm (t, J =
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4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 190.2, 165.8, 164.7, 136.1, 135.3, 130.1,
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129.6, 66.7, 66.6, 52.6, 46.2, 41.7 ppm ; mp 140.2–140.6 °C.
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1ꢀMorpholinoꢀ2ꢀ(naphthalenꢀ1ꢀyl)ethaneꢀ1,2ꢀdione (3nb).17 Following general
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procedure A, 3nb was isolated as a white solid (121 mg, 90%). H NMR (400 MHz,
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CDCl3) δ 9.22 (d, J = 8.8 Hz, 1 H), 8.11 (d, J = 8 Hz, 1 H), 8.01 (dd, J = 8, 1.2 Hz, 1 H),
7.91 (d, J = 8 Hz, 1 H), 7.71–7.67 (m, 1 H), 7.61–7.52 (m, 2 H), 3.81 (m, 4 H), 3.65 (t, J
13
= 4 Hz, 2 H), 3.42 ppm (t, J = 4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 193.5, 166.0,
136.1, 134.5, 134.0, 130.9, 129.4, 128.8, 128.4, 127.1, 125.7, 124.5, 66.6, 46.4, 41.7 ppm;
mp 123.8–124.1 °C.
1ꢀMorpholinoꢀ2ꢀ(thiophenꢀ3ꢀyl)ethaneꢀ1,2ꢀdione
(3ob).
Following
general
1
procedure A, 3ob was isolated as a yellow liquid (97 mg, 86%). H NMR (400 MHz,
CDCl3) δ 8.21 (dd, J = 4, 1.2 Hz, 1 H), 7.55 (dd, J = 4, 1.2Hz, 1 H), 7.34 (dd, J = 5.2, 3.2
13
Hz, 1 H), 3.75–3.69 (m, 4 H), 3.63 (t, J = 4 Hz, 2 H), 3.40 ppm (t, J = 4 Hz, 2 H); C
NMR (100 MHz, CDCl3) δ 184.3, 165.1, 138.4, 136.7, 127.2, 126.9, 66.7, 66.6, 46.3, 41.7
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C10H11NO3SNa 248.0351; found 248.0354;
IR νmax (KBr)/ cmꢀ1 3103, 2974, 2923, 2853, 1643, 1508, 1467, 1444, 1414, 1182, 1117,
1071, 794, 754.
1ꢀMorpholinoꢀ2ꢀ(thiophenꢀ2ꢀyl)ethaneꢀ1,2ꢀdione (3pb).15 Following general
1
procedure A, 3pb was isolated as a yellow liquid (74 mg, 66%). H NMR (400 MHz,
CDCl3) δ 7.81 (dd, J = 4, 1.2 Hz, 1 H), 7.78 (dd, J = 8, 1.2 Hz, 1 H), 7.16 (dd, J = 5.2, 4
13
Hz, 1 H), 3.76–3.71 (m, 4 H), 3.64 (t, J = 4 Hz, 2 H), 3.46 ppm (t, J = 4 Hz, 2 H); C
NMR (100 MHz, CDCl3) δ 182.7, 164.3, 140.2, 136.7, 136.2, 128.7, 66.8, 66.6, 46.4, 41.9
ppm.
1ꢀ(3,5ꢀDimethylisoxazolꢀ4ꢀyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3qb): Following
1
general procedure A, 3qb was isolated as a white solid (114 mg, 96%). H NMR (400
MHz, CDCl3) δ 3.74 (t, J = 4 Hz, 2 H), 3.70–3.64 (m, 4 H), 3.38 (t, J = 8 Hz, 2 H), 2.58 (s,
3 H), 2.38 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 184.7, 176.6, 164.9, 159.3, 113.5,
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66.6, 66.4, 46.2, 41.6, 13.3, 11.4 ppm; mp 88.6–88.8 °C; HRMS (ESI) m/z: [M + Na]+
calcd for C11H14N2O4Na 261.0845; found 261.0852; IR νmax (KBr)/ cmꢀ1 2989, 2921,
2856, 1668, 1646, 1581, 1478, 1428, 1421, 1378, 1363, 1275, 1115, 1069, 974, 730.
1ꢀMorpholinoꢀ2ꢀ(4ꢀ(morpholinomethyl)phenyl)ethaneꢀ1,2ꢀdione (3rb): Following
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general procedure A, 3rb was isolated as a white solid (134 mg, 84%). H NMR (400
MHz, CDCl3) δ 7.88 (d, J = 8 Hz, 2 H), 7.48 (d, J = 8 Hz, 2 H), 3.78–3.73 (m, 4 H), 3.68
(t, J = 4 Hz, 4 H), 3.63 (t, J = 4.8 Hz, 2 H), 3.55 (s, 2 H), 3.35 (t, J = 4.8 Hz, 2 H),
2.47–2.38 ppm (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 190.7, 165.4, 132.1, 129.8,
129.6, 66.8, 66.7, 66.6, 62.8, 53.6, 46.2, 41.6 ppm; mp 127.2–127.9 °C; HRMS (ESI) m/z:
[M + Na]+ calcd for C17H22N2O4Na 341.1471; found 341.1479; IR νmax (KBr)/ cmꢀ1 3040,
2965, 2922, 2902, 2847, 1672, 1635, 1602, 1570, 1442, 1312, 1268, 1072, 823, 739.
1ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)ꢀ2ꢀmorpholinoethaneꢀ1,2ꢀdione (3sb): Following general
1
procedure B, 3sb was isolated as a yellow solid (97 mg, 66%). H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 8.8 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.60 (dd, J = 8, 4 Hz, 2 H),
7.47–7.42 (m, 2 H), 7.39 (tt, J = 8, 4 Hz, 1 H), 3.77 (s, 4 H), 3.63 (t, J = 4.4 Hz, 2 H), 3.38
ppm (t, J = 4.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 190.6, 165.4, 147.5, 139.3, 131.6,
130.1, 128.9, 128.6, 127.6, 127.2, 66.6, 66.5, 46.2, 41.5 pm; mp 138.7–139.5 °C; HRMS
(ESI) m/z: [M + Na]+ calcd for C18H17NO3Na 318.1100; found 318.1112; IR νmax (KBr)/
cmꢀ1 3059, 3024, 2995, 2981, 2916, 2851, 1676, 1637, 1599, 1557, 1442, 1175, 1311, 834,
745.
4ꢀ(2ꢀMorpholinoꢀ2ꢀoxoacetyl)benzoic acid (3tb): Following general procedure B,
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3tb was isolated as a white solid (106 mg, 81%). H NMR (400 MHz, DMSO) δ 8.14 (d,
J = 8 Hz, 2 H), 8.02 (d, J = 8 Hz, 2 H), 3.72 (t, J = 4 Hz, 2 H), 3.65 (t, J = 4 Hz, 2 H),
13
3.54 (t, J = 4 Hz, 2 H), 3.31 ppm (t, J = 4 Hz, 2 H); C NMR (100 MHz, DMSOꢀd6) δ
191.4, 164.9,137.1, 135.8, 130.5, 129.9, 66.5, 66.2, 46.1, 41.5 ppm; mp 203.8–204.7 °C;
HRMS (ESI) m/z: [M + Na]+ calcd for C13H13NO5Na 286.0685; found 286.0686; IR νmax
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(KBr)/ cmꢀ1 3429, 3055, 2983, 2915, 2865, 1702, 1676, 1630, 1570, 1505, 1465, 1317,
1114, 1288, 816, 735.
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procedure B, 3ub was isolated as a yellow solid (60 mg, 51%). H NMR (400 MHz,
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CDCl3) δ 7.73 (d, J = 8 Hz, 2 H), 6.63 (d, J = 8 Hz, 2 H), 3.77–3.71 (m, 4 H), 3.61 (t, J =
13
4.8 Hz, 2 H), 3.35 ppm (t, J = 4.8 Hz, 2 H); C NMR (100MHz, CDCl3) δ 189.3,166.4,
152.9, 132.4, 123.2, 114.0, 66.8, 66.7, 46.3, 41.5 ppm; mp 172.9–173.2 °C; HRMS (ESI)
m/z: [M + Na]+ calcd for C12H14N2O3Na 257.0896; found 257.0899; IR νmax (KBr)/ cmꢀ1
3434, 3344, 3042, 2976, 2915, 2846, 1644, 1613, 1583, 1445,1311, 1266, 1066, 845, 742.
2ꢀ(4ꢀChlorophenyl)ꢀN,Nꢀdiethylꢀ2ꢀoxoacetamide (3ac).6d Following general
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procedure A, 3ac was isolated as a white liquid (103 mg, 84%). H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 8 Hz, 2 H), 7.44(d, J = 8 Hz, 2 H), 3.53 (q, J = 8 Hz, 2 H), 3.21 (q,
13
J = 8 Hz, 2 H), 1.25 (d, J = 8 Hz, 3 H), 1.13 (t, J = 8 Hz, 3 H); C NMR (100 MHz,
CDCl3) δ 190.1, 166.2, 141.1,131.7, 130.9, 129.3, 42.1, 38.9, 14.1, 12.8 ppm.
Tertꢀbutyl((1ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoacetyl)piperidinꢀ4ꢀyl)methyl)carbamate
(3ad). Following general procedure A, 3ad was isolated as a white solid (164 mg, 86%).
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H), 4.65–4.61
(m, 2 H), 3.57–3.48(m, 1 H), 3.03–2.76 (m, 4 H), 1.85–1.60 (m, 2 H), 1.40 (s, 9 H),
1.24–1.11 ppm (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 190.3, 164.9, 156.0, 141.3,
131.5, 130.9, 129.4, 45.9, 41.2, 36.8, 30.0, 29.2, 28.3 ppm; mp 108.4–108.6 °C; HRMS
(ESI) m/z: [M + Na]+ calcd for C19H25ClN2O4Na 403.1395; found 403.139863; IR νmax
(KBr)/ cmꢀ1 3365, 2987, 2947, 2925, 2865, 1765, 1685, 1646, 1588, 1525, 1458, 1363,
1316, 1268, 1244, 1207, 1115, 1093, 1072, 841, 726.
1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ(pyrrolidinꢀ1ꢀyl)ethaneꢀ1,2ꢀdione (3ae).14 Following general
1
procedure C, 3ae was isolated as a brown liquid (96 mg, 82%). H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 8 Hz, 2 H), 7.42 (d, J = 8 Hz, 2 H), 3.59 (t, J = 8 Hz, 2 H), 3.38 (t, J
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= 8 Hz, 2 H), 1.93–1.88 ppm (m, 4 H); C NMR (100 MHz, CDCl3) δ 190.0, 164.2,
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2ꢀ(4ꢀChlorophenyl)ꢀNꢀ(2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀyl)ꢀ2ꢀoxoacetamide
(3af).
1
Following general procedure A, 3af was isolated as a yellow solid (76 mg, 66%). H
NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8 Hz, 2 H), 7.44 (d, J = 8 Hz, 2 H), 7.35 (d, J = 8
Hz, 1 H), 7.29 (d, J = 4 Hz, 1 H), 7.27–7.26 (m, 2 H), 7.23–7.20 (m, 1 H), 5.52 (dd, J
=15.7, 7.7, 1 H), 3.04 (ddd, J = 16, 12, 4 Hz, 1 H), 2.92 (dt, J = 16, 8 Hz, 1 H), 2.68–2.58
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(m, 1 H), 1.97–1.87 (m, 1 H); C NMR (100 MHz, CDCl3) δ 186.1, 161.0, 143.4, 142.0,
141.2, 132.7, 131.7, 128.8, 128.3, 126.9, 124.9, 124.1, 54.7, 33.6, 30.3 ppm; mp
81.6–82.0 °C; HRMS (ESI) m/z: [M + Na]+ calcd for C17H14ClNO2Na 322.0605; found
322.0603; IR νmax (KBr)/ cmꢀ1 3275, 3035, 2967, 2856, 1687, 1639, 1587, 1531, 1478,
1450, 1010, 817, 761, 751.
2ꢀ(4ꢀChlorophenyl)ꢀNꢀcyclopropylꢀ2ꢀoxoacetamide (3ag). Following general
procedure A, 3ag was isolated as a yellow solid (73 mg, 65%). Known compound (CAS:
1267006ꢀ97ꢀ2). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.2 Hz, 2 H), 7.42 (d, J = 8.4
Hz, 2 H), 7.15 (d, J = 2.4 Hz, 1 H), 2.87–2.79 (m, 1 H), 0.87 (dt, J = 12, 4 Hz, 2 H), 0.63
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ppm (dt, J = 8,4 Hz, 2 H); C NMR (100 MHz, CDCl3) δ 186.1, 162.6, 141.2, 132.7,
131.6, 128.9, 22.6, 6.5 ppm; mp 79.6–80.0 °C.
2ꢀ(4ꢀChlorophenyl)ꢀ2ꢀoxoꢀNꢀ(pyridinꢀ3ꢀylmethyl)acetamide
(3ah).
Following
general procedure A, 3ah was isolated as a yellow solid (111 mg, 81%). Known
1
compound (CAS: 1267254ꢀ48ꢀ7). H NMR (400 MHz, CDCl3) δ 8.60 (s, 1 H), 8.55 (dd,
J = 4.8, 1.6 Hz, 1 H), 8.33 (d, J = 8.8 Hz, 2 H), 7.69 (d, J = 8 HZ, 1 H), 7.60 (s, 1 H), 7.44
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(d, J = 8 Hz, 2 H), 7.30 (dd, J = 8, 4.8 Hz 1 H), 4.57 (d, J = 4 Hz, 2 H); C NMR (100
MHz, CDCl3) δ 185.6, 161.3, 148.1, 147.9,141.1, 137.0, 132.7, 131.1, 129.0, 124.3,
123.9, 40.9 ppm; mp 105.3–105.6 °C.
Nꢀ((1S,3S)ꢀadamantanꢀ1ꢀyl)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoacetamide (3ai). Following
general procedure A, 3ai was isolated as a white solid (88 mg, 56%). 1H NMR (400 MHz,
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CDCl3) δ 8.28 (d, J = 8 Hz, 2 H), 7.41 (d, J = 8 Hz, 2 H), 6.80 (s, 1 H), 2.11 (m, 3H), 2.07
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(d, J = 2.8 Hz, 6 H), 1.70 ppm (t, J = 4 Hz, 6 H); C NMR (100 MHz, CDCl3) δ 187.2,
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160.4, 140.9, 132.8, 131.8, 128.7, 52.5, 41.1, 36.2, 29.3 ppm; mp 114.9–117.6 °C; HRMS
(ESI) m/z: [M + H]+ calcd for C18H19ClNO2 316.1098; found 316.1123; IR νmax (KBr)/
cmꢀ1 3370, 2960, 2928, 2906, 2849, 1665, 1586, 1517, 1445, 1360, 1345, 1314, 1091,
1022, 1016, 845, 800.
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Nꢀ(tertꢀbutyl)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoacetamide (3aj).18 Following general
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procedure A, 3aj was isolated as a yellow solid (96 mg, 80%). H NMR (400 MHz,
CDCl3) δ 8.28 (d, J = 8 Hz, 2 H), 7.42 (d, J = 8 Hz, 2 H), 6.94 (s, 1 H), 1.43 ppm (s, 9 H);
13C NMR (100 MHz, CDCl3) δ 187.1, 160.9, 140.9, 132.7, 131.7, 128.7, 51.7, 28.3 ppm;
mp 49–51 °C
2ꢀ(4ꢀChlorophenyl)ꢀNꢀ(2ꢀmethylallyl)ꢀ2ꢀoxoacetamide (3ak). Following general
1
procedure A, 3ak was isolated as a yellow solid ( 89 mg, 75%). H NMR (400 MHz,
CDCl3) δ 8.31 (d, J = 8 Hz, 2 H), 7.42 (d, J =8 Hz, 2 H), 7.24 (s, 1 H), 4.884 (d, J = 1.2
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Hz, 1 H), 4.878 (d, J = 1.2 Hz, 1 H), 3.90 (d, J = 6.4 Hz, 2 H), 1.76 ppm (s, 3 H); C
NMR (100 MHz, CDCl3) δ 186.2, 161.2, 141.2, 140.7, 132.7, 131.6, 128.9, 111.8, 44.9,
20.3 ppm; mp 33.6–34.2 °C; HRMS (ESI) m/z: [M+Na]+ calcd for C12H12ClNO2Na
260.0448; found 260.0445; IR νmax (KBr)/ cmꢀ1 3379, 3080, 2980, 2914, 2844, 1669, 1589,
1525, 1484, 1456, 1090, 895.
2ꢀ(4ꢀChlorophenyl)ꢀNꢀdodecylꢀ2ꢀoxoacetamide (3al). Following general procedure
B, 3al was isolated as a white solid (129 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d,
J = 8.8 Hz, 2 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.11 (s, 1 H), 3.35 (q, J = 4 Hz, 2 H),
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1.61–1.54 (m, 2 H), 1.35–1.23 (m, 20 H), 0.85 ppm (t, J = 8 Hz, 3 H); C NMR (100
MHz, CDCl3) δ 186.4, 161.3, 141.1, 132.7, 131.7, 128.8, 39.5, 31.9, 29.6, 29.5, 29.3, 29.2,
29.2, 26.9, 22.7, 14.1 ppm; mp 57.0–57.5 °C; HRMS (ESI) m/z: [M + Na]+ calcd for
C20H30ClNO2Na 374.1857; found 374.1849; IR νmax (KBr)/ cmꢀ1 3346, 2962, 2916, 2845,
1672, 1651, 1589, 1524, 1477, 1469, 1389, 1098, 723.
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Nꢀcyclohexylꢀ2ꢀ(3,5ꢀdimethylphenyl)ꢀ2ꢀoxoacetamide (3ea). Following general
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procedure A, 3ea was isolated as a white solid (117 mg, 90%). H NMR (400 MHz,
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CDCl3) δ 7.90 (s, 2 H), 7.22 (s, 1 H), 6.90 (s, 1 H), 3.88–3.77 (m, 1H ), 2.34 (s, 6 H),
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1.98–1.72 (m, 4 H), 1.65–1.29 (m, 4 H), 1.27–1.21 ppm (m, 2 H); C NMR (100 MHz,
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CDCl3) δ 188.5, 161.1, 138.1, 136.1, 133.4, 128.8, 48.5, 32.7, 25.4, 24.7, 21.2 ppm; mp
87.5–88.0 °C; HRMS (ESI) m/z: [M + Na]+ calcd for C16H21NO2Na 282.1464; found
282.1465; IR νmax (KBr)/ cmꢀ1 3425, 3285, 3061. 2936, 2912, 2851, 1678, 1643, 1592,
1532, 1446, 1383, 808,687.
Nꢀcyclohexylꢀ2ꢀoxoꢀ2ꢀphenylacetamide (3fa).19 Following general procedure A, 3fa
was isolated as a white solid (96 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 8,
1.6 Hz, 2 H), 7.58 (tt, J = 8, 1.2 Hz, 1 H), 7.47–7.42 (m, 2 H), 6.96 (d, J = 8 Hz, 1 H),
3.87–3.78 (m, 1 H), 1.98–1.71 (m, 4 H), 1.65–1.29 (m, 4 H), 1.26–1.20 ppm (m, 2 H); 13C
NMR (100 MHz, CDCl3) δ 188.1, 160.9, 134.2, 133.4, 131.2, 128.4, 48.4, 32.7, 25.4, 24.7
ppm; mp 112.7–112.9 °C.
Nꢀcyclohexylꢀ2ꢀoxoꢀ2ꢀ(oꢀtolyl)acetamide (3ca). Following general procedure A, 3ca
was isolated as a yellow solid (102 mg, 80%). Known compound (CAS: 1029542ꢀ43ꢀ5).
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8 Hz, 1 H), 7.43–7.38 (m, 1 H), 7.28–7.24 (m,
1 H), 7.23 (d, J = 4 Hz, 1 H), 6.91 (d, J = 4 Hz, 1 H), 3.87–3.77 (m, 1 H), 2.46 (s, 3 H),
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1.99–1.71 (m, 4 H), 1.65–1.29 (m, 4 H), 1.27–1.21 ppm (m, 2 H) ; C NMR (100 MHz,
CDCl3) δ 191.8, 161.1, 140.0, 132.9, 132.6, 131.9, 131.6, 125.3, 48.5, 32.7, 25.4, 24.7,
20.8 ppm; mp 100.1–100.4 °C.
Nꢀcyclohexylꢀ2ꢀoxoꢀ2ꢀ(mꢀtolyl)acetamide (3da). Following general procedure A, 3da
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was isolated as a white solid (99 mg, 81%). H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 4
Hz, 1 H), 8.09 (s, 1 H), 7.40 (d, J = 8 Hz, 1 H), 7.35–7.31 (m, 1 H), 6.93 (d, J = 4 Hz, 1
H), 3.87–3.78 (m, 1 H), 2.38 (s, 3 H), 1.98–1.71 (m, 4 H), 1.66–1.29 (m, 4 H), 1.27–1.20
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ppm (m, 2 H); C NMR (100 MHz, CDCl3) δ 188.3, 161.0, 138.2, 135.1, 133.4, 131.5,
128.4, 128.3, 48.4, 32.7, 25.4, 24.7, 21.3 ppm; mp 107.2–107.6 °C; HRMS (ESI) m/z:
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[M+Na]+ calcd for C15H19NO2Na 268.1308, found 268.1307; IR νmax (KBr)/ cmꢀ1 3420,
3288, 3058, 3055, 2933, 2849, 1652, 1584, 1540, 1446, 1378, 783, 694.
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Nꢀcyclohexylꢀ2ꢀoxoꢀ2ꢀ(pꢀtolyl)acetamide (3ba). Following general procedure A, 3ba
was isolated as a yellow solid (97 mg, 79%). Known compound (CAS: 1266998ꢀ34ꢀ8). 1H
NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8 Hz, 2 H), 7.24 (d, J = 8 Hz, 2 H), 6.95 (d, J = 8
Hz, 1 H), 3.84–3.78 (m, 1 H), 2.39 (s, 3 H), 1.97–1.71 (m, 4 H), 1.65–1.28 (m, 4 H),
1.26–1.19 ppm (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 187.6, 161.1, 145.4, 131.3,
130.9, 129.2, 48.4, 32.7, 25.4, 24.7, 21.8 ppm; mp 105.9–106.5 °C.
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N,Nꢀdiethylꢀ2ꢀoxoꢀ2ꢀ(mꢀtolyl)acetamide (3dc). Following general procedure A, 3dc
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was isolated as a yellow liquid (87 mg, 79%). Known compound (CAS: 99821ꢀ90ꢀ6); H
NMR (400 MHz, CDCl3) δ 7.76 (s, 1 H), 7.74 (d, J = 8 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H),
7.40 (m, 1 H), 3.60–3.55 (m, 2 H), 3.28–3.22 (m, 2 H), 2.43 (s, 3 H), 1.30 (t, J = 8 Hz, 3
H), 1.16 ppm (t, J = 8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 191.8, 166.8, 138.8, 135.4,
133.2, 129.8, 128.8, 126.9, 42.1, 38.7, 21.3, 14.0, 12.8 ppm.
2ꢀ(3,5ꢀdimethylphenyl)ꢀN,Nꢀdiethylꢀ2ꢀoxoacetamide (3ec). Following general
1
procedure A, 3ec was isolated as a yellow liquid (84 mg, 72%). H NMR (400 MHz,
CDCl3) δ 7.55 (s, 2 H), 7.28 (s, 1 H), 3.58 (m, 2 H), 3.25 (m, 2 H), 2.39 (s, 6 H), 1.30 (t, J
= 7.2 Hz, 4 H), 1.17 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 192.1, 167.0,
138.7, 136.3, 133.3, 127.3, 42.1, 38.7, 21.2, 14.1, 12.8 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C14H19NO2Na 256.1308, found 256.1311; IR νmax (KBr)/ cmꢀ1 2973, 2935, 2869,
1678, 1640, 1603, 1440, 1382, 1306, 808, 680.
1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ(piperazinꢀ1ꢀyl)ethaneꢀ1,2ꢀdione (3am). Following general
procedure A, 3am was isolated as a yellow liquid (95 mg, 75%). Known compound (CAS:
1225832ꢀ82ꢀ5). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8 Hz, 2 H), 7.44 (d, J = 8 Hz,
2 H), 3.70 (t, J = 5.2 Hz, 2 H), 3.30 (t, J = 5.2 Hz, 2 H), 2.93 (t, J = 5.2 Hz, 2 H), 2.80 (t, J
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= 5.2 Hz, 2 H), 2.62 ppm (s, 1 H); C NMR (100 MHz, CDCl3) δ 189.9, 164.9, 141.4,
131.4, 130.9, 129.4, 46.5, 45.9, 45.4, 41.9 ppm.
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(S)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀNꢀ(2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀyl)ꢀ2ꢀoxoacetamide
(3an).
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Following general procedure A, 3an was isolated as a brown solid (86 mg, 75%). H
NMR (400 MHz, CDCl3) δ 8.36 (d, J = 9.6 Hz, 2 H), 7.45 (d, J = 9.6 Hz, 2 H), 7.30 (d, J
= 0.8 Hz, 1 H), 7.29 (s, 1 H), 7.27–7.26 (m, 2 H), 7.23–7.20 (m, 1 H), 5.52 (dd, J = 16, 8
Hz, 1 H), 3.04 (ddd, J = 16, 8, 4 Hz, 1 H), 2.92 (dt, J = 16, 8 Hz, 1 H), 2.69–2.61 (m, 1 H),
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1.96–1.89 (m, 1 H); C NMR (100 MHz, CDCl3) δ 186.1, 161.0, 143.4, 142.0, 141.2,
132.8, 131.8, 128.9, 128.4, 126.9, 125.0, 124.1, 54.8, 33.6, 30.3 ppm; mp 104.6–105.2 °C;
HRMS (ESI) m/z: [M + Na]+ calcd for C17H14ClNO2Na 322.0605; found 322.0610; IR
ν
max (KBr)/ cmꢀ1 3458, 3262, 3065, 2971, 2911, 2844, 1687, 1641, 1585, 1546, 1480,
1454, 1014, 817, 762, 750; chiral HPLC conditions: Chiralcel ODꢀH,
(nꢀhexane/isopropanol, 80:20), flow rate = 1.0 mL/min, Rt = 5.7, and 8.6 min,
respectively. Enantiomeric excess was determined to be >99% ee using the HPLC
conditions.
(R)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀNꢀ(2ꢀhydroxypropyl)ꢀ2ꢀoxoacetamide (3ao). Following
general procedure C, 3ao was isolated as a gray solid (98 mg, 81%). 1H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 8.8 Hz, 2 H), 7.56 (s, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 4.01–3.97 (m,
1 H), 3.52 (dd, J=12, 8 Hz, 1 H), 3.23 (dd, J = 12, 8 Hz, 1 H), 2.50 (s, 1 H), 1.22 ppm (d,
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J = 8 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 186.3, 162.1, 141.2, 132.6, 131.5, 128.9,
66.9, 46.6, 20.9 ppm; mp 87.0–87.5 °C; HRMS (ESI) m/z: [M + Na]+ calcd for
C11H12ClNO3Na 264.0397; found 264.0399; IR νmax (KBr)/ cmꢀ1 3401, 3246, 3100, 2966,
2933, 2875, 1682, 1653, 1636, 1584, 1447, 1376, 813, 737; chiral HPLC conditions:
Chiralcel ODꢀH, (nꢀhexane/isopropanol, 80:20), flow rate = 1.0 mL/min, Rt = 23.0, and
24.1 min, respectively. Enantiomeric excess was determined to be >99% ee using the
HPLC conditions.
1ꢀ(4ꢀBenzoylpiperazinꢀ1ꢀyl)ꢀ2ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ethaneꢀ1,2ꢀdione
(3vp).20
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Following general procedure B, 3vp was isolated as a white solid (122 mg, 65%). H
NMR (400 MHz, CDCl3) δ 8.29 (s, 1 H), 7.87 (s, 1 H), 7.36 (d, J = 22.4 Hz, 8 H),
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3.87–3.44 ppm (m, 11 H); C NMR (100 MHz, CDCl3) δ 184.3, 170.6, 166.1, 139.6,
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137.6, 134.9, 130.1, 128.6, 127.0, 126.0, 124.1, 123.4, 122.2, 113.2, 110.0, 45.9, 41.6,
33.8 ppm; mp 237.6–238.3 °C.
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(2S,3S,5S,6R)ꢀ2ꢀ(acetoxymethyl)ꢀ6ꢀ(4ꢀ(2ꢀmorpholinoꢀ2ꢀoxoacetyl)phenoxy)tetrahy
droꢀ2Hꢀpyranꢀ3,4,5ꢀtriyl triacetate (3wb). Following general procedure A, 3wb was
isolated as a white oil (192 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz,
2 H), 7.03 (d, J = 8.8 Hz, 2 H), 5.27 (t, J = 6.4 Hz, 2 H), 5.19 (d, J = 7.6 Hz, 1 H), 5.14 (t,
J = 9.6 Hz, 1 H), 4.24 (dd, J=12.4, 5.2 Hz, 1 H), 4.13 (dd, J=12.4, 2 Hz, 1 H), 3.89 (ddd,
J=10, 5.2, 2.4 Hz, 1 H), 3.76–3.69 (m, 4H), 3.61 (t, J =4 Hz, 2 H), 3.33 (t, J =4 Hz, 2 H),
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2.02 (s, 3 H), 2.01 (s, 6 H), 2.00 ppm (s, 3 H); C NMR (100 MHz, CDCl3) δ 189.6,
170.4, 170.1, 169.3, 169.2, 165.3, 161.5, 132.0, 128.1, 116.7, 97.8, 72.3, 72.2, 70.8, 67.9,
66.7, 66.6, 61.7, 46.2, 41.5, 20.6, 20.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C26H31NO13Na 588.1687; found 588.1668; IR νmax (KBr)/cmꢀ1 2967, 2931, 2859, 1726,
1641, 1596, 1575, 1506, 1447, 1436, 1373, 1227, 1113, 1067, 1033, 847, 700.
Hg(0) Poisoning Test. As general procedure A, a reaction of 1ꢀchloroꢀ4ꢀiodobenzene 1a
(0.5 mmol, 122.9 mg), cyclohexylamine 2a (0.75 mmol, 58 µL), Pd(OAc)2 (0.01 mmol,
2.3 mg), sodium carbonate (1.0 mmol, 106.5 mg), and PEGꢀ400 (2.0 mL), with the
addition of Elemental mercury (1.0 mmol, 100equiv., 201 mg) (relative to palladium) was
conducted. Following the reaction for 6 h at room temperature, the desired product 3aa
was formed in a trace amount, suggesting that the reaction is completely inhibited by the
introduction of Hg(0).
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Acknowledgements
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The work was sponsored by the Natural Science Foundation of China (21302099), the
Natural Science Foundation of Jiangsu Province (BK2012449), the SRF for ROCS, SEM,
and the Priority Academic Program Development of Jiangsu Higher Education
Institutions.
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Supporting Information.
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1H NMR and C NMR spectra for products. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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