Amide Bond Formation Assisted by Vicinal Alkylthio Migration in Enaminones: Metal- and CO-Free Synthesis of α,β-Unsaturated Amides

Article abstract of DOI:10.1021/acs.joc.8b00775

Amide bond formation is one of the most important transformations in organic synthesis, drug development, and materials science. Efficient construction of amides has been among the most challenging tasks for organic chemists. Herein, we report a concise m

Full text of DOI:10.1021/acs.joc.8b00775

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Amide Bond Formation Assisted by Vicinal Alkylthio Migration in
Enaminones: Metal and CO-Free Synthesis of #,#-Unsaturated Amides
Zhuqing Liu, Fei Huang, Ping Wu, Quannan Wang, and Zhengkun Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00775 • Publication Date (Web): 17 Apr 2018
Downloaded from http://pubs.acs.org on April 17, 2018
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Amide Bond Formation Assisted by Vicinal Alkylthio Migration in Enaminones:
Metal and COꢀFree Synthesis of α,
β
ꢀUnsaturated Amides
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†
,≠,§
†,‡,§
†,≠
†,≠
†,⊥,
Zhuqing Liu,
Fei Huang,
Ping Wu, Quannan Wang, and Zhengkun Yu
*
†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian
116023, People’s Republic of China
‡
College of Pharmacy, Nanjing Tech University, Nanjing 211800, People’s Republic of China
University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People’s Republic of China
≠
⊥
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
_____________________________________________________________________
ABSTRACT: Amide bond formation is one of the most important transformations in
organic synthesis, drug development, and materials science. Efficient construction of
amides has been among the most challenging tasks for organic chemists. Herein, we
report a concise methodology for amide bond (ꢀCONHꢀ) formation assisted by vicinal
group migration in alkylthioꢀfunctionalized enaminones (αꢀoxo ketene N,Sꢀacetals)
under mild conditions. Simple treatment of such enaminones with PhI(OAc)
ambient temperature in air afforded diverse multiply functionalized α, ꢀunsaturated
amides including ꢀcyclopropylated acrylamides, in which a wide array of functional
2
at
β
β
groups such as aryl, (hetero)aryl, alkenyl, and alkyl can be conveniently introduced to
a ketene moiety. The reaction mechanism was investigated by exploring the origins of
the amide oxygen and carbon atoms, isolation and structural characterization of the
reaction intermediates. The amide bond formation reactions could also be efficiently
performed under solventless mechanical milling conditions.
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INTRODUCTION
Amide bond is the basic linkage of peptides and proteins, and also acts as the key
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functionality in many pharmaceuticals and functional polymeric materials. Amide
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bond formation has been among the most challenging organic transformations.
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However, direct condensation of a carboxylic acid and a primary or secondary amine
can not form an amide by loss of water as the byꢀproduct. The conventional method
for chemical formation of an amide bond usually involves activation of a carboxylic
acid by an activating (coupling) reagent, and subsequent coupling of the inꢀsitu
generated activated form of the carboxylic acid with a free amine through
nucleophilic displacement. Without an activator (coupling reagent) the carboxylic acid
and amine only form a carboxylateꢀammonium salt, instead of an amide, because the
reaction thermodynamics is not favorable for amide formation. Although continuous
3
efforts have been devoted to this area, the state of the art in the conventional method
4
for amide bond formation is approaching its inherent limit.
_____________________________________________________________________
Scheme 1. Selected Pharmaceutical Reagents Containing an α,βꢀUnsaturated Amide
Functionality
_____________________________________________________________________
α,βꢀUnsaturated amide, that is, acrylamide, is a key structural motif in a variety of
natural products and pharmaceutical agents (Scheme 1). For example, (E)ꢀNꢀallylꢀα,βꢀ
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5a
dimethylcinnamamide has been pharmaceutically tested as an anticonvulsant agent.
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ꢀCyanobutꢀ2ꢀenamide can be used to treat cell proliferative disorders characterized
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by inappropriate platetet derived growth factor receptor (PDGFꢀR) activity.
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c
Retinamide VNHMꢀ1ꢀ73 exhibits strong in vivo antibreast cancer activity, and
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d
crotamiton is a scabicidal and antipruritic drug. Cyclopropyl ring is ranked the 10th
in a top 100 list of the most frequently used rings in the synthesis of small molecule
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drugs, which can lock and orient a molecule into its bioactive conformation. Thus,
cyclopropylated α,βꢀunsaturated amides have been applied as important
pharmaceutical agents. The analog of leflunomide metabolite is active in the clinical
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trials for rheumatoid arthritis, a chronic inflammatory disease. The grenadamide
precursor can be efficiently hydrogenated to give grenadamide which has exhibited
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modest cannabinoid receptorꢀbinding activity.
The metabolite Uꢀ106305 of
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jawsamycin is an inhibitor of the cholesteryl ester transfer protein (CETP). Direct
synthesis of α,βꢀunsaturated amides has been strongly desired due to the limitations of
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the conventional preparation methods (Scheme 2a). Transitionꢀmetalꢀcatalyzed
8
procedures have recently been paid considerable attention for this purpose. Palladium
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and iron ꢀcatalyzed aminocarbonylation of alkynes with amines and CO gave highly
chemꢀ and regioselective α,βꢀunsaturated amides (Scheme 2b). Bimetallic
Pd/Cuꢀcatalyzed aerobic oxidative Nꢀdealkylative carbonylation of tertiary amines
1
0
and alkenes produced (E)ꢀα,βꢀunsaturated amides using a COꢀO
2
mixed gas
(Scheme 2c). Nickelꢀcatalyzed intermolecular hydrocarbamoylation of alkynes with
11
formamides afforded α,βꢀunsaturated amides (Scheme 2d). However, these methods
usually suffer from multiꢀstep manipulations, use of transitionꢀmetal catalysts and
additives, high pressure CO, and/or strong reducing reagents. In the context of drug
development it is always desired to avoid the detrimental effect of transitionꢀmetal
residues originated from both the transitionꢀmetalꢀcatalyzed procedures and use of
transitionꢀmetal additives, and the strategy to develop a green process usually requires
2
mild reaction conditions and high atomꢀeconomy with less wastes. Very recently, Loh
and Jiang, et al. reported hypervalent iodine(III)ꢀpromoted acyloxylation/amidation of
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stable enamines to generate secondary amineꢀbased amides.
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_____________________________________________________________________
Scheme 2. Representative Strategies for the Synthesis of α,βꢀUnsaturated Amides
a) The traditional protocol for amide synthesis
activator
O
(coupling reagent)
O
2
R2
+
R NH2
R1
R1
N
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OH
H
b) Aminocarbonylation of alkynes
NR R4
3
MT cat.
R1
R2
3
4
+
R R NH
+
CO
R1
O
R2
c) Oxidative aminocarbonylation of alkenes
Pd/Cu catalyst
O
Ar
+
NR3
CO/O2
Ar
NR2
d) Hydrocarbamoylation of alkynes
O
NR R4
3
Ni catalyst
AlMe3
R1
R2
+
R1
NR3R4
O
H
R2
e) This work: the tautomerization-alkylthio migration strategy
H
H
H
H
O
NHR3
R3
O
NR3
O
N
O
NR
R1
SR2
3
R1
SR2
R1
SR2
R1
H
H
SR
H
1
2
H
H
NR3
OR O
O
[
O]
O
O
stabilization
R1
NHR3
R1
oxidant
O
R1
NHR3
SR2
SR2
H
SR2
2
_____________________________________________________________________
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During the continuous investigation of sulfurꢀfunctionalized internal alkenes, we
envisioned that alkylthioꢀfunctionalized enaminones, that is, αꢀoxo ketene
14
N,Sꢀacetals, which exist in various tautomers upon the reaction conditions, might
undergo oxidative vicinal alkylthio group migrationꢀassisted transformation to form
α,βꢀunsaturated amides (Scheme 2e). The challenge is that enaminones can undergo
olefinic C=C bond cleavage to afford αꢀketo amides in the presence of a
1
5
transitionꢀmetal catalyst under oxidative conditions, and an applicable approach for
potential drug development often requires mild and metalꢀfree conditions. Herein, we
disclose a concise and efficient protocol for amide bond (−CONH−) formation from
alkylthioꢀfunctionalized enaminones and hypervalent iodine(III) reagents under mild
conditions.
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RESULTS AND DISCUSSION
The reaction of enaminone 1a, that is, (E)ꢀ3ꢀ(benzylamino)ꢀ3ꢀ(methylthio)ꢀ1ꢀ
phenylpropꢀ2ꢀenꢀ1ꢀone, with phenyliodine(III) diacetate PhI(OAc) (PIDA) was
2
conducted to optimize the reaction conditions (Table 1). Enaminone 1a reacted with
PIDA in a 1:1.5 molar ratio in DMF and ethanol at ambient temperature gave the
target product α,βꢀunsaturated amide 2a in 17ꢀ22% yields (Table 1, entries 1 and 2). It
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is noteworthy that with 10 mol % Pd(OAc)
2
as the catalyst and excess of PIDA as the
o
oxidant, αꢀacetyl ketene di(ethylthio)acetal reacted with acetic acid at 50 C to form
1
6
the olefinic C−H acetoxylation product in 23% yield. These results have suggested
that the functional groups at the termini of the internal olefinic C=C bond of
enaminone 1a are crucial to determine the substrate reactivity and direct the reaction
towards formation of the α,βꢀunsaturated amide product. The solvent effect was
remarkable in the cases of using dichloromethane, diethyl ether, 1,4ꢀdioxane, and
1,2ꢀdichloroethane (DCE) as the reaction media, leading to 2a in 55ꢀ75% yields
(Table 1, entries 3ꢀ6). Varying the amounts of PIDA or elevating the temperature to
o
4
0ꢀ60 C diminished the reaction efficiency (Table 1, entries 7ꢀ10). It should be noted
that phenyl iodide and acetic acid were detected as the byꢀproducts by GC analysis of
the resultant reaction mixture.
The scope of enaminones 1 was then explored (Table 2) under the optimized
reaction conditions as shown in entry 6 of Table 1. In the cases of using unsubstituted
αꢀbenzoyl enaminones 1aꢀj, alkyl groups such as benzyl, methyl, ethyl, nꢀbutyl,
cyclohexyl, 1ꢀphenylethyl, allyl, diphenylmethyl, 2ꢀtetrahydrofuranylmethyl, and 2ꢀ
3
furanylmethyl could be tolerated in the amino moiety (NHR ), and the reactions
afforded the target products 2aꢀj in 60ꢀ90% yields. substituted benzoyl enaminones
1kꢀn also efficiently reacted to produce products 2kꢀn (69ꢀ86%). 2ꢀNaphthoyl
enaminone 1o did not exhibit an obvious steric effect, forming product 2o in 80%
yield with isolation of αꢀmethylthioꢀβꢀketoamide 2o′ (5%) as the minor product.
However, electronꢀwithdrawing substituent CF diminished the substrate reactivity to
3
generate the target product 2p in a relatively low yield (55%), and the minor product
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a
Table 1. Screening of Conditions
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entry
PhI(OAc)
2
solvent
temp
yield
(%)
(
equiv)
(°C)
1
2
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.0
1.5
1.5
DMF
EtOH
25
25
25
25
25
25
25
25
40
17
22
3
CH
2
Cl
2
55
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Et
2
O
63
5
1,4ꢀdioxane
DCE
73
c
6
75 (72)
71
7
DCE
8
DCE
45
9
DCE
69
10
DCE
60
44
a
b
1
Conditions: 1a (0.5 mmol), solvent (5 mL), in air, 2 h. Determined by H
c
NMR analysis using 1,3,5ꢀtrimethoxylꢀbenzene as the internal standard.
Isolated yield given in parentheses. DCE = 1,2ꢀdichloroethane.
_____________________________________________________________________
αꢀacetoxyꢀαꢀmethylthioꢀβꢀketoamide 2p′′ was obtained in 18% yield. The formation
of compound 2p′′ was similar to the production of the αꢀketo amides from
copperꢀcatalyzed oxidative C=C activation of enaminones in the presence of a
15
hypervalent iodine(III) reagent. The furoyl and thienoyl enaminones 1q and 1r
exhibited a lower reactivity than their benzoyl analogs, and their reactions with PIDA
afforded 2q (76%) and 2r (68%), respectively. Both ethylthioꢀfunctionalized
enaminones 1s and 1t reacted slightly less efficiently than the corresponding
methylthio analogs, forming 2s (80%) and 2t (84%). Unexpectedly, the reaction of
benzylthio enaminone (1u) gave the target product 2u (53%) with formation of
αꢀacetoxyꢀαꢀbenzylthioꢀβꢀketoamide (2u′′) in 33% yield. Alkenoylꢀbased enaminones
1vꢀx also reacted well with PIDA to form βꢀvinylated acrylamides 2vꢀx (76ꢀ82%).
Acetyl enaminones 1yꢀz1 exhibited a reactivity lower than both the aroyl and alkenoyl
enaminones, and their reactions with PIDA afforded amides 2yꢀz1 (63ꢀ74%). These
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_
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a
Table 2. Scope of Enaminones 1
1
1
1
1
1
1
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9
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a
o
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Conditions: 1 (0.5 mmol), PhI(OAc) (0.75 mmol), DCE (5 mL), in air, 25 C, 2 h.
_____________________________________________________________________
results have demonstrated a promising protocol to introduce an aryl, (hetero)aryl,
alkenyl, and alkyl group onto a ketene moiety with formation of an amide bond under
mild conditions.
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Secondary amineꢀderived enaminones 1z2ꢀz4 reacted with PIDA less efficiently
than the primary amineꢀderived analogs to form 2z2ꢀz4 (71ꢀ79%). However, in most
of the cases using arylamineꢀderived enaminones the reactions formed complicated
products, and only in the case of 3,5ꢀdichloroanilineꢀbased enaminone 1z5 the
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reaction yielded the target product βꢀvinylꢀα,βꢀunsaturated amide 2z5 in a moderate
yield (53%). It was noted that the enaminone of a dienylamine, that is, geranylꢀamine,
reacted with PIDA to afford the target amide 2z6 (62%) with the dienyl moiety
remaining unchanged. 1,8ꢀOctylꢀdiamineꢀderived enaminone 1z7 reacted with 3 equiv
of PIDA to form the alkyl chainꢀbridged diamide 2z7 (71%). Interestingly, the
reaction of enaminone 1z8 from αꢀamino acid ester, that is, alanine methyl ester,
formed the peptideꢀtype product 2z8 (51%). Chiral enaminones from the
corresponding αꢀoxo ketene dithioacetals and chiral amines also efficiently reacted
with PIDA, forming chiral α,βꢀunsaturated amides 2z9ꢀz12 (73ꢀ88%) with retention
of the chirality (99% ee). To our delight, the enaminone of the resolving agent
dehydroabietylamine reacted with PIDA to form a complex α,βꢀunsaturated amide
2
z13 (78%). It is noteworthy that on a gramꢀscale (5 mmolꢀscale) enaminones 1s and
z9 reacted with PIDA to form the corresponding amide products 2s and 2z9 in 72%
1
(1.06 g) and 87% (1.70 g) yields, respectively, and the molecular structures of
compounds 2h, 2o′, and 2p′′ were further confirmed by the Xꢀray single crystal
structural analysis (see the Supporting Information for details).
The amide bond formation reactions of 1 with PhI(OAc)
performed under solventless milling conditions. Simple mechanical milling the
mixture of enaminone 1 and PhI(OAc) with a glass rod at ambient temperature in air
2
could also be efficiently
2
for 5ꢀ10 minutes initiated the reaction, affording the target amide product 2 in yields
comparative to those obtained in the presence of a solvent (Scheme 3). Less amount
of PIDA (1.2 equiv) was employed in these cases. Such a protocol was realized under
the mild conditions, avoided use of a reaction solvent, and is thus characteristic of
1
7
green chemistry, which has demonstrated a potential for its application in synthetic
chemistry.
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4
5
6
7
8
9
_____________________________________________________________________
Scheme 3. Amide Bond Formation Reactions Performed under the Solventless Milling
Conditions
milling
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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5
5
5
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0
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2
3
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5
6
7
8
9
0
1
2
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0
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2
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3
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7
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9
0
1
2
3
4
5
6
7
8
9
0
air, 25 o
-10 min
C
5
1
+ PhI(OAc)2
isolation
2 + PhI + HOAc
2
a, 73%; 2k, 72%
l, 78%; 2m, 80%
AcO
O
2
R1
NHR3
2t, 85%; 2v, 73%
2w, 69%; 2x, 76%
SMe
2y, 66%; 2z5, 52%
2
Conditions: 1 (0.5 mmol), PhI(OAc) (0.6 mmol), 25 °C, in air. The reaction mixture was mechanically milled by a
glass rod for 5ꢀ10 minutes, and then stayed without milling for 1ꢀ2 h to complete the reaction.
_____________________________________________________________________
Cyclopropanation has been a challenging reaction in synthetic chemistry. Direct
approaches to establish a cyclopropyl motif involves SimmonsꢀSmith cyclopropanaꢀ
tion using olefins and diiodomethane in the presence of activated zinc, and transitionꢀ
metal catalyzed cyclopropanation of alkenes with diazo compounds and surrogates,
18
which have been well defined and most widely used. Recently, transitionꢀmetal
1
9
catalyzed crossꢀcoupling protocols by means of prefunctionalized cyclopropanes,
2
0
and activated cyclopropane derivatives through C−H activation strategy have been
documented for indirect introduction of a cyclopropyl ring into a complex molecular
structure. Diverse synthesis of functionalized cyclopropanes under mild conditions is
becoming more and more important for the convenient construction of potentially
bioactive cyclopropylated acrylamides (Scheme 1).
Next, under the same optimal conditions enaminones of type 3, that is,
αꢀcyclopropylcarbonyl ketene N,Sꢀacetals, were treated with PIDA to form the target
βꢀcyclopropylꢀα,βꢀunsaturated amides (βꢀcyclopropylated acrylamides) 4 (Table 3).
Thus, unsubstitutited βꢀcyclopropylated acrylamide 4a was obtained in 75% yield.
The substituent on the aryl group in the benzylamino moiety (NHBn) exhibited an
obvious impact on the yields of 4bꢀi (70ꢀ80%), and electronꢀdonating 2ꢀmethyl and
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
3
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_____________________________________________________________________
a
Table 3. Scope of Cyclopropylated Enaminones 3
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a
o
2
Conditions: 1 (0.5 mmol), PhI(OAc) (0.75 mmol), DCE (5 mL), in air, 25 C, 2 h.
_____________________________________________________________________
2ꢀmethoxy groups favored formation of both products 4b and 4e (80%). Other
aliphatic acyclic or cyclic primary amineꢀderived cyclopropylated enaminones (3jꢀo)
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also efficiently reacted with PIDA to give the target products 4jꢀo in good to excellent
yields (79ꢀ88%) with tolerance of 2ꢀphenylethyl, allyl, isopropyl, cyclopropyl,
3
cyclohexyl, and cycloheptyl in the NHR moiety. However, enaminones 3pꢀr derived
from tetrahydrofuranylmethylamine and methyl αꢀaminoacetates reacted less
efficiently with PIDA to form 4pꢀr in 65ꢀ68% yields. Unexpectedly, the reactions of
anilineꢀderived enaminones 3s and 3t with PIDA only formed αꢀmethylthioꢀβꢀ
ketoamides of type 2′, that is, 4s′ (62%) and 4t′ (46%), respectively. These results
may be attributed to the extra stabilization of the aryl group in the NHAr moiety to
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
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5
5
5
5
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5
6
0
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2
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the reaction intermediate of type 2′ leading to the
βꢀcyclopropylated acrylamide
product, which thus prevented the reaction from proceeding to generate the target
α,βꢀunsaturated amide product. In a similar fashion, chiral enaminone 3u efficiently
reacted with PIDA to give chiral
βꢀcyclopropylꢀα,βꢀunsaturated amide 4u (74%) with
99% ee. The enaminone of dehydroabietylamine (3v) reacted to produce the
corresponding complex amide 4v (83%). It should be noted that the molecular
structures of compounds 4f and 4s′ were further confirmed by the Xꢀray single crystal
structural determinations (see the Supporting Information for details).
Substituted cyclopropylated enaminones 3wꢀz19 reacted well with PIDA to form
the target βꢀcyclopropylꢀα,βꢀunsaturated amides 4wꢀz19 in 68ꢀ88% yields. In most of
the cases, the substrates exhibited a reactivity similar to that of the unsubstituted
β
ꢀcyclopropylatedenaminones. Aryl, (hetero)aryl, alkenyl, and alkyl were tolerated as
the substituent(s) on the cyclopropyl ring, which did not exhibit an obvious impact on
the substrate reactivity. Increasing the steric hindrance on the cyclopropyl ring by
introducing both an aryl and a methyl only slightly reduced the reaction efficiency to
give 4z18 (70%) and 4z19 (68%). It is noteworthy that on a gramꢀscale (5ꢀmmol scale)
of enaminones 3a and 3w the target products 4a and 4w were prepared in 72% and
75% yields, respectively. Other PIDAꢀtype hypervalent iodine(III) reagents were also
applied as the oxidative amidation/acetoxylation reagents, leading to the target amide
products 2z14 and 4z20ꢀz22 in 62ꢀ79% yields (Scheme 4). Because a wide range of
carboxylic acids are available for the preparation of iodine(III) reagents
21
ArI(OCOR)
2
,
diverse ester groups can be conveniently introduced onto the ketene
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2
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moiety of an α,βꢀunsaturated amide.
____________________________________________________________________
_
Scheme 4. Exploration of the Hypervalent Iodine Reagents (Piv = Pivaloyl)
0
1
2
3
4
5
6
7
8
9
0
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_____________________________________________________________________
To gain insights into the reaction mechanism, control experiments were conducted.
18
Reacting enaminone 1f with PIDA in the presence of a mixture HOAc/H OAc
18
generated in situ from H
2
O and Ac
2
O afforded both the target amide 2f and
1
8
18
18
Oꢀlabelled amide 2f[ O] in 76% yield with a molar ratio of 2f:2f[ O] = 72:28 (eq
1
8
1). The O incorporation was identified in the amide carbonyl by the HRMS analysis
1
8
18
18
of the mixed products, whereas Oꢀlabelled amide 2f[ OAc] with O incorporation
in the acetoxyl group was not detected (see the Supporting Information). Exchange
1
8
18
18
between PhI(OAc)2 and H OAc formed
Oꢀlabelled PhI( OAc)(OAc) and
which then reacted with enaminone 1f to give a mixture of 2f and
f[ O], suggesting that the amide oxygen in 2 and 4 was originated from PIDA, while
the acetoxyl oxygen was from the original carbonyl group of 1 and 3. The
18
16
2
PhI( OAc) ,
18
2
1
1
1
3
3
3
13
Cꢀlabelled substrate 1c[ C] reacted with PIDA to form the corresponding
13
Cꢀlabelled amide product 2c[ C], which was unambiguously identified by the
1
C{ H} NMR analysis, revealing that carbonyl migration to form the amide bond did
not occur during the reaction (eq 2). In the presence of a radical scavengers such as
TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidyloxy) or BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylꢀ
phenol), the reaction of 1a with PIDA gave 2a in 63% or 69% yield (versus 72% yield
in the absence of a radical scavenger), implicating that a radical pathway was not
involved in the reaction. A crossꢀover experiment was performed by treatment of a
mixture of 3a and 3z8 in 1:1 molar ratio with PIDA under the standard conditions,
affording a mixture of amides 4a (74%) and 4z8 (68%), which suggests that the alkylꢀ
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thio group migration occurs via an intramolecular pathway (eq 3). Next, the role of
the alkylthio group was identified. Treatment of enaminones 5a and 5b bearing no
alkylthio group with PIDA gave none of the target amide products 6a and 6b.
However, in the case of using anilineꢀderived enaminone 5b olefinic C−H
acetoxylation underwent to generate the acetoxylated enaminone 7b (66%) without
occurrence of the methyl group transfer (eq 4). These results have demonstrated that
an alkylthio group at the Nꢀattached terminus of the ketene moiety of enaminones 1
12,16
and 3 is crucial to assist the oxidative amidation.
In particular, treatment of 2o′
and 2u′′ under the standard conditions formed the target products 2o and 2u,
respectively, revealing that both 2o′ and 2u′′ were the reaction intermediates.
Deacetoxylation of βꢀvinylꢀα,βꢀunsaturated amides 2w and 2x was carried out with
K
2
3
CO in methanol at ambient temperature, forming βꢀhydroxyꢀ2,4ꢀdienamides 8a
(74%) and 8b (71%), respectively, demonstrating a potential application of the
resultant α,βꢀunsaturated amide products (eq 5).
A plausible mechanism is proposed in Scheme 5. Initially, enaminone 1 interacts
with PIDA to form iodo(III) intermediate I with release of acetic acid by deprotonaꢀ
tion of the amino group. A redox process is followed to eliminate PhI and generate
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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4
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_
____________________________________________________________________
Scheme 5. Proposed Mechanism
_
____________________________________________________________________
threeꢀmembered alkylthionium species II through intramolecular partial alkylthio
group migration and nucleophilic attack of OAc anion at the imino carbon.
Ringꢀopening of alkylthionium ion II with 1,3ꢀacetyl migration accomplishes the
vicinal alkylthio group migration, affording intermediate species 2′ which has been
isolated and structurally identified by the Xꢀray single crystal structural determiꢀ
nations of 2o′ and 4s′. Enolization of species 2′ followed by Nꢀdeacetylation/
Oꢀacetylation affords the target α,
βꢀunsaturated amide product 2. Alternatively,
enaminone 1 reacts with PIDA to form the olefinic C−H acetoxylation intermediate
1
6
IV, which further interacts with PIDA to undergo deprotonative addition to give
species I′. A process similar to the formation of alkylthionium species II occurs to
generate species II′. Ringꢀopening of alkylthionium ion II′ accompanied by 1,3ꢀacetyl
migration leads to species V, which then reacts with acetic acid generated in situ to
afford intermediate species 2′′. Compounds 2′′ were isolated and structurally
confirmed by the Xꢀray single crystal structural analysis of 2p′′ and 2u′′.
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Conclusions
We have developed an amide bond formation protocol from readily available
alkylthioꢀfunctionalized enaminones (αꢀoxo ketene N,Sꢀacetals) with hypervalent
iodine(III) reagents under mild conditions. Both primary and secondary amineꢀbased
enaminones can be employed as the substrates. Solventless mechanical milling can
also be applied for the same purpose. Intramolecular vicinal alkylthio group migration
is crucial for the amide bond formation, and the process tolerates a wide range of
functional groups. The present work has provided a concise and convenient method to
access multiply functionalized α,βꢀunsaturated amides including βꢀcyclopropylated
acrylamides.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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EXPERIMENTAL SECTION
General Considerations. The solvents were dried and distilled prior to use by the
1
13
1
literature methods. H and C{ H} NMR spectra were recorded on a 400 MHz NMR
1
spectrometer and all chemical shift values refer to δTMS = 0.00 ppm or CDCl (δ( H),
3
1
3
7.26 ppm; δ( C), 77.16 ppm). The HRMS (EI) analysis was obtained on a QꢀTOF
mass spectrometer. Enantiomeric excess was determined by chiral HPLC analysis.
Optical rotations were measured by an polarimeter. All the melting points were
uncorrected. Analytical TLC plates, SigmaꢀAldrich silica gel 60F200 were viewed by
UV light at 254 nm. Column chromatographic purifications were performed on silica
gel. All the chemical reagents were purchased from commercial sources and used as
2
2
23
received unless otherwise indicated. Known compounds 1aꢀc, 1d, 1e, and 1h, 1j,
2
4
25
26
27
28
29
1k, 1o, 1r, and 1z3, 1l and 1m, 1w, 1x, and 1z5, 3s and 3t, 5a, and 5b were
30
prepared as reported. Compound 7b is known and its spectroscopic feature is in
good agreement with that reported in the literature.
A typical procedure for the preparation of enaminones (α–oxo ketene
N,S–acetals) 1aꢀu and 1yꢀz1 − Synthesis of 1a: A mixture of α–oxo ketene
S,S–acetal sm1a (448 mg, 2 mmol) and benzylamine (430 mg, 4 mmol) in EtOH (5
o
mL) was stirred at 80 C overnight. After compound sm1a was completely consumed
by TLC monitoring on silica gel, the resultant mixture was cooled to ambient
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2
2
2
2
2
2
2
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temperature and evaporated all the volatiles under reduced pressure. Purification by
silica gel column chromatography (eluent: petroleum ether (60–90 °C)/AcOEt = 30:1,
v/v) afforded enaminone 1a (489 mg, 86%) as a yellow solid.
A typical procedure for the preparation of enaminones 1z2ꢀz4 − Synthesis of
0
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1z2: In a fashion similar to the synthesis of enaminone 1a, compound sm1a (448 mg,
o
2
mmol) reacted with diethylamine (295 mg, 4 mmol) in CH
3
CN (5 mL) at 80 C to
afford enaminone 1z2 (280 mg, 53%) as a yellow liquid.
A typical procedure for the preparation of enaminones (α–alkenoyl ketene
N,Sꢀacetals) 1vꢀx − Synthesis of 1v: A mixture of BF ·OEt (0.142 g, 1 mmol),
3
2
compound sm1v (2.640 g, 10 mmol) and benzylamine (1.183 g, 11 mmol) in toluene
30 mL) was heated to reflux with stirring. When TLC monitoring on silica gel
(
indicated complete consumption of sm1v, the mixture was cooled to ambient
temperature and evaporated all the volatiles under reduced pressure. Purification by
silica gel column chromatography (eluent: petroleum ether (60−90 °C)/AcOEt = 30:1,
v/v) afforded enaminone 1v (2.200 g, 68%) as a yellow solid.
A typical procedure for the preparation of enaminones (α–cyclopropylꢀ
carbonyl ketene N,S–acetals) 3aꢀz19 − Synthesis of 3w: A mixture of compound
sm3w (500 mg, 2 mmol), trimethylsulfoxonium iodide (440 mg, 2 mmol), NaOH
(800 mg, 20 mmol), and tetrabutylammonium bromide (322, 1 mmol) in 20 mL
o
CH
2
Cl
2
/H
2
O (v/v = 1:1) was stirred at 50 C overnight. After TLC monitoring on
silica gel indicated complete consumption of compound sm3w, the mixture was
cooled to ambient temperature. The organic phase was separated and dried over
2 4
anhydrous Na SO , and evaporated all the volatiles under reduced pressure. The
resultant residue was purified by silica gel column chromatography (eluent: petroleum
ether (60−90 °C)/AcOEt = 10:1, v/v), affording α–oxo ketene dithioacetal sm3w′
(423 mg, 80%) as a white solid. And the preparation of enaminone 3w was
accompolished from the reaction of sm3w′ with benzylamine by following the
procedure used for the synthesis of enaminone 1a.
1
3
13
Preparation of C–labelled α–oxo ketene S,S–acetal sm1a[ C]: Iodomethane
13
(
4.260 g, 30 mmol) was added dropwise to a stirred mixture of acetoꢀ Cꢀphenone
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(
2
sm2) (1.170 g, 10 mmol), NaH (0.800 g, 60% in oil, 20 mmol), CS (1.145 g, 15
o
mmol), and DMF (1 mL) in 19 mL toluene at 0 C. The reaction was continued for 24
h. The resulting mixture was poured into 20 g of ice water, extracted with CH
2 2
Cl
(3×15 mL). The combined organic phase was dried over anhydrous Na SO , and
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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filtered. All the volatiles were removed under reduced pressure, and the residue was
purified by silica gel column chromatography (eluent: petroleum ether
13
(60−90 °C)/AcOEt = 30:1, v/v), affording sm1a[ C] (1.600 g, 71%) as a yellow
solid.
Preparation of C–labelled enaminone 1c[ C]: In a fashion similar to the
13
13
13
preparation of enaminone 1a, a mixture of α–oxo ketene S,S–acetal sm1a[ C] (225
o
mg, 1 mmol) and ethylamine (370 mg, 5 mmol) in EtOH (5 mL) was stirred at 80 C
13
overnight. After compound sm1a[ C] was completely consumed by TLC monitoring
on silica gel, the mixture was cooled to ambient temperature and evaporated all the
volatiles under reduced pressure. The resultant residue was purified by silica gel
column chromatography (eluent: petroleum ether (60−90 °C)/AcOEt = 30:1, v/v),
1
3
affording 1c[ C] (192 mg, 87%) as a colorless liquid.
A typical procedure for the synthesis of α,β–unsaturated amides 2 and 4 −
synthesis of (E)ꢀ3ꢀ(benzylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate
(2a): PhI(OAc)
2
(242 mg, 0.75 mmol) was added to a stirred solution of enaminone
1
a (142 mg, 0.5 mmol) in 1,2ꢀdichloroethane (DCE) (5 mL), and the reaction was
continued at ambient temperature for 2 h until compound 1a was completely
consumed by TLC monitoring on silica gel. The resultant mixture was purified by
o
silica gel column chromatography (eluent: petroleum ether (60−90 C)/AcOEt = 10:1,
v/v) to afford amide 2a (123 mg, 72%) as a white solid.
A typical procedure for the synthesis of α,β–unsaturated amides 2 under the
solventless mechanical milling conditions − synthesis of (2a): A mixture of
2
PhI(OAc) (194 mg, 0.6 mmol) and enaminone 1a (142 mg, 0.5 mmol) was
mechanically milled in a 5ꢀmL glass vial by a glass rod for 5 minutes, and the
resultant yellow liquid mixture was allowed to stay in air at ambient temperature
without milling for about 2 h until compound 1a was completely consumed by TLC
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monitoring on silica gel. The resulting mixture was purified by silica gel column
o
chromatography (eluent: petroleum ether (60−90 C)/AcOEt = 10:1, v/v) to afford
amide 2a (125 mg, 73%) as a white solid.
Gramꢀscale preparation − synthesis of (E)ꢀ3ꢀ(ethylamino)ꢀ2ꢀ(ethylthio)ꢀ3ꢀoxoꢀ
0
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ꢀphenylpropꢀ1ꢀenyl acetate (2s): PhI(OAc) (2.42 g, 7.5 mmol) was added to a
2
stirred solution of enaminone 1s (1.18 g, 5 mmol) in 1,2ꢀdichloroethane (10 mL) at
ambient temperature, and the reaction was continued for 2 h until compound 1s was
completely consumed by TLC monitoring on silica gel. The resultant mixture was
purified by silica gel column chromatography (eluent: petroleum ether (60−90
o
C)/AcOEt = 10:1, v/v) to afford amide 2s (1.06 g, 72%) as a white solid.
1
8
18
2 2
O−Labelling experiment: A mixture of Ac O (62 mg, 0.6 mmol) and H O (20
18
o
mg, 0.5 mmol, 90% O) was stirred at 60 C for 30 minutes. After cooled to ambient
temperature, 1,2ꢀdichloroethane (2 mL), enaminone 1f (89 mg, 0.3 mmol), and
2
PhI(OAc) (145 mg, 0.45 mmol) were successively added with stirring. The reaction
was continued at ambient temperature for 2 h until compound 1f was completely
consumed by TLC monitoring on silica gel. The resultant mixture was purified by
o
silica gel column chromatography (eluent: petroleum ether (60−90 C)/AcOEt = 10:1,
v/v) to afford a 72:28 molar ratio mixture of the target amide product 2f and
18
18
18
O−labelled amide product 2f[ O] as a white solid (76%). Amide 2f[ O] was
1
8
identified by the HRMS analysis, whereas amide 2f[ OAc] was not detected in the
reaction mixture.
Radical trapping experiments: PhI(OAc) (242 mg, 0.75 mmol) was added to a
2
stirred mixture of enaminone 1a (142 mg, 0.5 mmol), TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀ
piperidyloxy) or BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) (1.5 mmol) in 1,2ꢀdichloroꢀ
ethane (5 mL) at ambient temperature, and the reaction was continued for 2 h until 1a
was completely consumed by TLC monitoring on silica gel. The resultant mixture
was purified by silica gel column chromatography (eluent: petroleum ether (60−90
o
C)/AcOEt = 10:1, v/v) to afford 2a as a white solid (65% or 69%).
2
Crossꢀover experiment: PhI(OAc) (484 mg, 1.50 mmol) was added to a stirred
mixture of enaminones 3a (124 mg, 0.5 mmol) and 3z8 (169 mg, 0.5 mmol) in
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,2ꢀdichloroethane (5 mL) at ambient temperature. The reaction was continued for 2 h
until compounds 3a and 3z8 were completely consumed by TLC monitoring on silica
gel. The resultant mixture was purified by silica gel column chromatography (eluent:
o
petroleum ether (60−90 C)/AcOEt = 10:1, v/v) to afford 4a (113 mg, 74%) and 4z8
1
1
1
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8
9
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(134 mg, 68%), respectively.
Reactions of enaminones 5 with PhI(OAc) − synthesis of (E)ꢀ1ꢀoxoꢀ1ꢀphenylꢀ
2
2
3ꢀ(phenylamino)butꢀ2ꢀenꢀ2ꢀyl acetate (7b): PhI(OAc) (242 mg, 0.75 mmol) was
added to a stirred mixture of (Z)ꢀ1ꢀphenylꢀ3ꢀ(phenylamino)butꢀ2ꢀenꢀ1ꢀone (5b) (119
mg, 0.5 mmol), in 1,2ꢀdichloroethane (5 mL) at ambient temperature. The reaction
was continued for 2 h until compound 5b was completely consumed by TLC
monitoring on silica gel. Purification of the resultant mixture by silica gel column
o
chromatography (eluent: petroleum ether (60−90 C)/AcOEt = 10:1, v/v) afforded 7b
(97 mg, 66%) as a white solid. The target amide product 6b was not detected in the
reaction mixture.
Deacetoxylation with K
2
CO
3
− synthesis of (2E,4E)ꢀNꢀbenzylꢀ3ꢀhydroxyꢀ5ꢀ
(4ꢀmethoxyphenyl)ꢀ2ꢀ(thiomethyl)pentaꢀ2,4ꢀdienamide (8a): A mixture of amide 2l
(119 mg, 0.3 mmol) and K CO (21 mg, 0.15 mmol) in MeOH (3 mL) was stirred at
2
3
ambient temperature for five minute. Then 10 mL water was added and the mixture
was extracted with CH Cl (3×10 mL). The combined organic phase was dried over
anhydrous Na SO , and filtered. All the volatiles were evaporated under reduced
2
2
2
4
pressure. Purification by silica gel column chromatography (eluent: petroleum ether
o
(60−90 C)/AcOEt = 50:1, v/v) gave 8a (79 mg, 74%) as a yellow solid.
1
3
13
(
E)ꢀ3ꢀ(Ethylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀoneꢀ C
(1c[ C]):
1
192 mg, yield 87%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.78 (br s, 1 H),
7.83, 7.37 (m each, 2:3 H), 5.61 (d, J = 2.0 Hz, 1 H), 3.38 (m, 2 H), 2.40 (s, 3 H), 1.29
13
1
(t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 185.0, 169.3, 140.7 (d, J =
54.5 Hz), 130.3, 128.1 (d, J = 3.8 Hz), 126.8 (d, J = 2.4 Hz), 85.9 (d, J = 63.9 Hz),
13
+
38.7, 14.8, 14.1. HRMS (EI) calcd for C11 CH16NOS [M+H] : 223.0986; Found:
223.0982.
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(
E)ꢀ3ꢀ(Thiomethyl)ꢀ1ꢀphenylꢀ3ꢀ(1ꢀphenylethylamino)propꢀ2ꢀenꢀ1ꢀone
(1f):
o
1
2
.14 g, yield 72%, yellow solid, mp 80ꢀ82 C. H NMR (400 MHz, CDCl ) δ 12.35 (d,
3
J = 6.8 Hz, 1 H), 7.87, 7.42, 7.35, 7.27 (m each, 2:3:4:1 H), 5.68 (s, 1 H), 4.90 (m, 1
13
1
H), 2.40 (s, 3 H), 1.64 (d, J = 6.8 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 185.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
69.0, 143.5, 40.8, 130.7, 128.9, 128.4, 127.5, 127.1, 126.1, 86.9, 54.3, 24.6, 14.7.
+
HRMS (EI) calcd for C18H20NOS [M+H] : 298.1266; Found: 298.1266.
(E)ꢀ3ꢀ(Benzhydrylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1g): 1.04
o
1
g, yield 29%, white solid, mp 125ꢀ128 C. H NMR (400 MHz, CDCl
3
) δ 12.75 (d, J
= 7.8 Hz, 1 H), 7.90 (dd, J = 7.9 and 1.7 Hz, 2 H), 7.45, 7.38, 7.31 (m each, 3:8:2 H),
13
1
6
.05 (d, J = 8.1 Hz, 1 H), 5.78 (s, 1 H), 2.46 (s, 3 H). C{ H} NMR (100 MHz,
CDCl
3
) δ 185.9, 168.8, 141.4, 140.7, 130.8, 129.0, 128.4, 127.8, 127.4, 127.2, 87.5,
+
6
2.4, 14.8. HRMS (EI) calcd for C H NOS [M+H] : 360.1422; Found: 360.1420.
2
3
22
(E)ꢀ3ꢀ(Thiomethyl)ꢀ1ꢀphenylꢀ3ꢀ((tetrahydrofuranꢀ2ꢀyl)methylamino)propꢀ2ꢀe
1
nꢀ1ꢀone (1i): 1.99 g, yield 72%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.85 (t,
1 H), 7.75, 7.25 (m each, 2:3 H), 5.54 (s, 1 H), 4.96 (m, 1 H), 3.32 (m, 2 H), 1.79,
.51 (m each, 1:2:3:1 H), 3.80, 3.63 (dd each, J = 14.7 and 7.0 Hz, 1:1 H), 2.27 (s, 3
1
1
3
1
H). C{ H} NMR (100 MHz, CDCl
3
) δ 184.6, 169.0, 140.2, 129.9, 127.7, 126.4, 86.1,
+
7
6.6, 67.9, 28.5, 25.4, 47.4, 13.8. HRMS (EI) calcd for C15
78.1215; Found: 278.1215.
H
20NO
2
S [M+H] :
2
(E)ꢀ3ꢀ(Ethylamino)ꢀ1ꢀ(3ꢀfluorophenyl)ꢀ3ꢀ(thiomethyl)propꢀ2ꢀenꢀ1ꢀone (1n):
1
1.70 g, yield 71%, colorless liquid. H NMR (400 MHz, CDCl
3
) δ 11.68 (br s, 1 H),
7
.50 (d, J = 7.8 Hz), 7.44, 7.22, 6.98 (1:1:1:1 H), 5.47 (s, 1 H), 3.29 (m, 2 H), 2.32 (s,
1
3
1
3
3
H), 1.20 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 183.0 (d, J = 2.1
Hz), 169.9, 162.7 (d, J = 245.9 Hz), 143.1 (d, J = 6.2 Hz), 129.6 (d, J = 7.8 Hz), 122.3
(
d, J = 2.8 Hz), 117.0 (d, J = 21.5 Hz), 113.6 (d, J = 22.1 Hz), 85.8, 38.7, 14.6, 14.1.
+
HRMS (EI) calcd for C12
H
15NOSF [M+H] : 240.0858; Found: 240.0858.
(E)ꢀ3ꢀ(Ethylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propꢀ2ꢀenꢀ1ꢀ
1
one (1p): 1.82 g, yield 63%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.83 (br s,
1
1
H), 7.90, 7.61 (d each, J = 8.1 Hz, 2:2 H), 5.58 (s, 1 H), 3.39 (m, 2 H), 2.42 (s, 3 H),
13
1
3
.30 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 183.2, 170.4, 144.1,
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31.8 (q, J = 32.4 Hz), 127.16, 125.18 (q, J = 3.8 Hz), 124.1 (q, J = 272.3 Hz), 86.2,
+
38.9, 14.7, 14.2. HRMS (EI) calcd for C H NOSF [M+H] : 290.0826; Found:
13
15
3
290.0826.
(E)ꢀ3ꢀ(Ethylamino)ꢀ1ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀ(thiomethyl)propꢀ2ꢀenꢀ1ꢀone (1q): 1.90 g,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield 90%, yellow liquid. H NMR (400 MHz, CDCl ) δ 11.39 (br s, 1 H), 7.33 (m, 1
3
H), 6.88 (dd, J = 3.4 and 0.5 Hz, 1 H), 6.34 (dd, J = 3.4 and 1.7 Hz, 1 H), 5.52 (s, 1 H),
13
1
3.27 (m, 2 H), 2.33 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz,
CDCl
3
) δ 174.3, 169.5, 154.3, 143.4, 111.8, 111.6, 85.1, 38.6, 14.5, 14.0. HRMS (EI)
+
calcd for C10
H
14NO
2
S [M+H] : 212.0745; Found: 212.0740.
(E)ꢀ3ꢀ(Ethylamino)ꢀ3ꢀ(thioethyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1s): 1.20 g, yield
1
51%, colorless liquid. H NMR (400 MHz, CDCl
3
) δ 11.82 (br s, 1 H), 7.82, 7.37 (m
each, 2:3 H), 5.67 (s, 1 H), 3.39 (m, 2 H), 2.95 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H),
13
1
1
1
.29 (t, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 185.0, 168.5, 140.8, 130.3, 128.2,
+
26.8, 86.7, 38.7, 25.6, 14.8, 13.6. HRMS (EI) calcd for C13
H
18NOS [M+H] :
236.1109; Found: 236.1110.
E)ꢀ3ꢀ(Thioethyl)ꢀ1ꢀphenylꢀ3ꢀ(1ꢀphenylethylamino)propꢀ2ꢀenꢀ1ꢀone (1t): 2.39
(
o
1
g, yield 77%, yellow solid, mp 106ꢀ108 C. H NMR (400 MHz, CDCl
3
) δ 12.48 (d, J
=
7.3 Hz, 1 H), 7.92, 7.45, 7.39, 7.30 (m each, 2:3:4:1 H), 5.78 (s, 1 H), 4.98 (m, J =
6.9 Hz, 1 H), 2.95 (m, 2 H), 1.67 (d, J = 6.8 Hz, 3 H), 1.38 (t, J = 7.4 Hz, 3 H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 185.3, 168.0, 143.4, 140.6, 130.5, 128.7, 128.2,
127.3, 126.9, 125.9, 87.4, 54.1, 26.0, 24.4, 13.5. HRMS (EI) calcd for C19H22NOS
+
[
M+H] : 312.1422; Found: 312.1426.
(E)ꢀ3ꢀ(Benzylthio)ꢀ3ꢀ(ethylamino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1u): 1.72 g, yield
1
58%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.63 (br s, 1 H), 7.64, 7.18 (m
each, 2:8 H), 5.60 (s, 1 H), 4.01 (s, 2 H), 3.24 (m, 2 H), 1.12 (t, J = 7.2 Hz, 3 H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 167.9, 140.6, 134.8, 130.4, 128.9, 128.8,
+
128.1, 127.9, 126.8, 87.6, 38.8, 36.2, 14.9. HRMS (EI) calcd for C18
H
20NOS [M+H] :
2
98.1266; Found: 298.1267.
1E,4E)ꢀ1ꢀ(Benzylamino)ꢀ1ꢀ(thiomethyl)ꢀ5ꢀpꢀtolylpentaꢀ1,4ꢀdienꢀ3ꢀone (1v):
(
o
1
3
1.52 g, yield 47%, yellow solid, mp 81ꢀ84 C. H NMR (400 MHz, CDCl ) δ 12.28
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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(
br s, 1 H), 7.51, 6.65 (d each, J = 15.7 Hz, 1:1 H), 7.40, 7.12 (d each, J = 8.0 Hz, 2:2
H), 7.30, 7.23 (m each, 4:1 H), 5.16 (s, 1 H), 4.52 (m, 2 H), 2.34 (s, 3 H), 2.31 (s, 3 H).
1
3
1
3
C{ H} NMR (100 MHz, CDCl ) δ 183.0, 169.3, 139.1, 137.6, 127.5, 137.1, 133.1,
1
29.4, 128.7, 127.7, 127.2, 91.5, 47.8, 21.3, 14.2. HRMS (EI) calcd for C20H22NOS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[
M+H] : 324.1422; Found: 324.1415.
(E)ꢀ4ꢀ(Benzylamino)ꢀ4ꢀ(thiomethyl)butꢀ3ꢀenꢀ2ꢀone (1y): 1.10 g, yield 50%,
1
yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.68 (br s, 1 H), 7.36ꢀ7.25 (m, 5 H),
5
.03 (d, J = 2.4 Hz, 1 H), 4.53 (t, 2 H), 2.34 (dd, J = 6.5 and 1.5 Hz, 3 H), 2.08 (d, J =
1
3
1
2.5 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 192.1, 167.9, 137.4, 128.6, 127.4,
+
1
27.1, 89.7, 47.5, 29.0, 14.2. HRMS (EI) calcd for C12
Found: 222.0953.
E)ꢀ4ꢀ(Thiomethyl)ꢀ4ꢀ(4ꢀ(trifluoromethyl)benzylamino)butꢀ3ꢀenꢀ2ꢀone (1z):
H
16NOS [M+H] : 222.0953;
(
o
1
1
.01 g, yield 35%, yellow solid, mp 66ꢀ67 C. H NMR (400 MHz, CDCl
3
) δ 11.69
(br s, 1 H), 7.53, 7.35 (d, J = 8.2 Hz, 2:2 H), 5.01 (s, 1 H), 4.52 (d, J = 6.3 Hz, 2 H),
13
1
2.28 (s, 3 H), 2.03 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 192.9, 167.9, 141.7,
3
1
4
2
29.6 (q, J = 32.4 Hz), 127.2, 125.5 (q, J = 3.8 Hz), 124.0 (q, J = 272.1 Hz), 90.2,
+
6.9, 29.0, 14.0. HRMS (EI) calcd for C13
90.0827.
H
15NOSF
3
[M+H] : 290.0826; Found:
(E)ꢀ4ꢀ(Thiomethyl)ꢀ4ꢀ(1ꢀphenylethylamino)butꢀ3ꢀenꢀ2ꢀone (1z1): 1.53 g, yield
o
1
6
3
5%, yellow solid, mp 51ꢀ54 C. H NMR (400 MHz, CDCl ) δ 11.86 (br s, 1 H),
7.36, 7.30 (m each, 2:3 H), 5.00 (s, 1 H), 4.83 (p, J = 6.9 Hz, 1 H), 2.30 (s, 3 H), 2.11
13
1
(s, 3 H), 1.59 (d, J = 6.8 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 192.2, 167.4,
3
1
43.6, 128.8, 127.3, 125.9, 89.6, 53.9, 29.2, 24.6, 14.4. HRMS (EI) calcd for
+
C
13
H
18NOS [M+H] : 236.1109; Found: 236.1112.
(E)ꢀ3ꢀ(Diethylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1z2): 1.39 g,
1
yield 56%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 7.83, 7.36 (m each, 2:3 H),
13
1
5.83 (s, 1 H), 3.55 (m, 4 H), 2.45 (s, 3 H), 1.20 (m, 6 H). C{ H} NMR (100 MHz,
CDCl
3
) δ 184.3, 169.3, 142.3, 130.2, 128.0, 127.3, 92.9, 47.0, 18.2, 13.3. HRMS (EI)
+
calcd for C14
H
20NOS [M+H] : 250.1266; Found: 250.1273.
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(
E)ꢀ1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(diethylamino)ꢀ3ꢀ(thiomethyl)propꢀ2ꢀenꢀ1ꢀone
1
(
1z4): 1.22 g, yield 43%, yellow liquid. H NMR (400 MHz, CDCl ) δ 7.76 and 7.33
3
(d each, J = 8.5 Hz, 2:2 H), 5.76 (s, 1 H), 3.57 (m, 4 H), 2.46 (s, 3 H), 1.21 (m, 6 H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 182.7, 169.9, 140.7, 136.3, 128.8, 128.3, 92.4,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
4
2
7.2, 18.3, 13.4. HRMS (EI) calcd for C H NOSCl [M+H] : 284.0876; Found:
14
19
84.0876.
(E)ꢀ3ꢀ((Z)ꢀ3,7ꢀDimethyloctaꢀ2,6ꢀdienylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀphenylpropꢀ2
1
ꢀ
enꢀ1ꢀone (1z6): 409 mg, yield 62%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ
11.73 (t, 1 H), 7.78 (dd, J = 7.2 and 2.4 Hz, 2 H), 7.27 (m, 3 H), 5.55 (s, 1 H), 5.24
and 5.02 (t, 1:1 H), 3.87 (t, 2 H), 2.28 (s, 3 H), 2.03 (dd, J = 14.8 and 6.5 Hz, 2 H),
1
3
1
1
.95 (m, 2 H), 1.61, 1.60, and 1.53 (s each, 3:3:3 H). C{ H} NMR (100 MHz,
CDCl ) δ 184.4, 168.7, 140.4, 139.9, 131.2, 130.0, 127.8, 126.5, 123.5, 118.8, 85.7,
3
+
4
1.5, 39.1, 26.0, 25.3, 17.3, 16.0, 13.9. HRMS (EI) calcd for C20
30.1892; Found: 330.1887.
H
28NOS [M+H] :
3
(E)ꢀ3ꢀ(Thiomethyl)ꢀ3ꢀ(8ꢀ((E)ꢀ1ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropꢀ1ꢀenylamin
o)octylamino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1z7): 883 mg, yield 89%, white solid, mp
o
1
1
5
4
8
25ꢀ127 C. H NMR (400 MHz, CDCl
3
) δ 11.87 (s, 2 H), 7.84, 7.39 (m each, 4:6 H),
.63 (s, 2 H), 3.37 (dd, J = 12.8 and 6.8 Hz, 4 H), 2.46 (s, 6 H), 1.69, 1.42, 1.37 (m,
13
1
:4:4 H). C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 169.6, 140.9, 130.5, 128.3, 127.0,
+
6.2, 44.2, 29.6, 29.1, 26.9, 14.4. HRMS (EI) calcd for C28
H
37
N
2
O
2
S
2
[M+H] :
497.2296; Found: 497.2299.
(S,E)ꢀMethyl 2ꢀ(1ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropꢀ1ꢀenylamino)propanoate
1
(
1z8): 1.14 g, yield 41%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 11.97 (d, J =
8
2
1
.0 Hz, 1 H), 7.78, 7.29 (m each, 2:3 H), 5.62 (s, 1 H), 4.34 (m, 1 H), 3.63 (s, 3 H),
13
1
.31 (s, 3 H), 1.45 (d, J = 7.0 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 185.3,
3
71.7, 167.7, 139.9, 130.3, 127.8, 126.6, 87.1, 52.1, 51.9, 18.7, 14.0. HRMS (EI)
+
calcd for C14
H
18NO
3
S [M+H] : 280.1007; Found: 280.1009.
(R,E)ꢀ1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(thiomethyl)ꢀ3ꢀ(1ꢀphenylethylamino)propꢀ2ꢀenꢀ1
o
20
ꢀ
D
one (1z9): 2.55 g, yield 77%, yellow solid, mp 75ꢀ76 C, 99% ee, [α] = +573.56 (c
1
1
.00, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 12.37 (d, J = 6.6 Hz, 1 H), 7.82 (d, J =
2
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
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5
5
5
5
5
5
6
8
.5 Hz, 2 H), 7.36, 7.27 (m each, 6:1 H), 5.62 (s, 1 H), 4.90 (p, J = 6.9 Hz, 1 H), 2.38
13
1
(s, 3 H), 1.64 (d, J = 6.8 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 183.9, 169.3,
3
143.2, 139.0, 136.6, 128.8, 128.4, 128.3, 127.5, 125.9, 86.4, 54.2, 24.5, 14.6. HRMS
+
(EI) calcd for C18
H
19NOSCl [M+H] : 332.0876; Found: 332.0882. HPLC (OGꢀH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
i
column, PrOH/nꢀhexane 10/90, 0.7 mL/min, 254 nm): t = 9.92 min (major), t =
1
2
14.94 min.
(S,E)ꢀ3ꢀ(Thiomethyl)ꢀ3ꢀ(1ꢀphenylethylamino)ꢀ1ꢀ(thiophenꢀ2ꢀyl)propꢀ2ꢀenꢀ1ꢀo
o
20
ne (1z10): 1.79 g, yield 59%, yellow solid, mp 108ꢀ111 C, 98% ee, [α]
D
= ꢀ635.06
1
(c 1.00, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 11.86 (d, J = 7.1 Hz, 1 H), 7.44 (d, J =
3.6 Hz, 1 H), 7.32 (d, J = 4.9 Hz, 1 H), 7.23, 7.15 (m each, 4:1 H), 6.95 (m, 1 H), 5.46
13
1
(s, 1 H), 4.76 (p, J = 6.9 Hz, 1 H), 2.25 (s, 3 H), 1.50 (d, J = 6.8 Hz, 3 H). C{ H}
NMR (100 MHz, CDCl ) δ 178.4, 168.6, 147.1, 143.3, 129.7, 128.8, 127.7, 127.3,
3
+
1
3
27.2, 125.9, 86.3, 54.1, 24.5, 14.5. HRMS (EI) calcd for C16
H18NOS
2
[M+H] :
04.0830; Found: 304.0826. HPLC (OGꢀH column, iPrOH/hexane 15/85, 0.8 mL/min,
254 nm): t = 9.62 min (major), t = 15.69 min.
1
2
(1E,4E)ꢀ1ꢀ(Thiomethyl)ꢀ1ꢀ((S)ꢀ1ꢀphenylethylamino)ꢀ5ꢀoꢀtolylpentaꢀ1,4ꢀdienꢀ3
20
D
ꢀone (1z11): 1.41 g, yield 42%, yellow liquid, 99% ee, [α] = +671.54 (c 1.00,
1
CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 12.56 (d, J = 7.7 Hz, 1 H), 7.93, 6.68 (d each,
J = 15.5 Hz, 1:1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.35 (d, J = 4.4 Hz, 4 H), 7.26, 7.20 (m,
:3 H), 5.17 (s, 1 H), 4.87 (p, J = 6.8 Hz, 1 H), 2.49 (s, 3 H), 2.28 (s, 3 H), 1.63 (d, J =
1
1
3
1
6.8 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 182.4, 168.9, 143.0, 137.2, 134.6,
1
1
35.0, 127.2 , 130.5, 129.5, 128.7, 128.6, 125.9, 125.8, 125.7, 91.6, 54.0, 24.3, 19.8,
+
4.1. HRMS (EI) calcd for C21
H
24NOS [M+H] : 338.1579; Found: 338.1580. HPLC
(
ODꢀH column, iPrOH/hexane 30/70, 0.7 mL/min, 230 nm): t
5.3 min.
1E,4E)ꢀ5ꢀ(4ꢀChlorophenyl)ꢀ1ꢀ(thiomethyl)ꢀ1ꢀ((R)ꢀ1ꢀphenylethylamino)penta
1
= 5.8 min (major), t =
2
1
(
20
ꢀ1,4ꢀdienꢀ3ꢀone (1z12): 0.75 g, yield 21%, yellow liquid, 99% ee, [α]
D
= ꢀ237.71 (c
1
1.00, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 12.53 (d, J = 7.6 Hz, 1 H), 7.52, 6.67 (d
each, J = 15.7 Hz, 1:1 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.33 and 7.26 (m each, 6:1 H),
13
1
5.13 (s, 1 H), 4.85 (q, J = 6.8 Hz, 1 H), 2.33 (s, 3 H), 1.61 (d, J = 6.8 Hz, 3 H). C{ H}
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NMR (100 MHz, CDCl
3
) δ 182.2, 169.4, 143.2, 134.8, 134.5, 136.2, 127.4 , 129.1,
129.0, 128.9, 128.8, 125.9, 91.7, 54.3, 24.5, 14.5. HRMS (EI) calcd for C H NOSCl
20 21
+
[M+H] : 358.1032; Found: 358.1033. HPLC (ADꢀH column, iPrOH/hexane 3/97, 0.7
mL/min, 254 nm): t = 10.0 min (major), t = 11.1 min.
E)ꢀ3ꢀ(((1R,4aS,10aR)ꢀ7ꢀisopropylꢀ1,4aꢀdimethylꢀ1,2,3,4,4a,9,10,10aꢀoctahyd
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
rophenanthrenꢀ1ꢀyl)methylamino)ꢀ3ꢀ(thiomethyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone
1
(1z13): 489 mg, yield 53%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 12.31 (br s,
1
H), 7.93, 7.46, 7.26 (m each, 2:3:1 H), 7.08 (d, J = 8.1 Hz, 1 H), 6.99 (s, 1 H), 5.73
(d, J = 2.1 Hz, 1 H), 3.46 (dd, J = 13.0 and 6.3 Hz, 1 H), 3.31 (dd, J = 13.1 and 5.8 Hz,
1
=
1
1
H), 3.03 (s, 2 H), 2.91 (m, 1 H), 2.51 (s, 3 H), 2.39 (d, J = 12.8 Hz, 1 H), 1.92 (dd, J
10.5 and 7.0 Hz, 2 H), 1.84 (d, J = 11.7 Hz, 2 H), 1.80 (s, 1 H), 1.66 (d, J = 11.4 Hz,
H), 1.56 (s, 1 H), 1.53 (d, J = 2.3 Hz, 2 H), 1.33, 1.31 (3:3 H), 1.14 (s, 3 H), 0.97 (m,
13
1
H). C{ H} NMR (100 MHz, CDCl
30.4, 128.2, 126.9, 126.8, 124.3, 123.9, 86.5, 56.1, 46.4, 38.2, 38.0, 37.6, 36.4, 33.5,
30.3, 26.9, 25.5, 24.0, 19.4, 18.7, 18.3, 14.4. HRMS (EI) calcd for C H NOS
3
) δ 185.2, 169.9, 147.0, 145.6, 140.8, 134.6,
1
30
40
+
[
M+H] : 462.2831; Found: 462.2833.
(E)ꢀ3ꢀ(Benzylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate (2a):
o
1
1
7
1
23 mg, yield 72%, white solid, mp 101ꢀ104 C. H NMR (400 MHz, CDCl
3
) δ 7.53,
.37, 7.30 (m each, 2:7:1 H), 6.73 (br s, 1 H), 4.53 (d, J = 6.0 Hz, 2 H), 2.21 (s, 3 H),
1
3
1
3
.98 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.4, 164.2, 148.8, 138.2, 134.3,
129.7, 128.9, 128.8, 128.21, 128.20, 127.8, 122.2, 43.9, 20.8, 17.0. HRMS (EI) calcd
+
for C H NO S [M+H] : 342.1164; Found: 342.1160.
19 20
3
(E)ꢀ3ꢀ(Methylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate (2b):
o
1
8
7
3
0 mg, yield 60%, white solid, mp 106ꢀ109 C. H NMR (400 MHz, CDCl
3
) δ 7.54,
.37 (m each, 2:3 H), 6.46 (br s, 1 H), 2.91 (d, J = 5.0 Hz, 3 H), 2.21 (s, 3 H), 2.17 (s,
1
3
1
H). C{ H} NMR (100 MHz, CDCl
3
) δ 169.4, 165.0, 149.2, 134.4, 129.6, 128.8,
+
128.2, 122.1, 26.7, 21.0, 17.1. HRMS (EI) calcd for C13
88.0670; Found: 288.0670.
E)ꢀ3ꢀ(Ethylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate (2c): 116
H15NO
3
SNa [M+Na] :
2
(
o
1
3
mg, yield 83%, white solid, mp 109ꢀ112 C. H NMR (400 MHz, CDCl ) δ 7.52, 7.34
2
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
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6
(
m each, 2:3 H), 6.42 (br s, 1 H), 3.35 (p, J = 6.9 Hz, 2 H), 2.19 (s, 3 H), 2.13 (s, 3 H),
13
1
1
.16 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.2, 164.0, 147.8,
3
134.2, 129.4, 128.6, 128.0, 122.5, 34.6, 20.9, 16.7, 14.9. HRMS (EI) calcd for
+
C
14
H
17NO
3
SNa [M+Na] : 302.0827; Found: 302.0824.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
(E)ꢀ3ꢀ(Ethylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl
acetateꢀ C
13
o
1
(
2c[ C]): 104 mg, yield 74%, white solid, mp 118ꢀ121 C. H NMR (400 MHz,
CDCl ) δ 7.53, 7.36 (m each, 2:3 H), 6.41 (br s, 1 H), 3.37 (m, 2 H), 2.21 (s, 3 H),
.15 (s, 3 H), 1.18 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
J = 4.2 Hz), 164.1, 148.1, 134.2 (d, J = 67.7 Hz), 129.6 (d, J = 0.9 Hz), 128.7 (d, J =
.6 Hz), 128.2 (d, J = 4.5 Hz), 122.5 (d, J = 91.8 Hz), 34.7, 21.0 (d, J = 1.9 Hz), 16.8
3
1
3
1
2
3
) δ 169.4 (d,
1
1
3
(d, J = 2.3 Hz), 15.0. C DEPT135 NMR (100 MHz, CDCl
3
) δ 148.0, 129.5 (d, J =
0
.9 Hz), 128.6 (d, J = 1.7 Hz), 128.1 (d, J = 4.5 Hz), 34.6, 20.9 (d, J = 2.0 Hz), 16.8 (d,
13
+
3
J = 2.3 Hz), 14.9. HRMS (EI) calcd for C13 CH17NO SNa [M+Na] : 303.0860;
Found: 303.0856.
(E)ꢀ3ꢀ(Butylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate (2d):
1
1
2
=
32 mg, yield 86%, yellow liquid. H NMR (400 MHz, CDCl
3
) δ 7.52, 7.35 (m each,
:3 H), 6.41 (br s, 1 H), 3.32 (q, J = 6.6 Hz, 2 H), 2.20 (d, J = 0.6 Hz, 3 H), 2.14 (d, J
13
1
0.6 Hz, 3 H), 1.52 (m, 2 H), 1.37 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H). C{ H} NMR
(100 MHz, CDCl
3
) δ 169.3, 164.1, 147.9, 134.2, 129.5, 128.6, 128.1, 122.5, 39.5, 31.7,
+
2
0.9, 20.1, 16.8, 13.7. HRMS (EI) calcd for C16
H
22NO
3
S [M+H] : 308.1320; Found:
308.1316.
E)ꢀ3ꢀ(Cyclohexylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl
(
acetate
2e): 132 mg, yield 79%, white solid, mp 120ꢀ121 C. H NMR (400 MHz, CDCl ) δ
.53 (dd, J = 7.6 and 1.9 Hz, 2 H), 7.34 (m, 3 H), 6.22 (d, J = 8.0 Hz, 1 H), 3.85 (m, 1
H), 2.21 (s, 3 H), 2.14 (s, 3 H), 1.93, 1.71, 1.61, 1.38, 1.18 (m each, 2:2:1:2:3 H).
o
1
(
3
7
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 169.4, 163.0, 146.9, 134.1, 129.4, 128.6, 128.1,
+
122.9, 48.4, 33.1, 25.5 24.8, 20.9, 16.5. HRMS (EI) calcd for C18
34.1477; Found: 334.1481.
E)ꢀ2ꢀ(Thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylꢀ3ꢀ(1ꢀphenylethylamino)propꢀ1ꢀenyl acetate
H24NO
3
S [M+H] :
3
(
o
1
3
(2f): 151 mg, yield 85%, white solid, mp 128ꢀ131 C. H NMR (400 MHz, CDCl ) δ
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7
.56, 7.39, 7.30 (m each, 3:6:1 H), 6.63 (d, J = 7.9 Hz, 1 H), 5.27 (m, 1 H), 2.21 (s, 3
13
1
H), 1.99 (s, 3 H), 1.57 (d, J = 6.9 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.4,
3
163.2, 147.4, 142.8 134.1, 129.5, 128.8, 128.6, 128.1, 127.6, 126.4, 122.6, 49.0, 21.8,
+
20.7, 16.6. HRMS (EI) calcd for C20
H22NO
3
S [M+H] : 356.1320; Found: 356.1314.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Z)ꢀ3ꢀ(Benzhydrylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl
acetate
2g): 188 mg, yield 90%, white solid, mp 128ꢀ130 C. H NMR (400 MHz, CDCl ) δ
.88, 7.71, 7.62 (m each, 2:7:6 H), 7.34 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1 H),
o
1
(
3
7
2
13
1
3
.52 (s, 3 H), 2.22 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.6, 163.5, 148.2,
141.4, 128.9, 128.8, 128.2, 127.7 127.6, 134.2 129.7, 122.4, 57.0, 20.7, 16.9. HRMS
+
(EI) calcd for C25
H
24NO
3
S [M+H] : 418.1477; Found: 418.1472.
(E)ꢀ3ꢀ(allylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl acetate (2h): 108
o
1
mg, yield 74%, white solid, mp 89ꢀ92 C. H NMR (400 MHz, CDCl ) δ 7.54, 7.39
3
(m each, 2:3 H), 6.51 (br s, 1 H), 5.88 (m, 1 H), 5.26 (dd, J = 17.2 and 1.4 Hz, 1 H),
13
1
5.19 (dd, J = 10.2 and 1.2 Hz, 1 H), 3.98 (m, 2 H), 2.23 (s, 3 H), 2.16 (s, 3 H). C{ H}
NMR (100 MHz, CDCl ) δ 169.4, 164.2, 149.1, 134.3, 133.9 117.1, 129.7, 128.8,
3
+
1
28.2, 122.1, 42.3, 21.1, 17.1. HRMS (EI) calcd for C15
14.0827; Found: 314.0823.
H17NO
3
SNa [M+Na] :
3
(E)ꢀ2ꢀ(Thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylꢀ3ꢀ((tetrahydrofuranꢀ2ꢀyl)methylamino)pro
1
3
pꢀ1ꢀenyl acetate (2i): 141 mg, yield 84%, yellow liquid. H NMR (400 MHz, CDCl )
δ 7.52, 7.35 (m each, 2:3 H), 6.76 (br s, 1 H), 3.85 3.73 (dd, J = 15.0 and 7.0 Hz, 1:1
H), 3.99 (m, 1 H), 3.62, 3.21 (m each, 1:1 H), 1.97, 1.87, 1.55 (m each, 1:2:1 H), 2.20
13
1
(s, 3 H), 2.14 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.1, 164.3, 149.0, 134.4,
3
129.5, 128.7, 128.1, 122.2, 77.5, 68.1, 28.8, 25.8, 43.6, 20.9, 16.9. HRMS (EI) calcd
+
for C17
H
22NO
4
S [M+H] : 336.1270; Found: 336.1275.
(Z)ꢀ3ꢀ(Furanꢀ2ꢀylmethylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenyl
o
1
acetate (2j): 121 mg, yield 73%, white solid, mp 99ꢀ102 C. H NMR (400 MHz,
CDCl ) δ 7.54, 7.37 (m each, 1:4 H), 7.53, 6.33 (d, J = 1.9 Hz, 1:1 H), 6.72 (br s, 1 H),
.29 (d, J = 3.1 Hz, 1 H), 4.52 (d, J = 5.8 Hz, 2 H), 2.19 (s, 3 H), 2.07 (s, 3 H). C{ H}
NMR (100 MHz, CDCl ) δ 169.4, 164.0, 151.1, 148.8, 142.4, 110.7, 107.9, 134.2,
29.6, 128.7, 128.2, 122.0, 36.7, 20.8, 16.8. HRMS (EI) calcd for C17 SNa
3
13
1
6
3
1
H17NO
4
2
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2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
[
M+Na] : 354.0776; Found: 354.0773.
(
E)ꢀ3ꢀ(Benzylamino)ꢀ1ꢀ(2ꢀchlorophenyl)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxopropꢀ1ꢀenyl
o
1
acetate (2k): 158 mg, yield 84%, white solid, mp 117ꢀ119 C. H NMR (400 MHz,
CDCl ) δ 7.49, 7.42, 7.36, 7.31, 7.27 (m each, 1:1:4:2:1 H), 6.85 (br s, 1 H), 4.55 (d, J
6.0 Hz, 2 H), 2.19 (s, 3 H), 1.99 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 168.9,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
=
3
1
1
63.5, 148.0, 138.2, 133.7, 133.6, 131.6, 130.7, 129.8, 129.0, 128.2, 127.8, 126.7,
+
24.9, 44.0, 20.8, 16.9. HRMS (EI) calcd for C19
H
19NO
3
SCl [M+H] : 376.0774;
Found: 376.0773.
(E)ꢀ3ꢀ(Benzylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀpꢀtolylpropꢀ1ꢀenyl acetate (2l):
o
1
1
7
6
44 mg, yield 81%, white solid, mp 139ꢀ142 C. H NMR (400 MHz, CDCl
3
) δ 7.46,
.20 (d each, J = 8.1 Hz, 2:2 H), 7.37, 7.32 (m each, 4:1 H), 6.75 (s, 1 H), 4.55 (d, J =
13
1
.0 Hz, 2 H), 2.38 (s, 3 H), 2.24 (s, 3 H), 2.00 (s, 3 H). C{ H} NMR (100 MHz,
CDCl
3
) δ 169.5, 164.4, 149.2, 139.9, 138.2, 131.4, 128.94, 128.92, 128.7, 128.2,
+
1
27.8, 121.5, 43.9, 21.6, 20.8, 17.1. HRMS (EI) calcd for C20
356.1320; Found: 356.1327.
E)ꢀ3ꢀ(Benzylamino)ꢀ1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxopropꢀ1ꢀenyl
H
22NO
3
S [M+H] :
(
o
1
acetate (2m): 162 mg, yield 86%, white solid, mp 148ꢀ151 C. H NMR (400 MHz,
CDCl ) δ 7.47 (d, J = 8.5 Hz, 2 H), 7.34, 7.28 (m, 6:1 H), 6.72 (br s, 1 H), 4.51 (d, J =
3
1
3
1
6
1
3
.1 Hz, 2 H), 2.21 (s, 3 H), 1.97 (s, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.3,
63.9, 147.3, 138.1, 135.5, 132.6, 130.1, 128.9, 128.5, 128.2, 127.8, 122.9, 43.9, 20.7,
+
16.9. HRMS (EI) calcd for C19
H19NO
3
SCl [M+H] : 376.0774; Found: 376.0765.
(
E)ꢀ3ꢀ(Ethylamino)ꢀ1ꢀ(3ꢀfluorophenyl)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxopropꢀ1ꢀenyl
o
1
acetate (2n): 103 mg, yield 69%, white solid, mp 93ꢀ96 C. H NMR (400 MHz,
CDCl ) δ 7.32, 7.25, 7.03 (m each, 2:1:1 H), 6.37 (br s, 1 H), 3.36 (m, 2 H), 2.22 (s, 3
H), 2.15 (s, 3 H), 1.16 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl ) δ 169.3,
3
13
1
3
1
63.7, 162.3 (d, J = 246.4 Hz), 145.8 (d, J = 2.5 Hz), 136.1 (d, J = 8.0 Hz), 129.8 (d, J
= 8.3 Hz), 124.4 (d, J = 3.0 Hz), 116.4 (d, J = 21.2 Hz), 115.6 (d, J = 23.1 Hz), 123.7,
+
3
4.7, 20.8, 16.6, 14.9. HRMS (EI) calcd for C14
Found: 320.0731.
NꢀAcetylꢀNꢀethylꢀ3ꢀ(3ꢀfluorophenyl)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxopropanamide (2n′):
H
16NO
3
SFNa [M+Na] : 320.0733;
2
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2
3
4
5
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7
8
9
o
1
8
2 mg, yield 92%, white solid, mp 60ꢀ63 C. H NMR (400 MHz, CDCl
7.7 Hz, 1 H), 7.68 (d, J = 9.5 Hz, 1 H), 7.44 (dd, J = 13.6 and 7.9 Hz, 1 H), 7.24 (m,
1 H), 5.91 (s, 1 H), 3.81 (q, J = 7.1 Hz, 2 H), 2.24 2.07 (s each, 3:3 H), 1.25 (t, J = 7.2
3
) δ 7.79 (d, J
=
13
1
Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
) δ 188.2 (d, J = 2.2 Hz), 173.4, 168.9,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
62.8 (d, J = 247.4 Hz), 137.6 (d, J = 6.5 Hz), 130.3 (d, J = 7.7 Hz), 124.6 (d, J = 3.0
Hz), 120.1 (d, J = 21.4 Hz), 115.6 (d, J = 22.7 Hz), 56.8, 41.1, 24.8, 14.0, 13.9.
+
HRMS (EI) calcd for C14
H16NO
3
SFNa [M+Na] : 320.0733; Found: 320.0722.
(
E)ꢀ3ꢀ(Benzylamino)ꢀ2ꢀ(thiomethyl)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxopropꢀ1ꢀenyl
o
1
acetate (2o): 156 mg, yield 80%, white solid, mp 125 C. H NMR (400 MHz, CDCl
δ 8.01 (s, 1 H), 7.84 (t, J = 7.5 Hz, 3 H), 7.67 (dd, J = 8.6 and 1.5 Hz, 1 H), 7.51, 7.33
m each, 2:5 H), 6.81 (br s, 1 H), 4.56 (d, J = 6.0 Hz, 2 H), 2.24 (s, 3 H), 2.02 (s, 3 H).
3
)
(
13
1
C{ H} NMR (100 MHz, CDCl ) δ 169.5, 164.2, 148.8, 138.2, 133.7, 132.7, 131.6,
3
1
28.9, 128.8, 128.6, 128.2, 127.9, 127.8, 127.3, 126.6, 125.7, 122.5, 43.9, 20.8, 17.0.
+
HRMS (EI) calcd for C23
H22NO
3
S [M+H] : 392.1320; Found: 392.1317.
NꢀAcetylꢀNꢀbenzylꢀ2ꢀ(thiomethyl)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxopropanamide (2o′):
o
1
1
1
0 mg, yield 5%, white solid, mp 109ꢀ112 C. H NMR (400 MHz, CDCl
3
) δ 8.63 (s,
H), 8.08 (dd, J = 8.6 and 1.6 Hz, 1 H), 7.98, 7.89 (d each, J = 8.1 Hz, 1:1 H), 7.93 (d,
J = 8.7 Hz, 1 H), 7.58, 7.38 (m each, 2:2 H), 7.31 (s, 1 H), 7.29 (d, J = 2.1 Hz, 2 H),
6
.26 (s, 1 H), 5.28, 4.94 (d each, J = 16.8 Hz, 1:1 H), 2.18 (s, 3 H), 2.16 (s, 3 H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 189.9, 174.1, 170.2, 136.4, 135.8, 132.8, 132.7,
130.7, 129.9, 129.2, 128.6, 128.5, 127.9, 127.7, 126.8, 126.3, 124.6, 56.9, 48.6, 25.4,
+
1
4.1. HRMS (EI) calcd for C H NO S [M+H] : 392.1320; Found: 392.1315.
23 22
3
(
E)ꢀ3ꢀ(Ethylamino)ꢀ2ꢀ(thiomethyl)ꢀ3ꢀoxoꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propꢀ1ꢀ
o
1
enyl acetate (2p): 95 mg, yield 55%, white solid, mp 101ꢀ103 C. H NMR (400
MHz, CDCl ) δ 7.65, 7.60 (d each, J = 8.5 Hz, 2:2 H), 6.38 (br s, 1 H), 3.37 (m, 2 H),
3
13
1
2
.23 (s, 3 H), 2.15 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H). C{ H} NMR (100 MHz, CDCl
3
)
δ 169.3, 163.5, 145.9, 137.7, 131.1 (q, J = 32.6 Hz), 129.0, 125.2 (q, J = 3.8 Hz),
1
24.4, 123.8 (q, J = 270.6 Hz), 34.7, 20.8, 16.5, 14.9. HRMS (EI) calcd for
+
C
15
H
17NO
3
SF
3
[M+H] : 348.0881; Found: 348.0876.
1
ꢀ(Ethylamino)ꢀ2ꢀ(thiomethyl)ꢀ1,3ꢀdioxoꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)propanꢀ
2
9
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