Substituent-controlled selective synthesis of N -Acyl 2-aminothiazoles by intramolecular zwitterion-mediated C-N bond cleavage

Article abstract of DOI:10.1021/jo502123k

The cleavage of C-N bonds is an interesting and challenging subject in modern organic synthesis. We have achieved the first zwitterion-controlled C-N bond cleavage in the MCR reaction among lithium alkynethiolates, bulky carbodiimides, and acid chlorides to construct N-acyl 2-aminothiazoles. This is a simple, highly efficient, and general method for the preparation of N-acyl 2-aminothiazoles with a broad range of substituents. The selective synthesis of N-acyl 2-aminothiazoles significantly depends on the steric hindrance of carbodiimides. The result is in striking contrast with our previous convergent reaction giving 5-acyl-2-iminothiazolines via 1,5-acyl migration. It is indeed interesting that the slight change of the substituents on the carbodiimides can completely switch the product structure. Experimental and theoretical results demonstrate the reason why the C-N bond cleavage in the present system is prior to the acyl migration. The intramolecular hydrogen relay via unprecedented Hofmann-type elimination is essential for this totally new zwitterion-controlled C-N bond cleavage.

Full text of DOI:10.1021/jo502123k

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Article
Substituent-Controlled Selective Synthesis of N-Acyl 2-Aminothiazoles
by Intramolecular Zwitterion-Mediated C–N Bond Cleavage
Yang Wang, Fei Zhao, Yue Chi, Wen-Xiong Zhang, and Zhenfeng Xi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502123k • Publication Date (Web): 31 Oct 2014
Downloaded from http://pubs.acs.org on November 6, 2014
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SubstituentꢀControlled Selective Synthesis of NꢀAcyl 2ꢀAminothiazoles by
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Intramolecular ZwitterionꢀMediated C–N Bond Cleavage
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Yang Wang,†,§ Fei Zhao,†,§ Yue Chi,†,§ WenꢀXiong Zhang,*,†,‡ and Zhenfeng Xi†
† Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China;
‡ State Key Laboratory of ElementoꢀOrganic Chemistry, Nankai University, Tianjin, 300071, China
Tel: 86 10 62758294; Fax: 86 10 62751708; Eꢀmail: wx_zhang@pku.edu.cn
The cleavage of C−N bonds is an interesting and challenging subject in modern organic synthesis. We have achieved
the first zwitterion controlled C–N bond cleavage in the MCR reaction among lithium alkynethiolates, bulky
carbodiimides, and acid chlorides to construct Nꢀacyl 2ꢀaminothiazoles. This is a simple, highly efficient and general
method for the preparation of Nꢀacyl 2ꢀaminothiazoles with a broad range of substituents. The selective synthesis of Nꢀ
acyl 2ꢀaminothiazoles significantly depends on the steric hindrance of carbodiimides. The result is in striking contrast
with our previous convergent reaction giving 5ꢀacylꢀ2ꢀiminothiazolines via 1,5ꢀacyl migration. It is indeed interesting
that the slight change of the substituents on the carbodiimides can completely switch the product structure.
Experimental and theoretical results demonstrate the reason why the C–N bond cleavage in the present system is prior
to the acyl migration. The intramolecular hydrogen relay via unprecedented Hofmannꢀtype elimination is essential for
this totally new zwitterion controlled C–N bond cleavage.
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INTRODUCTION
The cleavage of C−N bonds is an interesting and challenging subject in modern organic synthesis.1 The C−N bonds are
usually activated by oxidative addition of a lowꢀvalent transitionꢀmetal complex2 or conversion to diazonium salts,1b
ammonium salts,3 triazenes,4 imidazoles,5 and so on.6 However, as far as we are aware, the zwitterion controlled C−N
bond activation has not yet been achieved (Scheme 1). On the other hand, the Hofmann elimination reaction, which is
the thermal decomposition of a quaternary ammonium salt in the presence of base, is considered generally as a
classical method to construct useful olefins by the expulsion of the tertiary amine. In the whole process, the cleavage of
both C−N bond and C−H bond is observed by the E2 elimination or the cisꢀylide mechanism.7 To date, no example of
Hofmann elimination has been reported via sixꢀmemberedꢀring transition state by the intramolecular zwitterion
hydrogen relay.
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Scheme 1. The New Modes of Zwitterion Controlled C–N Bond cleavage.
We reported a procedureꢀcontrolled selective synthesis of 5ꢀacylꢀ2ꢀiminothiazolines by a convergent multiꢀ
component reaction (MCR) from lithium alkynethiolates, carbodiimides (R1N=C=NR2, R2 = Ph, iPr, and Cy ), and acid
chlorides,8ꢀ10 in which 1,5ꢀacyl migration was considered to be important for the transformation (Scheme 1a). Herein
we wish to report the substituentꢀcontrolled selective synthesis of Nꢀacyl 2ꢀaminothiazoles by reaction of lithium
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t
t
alkynethiolate, bulky carbodiimides (R2 = Bu, Oct, and 1ꢀadamantyl(Ad)), and acid chlorides via the first zwitterion
controlled C−N bond cleavage (Scheme 1b). It is indeed interesting that the slight change of the substituents on the
carbodiimides can completely switch the product structure. The new approach permits a concise and straightforward
route to a wide range of Nꢀacyl 2ꢀaminothiazoles. Experimental and theoretical results demonstrate the reason why the
C–N bond cleavage in the present system is prior to the acyl migration. The intramolecular hydrogen relay via
unprecedented Hofmannꢀtype elimination is essential for this totally new zwitterion controlled C–N bond cleavage.
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RESULTS AND DISCUSSION
Synthesis of NꢀAcyl 2ꢀaminothiazoles. When NꢀtertꢀbutylꢀN’ꢀethylcarbodiimide (EtN=C=NtBu) was allowed to
react with 4ꢀtrifluoromethyl benzoyl chloride at room temperature for 48 h, and then the mixture was treated with
lithium phenylalkynethiolate at 80 °C for 12 h in THF, the new compound 1a could be obtained in 81% yield upon
isolation. Xꢀray crystallographic analysis of 1a revealed unambiguously it Nꢀacyl 2ꢀaminothiazole. The acyl group is
still attached on the nitrogen atom and no tBu is observed in the skeleton of 1a (See Supporting Information for Xꢀray
structure of 1a).
This result clearly shows C−N bond cleavage occurs in carbodiimide. The selective synthesis of Nꢀacyl 2ꢀ
aminothiazole significantly depends on the steric hindrance of the R2 substituent (R2 = tBu). The result is in striking
contrast with our previous convergent reaction giving 5ꢀacylꢀ2ꢀiminothiazolines from lithium alkynethiolates,
carbodiimides (R1, R2 = Pr, Cy, Ph), and acid chlorides.8 Although carbodiimides can act as versatile reagents for
i
organic synthesis and organometallic chemistry,11ꢀ13 the cleavage of chemical bonds in carbodiimide is relatively less
explored in chemical transformations.14ꢀ16
As summarized in Table 1, this substituentꢀcontrolled reaction displayed a broad scope for terminal alkynes.
Aromatic terminal alkynes with either electronꢀdonating or electronꢀwithdrawing substituents all performed well,
giving the corresponding 2ꢀaminothiazoles 1aꢀf. Comparatively, when the substituent was on the orthoꢀposition of
phenyl ring, the reaction proceeded sluggishly and the yield was relatively lower than that of metaꢀ or paraꢀpositions.
Besides, heteroaromatic terminal alkyne such as 2ꢀethynylthiophene, enyne such as cyclohexenylacetylene, and
aliphatic terminal alkynes such as 1ꢀhexyne and cyclohexylacetylene, were also well tolerated, furnishing the
corresponding products 1gꢀj. Then, a series of acid chlorides were suitable acyl source for this reaction. Both the
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electronꢀdonating benzoyl chlorides and electronꢀwithdrawing benzoyl chlorides reacted well, and the desired products
1kꢀr were formed. It was noteworthy that 3ꢀphenylacryloyl chloride could afford 1s. Additionally, aliphatic acid
chlorides gave the corresponding product 1t with slightly lower yield as compared to the aromatic acid chlorides.
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t
t
When R1N=C=NR2 (R1 = Me, hexenyl, and Bn; R2 = Bu, Oct, and Ad) were utilized, the corresponding compounds
1uꢀy could be obtained in good yields. Meanwhile, when R2 = tOct and Ad, similar C–N bond cleavage occurred.
Table 1. Formation of Various NꢀAcyl 2ꢀaminothiazolesa,b
R
SLi
O
N
1) THF, r.t., 48 h
2) 80 C, 12 h
R3
H
+
S
N
R1
N
C
+
N
R2
R1
R
R3COCl
1a-y
from
Et
N
C
N
tBu
O
N
O
H
H
Ar'
S
CF3
S
N
N
N
Ph
Ar
1a
Et
Et
1k: Ar' = Ph, 68%
: Ar = Ph, 81%
1b: Ar = 2-MeC6H4, 57%
1c
1l: Ar' = 2-MeC6H4, 55%
1m: Ar' = 3-MeC6H4, 65%
1n: Ar' = 4-FC6H4, 84%
1o: Ar' = 4-ClC6H4, 72%
1p: Ar' = 2-BrC6H4, 72%
1q: Ar' = 3-MeOC6H4, 64%
1r: Ar' = 4-PhC6H4, 70%
: Ar = 4-MeC6H4, 70%
1d: Ar = 4-NMe2C6H4, 80%
1e
: Ar = 4-MeOC6H4, 83%
1f: Ar = 4-PhC6H4, 75%
1g
: Ar = 2-Thienyl, 60%
O
S
N
O
N
Ph
H
H
CF3
S
N
N
Ph
Et
Et
Et
1s: 65%
1h: 68%
O
S
N
O
H
H
CF3
S
N
N
N
R
Ph
Et
1i: R = nBu, 65%
1j: R = Cy, 54%
1t: 52%
R1
N
C
N
R2
Ar'
from
O
O
N
H
H
CF3
S
N
N
S
N
nhex
Ph
Ph
Me
Ar' = Ph, 62% from R2 = Ad
Ar' = 4-FC6H4 73% from R2 = Ad
1w: 64% from R2 = tBu
1u:
1v:
54% from R2 tOct
=
O
1x: Ar = 4-MeOC6H4, 61%
H
CF3
S
N
from R2 = tBu
N
1y
: Ar = Ph, 73%
from R2 = tBu
Ar
Bn
a Conditions: terminal alkynes, 1 mmol; sulfur, 1 mmol; carbodiimides, 1 mmol;
acid chlorides, 1 mmol; THF, 10 mL, unless otherwise noted. b Isolated yield.
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NꢀAcyl 2ꢀaminothiazole is considered as an important class of small molecule in medicinal and pharmaceutical
chemistry because of their good bioactivities.17 Especially, when Nꢀsubstituent is methyl group, NꢀacylꢀNꢀmethylꢀ2ꢀ
aminothiazoles has been reported to be the cancer cell inhibitors, antiprion molecules, and ligand for the positron
emission tomography (PET) imaging. For example, compound 1u, which could be conveniently synthesized by present
method, was reported to be the inhibitor of cancer cell migration. The low toxicity to healthy cells might lead this
compound 1u to be a therapeutic agent to block tumor metastasis.17a The syntheses of Nꢀacyl 2ꢀaminothiazoles are
usually obtained by the reaction of 2ꢀaminothiazoles with carboxylic acid derivatives,18 or the reaction of 2ꢀ
thioureidoacetic acids and thioacetic acids.19 However, the scope of the reported Nꢀacyl 2ꢀaminothiazoles is limited
because of the unavailability of the starting materials. The present route with a wide range of substrate scope is a
valuable complement to the existing arsenal of Nꢀacyl 2ꢀaminothiazole synthesis.
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Mechanistic Study.
1) The Proposed Mechanisms. Three main pathways were proposed in Scheme 2. In pathway IꢀꢀNucleophilic
addition/LiCl elimination/cyclization/isobutylene elimination, the elimination of LiCl took place before cyclization.
The reaction of R1N=C=NR2 with acid chloride at room temperature for 48 h yielded efficiently Nꢀacyl
chloroformamidine.20 The nucleophilic attack of the lithium alkynethiolate (A) on Nꢀacyl chloroformamidine should
yield the intermediate B with the elimination of LiCl. The fiveꢀmemberedꢀring zwitterion intermediate C would then be
produced by intramolecular cyclization. An intramolecular hydrogen atom relay, the overꢀall result similar to that of
intramolecular Hofmannꢀtype elimination,7 occurred synergistically in the zwitterion intermediate D giving 1 with the
elimination of isobutylene. Alternatively, the stepwise process was also possible. The tertꢀbutyl group in intermediate
C would be eliminated in the cation form. The formed 2ꢀaminothiazole anion intermediate D′ would abstract one
proton from the tertꢀbutyl cation, delivering 1 with the elimination of isobutylene.
In pathway IIꢀꢀNucleophilic addition/cyclization/LiCl elimination/isobutylene elimination, elimination of LiCl took
place after cyclization. The nucleophilic attack of A on Nꢀacyl chloroformamidine resulted in the formation of anion
intermediate B′. The fiveꢀmembered anion intermediate C′ was then produced by intramolecular nucleophilic
cyclization. Then, the elimination of LiCl took place to yield D or D′. Similar to the trapping of proton atom in
pathway I, 1 was finally obtained by concerted or stepwise processes.
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In pathway IIIꢀꢀtBuCl Elimination/nucleophilic addition/cyclization/isobutylene elimination, the elimination of
tBuCl in the Nꢀacyl chloroformamidine occurred in the first step to give Nꢀacyl cyanamide. Then, Nꢀacyl cyanamide
reacted with A, giving the intermediate B′′. The following intramolecular nucleophilic cyclization in B'' gave D′.
Finally, D′ would extract one proton from the eliminated tertꢀbutyl group, delivering the final product 1.
Scheme 2. Proposed Mechanisms.
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In the proposed mechanistic processes, there are four core aspects to be dealt with: (i) The origin of the hydrogen
attached to the C5 atom in 2ꢀaminothiazole ring. No external proton was added in the present system, so the hydrogen
atom should be from the reaction substrates; (ii) The fate or existence form of the cleaved tertꢀbutyl or tertꢀoctyl group
via C−N bond cleavage; (iii) The key steps of C−N and C−Cl bond cleavage in Nꢀacyl chloroformamidine. The C−Cl
bond cleavage takes place before or after C−N bond cleavage or both occur simultaneously. In other words, the
elimination sequence of LiCl in the reaction process is the key; (iv) The reason why C–N bond cleavage in the present
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system is prior to the acyl migration. Thus, we expected to explore the reaction mechanism by the combined
experimental and theoretical studies.
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2) Experimental Studies. To gain mechanistic insight into the origin of the hydrogen at the C5ꢀposition of Nꢀacyl
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n
2ꢀaminothiazole ring, the isotopic labeling experiment was performed. When HexN=C=NC(CD3)3 was used under
above conditions, the deuterium was incorporated exclusively to the C5ꢀposition of the product 1wꢀD (Scheme 3).21
Deuteriumꢀlabeling study unambiguously indicated that the hydrogen atom at the C5ꢀposition of 2ꢀaminothiazole ring
was from the tertꢀbutyl group of carbodiimide.
Next, the tertꢀoctyl substituted carbodiimide (nBuN=C=NtOct) was chosen to detect the byꢀproduct alkene by gas
chromatography mass spectrometry (GCꢀMS) spectroscopic analysis (Scheme 3). The GC retention time and
molecularꢀweight mass fragment ion (m/z = 112) of the alkene was consistent with the standard sample 2,4,4ꢀ
trimethylpentꢀ1ꢀene (See supporting information (SI)). These results of GCꢀMS analysis demonstrated that the
eliminated tertꢀoctyl group was converted into the corresponding alkenes.
In principle, the reaction between Nꢀacyl cyanamide and lithium alkynethiolate might also yield Nꢀacyl 2ꢀ
aminothiazole (pathway III). Therefore, we synthesized the pure Nꢀacyl cyanamide compound 2 by the thermal
decomposition of Nꢀacyl chloroformamidine (Scheme 3).20 No expected reaction between 2 and lithium alkynethiolate
t
was observed. This result illustrated that Bu and chloride atom in Nꢀacyl chloroformamidine was not released before
the reaction, and the C−N bond cleavage should take place after nucleophilic attack of lithium alkynethiolate on Nꢀacyl
chloroformamidine. So the result ruled out the possibility of pathway III.
These experimental results have clearly demonstrated: (i) The hydrogen attached to the C5 atom in 2ꢀaminothiazole
ring was from the eliminated tertꢀbutyl or tertꢀoctyl group of carbodiimide. (ii) The cleaved tertꢀbutyl or tertꢀoctyl
t
group was converted into the corresponding alkenes; (iii) The elimination of BuCl from Nꢀacyl chloroformamidine
giving Nꢀacyl cyanamide does not occur in this process.
Although we could exclude the possibility of the proposed pathway III in Scheme 2, it was still difficult to
distinguish I from II by experiments. In other words, based on the experimental results, we could not know in which
step the elimination of LiCl would occur and whether the proton shift was concerted or stepwise. In addition, the
reason why C–N bond cleavage pathway in the present system was more favored than the acyl migration process was
still unclear. Thus, computational studies were performed to probe this process.
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Scheme 3. Experimental Evidence of Reaction Mechanisms.
3) Computational Studies. DFT calculations were carried out with the GAUSSIAN 03 program package using
the B3LYP method and 6ꢀ31G(d) basis set.22 The computational results of two possible pathways are shown in Figure
2 and discussed as follows. Both pathways start with the same cyclization procedure to give a zwitterion thiazoline
intermediate IM4. IM4 then undergoes either a C–N bond cleavage process to generate the Nꢀacyl 2ꢀaminothiazole
product IM5, or an acyl migration to generate the 5ꢀacylꢀ2ꢀiminothiazoline product IM8.
The Reaction Pathway to Generate the NꢀAcyl 2ꢀaminothiazole IM5. The computational results of C–N bond
cleavage are shown in Figure 1. The reaction between lithium alkynethiolate IM1 and Nꢀacyl chloroformamidine IM2
gives IM3. The large decrease of thermal energy in this step is attributed to the elimination of LiCl, so this calculation
result excludes the possibility of pathway II. However, the released LiCl is still coordinated to the molecule and
behaves as the linker in the dimerization and following steps. IM3 undergoes further transformation via a single
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intramolecular cyclization transition state TS1 with an energy barrier of 29.3 kcal/mol, giving the zwitterion
intermediate IM4, which is 21.1 kcal/mol more unstable than IM3. Due to the IM4’s zwitterionic nature, the Gibbs
free energy of the dimer 2IM4 is favored by 6.2 kcal/mol. Affected by this, the C–N bond cleavage based on 2IM4 is
more favored than that based on monomeric intermediate IM4 (see SI for details).
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The transformation of 2IM4 to IM5 and isobutylene, in which C–N bond cleavage and the C–H bond formation
occurred, is a single step with only one transition state TS2 involved. The Gibbs free energy of IM5 and isobutylene is
52.4 kcal/mol lower than 2IM4 and 37.5 kcal/mol lower than IM3. The energy barrier for the C–N bond cleavage step
is 27.9 kcal/mol, lower than that of the cyclization step (29.3 kcal/mol). These results clearly revealed that pathway I in
which concerted proton shift occurs in C is reasonable, and the mechanism of C–N bond cleavage involves
nucleophilic addition/LiCl elimination/intramolecular cyclization/intramolecular Hofmannꢀtype elimination as key
steps.
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Figure 1. Calculated potential energy surfaces. Coordinated LiCl is omitted for clarity.
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The Reaction Pathway to Generate the 5ꢀAcylꢀ2ꢀiminothiazoline IM8. The transformation of 2IM4 to 5ꢀacylꢀ
2ꢀiminothiazoline product by acyl migration mechanism is also explored (Figure 1). The acyl migration undergoes
through an intermolecular nucleophilic additionꢀelimination mechanism. For the whole acyl migration pathway,
although the Gibbs free energy decreases by 32.3 kcal/mol, the highest energy barrier is 45.2 kcal/mol (TS4), much
higher than that of the C–N bond cleavage pathway. Thus, when one of the substituents on the carbodiimide is tertꢀ
butyl group, the C–N bond cleavage is more preferred than the acyl migration. The calculation results above are in well
agreement with the experiments that only C–N bond cleavage product Nꢀacyl 2ꢀaminothiazole could be obtained in the
present reaction.
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The DFT calculations of C–N bond cleavage pathway and acyl migration pathway clearly displayed the selectivity
of this unique C–N bond cleavage reaction and explained why different class of Nꢀcontaining heterocyclic compounds
could be obtained from the same starting materials by simply switching one of the substituents on the carbodiimide to
the tertꢀbutyl group.
CONCLUSION
We have achieved the first zwitterion controlled C–N bond cleavage in the MCR reaction among lithium
alkynethiolates, bulky carbodiimides, and acid chlorides to construct Nꢀacyl 2ꢀaminothiazoles. This is a simple, highly
efficient and general method for the preparation of 2ꢀaminothiazoles with the broad range of the substituents. The
reaction for the selective synthesis of 2ꢀaminothiazoles is significantly dependent on the steric hindrance of tBu, tOct or
Ad. In this process, the formation of C(sp2)–N, C(sp2)–S, and C(sp2)–H bonds as well as the cleavage of C(sp3)–N and
C(sp2)–Cl bonds are observed. The combined experimental and theoretical studies strongly support the idea that the
reaction proceeds through nucleophilic addition/LiCl elimination/intramolecular cyclization/intramolecular Hofmannꢀ
type elimination as key steps. These results show that: (i) The reaction rateꢀdetermining step is intramolecular
cyclization, and the elimination of LiCl occurs before cyclization; (ii) The hydrogen attached to the C5 atom in 2ꢀ
aminothiazole ring is from the eliminated tBu, tOct or Ad which are finally converted into alkenes; (iii) The proton shift
is concerted by an unprecedented Hofmannꢀtype elimination via the zwitterionꢀmediated sixꢀmemberedꢀring transition
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state; and (iv) When one of the substituents on the carbodiimide was changed to the bulky group, C–N bond cleavage
is more favored than the acyl migration.
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EXPERIMENTAL SECTION
General Method: Unless otherwise noted, all starting materials were commercially available and were used
without further purification. Solvents were purified by a solvent purification system and dried over fresh Na chips in
the glovebox. C6D6 (all 99+ atom% D) was dried over fresh Na chips in the glovebox for NMR analysis. All reactions
were carried out under a dry and oxygenꢀfree nitrogen atmosphere in slightly positive pressure by using Schlenk
techniques or under a nitrogen atmosphere in the glovebox. The nitrogen in the glovebox was constantly circulated
through a copper/molecular sieve catalyst unit. The oxygen and moisture concentrations in the glovebox atmosphere
were monitored by an O2/H2O CombiꢀAnalyzer to ensure both were always below 1 ppm. H and 13C NMR spectra
1
were recorded at room temperature in C6D6 solutions, or in CDCl3 solutions and with tetramethylsilane (0.00 ppm) as
internal standard, unless otherwise noted. Infrared spectra (IR) were recorded on a FTꢀIR spectrometer. Highꢀresolution
mass spectra (HRMS) were recorded on a FTMS mass spectrometer using ESI (electrospray ionization), and the mass
analyzer of the HRMS was ICR (ion cyclotron resonance).
Synthesis of NꢀAcyl 2ꢀaminothiazoles 1aꢀz: In a 25 mL of flask, an acid chloride (1 mmol) was added to a
carbodiimide (1 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 48 h. In another 25 mL of
flask, nꢀBuLi (1 mmol, 1.6 M in hexane) was added dropwise at −78 °C to a stirred solution of terminal alkynes (1
mmol) in THF (5 mL). After stirring at −78 °C for 0.5 h, sulfur (1 mmol, 32 mg) was added and the reaction mixture
was allowed to warm to room temperature for 2 h. The above two reaction solutions were mixed into one flask, which
o
was allowed to heat up to 80 C for 12 h in THF. The solvent of the reaction mixture was evaporated under vacuum.
The residue was purified by chromatography to give products 1aꢀz.
1a: Yellow solid, isolated yield 81% (305 mg); mp: 52.7ꢀ53.3 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.39 (t, J
= 6.9 Hz, 3H), 4.23 (q, J = 6.9 Hz, 2H), 7.27 (s, 1H), 7.31ꢀ7.35 (m, 1H), 7.40ꢀ7.46 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H),
7.73 (d, J = 8.0 Hz, 2H) 7.91 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 109.4, 123.6 (q, J
= 272.5 Hz), 125.8 (q, J = 3.7 Hz), 126.0, 127.1, 128.0, 128.7, 128.8, 132.3 (q, J = 33.0 Hz), 134.6, 138.7, 149.7,
169.1. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C19H16F3N2OS [M+H]+: 377.0935, found 377.0933.
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1b: Yellow solid, isolated yield 57% (223 mg); mp: 145.4ꢀ145.8 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.35 (t,
J = 6.9 Hz, 3H), 2.46 (s, 3H), 4.19 (q, J = 6.9 Hz, 2H), 7.06 (s, 1H), 7.25ꢀ7.27 (m, 3H), 7.58ꢀ7.60 (m, 1H), 7.65 (d, J =
8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 21.3, 45.1, 112.8, 123.6 (q, J =
272.4 Hz), 125.8 (q, J = 3.7 Hz), 125.9, 127.1, 128.0, 129.0, 129.6, 130.9, 132.3 (q, J = 32.9 Hz), 134.7, 136.1, 138.8,
150.3, 169.0. IR (film): ν 1649 (C=O) cmꢀ1; HRMS calcd. for C20H18F3N2OS [M+H]+: 391.1092, found 391.1086.
1c: Yellow solid, isolated yield 70% (273 mg); mp: 96.9ꢀ97.8 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.38 (t, J
= 6.9 Hz, 3H), 2.39 (s, 3H), 4.23 (q, J = 6.9 Hz, 2H), 7.21ꢀ7.24 (m, 3H), 7.63ꢀ7.65 (m, 2H), 7.75ꢀ7.80 (m, 4H); 13C
NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 21.2, 45.2, 108.7, 123.6 (q, J = 272.5 Hz), 125.8 (q, J = 3.7 Hz), 125.9, 127.1,
129.3, 131.9, 132.2 (q, J = 32.8 Hz), 137.8, 138.7, 149.8, 158.4, 169.0. IR (film): ν 1639 (C=O) cmꢀ1; HRMS calcd. for
C20H18F3N2OS [M+H]+: 391.1092, found 391.1094.
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1d: Yellow solid, isolated yield 80% (335 mg); mp: 193.5ꢀ194.5 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.38 (t,
J = 6.9 Hz, 3H), 3.00 (s, 6H), 4.22 (q, J = 6.8 Hz, 2H), 6.77 (d, J = 7.3 Hz, 2H), 7.05 (s, 1H), 7.63ꢀ7.65 (m, 2H), 7.74ꢀ
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7.89 (m, 4H); C NMR (125 MHz, CDCl3, Me4Si): δ 14.1, 45.5, 45.2, 106.2, 122.4 (2C), 123.3, 123.6 (q, J = 280.8
Hz), 125.8 (q, J = 3.4 Hz), 127.0 (2C), 127.2, 132.2 (q, J = 32.9 Hz), 139.0, 150.4, 168.9. IR (film): ν 1649 (C=O) cmꢀ
1; HRMS calcd. for C21H21F3N3OS [M+H]+: 420.1357, found 420.1361.
1e: Yellow solid, isolated yield 83% (337 mg); mp: 67.8ꢀ68.4 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.38 (t, J
= 6.9 Hz, 3H), 3.85 (s, 3H), 4.22 (q, J = 6.9 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H),
7.76 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 55.3, 107.7,
114.0, 123.6 (q, J = 272.6 Hz), 125.8 (q, J = 3.7 Hz), 127.1, 127.3, 127.6, 130.9, 132.4 (q, J = 32.6 Hz), 138.8, 149.5,
159.5, 169.0. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C20H18F3N2O2S [M+H]+: 407.1041, found 407.1039.
1f: Yellow solid, isolated yield 75% (340 mg); mp: 129.7ꢀ130.3 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.39 (t,
J = 6.9 Hz, 3H), 4.23 (q, J = 6.9 Hz, 2H), 7.29 (s, 1H), 7.33ꢀ7.37 (m, 1H), 7.43ꢀ7.47 (m, 2H), 7.62ꢀ7.66 (m, 6H), 7.75
(d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 109.5, 123.6 (q, J =
272.4 Hz), 125.8 (q, J = 3.6 Hz), 126.4, 126.9, 127.1, 127.3, 127.4, 128.8 (2CH), 132.3 (q, J = 33.0 Hz), 133.5, 138.7,
140.6, 149.3, 158.5, 169.1. IR (film): ν 1632 (C=O) cmꢀ1; HRMS calcd. for C25H20F3N2OS [M+H]+: 453.1248, found
453.1250.
1g: Red solid, isolated yield 60% (229 mg); mp: 128.5ꢀ129.1 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.37 (t, J
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= 6.9 Hz, 3H), 4.21 (q, J = 6.9 Hz, 2H), 7.10 (s, 1H), 7.35ꢀ7.37 (m, 1H), 7.47ꢀ7.48 (m, 1H), 7.65 (d, J = 8.1 Hz, 2H),
7.62ꢀ7.78 (m, 3H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 109.0, 121.7, 123.6 (q, J = 272.5 Hz), 125.8,
125.8 (q, J = 3.7 Hz), 126.2, 127.1, 128.8, 132.3 (q, J = 33.0 Hz), 136.9, 138.7, 145.9, 169.1. IR (film): ν 1648 (C=O)
cmꢀ1; HRMS calcd. for C17H14F3N2OS2 [M+H]+: 383.0500, found 383.0498.
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1h: Red solid, isolated yield 68% (258 mg); mp: 74.4ꢀ75.2 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.33 (t, J =
6.9 Hz, 3H), 1.68ꢀ1.69 (m, 2H), 1.78ꢀ1.79 (m, 2H), 2.24 (brs, 2H), 2.40 (brs, 2H), 4.16 (q, J = 6.9 Hz, 2H), 6.72ꢀ6.76
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(m, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H); C NMR (100 MHz, CDCl3, Me4Si): δ 14.0, 22.3, 22.6,
25.5, 25.8, 45.1, 107.5, 123.6 (q, J = 272.5 Hz), 125.7 (q, J = 3.7 Hz), 126.3, 127.1, 128.8, 131.1, 132.2 (q, J = 32.8
Hz), 138.9, 151.5, 169.0. IR (film): ν 3056 (CꢀH), 1670 (C=C), 1653 (C=O) cmꢀ1; HRMS calcd. for C19H20F3N2OS
[M+H]+: 381.1248, found 381.1253.
1i: Yellow oil, isolated yield 65% (232 mg); 1H NMR (400 MHz, CDCl3, Me4Si): δ 0.93 (t, J = 7.3 Hz, 3H), 1.29 (t,
J = 7.0 Hz, 3H), 1.34ꢀ1.42 (m, 2H), 1.63ꢀ1.65 (m, 2H), 2.69 (t, J = 7.3 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 6.64 (s, 1H),
7.61 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 13.8, 13.9, 22.2, 31.1, 31.4,
45.0, 109.6, 123.6 (q, J = 272.5 Hz), 125.6 (q, J = 3.3 Hz), 127.1, 129.9, 132.1 (q, J = 33.0 Hz), 139.0, 152.5, 168.7.
IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C17H20F3N2OS [M+H]+: 357.1248, found 357.1242.
1j: Yellow solid, isolated yield 54% (206 mg); mp: 60.7ꢀ61.7 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.30 (t, J
= 6.9 Hz, 3H), 1.36ꢀ1.41 (m, 4H), 1.71ꢀ1.80 (m, 4H), 2.01ꢀ2.03 (m, 2H), 2.63ꢀ2.67 (m, 1H), 4.12 (q, J = 6.9 Hz, 2H),
6.61 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.0, 26.2,
26.3, 32.6, 40.4, 45.0, 107.9, 123.6 (q, J = 272.6 Hz), 125.6 (q, J = 3.6 Hz), 127.1, 128.8, 132.0 (q, J = 32.8 Hz), 139.1,
157.6, 168.8. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C19H22F3N2OS [M+H]+: 383.1405, found 383.1399.
1k:23 Yellow solid, isolated yield 68% (210 mg); mp: 163.5ꢀ164.1 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.38
(t, J = 6.9 Hz, 3H), 4.27 (q, J = 6.9 Hz, 2H), 7.24 (s, 1H), 7.30ꢀ7.34 (m, 1H), 7.40ꢀ7.44 (m, 2H), 7.46ꢀ7.57 (m, 5H),
7.91ꢀ7.93 (m, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 109.1, 126.0, 126.6, 127.8, 128.60, 128.63,
130.3, 134.7, 135.2, 149.4, 158.8, 170.6. IR (film): ν 1654 (C=O) cmꢀ1; HRMS calcd. for C18H17N2OS [M+H]+:
309.1062, found 309.1056.
1l: Yellow solid, isolated yield 55% (178 mg); mp: 113.6ꢀ114.5 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.29 (t,
J = 6.9 Hz, 3H), 2.33 (s, 3H), 4.13 (brs, 2H), 7.25 (m, 1H), 7.28ꢀ7.43 (m, 7H), 7.92 (d, J = 7.7 Hz, 2H); 13C NMR (100
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MHz, CDCl3, Me4Si): δ 13.8, 19.1, 44.5, 109.0, 125.7, 125.9, 126.0, 127.8, 128.6, 129.7, 130.6, 134.3, 134.7, 135.1,
149.4, 158.3, 170.5. IR (film): ν 1654 (C=O) cmꢀ1; HRMS calcd. for C19H19N2OS [M+H]+: 323.1218, found 323.1217.
1m: Yellow solid, isolated yield 65% (200 mg); mp: 92.8ꢀ93.5 °C; 1H NMR (100 MHz, CDCl3, Me4Si): δ 1.38 (t, J
= 6.9 Hz, 3H), 2.42 (s, 3H), 4.25 (q, J = 6.9 Hz, 2H), 7.24 (s, 1H), 7.30ꢀ7.36 (m, 5H), 7.40ꢀ7.44 (m, 2H), 7.93 (d, J =
8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 21.4, 45.2, 109.1, 123.5, 126.0, 127.2, 127.8, 128.5, 128.6,
131.0, 134.8, 135.1, 138.6, 149.4, 158.9, 170.8. IR (film): ν 1652 (C=O) cmꢀ1; HRMS calcd. for C19H19N2OS [M+H]+:
323.1218, found 323.1218.
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1n: Yellow solid, isolated yield 84% (274 mg); mp: 90.9ꢀ91.5 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.39 (t, J
= 6.9 Hz, 3H), 4.29 (q, J = 6.9 Hz, 2H), 7.15ꢀ7.20 (m, 2H), 7.25 (s, 1H), 7.31ꢀ7.34 (m, 1H), 7.40ꢀ7.44 (m, 2H), 7.53ꢀ
7.57 (m, 2H), 7.91 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.2, 109.5, 123.6 (d, J = 272.4
Hz), 125.8 (d, J = 3.6 Hz), 126.4, 127.0, 127.1, 127.4, 132.3 (d, J = 33.0 Hz), 133.6, 138.7, 140.7, 149.3, 158.6, 169.1.
IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C18H16FN2OS [M+H]+: 327.0967, found 327.0964.
1o: Yellow solid, isolated yield 72% (247 mg); mp: 125.8ꢀ126.8 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.38 (t,
J = 7.0 Hz, 3H), 4.26 (q, J = 7.0 Hz, 2H), 7.25 (s, 1H), 7.31ꢀ7.34 (m, 1H), 7.40ꢀ7.48 (m, 6H), 7.91 (d, J = 7.3 Hz, 2H);
13C NMR (100 MHz, CDCl3, Me4Si): δ 14.1, 45.3, 109.3, 126.1, 127.9, 128.3, 128.7, 129.0, 133.6, 134.6, 136.7, 149.7,
158.9, 169.5. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C18H16ClN2OS [M+H]+: 343.0666, found 343.0669.
1p: Yellow solid, isolated yield 72% (279 mg); mp: 128.0ꢀ128.6 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.33 (t,
J = 6.9 Hz, 3H), 3.85ꢀ3.90 (m, 1H), 4.41ꢀ4.45 (m, 1H), 7.25ꢀ7.44 (m, 7H), 7.66 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.5 Hz,
2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 13.8, 45.6, 99.9, 109.2, 119.2, 126.0, 127.65, 127.8, 128.6, 131.0, 133.0,
134.7, 137.0, 149.5, 158.0, 168.1. IR (film): ν 1647 (C=O) cmꢀ1; HRMS calcd. for C18H16BrN2OS [M+H]+: 387.0163,
found 387.0167.
1q: Yellow solid, isolated yield 64% (217 mg); mp: 77.8ꢀ78.2 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.39 (t, J
= 6.7 Hz, 3H), 3.84 (s, 3H), 4.27 (q, J = 6.9 Hz, 2H), 7.03ꢀ7.10 (m, 3H), 7.24 (s, 1H), 7.30ꢀ7.34 (m, 1H), 7.37ꢀ7.44 (m,
3H), 7.92 (d, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.2, 45.2, 55.4, 109.2, 112.0, 116.3, 118.7,
1256.0, 127.8, 128.6, 129.8, 134.7, 136.4, 149.5, 158.8, 159.7, 170.3. IR (film): ν 1648 (C=O) cmꢀ1; HRMS calcd. for
C19H19N2O2S [M+H]+: 339.1167, found 339.1160.
1r: Yellow solid, isolated yield 70% (269 mg); mp: 109.4ꢀ110.2 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.42 (t,
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J = 6.9 Hz, 3H), 4.33 (q, J = 6.9 Hz, 2H), 7.25 (s, 1H), 7.30ꢀ7.34 (m, 1H), 7.38ꢀ7.49 (m, 5H), 7.60ꢀ7.64 (m, 4H), 7.69ꢀ
7.71 (m, 2H), 7.93 (d, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.2, 45.3, 109.1, 126.0, 127.1, 127.3
(2CH), 127.8, 128.0, 128.6, 128.9, 133.8, 134.7, 139.9, 143.2, 149.5, 158.9, 170.4. IR (film): ν 1654 (C=O) cmꢀ1;
HRMS calcd. for C24H21N2OS [M+H]+: 385.1375, found 385.1361
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1s: Yellow solid, isolated yield 65% (217 mg); mp: 119.8ꢀ120.4 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 1.50 (t,
J = 7.0 Hz, 3H), 4.52 (q, J = 6.7 Hz, 2H), 7.04 (d, J = 15.3 Hz, 1H), 7.20 (s, 1H), 7.28ꢀ7.32 (m, 2H), 7.39ꢀ7.42 (m, 4H),
7.58ꢀ7.60 (m, 2H), 7.91ꢀ7.98 (m, 3H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 14.4, 42.9, 109.3, 116.0, 125.9, 127.7,
128.2, 128.5, 128.9, 130.4, 134.6, 134.7, 145.9, 149.2, 159.0, 165.1. IR (film): ν 3127 (CꢀH), 1649 (C=C), 1616 (C=O)
cmꢀ1; HRMS calcd. for C20H19N2OS [M+H]+: 335.1218, found 335.1213.
1t: Yellow solid, isolated yield 52% (142 mg); 1H NMR (400 MHz, CDCl3, Me4Si): δ 0.99ꢀ1.03 (m, 2H), 1.22ꢀ1.26
(m, 2H), 1.51 (t, J = 7.0 Hz, 3H), 2.01ꢀ2.07 (m, 1H), 4.56 (q, J = 6.9 Hz, 2H), 7.15 (s, 1H), 7.29ꢀ7.32 (m, 1H), 7.39ꢀ
7.43 (m, 2H), 7.91 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 9.3, 12.4, 14.1, 43.0, 108.7, 126.0,
127.7, 128.6, 129.3, 134.9, 149.3, 172.9. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C15H17N2OS [M+H]+:
273.1062, found 273.1051.
1u:17a Yellow solid, isolated yield 62% (182 mg); mp: 82.3ꢀ83.0 °C; 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.76 (s,
3H), 7.26 (d, J = 2.8 Hz, 1H), 7.31ꢀ7.34 (m, 1H), 7.41ꢀ7.44 (m, 2H), 7.50ꢀ7.53 (m, 3H), 7.57ꢀ7.59 (m, 2H), 7.93 (d, J =
7.4 Hz, 2H); 13C NMR (125 MHz, CDCl3, Me4Si): δ 38.4, 109.2, 126.1, 127.6, 127.9, 128.6, 128.7, 130.9, 134.7,
134.8, 149.5, 160.1, 170.4. IR (film): ν 1652 (C=O) cmꢀ1; HRMS calcd. for C17H15N2OS [M+H]+: 295.0905, found
295.0900.
1v:24 Yellow solid, isolated yield 73% (225 mg); mp: 73.1ꢀ73.9 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 3.76 (s,
3H), 7.16ꢀ7.20 (m, 2H), 7.25 (s, 1H), 7.30ꢀ7.34 (m, 1H), 7.40ꢀ7.44 (m, 2H), 7.59ꢀ7.62 (m, 2H), 7.92 (d, J = 7.4 Hz,
2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 38.5, 109.2, 115.8 (d, J = 22.0 Hz), 126.0, 127.9, 128.7, 130.1 (d, J = 8.8
Hz), 130.7, 134.6, 149.5, 160.0, 164.1 (d, J = 252.0 Hz), 169.3. IR (film): ν 1658 (C=O) cmꢀ1; HRMS calcd. for
C17H14FN2OS [M+H]+: 313.0811, found 313.0806.
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1w: Yellow solid, isolated yield 64% from R = tBu (276 mg), 54% from R = Oct (233 mg); mp: 48.5ꢀ49.4 °C; 1H
NMR (400 MHz, CDCl3, Me4Si): δ 0.83 (t, J = 6.5 Hz, 3H), 1.21ꢀ1.26 (m, 6H), 1.78ꢀ1.81 (m, 2H), 4.16 (t, J = 7.2 Hz,
2H), 7.26 (s, 1H), 7.31ꢀ7.35 (m, 1H), 7.41ꢀ7.44 (m, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.90 (d, J =
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7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 13.9, 22.4, 26.2, 28.3, 30.2, 50.0, 109.4, 123.6 (q, J = 272.7 Hz),
125.7 (q, J = 3.3 Hz), 126.0，127.3, 127.9, 128.7, 132.7 (q, J = 33.0 Hz), 134.5, 138.7, 149.6, 158.8, 169.2. IR (film):
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ν 1653 (C=O) cmꢀ1; HRMS calcd. for C23H24F3N2OS [M+H]+: 433.1561, found 433.1550.
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1x: Yellow solid, isolated yield 61% (286 mg); mp: 105.4ꢀ106.1 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 3.82 (s,
3H), 5.47 (s, 2H), 6.89ꢀ6.97 (m, 2H), 7.09ꢀ7.13 (m, 3H), 7.23ꢀ7.26 (m, 3H), 7.51 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2
Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 52.9, 55.3, 108.0, 114.0, 123.5 (q, J = 273.6
Hz), 125.5 (q, J = 3.8 Hz), 126.8, 127.3, 127.4, 127.5, 127.6, 128.6 (2CH), 132.4 (q, J = 32.7 Hz), 136.8, 138.3, 149.5,
159.5, 169.5. IR (film): ν 1653 (C=O) cmꢀ1; HRMS calcd. for C25H20F3N2O2S [M+H]+: 469.1198, found 469.1194.
1y: Yellow solid, isolated yield 73% (320 mg); mp: 117.7ꢀ118.7 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 5.48 (s,
2H), 7.08ꢀ7.10 (m, 2H), 7.23ꢀ7.31 (m, 5H), 7.35ꢀ7.39 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.80
(d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 53.0, 109.7, 123.5 (q, J = 272.5 Hz), 125.6 (q, J = 3.6 Hz),
126.0, 126.8, 127.5, 127.6, 128.0, 128.6 (2CH), 129.1, 132.4 (q, J = 32.1 Hz), 134.3, 136.7, 138.2, 149.7, 169.5. IR
(film): ν 1666 (C=O) cmꢀ1; HRMS calcd. for C24H18F3N2OS [M+H]+: 439.1092, found 439.1087.
1z: Red oil, isolated yield 61% (216 mg); 1H NMR (400 MHz, CDCl3, Me4Si): δ 0.83ꢀ0.88 (m, 3H), 1.24ꢀ1.31 (m,
2H), 1.76ꢀ1.81 (m, 2H), 4.21ꢀ4.26 (m, 2H), 7.15ꢀ7.21 (m, 1H), 7.25ꢀ7.27 (m, 1H), 7.32ꢀ7.36 (m, 1H), 7.41ꢀ7.46 (m,
2H), 7.53ꢀ7.58 (m, 2H), 7.70ꢀ7.75 (m, 1H), 7.90ꢀ7.93 (m, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 13.6, 19.9, 30.5,
49.9, 109.2, 115.8 (d, J = 22.0 Hz), 126.0, 127.9, 128.5 (d, J = 12.5 Hz), 128.7, 129.4 (d, J = 8.6 Hz), , 131.4 (d, J =
27.4 Hz), 132.3 (d, J = 10.7Hz), 134.6, 1149.6, 159.3, 163.8 (d, J = 255.1 Hz), 169.8. IR (film): ν 1654 (C=O) cmꢀ1;
HRMS calcd. for C20H20FN2OS [M+H]+: 355.1275, found 355.1284.
Deuterium Labeling Study: In a 25 mL of flask, 4ꢀ(trifluoromethyl)benzoyl chloride (1 mmol, 208 mg) was added
to deuterated NꢀtertꢀbutylꢀN’ꢀnonꢀhexyl carbodiimide (1 mmol, 191 mg) in THF (10 mL), and the mixture was stirred
at room temperature for 48 h. In another 25 mL of flask, nꢀBuLi (1 mmol, 1.6 M in hexane) was added dropwise at
−78 °C to a stirred solution of phenylacetylene (1 mmol, 102 mg) in THF (5 mL). After stirring at −78 °C for 0.5 h,
sulfur (1 mmol, 32 mg) was added and the reaction mixture was allowed to warm to room temperature for 2 h. The
o
above two reaction solutions were mixed into one flask, which was allowed to heat up to 80 C for 12 h in THF. The
solvent of the reaction mixture was evaporated under vacuum. The residue was purified by chromatography to give the
deuterated 2ꢀaminothiazole 1wꢀD.
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1wꢀD: Yellow solid, isolated yield 61% (264 mg); mp: 80.5ꢀ81.2 °C; 1H NMR (400 MHz, CDCl3, Me4Si): δ 0.83 (t,
J = 6.4 Hz, 3H), 1.21ꢀ1.26 (m, 6H), 1.77ꢀ1.81 (m, 2H), 4.16 (t, J = 7.2 Hz, 2H), 7.31ꢀ7.34 (m, 1H), 7.40ꢀ7.44 (m, 2H),
7.64 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.89ꢀ7.91 (m, 2H); 13C NMR (100 MHz, CDCl3, Me4Si): δ 13.9,
22.4, 26.2, 28.3, 31.1, 50.0, 109.4, 123.6 (q, J = 270.9 Hz), 125.7 (q, J = 3.6 Hz), 126.0，127.4, 128.0, 128.7, 132.4 (q,
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J = 32.7 Hz), 134.6, 138.7, 149.7, 158.9, 169.2. IR (film): ν 1655 (C=O) cmꢀ1; HRMS calcd. for C23H23DF3N2OS
[M+H]+: 434.1624, found 434.1621.
2,4,4ꢀTrimethylpentꢀ1ꢀene Detected by GCꢀMS Analyses: In a 25 mL of flask, 4ꢀfluorobenzoyl chloride (1
mmol, 158 mg) was added to NꢀtertꢀoctylꢀN’ꢀnonꢀbutyl carbodiimide (1 mmol, 210 mg) in THF (10 mL), and the
mixture was stirred at room temperature for 48 h. In another 25 mL of flask, nꢀBuLi (1 mmol, 1.6 M in hexane) was
added dropwise at −78 °C to a stirred solution of phenylacetylene (1 mmol, 102 mg) in THF (5 mL). After stirring at
−78 °C for 0.5 h, sulfur (1 mmol, 32 mg) was added and the reaction mixture was allowed to warm to room
temperature for 2 h. The above two reaction solutions were mixed into one flask, which was allowed to heat up to 80
oC for 12 h in THF. Then, 200 ꢁL of the reaction mixture was taken using a syringe and GCꢀMS analyse was carried
out. GCꢀMS analyses were performed on a gas chromatograph coupled to MS detector (EI, quadrupole mass
spectrometer, diffusion pump; 1100 ChemStation). GCꢀMS conditions were as follows: 30 m × 0.25 mm i.d. fused
silica capillary column with 0.25 ꢁm film thickness and a carrier gas of helium (8.8 psi) with total flow rate of 23.9
mL/min were used; initial temperature was 40 °C; temperature increased at 30 °C/min up to 300 °C; injector and
detector temperatures were 250 °C.
Isolation and Reaction of NꢀAcyl Cyanamide: In a 25 mL of flask, cyclohexanecarbonyl chloride (1 mmol, 146
mg) was added with stirring to NꢀtertꢀbutylꢀN’ꢀethyl carbodiimide (1 mmol, 126 mg) in THF (10 mL) at room
temperature. After 72 h, the reaction mixture was concentrated in vacuum to give Nꢀacyl cyanamide 2. No reaction
t
between 2 and lithium alkynethiolate was observed. This result illustrated that Bu and chloride atom in Nꢀacyl
chloroformamidine were not be released before the reaction, and the C−N bond cleavage takes place after nucleophilic
attack of lithium alkynethiolate on Nꢀacyl chloroformamidine. So it ruled out the possibility of pathways III.
1
2: Yellow oil, isolated yield 44% (79 mg); H NMR (300 MHz, C6D6): δ 0.22ꢀ0.28 (m, 3H), 0.40ꢀ0.48 (m, 2H),
13
0.73ꢀ0.82 (m, 4H), 0.90ꢀ0.95 (m, 2H), 1.13ꢀ1.17 (m, 2H), 2.05ꢀ2.14 (m, 1H), 2.49ꢀ2.57 (m, 2H); C NMR (75 MHz,
C6D6): δ 12.7, 25.2, 25.7, 29.1, 41.1, 42.9, 110.5, 174.5. HRMS calcd. for C10H17N2O [M+H]+: 181.1341, found
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181.1333.
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Computational Methods: All calculations were carried out with the GAUSSIAN 03 program package.25 All the
minima and transition states were fully optimized at the B3LYP level26 using the 6ꢀ31G(d) basis set. Harmonic
frequency calculations were performed at the same level for every structure to confirm it as a local minimum or
transition state and to derive the thermochemical corrections for enthalpies and free energies. The intrinsic reaction
coordinate (IRC) analysis27 was carried out throughout the pathways to confirm that all stationary points are smoothly
connected to each other. Solvent effects in THF (ε = 7.58) were evalulated by single point calculations using the PCM
model28 for all the stationary points. All enthalpies and the Gibbs free energies in the text were given in kcal/mol and
calculated for standard conditions (298 K, 1 atm). All distances were given in Å.
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Xꢀray Crystallographic Studies: Single crystals of 1a suitable for Xꢀray analysis were grown in CH2Cl2/hexane at
room temperature for 3 days. Data collections for 1a were performed at 20 °C on an IP diffractometer, using graphiteꢀ
monochromated Mo Kα radiation (λ = 0.71073 Ǻ). The determination of crystal class and unit cell parameters was
carried out by RapidꢀAUTO program package for 1a. The raw frame data was processed using Crystal Structure for 1a
to yield the reflection data file. The structure of 1a was solved by use of SHELXTL program. Refinement was
performed on F2 anisotropically for all the nonꢀhydrogen atoms by the fullꢀmatrix leastꢀsquares method. The hydrogen
atoms were placed at the calculated positions and were included in the structure calculation without further refinement
of the parameters. Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDCꢀ929572(1a). Copies of these data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ASSOCIATED CONTENT
Supporting Information
Xꢀray data for 1a, scanned NMR spectra of all new products, and computational details. This material is available free
of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail: wx_zhang@pku.edu.cn
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Author Contribution
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§ These authors contribute equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Natural Science Foundation of China, and the 973 Program (2011CB808600).
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