Procedure-controlled selective synthesis of 5-acyl-2-iminothiazolines and their selenium and tellurium derivatives by convergent tandem annulation

Article abstract of DOI:10.1002/anie.201101948

Concise and selective: The procedure-controlled synthesis of the title compounds has been achieved for the first time by an organolithium-promoted convergent tandem annulation involving readily available terminal alkynes, chalcogen elements (S, Se, and Te

Full text of DOI:10.1002/anie.201101948

Communications
DOI: 10.1002/anie.201101948
Synthetic Methods
Procedure-Controlled Selective Synthesis of 5-Acyl-2-iminothiazolines
and their Selenium and Tellurium Derivatives by Convergent Tandem
Annulation**
Yang Wang, Wen-Xiong Zhang,* Zitao Wang, and Zhenfeng Xi*
Convergent synthesis is of considerable importance in the
construction of complex molecules, with the aim of improving
the efficiency of multistep organic synthesis.[1] Tandem
annulation enables the quick and efficient construction of
important cyclic compounds using common and readily
available chemicals.[2] The combination of convergent syn-
thesis and tandem annulation not only improves step
economy and operational simplicity for the synthesis of
important molecules, but can also change the reaction path-
way and lead to unexpected discoveries.
In the course of our study of the tandem sequential
synthesis of 2,3-dihydropyrimidinthione from terminal
alkynes, elemental sulfur, carbodiimides, and acid chlorides
(Scheme 1),[9] we tried adding carbodiimides and acid chlor-
2-Iminothiazoline is a considerably important building
block for pharmaceuticals that have powerful biological and
pharmacological activities.[3] Although the synthesis of 2-
iminothiazolines has received much interest,[4–8] 5-acyl-2-
iminothiazoline is rarely seen because of the difficulty in
introducing an acyl group at the 5-position of 2-iminothiazo-
line. Only one method was reported for the synthesis of 5-
acyl-2-iminothiazolines and the yields were low.[6] More
importantly, the synthesis of 5-acyl-2-iminoselenazolines and
5-acyl-2-iminotellurazolines, which are new types of hetero-
cyclic compounds, are not reported. Thus, a simple, efficient,
and general method to synthesize 5-acyl-2-iminothiazolines
and their selenium and tellurium derivatives is of great
importance to academia and to the pharmaceutical industry.
Herein, we report a concise and efficient synthesis of 5-acyl-2-
iminothiazolines and their selenium and tellurium derivatives
by a convergent tandem annulation using readily available
terminal alkynes, chalcogen elements (S, Se, and Te),
carbodiimides, and acid chlorides.
Scheme 1. Procedure-controlled selective synthesis of different N,E-
containing compounds from the same starting materials.
ides simultaneously to lithium alkynethiolate, which had been
generated in situ from a lithium acetylide and sulfur.[10]
Interestingly, the simultaneous addition of a carbodiimide
and an acid chloride, instead of the sequential addition, led to
the observation of trace amounts of 5-acyl-2-iminothiazoline.
After many screening experiments, a new protocol was
established. Thus, after N,N’-diisopropylcarbodiimide
=
(iPrN = C NiPr) was treated with benzoyl chloride at room
temperature for 48 h, then treated with lithium alkynethiolate
at 808C for 12 hours in THF, 5-acyl-2-iminothiazoline 1a was
obtained in 67% yield upon isolation (Scheme 2). X-ray
crystallographic analysis of 1a revealed unambiguously that
the acyl group was at the 5-position of 2-iminothiazoline
(Figure 1).
The reaction is dependent on the convergent procedure as
the result is in striking contrast with our reported tandem
sequential reaction, which yielded 2,3-dihydropyrimidin-
thione,[9] even though the four starting materials: phenyl-
ethyne, sulfur, carbodiimide, and acid chloride, remained
unchanged (Scheme 1). Representative examples of 5-acyl-2-
iminothiazolines, 5-acyl-2-iminoselenazolines, and 5-acyl-2-
iminotellurazolines, which were all obtained from the nBuLi-
mediated convergent coupling of terminal alkynes, chalcogen
elements (S, Se, and Te), carbodiimides, and acid chlorides,
are shown in Scheme 2.
[*] Y. Wang, Prof. Dr. W.-X. Zhang, Z. Wang, Prof. Dr. Z. 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)
E-mail: wx_zhang@pku.edu.cn
zfxi@pku.edu.cn
Prof. Dr. W.-X. Zhang
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
[**] This work was supported by the Natural Science Foundation of
China, the Key Project of International Cooperation of NSFC
(20920102030), and the “973” program from MOST of China
(2011CB808601). We also thank Yue Chi for experimental assistance
and Prof. Pixu Li of Soochow University for useful discussion.
= =
As shown in Scheme 2, carbodiimides, such as iPrN C
= =
= =
=
NiPr, CyN C NCy, PhN C NCy, and PhN = C NPh, could
be used as suitable nitrogen sources to give the corresponding
compounds 1a–z in moderate to high yields upon isolation. A
Supporting information (including full experimental details and
compound characterization) for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101948.
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Angew. Chem. Int. Ed. 2011, 50, 8122 –8126

Figure 1. ORTEP drawing of 1a with 20% thermal ellipsoids. Hydrogen
atoms are omitted for clarity. Selected bond lengths [ꢀ]: C1–C3
1.364(2), C2–S1 1.7718(16), C3–S1 1.7625(16), C1–N2 1.3785(19), C2–
N2 1.4090(19), C2–N1 1.268(2), C13–N2 1.4879(19), C16–O1
1.232(2).
ring were converted into the corresponding products with
high efficiency. The heteroaromatic terminal alkynes, such as
3-ethynylthiophene (!1h), showed good reactivity as well.
Furthermore, the aliphatic terminal alkynes could also be
applied in this reaction to provide the compounds 1e, 1o, 1s,
and 1t. In addition, the nBuLi-promoted convergent reaction
= =
of the diyne 1,4-diethynylbenzene, elemental sulfur, CyN C
NCy, and 4-trifluoromethylbenzoyl chloride afforded the
corresponding bis(5-acyl-2-iminothiazoline) 1u in 75% yield
upon isolation.
Notably selenium, which like sulfur is in the chalcogen
group, could be utilized in the present procedure to produce
5-acyl-2-iminoselenazolines 1v–x in quantitative yields.[11]
Similarly, 5-acyl-2-iminotellurazolines 1y and 1z were
obtained with excellent selectivity and quantitative yields
ꢀ
(Scheme 2). The reaction conditions required for RC CSeLi
ꢀ
and RC CTeLi were much milder and faster (RT, 5 min) than
ꢀ
those required for RC CSLi (808C, 12 h). To the best of our
knowledge, our method demonstrates the first synthesis of the
5-acyl-2-iminoselenazolines and 5-acyl-2-iminotellurazolines,
which represent new types of compounds that contain nitro-
gen and selenium, and nitrogen and tellurium.
These interesting and novel results intrigued us and
encouraged us to explore the reaction mechanism, especially
with regards to the position of the acyl group. It is reported in
the literature that the reaction of a carbodiimide[12–15] with an
acid chloride gives either an N-acyl chloroformamidine[16] or
an N-acyliminium salt.[17] So we aimed to isolate and
characterize the species produced by the reaction of a
carbodiimide with an acid chloride. The reaction between a
symmetric carbodiimide and an acid chloride afforded com-
pound 2a in a quantitative yield at room temperature after
48 hours (Scheme 3). When the unsymmetrical carbodiimide
Scheme 2. Isolation and reaction of 2a–c from symmetric or unsym-
metrical carbodiimides and acid chlorides.
= =
PhN C NCy was treated with 4-trifluoromethylbenzoyl
chloride, compound 2b was obtained as the only regioisomer.
X-ray crystallographic analysis of 2a and 2b revealed
unambiguously that they are N-acyl chloroformamidines
wide range of aromatic benzoyl chlorides with either electron-
donating and electron-withdrawing groups on either the meta
or para position of the phenyl skeleton gave the correspond-
ing products 1a–o in good yields. The heteroaromatic acid
chloride 2-thienyl chloride (!1p) was also an appropriate
substrate. Aliphatic acid chlorides also acted as a suitable acyl
source to yield the corresponding compounds 1q and 1r. As
far as the alkynes were concerned, the aromatic terminal
alkynes with ortho, meta, and para substituents on the phenyl
=
and that the imine C N bond adopts a Z configuration
(Figure 2). In addition, the acyl group in 2b is clearly attached
to the nitrogen atom neighboring the phenyl group (Figure 2).
These results are the first assured evidence of the structure of
the adduct between a carbodiimide and an acid chloride.
Next the isolated N-acyl chloroformamidine 2a was
treated with the lithium alkynethiolate and lithium alkyne-
selenolate. 5-Acyl-2-iminothiazoline 1b and 5-acyl-2-imino-
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Communications
Scheme 3. Formation of 5-acyl-2-iminothiazolenes, 5-acyl-2-iminosele-
nazolines, and 5-acyl-2-iminotellurazolines. Reaction conditions: termi-
nal alkynes (1 mmol), sulfur, selenium, or tellurium (1 mmol), nBuLi
(1 mmol), carbodiimides (1 mmol), acid chlorides (1 mmol), THF
(10 mL), unless otherwise noted. The yields (%) are of the isolated
products. [a] Reaction conditions: terminal dialkyne (1 mmol), sulfur
(2 mmol), nBuLi (2 mmol), carbodiimide (2 mmol), acid chloride
(2 mmol).
Scheme 4. Possible mechanisms for the formation of 1.
chloroformamidine, the intermediate B would be formed. A
five-membered-ring intermediate C would then be produced
by intramolecular cyclization. The carbanion in C could
attack the carbon atom of the amide group to give the bicyclic
intermediate D.[18] Finally, 1 would be generated by an acyl
ꢁ
shift through a C N bond cleavage with LiCl elimination
(Scheme 4, pathway a). Alternatively, as shown in pathway b,
elimination of LiCl may initially take place, thus affording the
final products 1 through intermediates B’, C’, and D’.
These results show a novel acyl 1,5-migration. Acyl
migration is one of the fundamental bond-forming trans-
formations in organic chemistry. Although 1,n-acyl migrations
(n = 2, 3, 4) are well established[19,20] the remote 1,5-acyl
migration is rare.[21]
In summary, a concise and procedure-controlled selective
synthesis of 5-acyl-2-iminothiazolines and their selenium and
tellurium derivatives has been achieved for the first time by
an organolithium-promoted convergent tandem annulation
involving readily available terminal alkynes, chalcogen ele-
ments (S, Se, and Te), carbodiimides, and acid chlorides. A
novel 1,5-acyl migration is considered to be essential for such
a useful and interesting transformation. The application of the
5-acyl-2-iminothiazolines and their selenium and tellurium
derivatives as well as a study of the reactions of N-acyl
chloroformamidines are in progress.
Figure 2. ORTEP drawing of 2a (left) and 2b (right) with 20% thermal
ellipsoids. Hydrogen atoms are omitted for clarity. Selected bond
lengths [ꢀ]: 2a: C7–Cl1 1.794(2), C7–N1 1.1.242(3), C7–N2 1.406(3),
C8–N2 1.485(3), C1–N1 1.461(3), C14–N2 1.387(3), C14–O1 1.214(3);
2b: C1–Cl1 1.780(5), C1–N1 1.217(5), C1–N2 1.411(5), C2–N2
1.423(5), C8–N1 1.474(5), C14–N2 1.417(5), C14–O1 1.211(4).
selenazoline 1w’ were obtained in 71% and 99% yields,
respectively, upon isolation (Scheme 2). Similarly, 1d and 1v
were obtained in high yields. The phenyl group from the
carbodiimide is positioned regioselectively on the nitrogen
=
atom of the imine C N bond in 1d.
A cross-over experiment was carried out to determine
whether the transfer of the acyl group occurs by an intra-
molecular or intermolecular process. When a 1:1 molar
mixture of 2a and 2c was treated with 2 equivalents of the
lithium alkyneselenolate, their respective products, 1w’ and
1v, were quantitatively formed in a 1:1 molar ratio, according
to 1H NMR analysis (see the Supporting Information for
details), and no cross-over products were detected. This
experiment indicated that an intramolecular acyl transfer was
operating in the reaction process.
Based on the preliminary results, the proposed mecha-
nisms for the formation of 5-acyl-2-iminothiazolines and their
selenium and tellurium derivatives 1 are shown in Scheme 4.
The reaction between a lithium acetylide and chalcogen
elements (E = S, Se, and Te) should yield the lithium
intermediate A. After nucleophilic attack by A on N-acyl
Experimental Section
Preparation of 5-acyl-2-iminothiazoline 1a: In a 25 mL flask, benzoyl
chloride (1 mmol) was added to N,N’-diisopropylcarbodiimide
(1 mmol) in THF (10 mL), and the mixture was stirred at room
temperature for 48 h. In another 25 mL flask, nBuLi (1 mmol, 1.6m in
n-hexane) was added dropwise at ꢁ788C to a solution of phenyl-
ethyne (1 mmol) in THF (5 mL), and the mixture was stirred at
ꢁ788C for 0.5 h. Then sulfur (1 mmol, 32 mg) was added and the
reaction mixture was warmed to room temperature for 2 h. The above
two reaction solutions were mixed into one flask, which was heated to
808C for 12 h in THF. The solvent was evaporated under vacuum and
the residue was purified by flash column chromatography on silica gel
(eluent 1:1 dichloromethane/petroleum ether) to give product 1a.
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Angew. Chem. Int. Ed. 2011, 50, 8122 –8126

Single crystals of 1a suitable for X-ray crystallographic analysis were
grown in CH2Cl2/n-hexane at room temperature for 3 days. Yellow
solid, yield 67% (243 mg); m.p. 128.3–129.18C; H NMR (400 MHz,
CDCl3, Me4Si): d = 1.21 (d, J = 6.2 Hz, 6H, CH3), 1.44 (d, J = 6.8 Hz,
6H, CH3), 3.15–3.22 (m, 1H, CH), 3.85–3.92 (m, 1H, CH), 6.96–
7.20 ppm (m, 10H, CH); 13C NMR (100 MHz, CDCl3, Me4Si): d =
18.99, 22.97, 51.21, 56.59, 112.57, 127.24, 127.64, 128.11, 129.30, 129.47,
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~
129.89, 130.71, 139.13, 150.19, 151.24, 187.69 ppm; IR (film): n = 1622
ꢁ1
=
=
(C O), 1544 cm (C N); HRMS (ESI): m/z: calcd for C22H25N2OS:
365.1682 [M+H]+; found: 365.1684.
Isolation of N-acyl chloroformamidine 2b: In a 25 mL flask, 4-
trifluoromethylbenzoyl chloride (1 mmol) was added with stirring to
N-cyclohexyl-N’-phenylcarbodiimide (1 mmol) in THF (10 mL) at
room temperature. After 48 h, the reaction mixture was concentrated
under vacuum to leave N-acyl chloroformamidine 2b. Single crystals
of 2b that were suitable for X-ray crystallographic analysis were
grown in THF/n-hexane at room temperature under nitrogen for
2 days. Colorless solid, yield > 99% (408 mg); m.p. 73.6–74.38C;
1H NMR (300 MHz, C6D6): d = 1.00–1.35 (m, 10H, CH2), 3.41 (brs,
1H, CH), 6.91–7.12 (m, 5H, CH), 7.23 (d, J = 7.2 Hz, 2H, CH),
7.53 ppm (d, J = 7.8 Hz, 2H, CH); 13C NMR (75 MHz, C6D6): d =
23.79, 25.567, 31.75, 61.64, 124.30 (q, JC-F = 270.7 Hz), 125.44 (q, JC-F
3.7 Hz), 127.25, 128.32, 128.78, 129.59, 130.96, 132.49 (q, JC-F
=
=
=
~
32.1 Hz), 138.45, 139.88, 169.18 ppm; IR (film): n = 1678 (C O),
1596 cmꢁ1 (C N); HRMS (ESI): m/z: calcd for C21H21ClF3N2O:
=
409.1289 [M+H]+; found: 409.1300.
Crystallographic data for 1a: C22H24N2OS, Mr = 364.49 gmolꢁ1
,
T= 293(2) K, monoclinic, space group P21/c, a = 10.780(2), b =
11.792(2), c = 16.146(3) ꢀ, b = 99.50(3)8, V= 2024.2(7) ꢀ3, Z = 4,
1calcd = 1.196 Mgmꢁ3, m = 0.172 mmꢁ1, GOF = 1.012, reflections col-
lected: 18372, independent reflections: 4628 (Rint = 0.0718), final R
indices [I > 2sI]: R1 = 0.0471, wR2 = 0.1037, R indices (all data): R1 =
0.0754, wR2 = 0.1099.
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Crystallographic data for 2b: C21H20ClF3N2O, Mr =
408.84 gmolꢁ1
,
T= 293(2) K, triclinic, space group P1, a =
ꢀ
5.9765(12), b = 12.421(3), c = 13.768(3) ꢀ, a = 81.27(3), b = 86.25(3),
g = 84.71(3)8, V= 1004.5(4) ꢀ3, Z = 2, 1calcd = 1.352 Mgmꢁ3
,
m =
0.231 mmꢁ1, GOF = 1.002, reflections collected: 5259, independent
reflections: 3899 (Rint = 0.0534), final R indices [I > 2sI]: R1 = 0.0746,
wR2 = 0.1776, R indices (all data): R1 = 0.1708, wR2 = 0.1993.
CCDC 804431 (1a), 804429 (2a), and 804430 (2b) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Received: March 19, 2011
Published online: July 14, 2011
Keywords: 1,5-acyl migration · cyclization · heterocycles ·
.
selenium · tellurium
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