Silver-catalysed tandem hydroamination and cyclization of 2-trifluoromethyl-1,3-enynes with primary amines: modular entry to 4-trifluoromethyl-3-pyrrolines

Article abstract of DOI:10.1039/c6cc09595j

A highly efficient tandem hydroamination and cyclization reaction of 2-trifluoromethyl-1,3-enynes with primary amines leading to 4-trifluoromethyl-3-pyrrolines was developed by using AgNO₃ as a catalyst under mild reaction conditions. This new method is compatible with alkyl, aryl, and allyl primary amines, representing an atom-economical protocol for the construction of 4-trifluoromethyl-3-pyrrolines for the first time.

Full text of DOI:10.1039/c6cc09595j

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Silver-Catalysed Tandem Hydroamination and Cyclization
of 2-Trifluoromethyl-1,3-Enynes with Primary Amines: A
Modular Entry to 4-Trifluoromethyl-3-Pyrrolines †
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Xiaofan Zhou, Chaoqian Huang, Yu Zeng, Jiarui Xiong, Yuanjing Xiao* and Junliang
Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient tandem hydroamination and cyclization
reaction of 2-trifluoromethyl-1,3-enynes with primary amine
leading to 4-trifluoromethyl-3-pyrrolines was developed by
using AgNO3 as a catalyst under mild reaction conditions.
This new method is compatible with alkyl, aryl, and allyl
primary amines, representing an atom-economic protocol for
the construction of 4-trifluoromethyl-3-pyrrolines for the first
time.
3-Pyrrolines, also called 2,5-dihydropyrroles, present an important
class of five-membered nitrogen-containing heterocycles due to their
presence in natural and synthetic biologically active compounds. 1 3-
Pyrrolines are also widely used as important versatile precursors for
the synthesis of pyrrolidines, pyrroles and pyrrolidinones, common
structural scaffolds in natural products,2 bioactive molecules,3 and
useful building blocks.4 Consistent with their biological and
synthetic importance, various methods for the synthesis of 3-
pyrrolines via transition-metal or organo-catalysis have been
developed.5 Meanwhile, fluorine-containing organic molecules often
possess elevated reactivity, lipophilicity, and bioactivity compared to
their nonfluorinated counterparts.6 For example, the inclusion of the
electron-withdrawing CF3 group in drug candidates has appeared as
a general strategy to increase robustness against metabolic oxidation
in the “hit to lead” approach.7 In this context, the development of
efficient methods for fluorinated 3-pyrrolines synthesis has
continuously attracted the attention of many chemists.8 With regard
Scheme 1. The transition metal-catalysed transformations of 2-
trifluoromethyl-1,3-enynes.
to their significance in organic synthesis and interest in bioactive
molecules (Figure 1),9 the development of novel, general and
efficient methods for synthesis of 4-trifuoromethyl-3-pyrrolines from
readily available starting materials, especially in an atom-economic
manner, is still highly desirable.
2-Trifluoromethyl-1,3-enynes are easily prepared from
commercially available terminal alkynes with 2-bromo-3,3,3-
trifluoroprop-1-ene in large scale via the Sonagashira cross-coupling
reaction. Gevorgyan and Trost have reported palladium catalyzed
intermolecular formal [4+2] or [3+2] cycloaddition reactions with
diynes10 or trimethylene-methane (TMM),11 leading to
trifluoromethyl benzenes or exomethylene cyclopentanes
derivatives, in which the 2-trifluoromethyl-1, 3-enynes act as four-
or two-carbon component, respectively (Scheme 1a). As part of our
ongoing program on the synthesis of fluorine-containing
heterocycles,12 and continuous interest in the chemistry of 2-
trifluoromethyl-1,3-enynes with bisnucleo-philes,13 we became
interested in whether simple primary amine could be employed in
Figure 1. Bioactive molecules featuring with trifluoromethyl-3-
pyrroline.
This journal is © The Royal Society of Chemistry 2012
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DOI: 10.1039/C6CC09595J
transition-metal catalysed tandem hydroamination and cyclization to excellent (3pa-3ra). Notably, ferrocene framework could be well
(double hydroaminations) reaction with 2-trifluoromethyl-1,3- introduced onto 3-pyrroline ring (3sa). It is noteworthy that
enynes to construct 4-trifluoromethyl-3-pyrroline through allenyl
amine intermediate Int-I (Scheme 1b). If this approach is successful,
it will provide an atom-economic protocol access to valuable 4-
trifluoromethyl-3-pyrroline framework. Herein, we wish to report a
silver-catalysed tandem hydroamination14 and cyclization reaction of
2-trifluoromethyl-1,3-enynes with primary amines furnishing
valuable 4-trifluoromethyl-3-pyrrolines through allenyl amine
8d,15
intermediate
We found that silver catalyst enhances the
electrophilicity of the enynes towards primary amines and accelerate
the allene intermediate formation.
Scheme 3. Scope of primary amine.
differently substituted alkyl possessing valuable functionalities, such
as free primary hydroxyl (3ua), free tertiary hydroxyl (3ya), ester
group (3va), silyloxy (3wa), benzyl ether (3xa), were well tolerated.
Next, the scope of primary amine toward this tandem reaction was
investigated (Scheme 3). Several points are noteworthy: (1) The
substituted benzylamines bearing electron-withdrawing or electron-
donating groups on phenyl ring were all tolerant, affording the
corresponding products 3ab-3ag in moderate to excellent yields; (2)
This reaction also permitted the use of a range of other aliphatic
amines such as 2-phenylethanamine, isopropylamine, allylamine, as
well as aliphatic primary amines containing heteroaryl moieties
such as furan-2-ylmethanamine, thiophen-2-ylmethanamine and
pyridine-2-ylmethanamine, furnishing the corresponding 3-
pyrrolines 3ah-3am in 63% to 81% yields; (3) The reaction of enyne
1a with chiral 1-phenylethan-1-amine (R)-2n afforded a mixture of
diastereoisomers (3an/3an’) in 84% combined yield in a ratio of 1.3
: 1; (4) Aliphatic amine possessing another functional group such as
free hydroxyl or amine gave relative lower yields (3ao, 31% and
3ap, 27%, respectively), due to the further cyclization between the
functional group with the alkene moiety in the product. This issue
could be well addressed by introduction of a bulky protecting group
(3ar, 73%); (5) The reaction also works well for aniline, furnishing
78% yield of 3-pyrroline 3as albeit requiring higher temperature.
To gain insight into this tandem reaction and the role of silver
catalyst, some control experiments were then carried out. Treatment
of enyne 1a with benzylamine 2a in chlorobenzene at room
temperature in the absence of AgNO3 catalyst for 45 h, both allenyl
amine 4 and homopropargylic amine 5 were obtained in 41% and
26% isolated yield, respectively, along with 28% enyne 1a substrate
Scheme 2. Scope of 2-trifluoromethyl-1,3-enyne.
After many attempts, we are pleased to find that 10 mol % of
AgNO3 could catalyse the tandem reaction well in chlorobenzene at
room temperature, leading to 85% yield of 3aa (see ESI).16 The
enyne substrate scope was then examined and demonstrated with
twenty four examples shown in Scheme 2. In general, this new
method is broad in scope, and diverse 4-trifluoromethyl-3-pyrrolines
could be obtained in moderate to excellent yields. Enynes possessing
different aryl groups on the alkyne moiety are suitable, delivering
the corresponding products 3ba-3oa in 52%-94% isolated yield.
Meanwhile the reactions also tolerate various substitution patterns
(o-, m-, and p-) on the phenyl ring (3ba, 3ca and 3da). Furthermore,
enynes bearing heteroaryls such as 2-thiophenyl and 2-pyridyl and
alkenyl such as 1-cyclohexenyl on the alkyne moiety also exhibited
acceptable or good reactivity, and the reaction yields were moderate
2 | J. Name., 2012, 00, 1-3
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DOI: 1C0.O10M39M/CU6CNCI0C9A5T95IOJ N
recovered [eqn (1)]. It is noteworthy that the homopropargylic amine pyrroline 3aa exhibits diverse chemical reaction properties towards
5 could not undergo isomerization to allenyl amine 4 under basic different electrophilic halogenating agents such as bromine, N-
conditions.17 Allenyl amine 4 could afford 95% isolated yield of 3aa halosuccinimides (NXS), N-fluorobenzenesulfonimide (NFSI)
in the presence of AgNO3 catalyst [eqn (2)], which was consistent affording diverse halogenated products and halogen atoms could be
with our original hypothesis. With or without benzylamine 2a, selectively introduced to 3- and (or) 5-positons of pyrroline ring. For
homopropargylic amine 5 could undergo smoothly the 5-endoꢀdig example, treatment of 3aa with two equivalents of bromine in DCM
o
cyclization to afford the acid and air-sensitive 2-pyrroline 4aa18 [eqn at 0 C, after a warming period at room temperature, the resulting
(3)], which easily decomposed during the purification process via solution was treated with excess of Et3N only affording 3-bromo-
silica-gel chromatography. These results indicated that the pyrrole 13 in 70% isolated yield. Interestingly, synthetically valuable
coordination of the triple bond of 2-trifluoromethyl-1,3-enyne 1 to 2,4-dibromo-pyrrole 14 could be delivered in 87% isolated yield
the silver catalyst enhances the electrophilicity of the enynes towards upon treatment of 3aa with three equivalents of N-bromosuccinimide
primary amines,19 thus accelerates the allene intermediate formation (NBS) in acetonitrile. However, the replacement of N-
and then catalyses the subsequent cyclization.
bromosuccinimide (NBS) with N-iodosuccinimide (NIS) led to the
corresponding 3-iodo-pyrrole 1516 under identical reaction
conditions. By employing N-fluorobenzenesulfonimide (NFSI) as the
fluorinating reagent under same reaction conditions, unexpectedly 2-
fluoro-pyrrole 16 along with pyrrole 11 was delivered.
Bn-NH2
Chlorobenzene
RT, 24h
CF3
CF3
CF3
Bn-NH2 2a
+
Ph
(1)
Chlorobenzene
RT, 45 h
Ph
Ph
NH Ph
NH
1a
CF3
Bn
4, 41%
Bn
5, 26%
F3C
AgNO3 (10 mol%)
(2)
(3)
Chlorobenzene
RT, 24h
Ph
NH
N
Bn
4
Bn
3aa, 95%
F3C
CF3
AgNO3 (10 mol%)
Chlorobenzene
RT, 24h
Ph
N
Bn
4aa
Ph
NHBn
5
with 2a, quantitive NMR yield
without 2a, 60% NMR yield
To highlight the synthetic utilities of this transformation, diverse
transformations of the representative products 3aa, 3fa and 3ua are
showcased in Scheme 4. The results showed that 4-trifluoromethyl-
3-pyrrolines are versatile organic building blocks in organic
synthesis. For example, palladium-catalyzed Suzuki–Miyaura cross-
coupling reaction of 3fa with organoboronic acid could produce 6 in
excellent yield. Oxidative aromatization of 3fa was easily realized
by DDQ and 4-trifluoromethyl pyrrole 7 was obtained in 95%
isolated yield. Hydrogenations of 3aa under the catalysis of Pd/C in
ethanol at room temperature could deliver N-benzyl-pyrrolidine 8a
in 66% yield and further debenzylation pyrrolidine 8b in 74% yield,
respectively, with high diastereoselectivity (d.r.> 20:1). The trans-
configuration of 8a and 8b were further confirmed by HSQC and
NOESY spectra analysis (see ESI). Similarly, N-Boc-cis-4-
trifluoromethyl-prolinol 9 with high diastereoselectivity (d.r. > 20:
1) could be efficiently prepared from pyrroline 3ua in two steps.
According to the procedure of literature,20 an alternative synthetic
route to racemic-cis-4-trifluoromethyl-proline, the significant
subunit in bioactive molecules, was then well established. When
pyrroline 3aa was treated with 1.2 equivalent of mꢀCPBA in DCM,
pyrroline Nꢀoxide 10 other than epoxypyrrolidine was obtained in
70% isolated yield as a single diastereoisomer, along with minor
pyrrole 11 (26%).5c Moreover, pyrroline 3aa easily undergoes Heck-
Matsuda arylation21 with the aryldiazonium tetrafluoroborate salts
followed by dehydro-aromatization to afford diaryl-substituted
pyrrole 12 in quantitative yield. It is also important to highlight that
Scheme 4. Diverse transformations of representative products.
In summary, we developed the first example of tandem
intermolecular hydroamination and cyclization reaction of 2-
trifluoromethyl-1,3-enynes with primary amines by the
employing
a cheap silver catalyst under mild reaction
conditions. This method provides a reliable strategy for
efficient construction of 4-trifluoromethyl-3-pyrrolines from
readily available starting materials in an atom-economical
manner. The salient features of this tandem include high
efficiency, general substrate scope, an inexpensive silver
catalyst, mild reaction conditions, outstanding functional-group
tolerance and diverse transformations. Financial supports by
National Natural Science Foundation of China (21372084,
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Table of graphic abstract
A highly efficient AgNO3-catalyzed tandem intermolecular hydroamination and cyclization reaction of 2-trifluoromethyl-1,3-enynes
with primary amines, leading to 4-trifluoromethyl-3-pyrrolines under mild conditions was developed. Diverse valuable
transformations of the products were demonstrated.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5