A new strategy to construct a C=C-CF3 subunit via CuBr-catalyzed domino reaction of homopropargyl amines: An efficient synthesis of trifluoromethyl containing building blocks 4-trifluoromethyl-2,3-dihydro- pyrroliums

Article abstract of DOI:10.1039/c3cc49059a

A new strategy for the construction of a C=C-CF₃ subunit has been developed via CuBr-catalyzed domino cyclization-trifluoromethylation of homopropargyl amines with Umemoto's reagent. 4-Trifluoromethyl-2,3-dihydro- pyrroliums were produced in high yields. The usefulness of these products has been demonstrated by the transformation of them into various other trifluoromethylated molecules. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc49059a

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COMMUNICATION
Q
A new strategy to construct a C C–CF3 subunit
via CuBr-catalyzed domino reaction of
homopropargyl amines: an efficient synthesis
of trifluoromethyl containing building blocks
4-trifluoromethyl-2,3-dihydro-pyrroliums†‡
Cite this: Chem. Commun., 2014,
50, 3048
Received 27th November 2013,
Accepted 24th January 2014
DOI: 10.1039/c3cc49059a
Guang-Cun Ge,a Xiao-Jun Huang,a Chang-Hua Ding,*a Shi-Li Wan,a Li-Xin Daia
and Xue-Long Hou*ab
www.rsc.org/chemcomm
Q
A new strategy for the construction of a C C–CF3 subunit has been
On the other hand, alkynes are important and easily available
developed via CuBr-catalyzed domino cyclization–trifluoromethylation compounds in organic synthesis. Transformation of carbon–
of homopropargyl amines with Umemoto’s reagent. 4-Trifluoromethyl- carbon triple bonds into other functional groups has been well
2,3-dihydro-pyrroliums were produced in high yields. The usefulness of documented.9 Trifluoromethylation of terminal alkynes has been
these products has been demonstrated by the transformation of them developed by Qing, affording trifluoromethylalkynes in high
into various other trifluoromethylated molecules.
yields.7 However, there is no report on the conversion of triple
bonds to trifluoromethylated alkenes with additional functional
Trifluoromethyl-containing compounds are one of the most groups. Metal-catalyzed 5-endo-dig cyclization of homopropargyl
important classes of selectively fluorinated molecules in pharma- amines has been well developed to synthesize five-membered
ceuticals and agrochemicals because the introduction of trifluoro- N-containing heterocyclic compounds.10 This cyclization usually
methyl groups into organic molecules often leads to the significant involves the formation of a sp2 C–M bond, however, trapping of a
improvements in their physical, metabolic, and biological proper- sp2 C–M bond by a proton is among the most cases.11 Recently,
ties.1 For these reasons trifluoromethylation of molecules has some examples of exploration of this sp2 C–M bond to generate a
attracted great attention of synthetic chemists for more than half C–C bond have been reported,12 which would offer a new avenue
century. Tremendous progress has been achieved in recent years in to fabricate substituted N-containing heterocyclic compounds.
the realm of C–CF3 bond formation reaction.2 To date, a wide As a program aimed at the applications of alkynes in organic
range of substrates, such as halides,3 boronic acids,4 carboxylic synthesis,13 we found that pyrroles were afforded using amino
acids,5 alkenes6 and alkynes,7 can be converted to trifluoromethyl alkynes.13d We envisioned that the cyclization of homopropargyl
derivatives efficiently in the presence of transition metal catalysts, amines in the presence of triple bond activators will produce an
and many types of trifluoromethyl-bearing molecules have been intermediate having a sp2 C–M bond, which might be trapped by a
synthesized. However, most of them are aromatic and hetero- trifluoromethylation reagent to produce the trifluoromethylated
aromatic trifluoromethyl compounds as well as those having nitrogen-containing cyclic products, an important structural frame-
sp3 C–CF3 bonds. Only a few compounds bearing olefinic trifluoro- work found abundantly in both naturally occurring and biologically
methyl groups were obtained, most of which used CQC–X as active compounds (Scheme 1).14,15 In this communication, we
starting material,4b,5,8 in spite of the fact that carbon–carbon report our preliminary results of the CuBr-catalyzed domino
double bonds can easily be converted into many other functional reaction of amino alkynes with Umemoto’s reagent, affording
groups. To explore strategies to construct a CQC–CF3 subunit in trifluoromethyl dihydropyrroliums. The usefulness of the
a simple and efficient manner is highly demanding.
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry (SIOC), Chinese Academy of Sciences (CAS), 345 Lingling Road,
Shanghai 200032, China. E-mail: dingch@sioc.ac.cn, xlhou@sioc.ac.cn;
Fax: +86 21 54925100; Tel: +86 21 54925144
b Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, SIOC, CAS, China
† This communication is dedicated to Professor Guo-Qiang Lin on the occasion
of his 70th birthday.
Scheme 1 Proposed metal-catalyzed cyclization/trifluoro-methylation
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/
of amino-alkyne with the CF3 reagent.
c3cc49059a
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Table 1 Impact of the reaction parameters on the CuBr-catalyzed reac-
tion of homopropargyl amine 1a with Umemoto’s reagenta
Table 2 Substrate scope of CuBr-catalyzed reaction of homopropargyl
amines 1 with Umemoto’s reagenta
Entry
2
Cat. (mol%)
Temp. (1C)
Solvent
3ab (%)
1
2
3
4
5
6
7
8
2a
2b
2cc
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuBr (100)
CuI (100)
CuCl (100)
CuCl2 (100)
AgOAc (100)
AuCl3 (100)
CuBr (100)
CuBr (100)
CuBr (50)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
rt
DMA
DMA
DMA
DMF
DMSO
CH2Cl2
DCE
THF
EA
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
79
—
—
75
50
83
74
76
76
Trace
78
78
62
12
Trace
84
9
10
11
12
13
14
15
16
17
18
19
20
a
b
Mol ratio: 1/2a/CuBr = 1/1.2/0.1; isolated yield. 20 mol% of CuBr was
c
used. 50 mol% of CuBr was used.
88
rt
rt
rt
83
CuBr (20)
CuBr (10)
83 (79)d
80 (78)d as Fe(acac)3, In(OTf)3 and Zn(OTf)2 failed to promote the reaction
(not shown in the table). The yield remained unchanged when the
Mol ratio: 1a/2a = 1/1.2. Determined by 19F NMR using Umemoto’s
a
b
c
d
reaction temperature was lowered from 80 1C to 50 1C (entry 16 vs.
entry 6) but increased slightly to 88% when the reaction was run at
room temperature (entry 17 vs. entry 6). Importantly, the reaction
reagent as internal standard. 2c: Me3SiCF3. Isolated yield shown in
parentheses.
products as versatile trifluoromethyl-containing building blocks gave product 3a in good yield when a substoichiometric amount of
has also been revealed. CuBr was used (entries 18 and 19). Product 3a was obtained in 80%
We initially tested the reaction of N-Ts substituted homo- yield even when only 10 mol% of CuBr was used (entry 20).
propargyl amines with trifluoromethylation reagents, such as The substrate scope of the reaction was then examined
Togni’s reagent and Umemoto’s reagent, in the presence of CuBr under the optimized reaction conditions (Table 2). A wide range
in dimethylacetamide (DMA), respectively, but failed to obtain any of substrates, not only N,N-dimethyl homopropargyl amines,
desired trifluoromethylated products. The same phenomena were but also N,N-dialkylhomopropargyl amines, are suitable for the
observed when N-Bn substituted homopropargyl amines were reaction, providing the corresponding 4-trifluoromethyl-dihydro-
used. However, trifluoromethylated product 3a was produced in pyrroliums in high yields (3a–3i vs. 3j–3l). The electron withdrawing
79% yield when N,N-dimethyl homopropargyl amine 1a reacted or electron donating substituents at the para, meta, or ortho position
with Umemoto’s reagent in the presence of CuBr (Table 1, entry 1). of the phenyl ring on the homopropargyl amines 1 was well tolerated
The investigation of the impact of various parameters on the (3b–3f). Homopropargyl amines with a 1-naphthalenyl substituent
reaction was conducted. It was found that the use of Togni’s gave product 3g in low yield due to low conversion of substrates.
reagent 2b made the reaction complicated (entry 2) while no Pleasingly, the yield of product 3g increased significantly to
reaction took place when using Me3SiCF3 2c as the reagent 73% by using 50 mol% of CuBr. It is worthwhile to note that the
(entry 3). Various solvents were found to be suitable media for alkyl substituted homopropargyl amines were suitable starting
the reaction (entries 4–9), except toluene, which suppressed the materials in the reaction to produce the desired products in
reaction heavily (entry 10) while dichloromethane (CH2Cl2) was high yields (3h and 3i).
identified as the best among those we screened (entry 6), which
The 4-trifluoromethyl-2,3-dihydro-pyrroliums 3 were demon-
was selected as the solvent for further investigation. It was strated as the versatile building blocks for the synthesis of other
found that the anion of copper salts had limited effect on the types of important trifluoromethyl-containing organic molecules
yield, similar results were obtained when using CuI, CuCl, and (Scheme 2). 3-Trifluoromethylbutylamine 4 was obtained in 73%
CuBr (entries 11 and 12 vs. entry 6) while a divalent copper salt yield when compound 3f was treated with hydrogen in the
such as CuCl2 has lower efficiency (entry 13). Other metals of presence of Pd/C via ring-opening and hydrogenation reactions.
group 11 such as AgOAc and AuCl3 showed low catalytic activity 3-Trifluoromethyl pyrrolidine 5 was afforded in 89% yield through
for the reaction (entries 14 and 15). Some other metal salts such debenzylation and hydrogenation reactions of compound 3l.
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under Cu(I)-catalysis, affording 4-trifluoromethyl-2,3-dihydro-
pyrroliums as the diverse trifluoromethyl-containing building
blocks in high yields. The versatile utility of these products
has been demonstrated by the transformation of products into
different types of trifluoromethylated molecules. Further studies
on the reaction mechanism, the extension of the reaction scope
as well as the utilities of the products in organic synthesis are
currently underway in our lab.
This work was financially supported by the Major Basic
Research Development Program (2011CB808706), the National
Natural Science Foundation of China (21272251, 21121062,
and 21032007), Chinese Academy of Sciences, the Technology
Commission of Shanghai Municipality, and the Croucher
Foundation of Hong Kong.
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Scheme 2 Transformations of 4-trifluoromethyl-dihydro-pyrroliums 3.
Furthermore, when compound 3l was treated with lithium
triisobutylborohydride (L-selectride) in n-hexane, only a C–N bond
cleavage took place, affording a trisubstituted trifluoromethylated
alkene 6 in 65% yield with the CQC bond untouched. 3-Trifluoro-
methylpyrrole 7 was also obtained in 56% yield by a one-pot reaction
of homopropargyl amine 1a and Umemoto’s reagent followed by
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A possible reaction mechanism was proposed on the basis of our
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Int-A, which undergoes cyclization to give intermediate Int-B bearing
a C–Cu bond.16 Final trifluoromethylated product 3 is afforded when
the Int-B reacts with Umemoto’s reagent.4b
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Scheme 3 Proposed reaction mechanism.
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