Efficient iron(iii)-catalyzed three-component coupling reaction of alkynes, CH2Cl2 and amines to propargylamines

Article abstract of DOI:10.1039/c2cc17616e

An iron(iii)-catalyzed three-component coupling reaction of alkynes, CH₂Cl₂ and amines was developed for facile synthesis of propargylamines. Preliminary mechanism investigation using in situ FT-IR reveals that the crucial Fe-acetyli

Full text of DOI:10.1039/c2cc17616e

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Efficient iron(III)-catalyzed three-component coupling reaction of alkynes,
CH2Cl2 and amines to propargylaminesw
Jian Gao, Qing-Wen Song, Liang-Nian He,* Zhen-Zhen Yang and Xiao-Yong Dou
Received 6th December 2011, Accepted 14th December 2011
DOI: 10.1039/c2cc17616e
An iron(III)-catalyzed three-component coupling reaction of
alkynes, CH2Cl2 and amines was developed for facile synthesis
of propargylamines. Preliminary mechanism investigation using
in situ FT-IR reveals that the crucial Fe-acetylide intermediate
Scheme 1 Iron(III)-catalyzed AHA coupling reaction of terminal
could be formed through C–H bond activation of alkynes thanks
alkyne, CH2Cl2 and secondary amine.
to cooperative effect of FeCl3 and 1,1,3,3-tetramethylguanidine.
1,1,3,3-tetramethylguanidine (TMG) to synthesize propargyl-
Propargylamines have been attracting considerable attention
over the last few years due to their wide applications in drug
discovery.1 However, stoichiometric highly moisture sensitive
alkynyl-metal reagents and harsh reaction conditions are
generally required in conventional synthetic procedures.2 In
this aspect, a three-component coupling reaction of aldehydes,
alkynes, and amines (A3) catalyzed by various transition-
amines as depicted in Scheme 1.
Various iron salts were screened by employing phenyl-
acetylene, dichloromethane and diethylamine as representative
substrates and the influences of other reaction parameters on
the reaction such as base, solvent, catalyst amount, and reaction
temperature were also investigated in detail.18 To our delight,
although relatively high catalyst loading and reaction tempera-
ture were needed, good yield of the product i.e. N,N-diethyl-3-
phenylprop-2-yn-1-amine was successfully attained with the aid
of both FeCl3 and TMG by using CH3CN as a solvent at
100 1C (entry 1, Table S4 and entry 5, Table S6, ESIw). In other
words, either FeCl3 or TMG alone did not work well; and
simultaneous presence of both FeCl3 and TMG is required for
the reaction. To further evaluate the role of traces of metal
impurities or contaminants, we used FeCl3 with the quality as
high as 99.99% to carry out the reaction under identical
reaction conditions (entry 1, Table 1). The results could suggest
that this is a real iron-catalyzed reaction. In addition, FeCl3 and
CuCl showed the same activity (entry 1 vs. 2). Subsequently, the
utility and generality of this protocol were evaluated by employing
various terminal alkynes with dichloromethane and piperidine.
As a result, aromatic alkynes with either electron-donating or
electron-withdrawing substituents reacted smoothly to afford
the corresponding propargylamine products in good to excel-
lent yields under the optimal reaction conditions (entries 3–8,
Table 1). Whereas, aliphatic alkynes, for instance 3,3-dimethyl-
1-butyne and 1-hexyne, were found to be inactive (entries 9 and 10),
probably being ascribed to the low activity of the aliphatic
alkynyl C–H.
metals represents
a more attractive and atom-efficient
approach to synthesize propargylamines.3–11 Recently, Contel
and coworkers reported that a Au-catalyzed three-component
coupling reaction of alkynes, haloalkanes and amines (AHA)
was smoothly performed to produce propargylamines, where
new C–C and C–N bonds are constructed via the activation of
C–H and C–halogen bonds.12 Later, Cu(I)13 and nano-In2O3
14
were also proved to be able to catalyze this kind of AHA
reaction. It is worth mentioning that much cheaper and readily
available haloalkanes such as dichloromethane as a reactant
can be used in an AHA coupling reaction. Unfortunately, a
precious transition metal such as Au or In is still needed.
In this context, iron compounds have found many applica-
tions in catalysis, presumably due to unique properties such
as distinct Lewis acid character besides environmental
and economic benefits.15 In particular, iron could be an
efficient catalyst for C–C bond-forming reactions through
C–H bond activation.16 As a part of our program aiming at
developing iron-catalyzed organic reactions,17 we herein
would like to report the FeCl3-catalyzed AHA coupling
reaction of aromatic terminal alkynes, CH2Cl2 and
secondary amines in combination with an organic base i.e.
On the other hand, various amines were further surveyed for
this AHA coupling reaction. As expected, acyclic and hetero-
cyclic secondary aliphatic amines gave moderate to excellent
yields under the given reaction conditions (entries 1, 11–14).
Diisopropylamine showed relatively low activity (entry 12).
Unfortunately, both aromatic primary amines like aniline and
aliphatic primary amines such as n-butylamine failed to give
the propargylamine product (entries 15 and 16).
State Key Laboratory and Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China.
E-mail: heln@nankai.edu.cn; Fax: +86 22 2350 1493;
Tel: +86 22 2350 1493
w Electronic supplementary information (ESI) available: General
experimental methods and procedures, optimization of reaction condi-
tions, characterization and spectra of products and other supplementary
information. See DOI: 10.1039/c2cc17616e
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Table 1 FeCl3-catalyzed AHA coupling reactiona
Dihalomethane Amine
(H)
Yieldb
(%)
Entry Alkyne (A1)
(A2)
1c
2d
CH2Cl2
CH2Cl2
95
94
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
78
64
86
81
7
CH2Cl2
CH2Cl2
88
84
Fig. 1 ReactIR spectra indicating the change in the acetylenic C–H
stretch band: (a) disappearance of the acetylenic C–H stretch reso-
nance at 3277 cmÀ1 due to deprotonation of phenylacetylene by FeCl3
and TMG and (b) time course of the successive addition of up to
3 equiv. of phenylacetylene to a mixture of FeCl3 (1 equiv.) and TMG
(2 equiv.) in CH3CN.
8e
9
CH2Cl2
CH2Cl2
0
0
10
spectroscopic study was undertaken to gain insight into the
reaction mechanism. As shown in Fig. 1(a), the alkynyl C–H
stretch signal of a solution of phenylacetylene in acetonitrile
was observed at 3277 cmÀ1. After addition of 1.1 equiv. of
TMG, a decrease in the absorbance intensity of the C–H stretch
was observed, which could be attributed to the dilution effect.
Accordingly, the deprotonation only induced by TMG itself
can be reasonably excluded. However, subsequent addition of
1.0 equiv. of FeCl3 in batches led to complete disappearance of
alkynyl C–H bond absorption within 3 h as the temperature
was increased from 30 to 100 1C. These results imply that FeCl3
could activate the alkynyl C–H bond and simultaneously a base
i.e. TMG could easily make phenylacetylene deprotonated, with
eventual generation of the Fe-acetylide intermediate.
11
12
CH2Cl2
CH2Cl2
67
37
13f
14f
CH2Cl2
CH2Cl2
72
50
15
16
a
CH2Cl2
CH2Cl2
0
0
C–H activation of the terminal alkyne upon synergistic effect
of both FeCl3 and a base (TMG) can be further supported by
the results obtained from Fig. 1(b). The background was
measured in the presence of FeCl3 and 2 equiv. of TMG in
CH3CN. A signal at 3277 cmÀ1 corresponding to the terminal
alkynyl C–H bond absorption was observed when 1 equiv. of
phenylacetylene was added and this signal disappeared within
50 min. On the other hand, when additional phenylacetylene
was introduced up to 3 equiv., the absorbance intensity of the
terminal alkynyl C–H bond increased with each addition.
Based on the in situ FT-IR exploration in this study and the
literature results,4,12,13 the reaction mechanism was proposed as
shown in Scheme 2. The precatalyst FeCl3 would presumably be
initially reduced to a low-valent FeII state in the presence of
amine and/or TMG, producing the FeII alkynylate complexes,20
being also identified by the XPS analytic results.21 As a result,
Reaction conditions: alkyne (1.0 mmol); dichloromethane (2.0 mmol,
128 mL); amine (2.0 mmol); TMG (2.0 mmol, 230.4 mg); FeCl3
(20 mol%, 32.4 mg, purchased from Aladdin with >99% purity, Cu
content was determined to be 0.026% w/w by using an ICP method);
b
CH3CN, 0.5 mL; 100 1C; 12 h. Determined by 1H NMR using
c
MeNO2 as the internal standard. Two kinds of FeCl3 from Sigma-
Aldrich with 99.99% purity and Aladdin with >99% purity gave
d
e
f
the same result. CuCl was used instead of FeCl3. 24 h. Phenyl-
acetylene (2.0 mmol); amine (1.0 mmol).
As for alkyne participated nucleophilic reaction, complexa-
tion of a terminal alkyne with a transition metal could generate
a p-complex,19 whereby the terminal alkynyl C–H bond can be
further deprotonated by a weak base like amine with the
formation of the metal-acetylide, which could be active nucleo-
philic species for the reaction. In this context, an in situ IR
c
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3 For selected examples of the A3 reactions, see: (a) C. Wei, L. Zhang
and C.-J. Li, Synlett, 2004, 1472; (b) M. K. Patil, M. Keller,
B. M. Reddy, P. Pale and J. Sommer, Eur. J. Org. Chem., 2008,
4440; (c) X. Zhang and A. Corma, Angew. Chem., Int. Ed., 2008,
47, 4358; (d) Y. Zhang, P. Li, M. Wang and L. Wang, J. Org.
Chem., 2009, 74, 4364; (e) N. Gommermann, C. Koradin,
K. Polborn and P. Knochel, Angew. Chem., Int. Ed., 2003,
42, 5763; (f) T. F. Knopfel, P. A. Aschwanden, T. Ichikawa,
T. Watanabe and E. M. Carreira, Angew. Chem., Int. Ed., 2004,
43, 5971; (g) K. A. Bisai and V. K. Singh, Org. Lett., 2006, 8, 2405.
4 For the iron-catalyzed A3 reaction, see: (a) P. Li, Y. Zhang and
L. Wang, Chem.–Eur. J., 2009, 15, 2045; (b) W.-W. Chen,
R. V. Nguyen and C.-J. Li, Tetrahedron Lett., 2009, 50, 2895;
(c) T. Zeng, W.-W. Chen, C. M. Cirtiu, A. Moores, G. Song and
C.-J. Li, Green Chem., 2010, 12, 570.
5 C. Wei, Z. Li and C.-J. Li, Org. Lett., 2003, 5, 4473.
6 C. Wei and C.-J. Li, J. Am. Chem. Soc., 2003, 125, 9584.
7 V. K. Y. Lo, Y. Liu, M. K. Wong and C. M. Che, Org. Lett., 2006,
8, 1529.
8 For other examples of the A3 reactions, see: (a) L. Shi, Y.-Q. Tu,
M. Wang, F.-M. Zhang and C.-A. Fan, Org. Lett., 2004, 6, 1001;
(b) H. Z. S. Huma, R. Halder, S. S. Karla, J. Das and J. Iqbal,
Tetrahedron Lett., 2002, 43, 6485; (c) G. W. Kabalka, L. Wang and
R. M. Pagni, Synlett, 2001, 676; (d) C. Wei and C.-J. Li, J. Am.
Chem. Soc., 2002, 124, 5638; (e) C. Wei, J. T. Mague and C.-J. Li,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5749; (f) F. Colombo,
M. Benaglia, S. Orlandi and F. Usuelli, J. Mol. Catal. A: Chem.,
2006, 260, 128; (g) N. Gommermann and P. Knochel, Chem.–Eur. J.,
2006, 12, 4380.
9 (a) C. Fischer and E. M Carreira, Org. Lett., 2001, 3, 4319;
(b) S. Sakaguchi, T. Kubo and Y. Ishii, Angew. Chem., Int. Ed.,
2001, 40, 2534; (c) S. Sakaguchi, T. Mizuta, M. Furuwan, T. Kubo
and Y. Ishii, Chem. Commun., 2004, 1638.
10 P. Li and L. Wang, Chin. J. Chem., 2005, 23, 1076.
11 C.-J. Li and C. Wei, Chem. Commun., 2002, 2689.
Scheme 2 Proposed reaction mechanism for the AHA coupling reaction.
this FeCl3 catalyzed AHA reaction could be a homogeneous
catalytic process. The catalytic cycle could start via the activa-
tion of the terminal alkyne C–H bond promoted by FeCl2 in
conjunction with TMG with the generation of a Fe-acetylide
intermediate A, which is considered to be the active nucleophilic
species. Then, the intermediate A reacts with CH2Cl2 to form
the iron(III) species B which further goes through a reductive
elimination to afford the propargylchloride C and regenerate
FeCl2. Finally, the reaction of C with a secondary amine in the
presence of TMG could furnish the propargylamine product.
As a result, a base like TMG would play a dual role including
co-activation of alkynyl C–H through deprotonation and trap-
ping the formed HCl to promote the reaction.
12 For an Au-catalyzed AHA reaction, see: D. Aguilar, M. Contel
and E. P. Urriolabeitia, Chem.–Eur. J., 2010, 16, 9287.
13 For a Cu-catalyzed AHA reaction, see: (a) D.-Y. Yu and
Y.-G. Zhang, Adv. Synth. Catal., 2011, 353, 163; (b) Z.-W. Lin,
D.-Y. Yu and Y.-G. Zhang, Tetrahedron Lett., 2011, 52, 4967.
14 For an In-catalyzed AHA reaction, see: M. Rahman, A. K. Bagdi,
A. Majee and A. Hajra, Tetrahedron Lett., 2011, 52, 4437.
In conclusion, we have developed an economical and prac-
tical protocol for facile synthesis of propargylic amines through
an iron(III)-catalyzed three-component coupling reaction of
aromatic terminal alkynes, CH2Cl2 and aliphatic secondary
amines. Notably, in situ IR spectroscopic investigation strongly
suggests that FeCl3 could activate the alkynyl C–H bond in
combination with TMG as a base. The study of the reactive
iron-acetylide intermediate would be of vital importance for the
continuing evolution of iron catalyzed reactions for direct C–C
bond formation through C–H bond activation.
15 For reviews on iron catalysis, see: (a) C. Bolm, J. Legros, J. Le Paih and
L. Zani, Chem. Rev., 2004, 104, 6217; (b) B. D. Sherry and A. Furstner,
¨
Acc. Chem. Res., 2008, 41, 1500; (c) A. Furstner and R. Martin, Chem.
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Lett., 2005, 624; (d) Iron Catalysis in Organic Chemistry: Reactions
and Applications, ed. B. Plietker, Wiley-VCH, Weinheim, Germany,
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¨
We are grateful to the National Natural Science Foundation
of China (No. 20872073, 21150110105, and 21172125), the
‘‘111’’ Project of Ministry of Education of China (Project No.
B06005), and the Committee of Science and Technology of
Tianjin for financial support.
16 For iron-catalyzed C–H activation, see: (a) A. A. O. Sarhan and
C. Bolm, Chem. Soc. Rev., 2009, 38, 2730; (b) E. Nakamura and
N. Yoshikai, J. Org. Chem., 2010, 75, 6061; (c) C.-L. Sun, B.-J. Li
and Z.-J. Shi, Chem. Rev., 2011, 111, 1293.
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18 See the ESIw for the details of optimization for the reaction conditions.
19 For the activation of alkynes by transition metals, see:
(a) J. W. Bode and E. M. Carreira, J. Am. Chem. Soc., 2001,
123, 3611; (b) N. Gommermann, C. Koradin, K. Polborn and
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21 See the ESIw for details of the XPS analysis.
c
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This journal is The Royal Society of Chemistry 2012